Alice C. Levine

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in American men. Most patients with metastatic disease respond initially to androgen deprivation therapy (ADT) but almost inevitably progress to castration-resistant prostate cancer (CRPC). Identification of markers and drivers of Metastatic CRPC (mCRPC) that (a) represent a progenitor-type cancer cell population, (b) persist in castration-resistant disease, (c) are actionable targets expressed on the cell surface, and (d) are induced by hypoxia is required to facilitate the development of novel targeted therapies. We identified prostatic acid phosphatase (PAP), particularly the transmembrane form (TMPAP), as one such potential target. PAP is both a phosphatase and a 5′ectonucleotidase that generates adenosine. PAP is a human tumor marker first described in 1936 and is still used as an important prognostic marker for advanced metastatic prostate cancer. Our group recently reported that the transmembrane form of the protein (TMPAP) is expressed in CRPC and can serve as a potential therapeutic target. We identified a lead human anti-TMPAP antibody clone 3D8 (3D8-Ab). 3D8-ADCs (Antibody Drug Conjugates) and 3D8-Ab were tested for their ability to reduce tumor size/volume in a xenograft model. The human PAP-expressing PCa cell line VCaP, originally derived from a vertebral metastasis from a patient with CRPC, was inoculated subcutaneously into SCID mice. Treatment with either 3D8-Ab or 3D8-ADC significantly reduced tumor size and increased animal survival. These data indicate that targeting PAP with monoclonal antibodies either alone or conjugated to toxins has the potential to treat CRPC.

Concurrent thyrotropin (TSH) secreting and growth hormone (GH) secreting pituitary adenomas are rare entities. Although tumors of the PIT-1 lineage may coexpress TSH and GH, concurrent biologically active secretion resulting in central hyperthyroidism and acromegaly is uncommon. We report the case of a 42-year-old woman presenting with weight loss, palpitations, amenorrhea, and progressive acromegalic features. Biochemical evaluation revealed central hyperthyroidism with elevated free T4 and inappropriately normal TSH, markedly elevated insulin-like growth factor 1 (IGF-1) and GH, hyperprolactinemia, and elevated α-subunit. Pituitary magnetic resonance imaging demonstrated a 2.7-cm macroadenoma with cavernous sinus extension. She underwent transsphenoidal resection without complications. Pathology confirmed a mature plurihormonal PIT-1 lineage adenoma immunopositive for TSH, GH, and prolactin with a Ki-67 of 3%. Immediately postoperatively, thyrotoxicosis and hyperprolactinemia resolved, IGF-1 levels declined, acromegalic features improved, and menses resumed. Over the ensuing months, thyroid and prolactin tests remained within normal range, but the IGF-1 level remained elevated. This case illustrates the rare presentation of a PIT-1 lineage adenoma secreting biologically active TSH, GH, and prolactin. Comprehensive hormonal evaluation and long-term biochemical and radiologic surveillance are essential, given the risk of incomplete remission despite apparent surgical cure.

Background/Objectives: Metastatic Prostate Cancer (mPCa) is generally treated with systemic therapy. Many of these treatments, particularly androgen ablation, are not curative and cause substantial morbidity. Oligometastasis is defined as a limited number of metastatic deposits, whose disease does not seem to progress to a widespread distribution of cancer. There have been some reports of trials of localized treatment of PCa oligometastatic disease with curative intent. We herein report a case of oligometastatic prostate cancer treated primarily with surgical removal of metastases, which has no evidence of active disease twenty years post-operatively. Methods: Extensive retrospective chart review, immunohistochemical staining, growth rate calculations, and imaging studies were performed to trace the progression of this patient’s disease course. Results: A detailed investigation of biochemical markers of recurrence revealed normal-low prostate specific antigen (PSA) despite advanced disease, early rather than metachronous dissemination of metastases to distant sites, and hypoxia-conditioned phenotypic plasticity and memory in disseminated tumor cells (DTCs). Conclusions: This rare outlier case of oligometastatic prostate adenocarcinoma challenges traditional linear models of metastatic progression and clinical reliance on PSA as a marker for PCa detection and treatment in advanced cases. By investigating key questions regarding the identity, timing, and trajectory of DTCs, we propose a biologically informed narrative of this patient’s disease progression and a reconsideration of metastases directed therapy (MDT) of oligometastases as primary therapy in select patients.

Context: Crinecerfont, a first-in-class corticotropin-releasing factor type 1 receptor antagonist, is FDA-approved as an adjunct to the physiologic glucocorticoid (GC) required to treat the underlying adrenal insufficiency in patients (≥4 years old) with classic congenital adrenal hyperplasia (CAH). By reducing elevated adrenocorticotropic hormone, crinecerfont controls excess adrenal androgens, thereby enabling lower GC doses. However, there are no published recommendations for how to reduce supraphysiologic GC doses after initiating crinecerfont. This manuscript aims to provide a framework developed by experienced endocrinologists for reducing supraphysiologic GC doses in patients taking crinecerfont. Evidence Acquisition: An experienced panel of 11 endocrinologists discussed strategies and considerations when reducing GC doses and developed an algorithm to guide GC dose reductions after introducing crinecerfont in adults with CAH. Evidence Synthesis: Approaches to GC reduction should be individualized based on the patient's therapeutic goals, cortisol needs, lifestyle preferences, and the clinician's experience to set appropriate targets for clinical parameters, androgens, and GC dose regimen. In general, GC doses should be reduced gradually to minimize the risks of developing symptoms of GC withdrawal or adrenal insufficiency. GC doses should be adjusted to the lowest level needed to maintain androgens at goal, without reducing below what is needed for cortisol replacement. Practical considerations during GC dose reduction include switching from longer- to shorter-acting GCs (eg, from dexamethasone to hydrocortisone), optimizing dose distribution to mimic normal circadian cortisol exposure, and consolidating or eliminating doses to improve adherence. Conclusion: This framework for reducing supraphysiologic GC doses in adult patients taking crinecerfont may become increasingly relevant as treatment of CAH shifts toward physiologic GC replacement with adjunctive control of adrenal androgens.

Background: Dopamine agonists (DAs) are first-line therapy for prolactin-secreting pituitary adenomas; however, a small proportion of tumors are resistant. Previous reports suggested that reduced D2R mRNA expression might cause resistance. This study aimed to determine if resistant prolactinomas express D2R protein. We also explored a role of estrogen receptor alpha (ERα) expression in DA resistance. Methods: We retrospectively selected 15 tumor specimens from 13 total patients (8 controls from 8 patients, 7 from 5 resistant patients) with resected lactotroph cell-type tumors. We reviewed age at diagnosis, tumor size, initial prolactin level, medical treatment, and reason for surgery. Immunohistochemistry was performed for D2R, prolactin, and ERα protein expression. Results: D2R expression was positive in seven of eight controls vs. two of seven in resistant tumors (p = 0.02). ERα expression did not significantly correlate with DA resistance. The two D2R expressing resistant tumors were ERα negative and both derived from a pre-pubertal female, supporting prior reports suggesting ERα may modulate DA therapy response. Conclusions: Our study introduces a reproducible method for assessing D2R protein expression in prolactinomas using commercially available D2R antibodies. Our findings align with current evidence indicating that lack of D2R expression, previously indicated by decreased mRNA levels, is common in DA-resistant prolactinomas and provide a basis for discontinuation of DA therapy to avoid potential harm to these patients.

Background and Aims: Glucocorticoid-induced adrenal insufficiency (GC-AI) is a potentially life-threatening side effect of glucocorticoid therapy. Currently, there is no consensus on monitoring and treating GC-AI in inflammatory bowel disease (IBD) patients. This systematic review and meta-analysis aimed to determine the prevalence of GC-AI in IBD patients following glucocorticoid use. Additionally, a Delphi panel was conducted to develop evidence-based expert opinions on evaluating and managing GC-AI in IBD patients. Methods: Thirty-four articles were included in this study. Of these, 26 articles reported the prevalence of GC-AI in IBD patients. Statements were generated and rated by a panel of adult and pediatric gastroenterologists using a 1-9 scale. Statements were classified as inappropriate, uncertain, or appropriate based on the median panel rating and the degree of disagreement. Results: The prevalence of GC-AI across all studies was 26.9% (95% CI: 18.9-36.8, I2: 96%). The panel emphasized the importance of maintaining a high suspicion for GC-AI in IBD patients treated with systemic glucocorticoids and considering risk factors such as exogenous glucocorticoid use ≥4 weeks at doses ≥5 mg of prednisone-equivalent. Recommendations for initial screening and management of GC-AI are provided. The management of GC-AI in special populations, such as those in the perioperative setting is also addressed. The panel underscored the need to consider GC-AI assessment in clinical trial design. Conclusions: GC-AI is a serious, often underrecognized side effect of glucocorticoid use. This study presents expert opinions on the evaluation and management of GC-AI in IBD patients, emphasizing the need for vigilance and appropriate management strategies.

Adrenal ganglioneuromas (AGNs) are rare benign neoplasms of neural crest origin that are typically asymptomatic and endocrinologically inactive. However, on occasion, AGNs have been noted to demonstrate secretion of various hormones. We present a case of a 23-year-old man who presented with hypertension and clinical symptoms concerning for a catecholamine excess state with evidence of a right adrenal mass with elevated Hounsfield units (HU) on abdominal computed tomography (CT) and laboratory values consistent with mild hypercortisolism concerning for adrenocorticotropin (ACTH)-producing pheochromocytoma leading to Cushing syndrome (CS). The patient underwent adrenalectomy with pathology results demonstrating a pure AGN with positive ACTH staining. While secretory AGNs are rare, it is important that providers remain cognizant of this pathology and consider it within the evaluation of adrenal lesions at large with an understanding that clinical presentation may be difficult to interpret and will likely vary based on the underlying hormone(s) being secreted. Additionally, secretory AGNs can mimic other adrenal neoplasms and histopathologic evaluation is required for definitive diagnosis. This case demonstrates how ACTH-producing AGNs should be considered when evaluating cases of ACTH-dependent CS.

Introduction Dopamine-agonist (DA) resistant prolactinomas are characterized by failure to achieve normal prolactin levels or reduce tumor size by at least 50% on maximal conventional DA dosages. This occurs in about 10% of patients on cabergoline and is more common in larger macroadenomas, and in men compared with women. The underlying cause of resistance may be a lack of D2 receptor (D2R) tumor expression. As high dose DA therapy may have serious cardiac side effects, it is important to determine the D2R expression. Further, the sexual dimorphism observed in resistant prolactinomas may be due to estrogen receptor alpha (ERα) expression in female tumors, as ERα signaling has been shown to enhance sensitivity to DAs. We investigated the possibility that androgen receptor (AR) signaling in males promotes resistance via induction of transmembrane serine protease 2 (TMPRSS2), a cell surface serine protease, a known promoter of tumor progression in prostate and lung cancer. Methods This is a retrospective, single-center study conducted at an academic quaternary-care center. Immunohistochemical (IHC) analysis was performed on 16 specimens from surgically removed lactotroph cell type tumors, including D2R, growth hormone (GH), prolactin (PRL), TMPRSS2, ERα, AR, and the stem cell marker, CD133. We simultaneously conducted a chart review of the Electronic Medical Record to determine age at diagnosis, tumor size, initial PRL level, medical treatment, and reason for surgical resection. Results A total of 14 patients were included in our study. Two patients had multiple surgeries for resistant prolactinomas such that the sample size included 16 specimens- 7 resistant prolactinomas and 9 controls (resected for another reason other than treatment resistance). There were 2 men and 3 women in the resistant group, and 5 women and 4 men in the control group. Baseline prolactin level was higher in the resistant group (2413ng/mL) than the control group (676.4ng/mL) and tumor size was larger—2.05cm vs. 1.57cm in the largest diameter in the resistant vs. control groups, respectively. D2R expression was positive in 8 out of 9 controls vs. 1 out of 7 in resistant tumors. ERα positivity did not correlate with DA resistance. AR expression was negative in all specimens although the majority of tumors in both groups did express TMPRSS2. CD133 was negative in all but one of the resistant tumors. Conclusion We found that 80% of specimens from patients with DA-resistant prolactinomas had negative D2R expression. The one resistant tumor that had positive D2R and negative TMPRSS2 expression was from an 11 year old girl who also had negative ERα expression that may explain the lack of response to dopamine agonist therapy. D2R IHC can identify lack of D2R expression in DA-resistant tumors and provide a rationale for discontinuation of high dose DA therapy to avoid toxicity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Neoplasms that secrete ectopic adrenocorticotropin (ACTH) may cause severe, life-threatening hypercortisolism. These tumors are often difficult to localize and treat, requiring a comprehensive and systematic management plan orchestrated by a multidisciplinary team. The Mount Sinai Adrenal Center hosted an interdisciplinary retreat of experts in adrenal disorders and neuroendocrine tumors (NETs) with the aim of developing a clinical pathway for the management of Cushing syndrome due to ectopic ACTH production. The result was institutional recommendations for the diagnosis, localization, surgical approaches to intrathoracic tumors and bilateral adrenalectomy, and perioperative and postoperative medical management of hypercortisolism and its sequelae. Specific recommendations were made regarding the timing and selection of therapies based on the considerations of our team as well as a review of the current literature. Our clinical pathway can be applied by other institutions directly or serve as a guide for institution-specific management.