bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Treatment With PARP Inhibitor and Immunotherapy for Aggressive Adrenocortical Carcinomawith Cushing’s Syndrome Refractory to Treatment With EDP Chemotherapy and Mitotane
Authors: Greb Alexandra C , Reikes Andrew R 
Published: May 2021

Abstract
A 39-year-old female with a past medical history of Ehlers-Danlos syndrome, Celiac disease, Hashimoto’s hypothyroidism and germline BRCA mutation presented with abdominal pain and distension. CT imaging demonstrated innumerable bilateral pulmonary nodules concerning for metastases, paraoesophageal adenopathy, multiple right adrenal masses, left adnexal cyst, and a small sclerotic lesion within the right iliac bone. CT guided biopsy of a 6 cm right adrenal mass revealed high grade carcinoma with areas of necrosis, and tumor markers were positive for synaptophysin, Melan-A and inhibin but negative for TTF1 and CK7, HMB45 and S100. A diagnosis of stage IV adrenocortical carcinoma was made and, at the time of diagnosis, a 24-hour urinary cortisol was elevated at 791.4 mcg (nl&lt;45.0 mcg). Surgery was deferred given widespread metastatic disease. She initially completed 4 cycles of chemotherapy with EDP-Mitotane along with Metyrapone to normalize her urine cortisol. Subsequent restaging CT imaging revealed a mixed response to chemotherapy with new focal sclerotic areas in the left fifth rib concerning for new metastases.
Due to suboptimal initial therapeutic response, less traditional treatment options were explored. PARP inhibitor and immunotherapy were considered, and she received Rucaparib followed by two cycles of Ipilimumab and Nivolumab, resulting in a limited response and complicated by reversible myocarditis likely due to immunotherapy. Further restaging CT imaging demonstrated disease progression, and patient then completed one month of Cisplatin and Etoposide and palliative radiation to the right adrenal tumor all while continuing Mitotane and Metyrapone. Her most recent restaging CT images indicated further disease progression. She was then transitioned to Sorafenib, Mebendazole, and Sulindac daily for CTNNB1 mutation with plans to rechallenge with a different PARP inhibitor (Olaparib) for BRCA1 mutation. Most recently, patient has self-discontinued Mitotane due to intolerable side effects. In conclusion, a highly aggressive adrenocortical carcinoma associated with Cushing’s syndrome was treated with PARP inhibitor and immunotherapy, after initial failure with a traditional EDP+Mitotane regimen, with limited benefit.
References:
1. Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005;12(3):657–666. doi:10.1677/erc.1.010252.
2. Mohan DR, Lerario AM, Hammer GD. Therapeutic Targets for Adrenocortical Carcinoma in the Genomics Era. J Endocr Soc. 2018;2(11):1259–1274. Published 2018 Sep 26. doi:10.1210/js.2018-00197
Hypercalcemia in an Infant With Pseudohypoaldosteronism Type 1
Authors: Jeng Henry , Broussard Julia Rodica 
Published: May 2021

Abstract
Background: Pseudohypoaldosteronism type 1 (PHA1) is an aldosterone resistance syndrome due to insensitivity of target tissues to aldosterone action, with supraphysiologic aldosterone and renin levels. PHA1 presents usually in infancy and is divided into autosomal dominant (AD) and autosomal recessive (AR) form. A secondary form of PHA1 associated with UTI and/or renal malformations was described. In AD PHA1, salt loss is due to renal mineralocorticoid resistance while hyponatremia in AR PHA1 is caused by multi-organ salt loss. PHA1 has variable signs/symptoms associated with hyponatremia and hyperkalemia; thus, this clinical picture can be attributed to more common conditions such as dehydration, poor feeding, congenital adrenal hyperplasia. Clinical Case: A 5-month old male was admitted for airway evaluation. He was a 23-week gestation preemie, with chronic lung disease, failure to thrive. Patient was found to have hyponatremia, hyperkalemia, high FeNa of 1.3% (intrinsic renal disease) and elevated BUN/Cr (92/1.15). Renal US found echogenic kidneys with poor cortical medullary differentiation suggesting renal disease. Further evaluation noted high aldosterone (1700 ng/dL) and renin (400 ng/mL/hr) levels. He was placed on low protein formula to help optimize BUN level. Baby was diagnosed with secondary PHA1 due to renal disease and started on NaCl supplementation. This led to normalization of BUN, creatinine and improvement in electrolytes. Patient also had high serum calcium ranging from 11.1 to 12.0 mg/dL. Hyponatremia, hyperkalemia, hypercalcemia could be attributed to possible CAH, however state screen and ACTH stimulation test were normal. Further workup showed high 25-OH-vitamin D &gt; 99 ng/mL, PTH 46.9 pg/mL, phosphorous 5.4 mg/dL and 1,25-OH-vitamin D 63.1 pg/mL. Urine Ca/cr ratio was 0.522. Vitamin D supplementation was stopped and daily total fluids increased. Subsequently, there was improvement in serum Ca at 10.9 mg/dL and 25-OH Vitamin D of 74 pg/mL. Next Generation Sequencing (NGS) was carried out, with a focus on the etiology of persisting hypercalcemia, including familial forms of hypercalcemia and Williams Syndrome. NGS revealed a likely pathogenic variant, c.2365 + 2T&gt;C (p.?), in NR3C2, consistent with a diagnosis of AD PHA 1. Conclusion: This is a case of AD PHA1, marked by renal mineralocorticoid receptor resistance associated with persisting hypercalcemia. Initial hypercalcemia could be explained by hypervitaminosis D. It is important to note that electrolyte abnormalities, including persistent hypercalcemia, could be also secondary to the kidney disease found on renal US. There are only few reports of hypercalcemia in patients with PHA1 in the literature. In children with electrolyte abnormalities and failure to thrive, monitoring of serum and urine electrolytes would facilitate early accurate diagnosis and timely treatment.
Limited Efficacy of Mifepristone Due to Poor Tolerance: A Clinical Challenge in Managing Cortisol Excess
Authors: Mora Osoria Gabriel Jose , Marin Luis Norberto Madera , Cruz Alegyari Figueroa , Torres Yineli Ortiz , Garcia-Mateo Jose M 
Published: May 2021

Abstract
A 53-year male with incidental bilateral adrenal masses along with symptoms of proximal muscle weakness, anxiety, and depression. Past medical history of uric acid nephrolithiasis, hypertension, hyperlipidemia, type 2 diabetes mellitus, anxiety, and depression. A right adrenal mass of 2.8cm and a left adrenal mass of 1.5cm both of &lt;10 HU on non-enhancing CT. Hormonal activity workup was ordered which showed cortisol levels of 4.7mcg/dL on 1mg ONDST suggestive of autonomous cortisol excess and workup for primary hyperaldosteronism was negative. On follow up CT adrenal masses remained stable, but the patient underwent the annual hormonal workup for incidentaloma with 1mg ONDST and found with cortisol 4.5mcg/dL, eventually repeated with 2-day LDDST which showed no suppression of cortisol with levels at 4.5 mcg/dL confirming the diagnosis of autonomous cortisol excess. ACTH found to be suppressed at 3.1pg/dL (7.2–63.3 pg/dL) which helped confirm the diagnosis of non-ACTH dependent autonomous cortisol excess. Referred to surgery evaluation due to complications associated with cortisol excess as osteoporosis and uncontrolled hyperglycemia however surgical intervention was deferred until the source of cortisol excess could be identified within the bilateral adrenal masses and it was recommended to continue with medical therapy.
As the cortisol excess source cannot be identified by localizing procedures and despite adequate medical therapy and stable adrenal masses on imaging, patient persisted with uncontrolled DM/hypertension and worsening BMD in the spine and hip with surgery not being an option. The patient was started on glucocorticoid receptor antagonist mifepristone in which upon reevaluation weakness and fatigue were noticeable along with hypokalemia of 3.1mmol/L after 2 weeks of therapy that was eventually replaced but 2 weeks later the patient discontinued therapy as he could not tolerate side effects related to adrenal insufficiency associated with mifepristone, such as weakness, fatigue, and dependence of potassium supplementation due to hypokalemia.
This effect is physiologically important, because cortisol binds as avidly as aldosterone to the mineralocorticoid receptor, and the plasma cortisol concentration is approximately 100-fold higher than the plasma aldosterone concentration and it can lead to hypokalemia by the mechanism of apparent mineralocorticoid excess. Also, as mifepristone blocks cortisol action, the levels of ACTH and cortisol increase so high that hormonal measurement cannot be used to judge either therapeutic efficacy or adrenal insufficiency, we must go based on signs and symptoms.
Metastatic Adrenocortical Carcinoma Co-Secreting Multiple Steroid Hormones
Authors: Lee Tien-Hao , Galagan Robert 
Published: May 2021

Abstract
Background: Adrenocortical carcinoma is a rare disease which may be complicated by co-secretion of multiple steroid hormones.
Clinical Case: A 53- year-old female was discovered to have 1 cm left and 1.7 cm right adrenal nodules by Chest CT scan in 2004. She had a follow-up abdominal CT scan in 2011 revealing enlargement of the left adrenal mass to 5.7 cm and a stable 1.8 cm right adrenal nodule. A laparoscopic left adrenalectomy was performed in 2012 and the surgical pathology diagnosis was benign adrenal hyperplasia. In 5/2016 the patient developed left abdominal pain and a CT scan revealed a 1.7 cm mass in the left adrenalectomy surgical bed, a 1.4 cm nodular density adjacent to the left diaphragm and the stable 1.8 cm right adrenal nodule. 6/2016 lab tests: 24 hr urinary cortisol 15 ug/24 hr (&lt;50 μg/24hr), aldosterone 8.7 ng/dL (&lt;31 ng/dL), renin activity 0.7 ng/ml/hr (0.5–4 ng/mL/hr) and DHEA-S 94 ug/dL (32–240 μg/dL). A re-examination of the 2012 surgical pathology resulted in an addendum diagnosis of an adrenal cortical neoplasm of indeterminate malignant potential. In 1/2018 she underwent an exploratory laparotomy with surgical resection of the 1.7 cm mass in left paracolic gutter and biopsy of numerous small retro-peritoneal and multiple liver lesions. Pathology revealed metastatic adrenocortical carcinoma with low grade mitotic activity (3 mitoses per 10 HPF) and intermediate grade Ki-67 (15–25%). 5/2018 lab results: 1. aldosterone 20 ng/dL, 2. renin activity 0.2 ng/mL/hr and 3. testosterone 34 ng/dL (&lt;75 ng/dL). Mitotane was started in 06/2018 but was discontinued in 9/2018 due to side effects. In 3/2020 she was hospitalized for generalized weakness and was discovered to be severely hypokalemic K+ 1.5 mmol/L (3.6–5.2 mmol/L) with an aldosterone of 300 ng/dL and renin activity of 0.1 ng/mL/hr. She was treated with IV KCl to correct her hypokalemia and was discharged on oral KCl 20 meq bid and spironolactone 50 mg bid. She was readmitted to the hospital on 10/12/2020 after a near-syncopal event and lab tests revealed a K+ of 1.4, aldosterone 508 ng/dL, renin activity 0.7 ng/mL/hr, AM cortisol 13.6 μg/dL (5–20 ug/dL), testosterone 161 ng/dL, and DHEA-S 377 ug/dL, indicating co-secretion of multiple steroid hormones. Her hypokalemia was treated with IV KCl and her spironolactone dose was increased to 100 mg bid.
Conclusion: This case report details the rare occurrence of an adrenocortical carcinoma which was hormonally silent but eventually metastasized and became hormonally active, co-secreting multiple steroid hormones with a predominance of aldosterone. Serial adrenal hormone lab profiles are important for optimal management of patients with this disease.
Mifepristone (Korlym ®) Use Interferes With Accurate Serum Measurement of Sex Steroids
Authors: Uwaifo Gabriel Ikponmosa 
Published: May 2021

Abstract
Introduction: Mifepristone (MFP) aka RU-486/Korlym is a synthetic steroid analog originally developed in 1980 as an abortifacient that is now used in the management of Cushing’s syndrome (CS). It is both a progesterone (PG) and glucocorticoid (GC) receptor blocker. CS is often associated with reproductive functional anomalies including hypogonadism, menstrual irregularities and infertility. Due to its mode of action, measurement of serum PG and/or cortisol in patients on MFP are inaccurate indices of systemic PG and/or GC deficiency or excess. However, the potential impact of MFP use on other serum steroid assays has not been widely studied. We report the case of a 55 yr old man on treatment with MFP for adrenal CS found to have striking artefactual changes in serum androgen and estrogen levels. Case Summary: A 55 yr old African American man was referred with poorly controlled type 2 diabetes, hypertension, hyperlipidemia, obesity and untreated hypogonadism. He had a 3.2cm left adrenal incidentaloma associated with adrenal CS and he chose medical management rather than surgery. Upon starting MFP at 300mg QD serum total estrogen (by radio-immunoassay; RIA) and estradiol (by chemiluminescence immunoassay; CIA) were markedly elevated while serum total, free, bioavailable testosterone and dihydrotestosterone were all markedly reduced. His HBA1c, weight and energy levels improved on MFP despite these findings. The serum steroid levels normalized to pre-treatment levels after stopping MFP for ~ 4weeks but the changes recurred after restarting therapy. After MFP dose escalation to 300mg BID the serum steroid levels normalized after stopping MFP for ~ 6 weeks. The artefactual low testosterone levels also occured with measurement by equilibrium dialysis but “normal accurate” results were obtained when measured by liquid chromatography-Tandem mass spectrometry (LC-TMS). He remains on MFP 300mg BID without need for androgen repletion. Discussion: With increased use of MFP for CS, indices for tracking its clinical and biochemical effects assume great importance. There are few reports of the possible effects of MFP on estrogen and testosterone serum assays despite its touted low cross reactivity with sex steroids. Our case suggests that the significance, extent and prevalence of artefactual changes on serum sex steroid assays may be underestimated and under- appreciated. Conclusions: Our case of wide disparities in serum estrogen and androgen measures in a patient on MFP indicates that caution needs to be exercised in the interpretation of such results in patients on current MFP therapy. Our clinical observations suggest depending on the dose that a wash out period of 4–6 weeks is required to ensure accurate measures. Studies to ascertain the prevalence of this artefactual effect are needed and it appears testosterone measurement by LC-TMS obviates the testosterone assay artefact.
Not Your Typical Low T - Hypogonadism From a Feminizing Adrenal Carcinoma
Authors: Patel Reshma , Angell Trevor E 
Published: May 2021

Abstract
Introduction: Adrenocortical Carcinoma (ACC) is a rare disease, with an incidence of 0.7–2 cases per million people. Approximately 80% of ACC tumors are functional, with the majority of tumors secreting glucocorticoids, however a small proportion concurrently secrete androgens in addition to glucocorticoids. Here, we describe a case of ACC presenting with feminization, without clinical evidence of Cushing’s syndrome.
Case Description: A 35 year old male with no significant history presented with sudden onset non-radiating, 7/10, abdominal pain 4 days prior to admission. On exam, the patient had diffuse tenderness to palpation in the right upper quadrant without other abdominal findings. He also was noted to have palpable breast tissue bilaterally. Upon persistent questioning, he reported an 8-month history of gradual breast development, decreased libido and decreased morning erections. He had no history of hypertension, headaches, diabetes, palpitations, flushing, sweating, weight gain, striae, bruising, or muscle weakness. Diagnostic CT imaging of the abdomen and pelvis showed a 14 cm right adrenal mass without invasion or lymphadenopathy. Laboratory testing showed a total testosterone of 37 ng/dL (reference range:249–846 ng/dL), estradiol of 181 pg/mL (8–43 pg/mL), prolactin of 14.5 ng/ml (4.0–15.2), and FSH and LH were both &lt;0.1 mIU/mL. Serum metanephrines and normetanephrines, renin and aldosterone showed no evidence of excess secretion. Urine free cortisol measurement was 111mcg over 24 hrs (&lt;50 mcg/24hr) and ACTH was &lt;1.0 pg/mL (7.2–63.3 pg/mL). Surgical resection was performed with histopathologic diagnosis of an 18cm ACC confined to the adrenal gland. Post-surgical prophylactic hydrocortisone replacement was given. At outpatient follow-up, testing revealed normalization of his estradiol and testosterone levels. The patient had no clinical evidence of adrenal insufficiency and plans were made to assess endogenous adrenal function.
Conclusion: This case highlights the importance of discussing symptoms of hypogonadism, virilization or feminization with patients in detail when evaluating for ACC. Careful history and physical exam may be key to identifying sex hormone excess and prompting preoperative workup. In this case of a feminizing ACC, pre-surgical assessment allows for estrogen to be as a marker of tumor progression. A sex steroid producing ACC should be evaluated for cortisol secretion as prompt detection can avoid post-operative adrenal insufficiency.
PD-1 Inhibitors Induced Primary Hypoadrenalism
Authors: Tan Zi , Ahmed Ammar , Zainal Abir , Salama Amr , Alweis Richard , Bingham Robert James 
Published: May 2021

Abstract
Background: Primary adrenal insufficiency is known to be induced by certain medications, including anesthetics, antimycotic and antiparasitic medications. However, it is rarely being reported that caused by antitumor immune checkpoint inhibitors PD-1. Clinical Case: A 82-year-old female with a significant history of lung adenocarcinoma status post of recent Pembrolizumab therapy. She presented with multiple complaints, including increasing confusion, mainly memory loss, generalized aches, and pains who was found to have recurrent hyponatremia with a sodium level of 122, treated with water restriction and sodium tablets. Initial screening labs were suggestive of adrenal insufficiency: level of ACTH was within the normal range (11 pg/dL, normal range 7.2–63 pg/dL), level of cortisol was low (1.6 ng/dL, normal range 3–23 pg/dL). MRI brain without contrast ruled out metastatic disease. An ACTH-stimulating test was performed, with the results revealing an inadequate cortisol response at 0, 30, and 60 minutes(1.4 ug/gl, 8.5 ug/dl, 11.9 ug/dl, normal range 18–20 ug/gl). Therefore, a diagnosis of primary adrenal insufficiency was made. The patient was prescribed a daily oral dose of 5 mg of hydrocortisone. Her symptoms improved after a few days, and her hydrocortisone gradually increased to 15 mg daily, and her energy and memory were back to baseline after six months.
Conclusion: This is a rare case of primary adrenal insufficiency caused by Pembrolizumab using for non-small lung cancer treatment. With the growing use of Pembrolizumab, it is necessary to be aware of possible adrenal insufficiency that could be associated with receiving pembrolizumab therapy amid any clinical suspicion. Reference: Chang, L.S., et al., Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr, Rev, 2019. 40(1): p. 17–65
Primary Hyperaldosteronism in Pregnancy: A Case Report
Authors: Li Jefferson , Kubbar Alaa , Kim Eunice , Pelaez Dennis Nunez , Rodriguez Giovanna , Bahtiyar Gul 
Published: May 2021

Abstract
Background: Primary aldosteronism (PA) is a renin-independent hypersecretion of aldosterone that remains an underdiagnosed etiology of hypertension. Less than 50 cases of primary hyperaldosteronism in pregnancy have been reported in literature that are associated with pregnancy complications including preeclampsia.
Clinical Case: A 41-year-old female G9P4 at 32 weeks gestation was admitted for suspected preeclampsia due to elevated blood pressure during a routine prenatal visit. Her comorbidities include type 2 diabetes, uncontrolled hypertension, and preeclampsia in a previous pregnancy. Home medications included Lisinopril 10 mg once daily which was discontinued upon pregnancy and switched to Labetalol 400 mg twice daily and Nifedipine ER 30 mg daily. She was on a total of 220 units of insulin daily.
On presentation, patient complained of anxiety but denied any headache, nausea, visual disturbances, chest pain, palpitations, muscle cramps, or fatigue. Her blood pressure was 180/100 mmHg with heat rate of 73. Laboratory values was notable for potassium: 2.8 mmol/L (n 3.5–5 mmol/L), bicarbonate: 28 mmol/L (n 24–31 mmol/L), and magnesium: 1.4 mEq/L (n 1.3–1.9 mEq/L). Liver function test and platelet count were normal. Spot protein-creatinine ratio was 0.3 (n 0–0.2). ECG was normal sinus rhythm with a heart rate of 82 without decreased T wave amplitude or U waves. She received three doses of oral 40 mEq potassium chloride over twelve hours and potassium level post repletion was 3.0 mmol/L.
Initially, her hypokalemia was attributed to high insulin dose requirements. Despite down titration of insulin, patient continued to have hypokalemic episodes (nadir 2.7 mmol/L) refractory to oral and parenteral potassium supplementation. She remained hypertensive despite Labetalol 600 mg every 8 hours, Nifedipine ER 30 mg every 12 hours, with as needed hydralazine 10 mg IV pushes, and underwent urgent cesarean delivery. Uncontrolled hypertension persisted postpartum with recurrent episodes of hypokalemia. Further investigations revealed a plasma aldosterone concentration (PAC) and plasma renin activity (PRA) levels of 43.5 ng/dL (n &lt;10 ng/dL) and 1.67 ng/mL/hr (n 0.17–5.38 ng/mL/hr) respectively, potassium at time of testing was 3.6 mmol/L. PAC to PRA ratio was greater than 20:1 with an absolute PAC greater than 15 ng/dL, which is highly suggestive of PA.
Conclusion: We present a case of suspected PA with spontaneous hypokalemia potentially masked by the use of ACE inhibitors uncovered during pregnancy. Given the changes to the renin-angiotensin-aldosterone system (RAAS) during pregnancy, the diagnosis of PA is difficult to establish during gestation. Still, little is known on how to optimally treat these patients.
Reference: Morton, A., 2015. Primary Aldosteronism and Pregnancy. Pregnancy and hypertension. An International Journal of Women’s Cardiovascular Health, Volume 5 Issue 4, 259–262.