Exploring the role of the tumor microenvironment in refractory pituitary tumor pathogenesis.

PURPOSE: Treatment-refractory pituitary tumors demonstrate characteristics resembling those of highly aggressive tumors, in which the local tumor microenvironment (TME) plays a dominant role in promoting aggressiveness and refractoriness. However, role of the TME in pituitary tumors is not well studied. METHODS: Literature on the TME and development of refractory pituitary tumors was reviewed RESULTS: TME harbors tumorigenic immune cells, cancer-associated fibroblasts (CAF), extracellular matrix, and other factors that have been shown to affect behavior of tumor tissue. For example, tumor-associated macrophages and tumor-infiltrating lymphocytes correlate with aggressive and invasive tumor behavior in nonfunctioning and growth hormone-secreting (GH) pituitary tumors, while CAF release of TGFß, FGF2, cytokines, chemokines, and growth factors may promote treatment resistance, tumor fibrosis, and inflammation in prolactinomas and GH-secreting tumors. In turn, Wnt pathway activation can further promote cell growth in dopamine-resistant prolactinomas. Finally, proteins secreted by extracellular matrix are associated with increased angiogenesis in invasive tumors. CONCLUSION: It is likely that multiple mechanisms, including TME, contribute to the development of aggressive refractory pituitary tumors. Given the increased morbidity and mortality associated with pituitary tumor refractoriness, more research on the role of TME is warranted.

Adrenocortical Carcinoma: The Value of Lymphadenectomy.

BACKGROUND: Adrenocortical carcinoma (ACC) staging does not account for the number of positive nodes. The prognostic value of quantitative metastatic nodal burden is unknown. METHODS: The National Cancer Database was retrospectively queried from 2004-2016 to identify patients with Stage I-III ACC undergoing adrenalectomy. Patients who underwent lymphadenectomy (LAD) were further studied. Demographics, TNM staging, tumor characteristics, and surgical approach were analyzed. RESULTS: 386 LADs were identified. The median number of nodes examined was 2 (IQR 2-6), with no difference by surgical approach '[laparoscopic, 3 (1-3); robotic, 1.5 (1-4.5); open, 2 (1-7), p = 0.493]. In LADs with cN0 disease, positive nodes were seen in 17.5% of patients; an average of 6 (1-12) nodes were examined in patients who upstaged to pN1 disease compared with an average of 2 (1-6) nodes in those who remained pN0. Median survival was incrementally worse for patients with more positive nodes (62.8 vs. 21.9 vs. 13.7 vs. 11.3 vs. 10.7 months for 0, 1, 2, 3, and ≥ 4 positive nodes, respectively, p < 0.01). On multivariate analysis, significant prognostic factors for poor survival included older age, ≥ 2 comorbidities, pT3, and pT4. The strongest prognostic factor for poor survival was the number of positive nodes (1 node, hazards ratio [HR] 2.3, 95% confidence interval [CI] 1.5-3.6; 2 nodes, HR 1.3, 95% CI 0.6-3.0; 3 nodes, HR 3.0, 95% CI 1.1-8.0; ≥ 4 nodes, HR 4.0, 95% CI 2.5-6.2). Lymphadenectomy was associated with improved survival (HR 0.82, 95% CI 0.67-0.99). CONCLUSIONS: Higher quantitative metastatic nodal burden is a robust prognostic factor for worse survival in ACC.

Operative approach and case volume are associated with negative resection margins for adrenocortical carcinoma.

BACKGROUND: Surgical resection with negative margins is the treatment of choice for adrenocortical carcinoma (ACC). This study was undertaken to determine factors associated with negative resection margins. METHODS: National Cancer Database was queried from 2010 to 2016 to identify patients with AJCC/ENSAT Stage I-III ACC who underwent adrenalectomy. Patient, tumor, facility, and operative characteristics were compared by margin status (positive-PM or negative-NM) and operative approach (open-OA, laparoscopic-LA, or robotic-RA). Multivariable logistic regression was used to identify factors associated with PM. RESULTS: Eight hundred and eighty-one patients were identified, of which 18.4% had PM and 81.6% had NM. Patients with advanced pathologic T stage and pathologic N1 stage were more likely to have PM (vs. NM) (T3, 49.7% vs. 24.8%, p < 0.01; T4, 26.2% vs. 10.0%, p < 0.01; N1, 6.7% vs. 3.5%, p < 0.01). Patients undergoing OA (vs. LA and RA) were more likely to have advanced clinical T stage (T4, 16.6% vs. 5.7% vs. 7.8%, p < 0.01) and larger tumors (> 6 cm, 84.6% vs. 64.1% vs. 62.3%, p < 0.01). High-volume centers (≥ 5 cases) were more likely to utilize OA. Patients undergoing LA (vs. RA) were more likely to require conversion to open (20.3% vs. 7.8%, p = 0.011). On multivariable analysis, factors associated with higher odds of PM included T3 disease (OR 7.02, 95% CI 2.66-18.55), T4 disease (OR 10.22, 95% CI 3.66-28.53), and LA (OR 1.99, 95% CI 1.28-3.09). High-volume centers were associated with lower odds of PM (OR 0.67, 95% CI 0.45-0.98). There was no significant difference in margin status between OA and RA (OR 1.44, 95% CI 0.71-2.90). CONCLUSION: Centers with higher ACC case volumes have lower odds of PM and utilize OA more often. LA is associated with higher odds of PM, whereas RA is not. These factors should be considered when planning the operative approach for ACC.

Opioids and pituitary function: expert opinion.

PURPOSE: Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. METHODS: Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. RESULTS: Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. CONCLUSIONS: Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Factors Associated with Non-Operative Management of Resectable Adrenocortical Carcinoma.

INTRODUCTION: Surgery is the initial treatment of choice for patients with resectable adrenocortical carcinoma (ACC). We sought to determine factors associated with non-operative management of resectable ACC. METHODS: 2004-2016 National Cancer Database (NCDB) was queried to identify patients with AJCC/ENSAT Stage I-III ACC. Patients who underwent surgery (S) were compared to those who did not undergo surgery (NS). Multivariate logistic regression was used to identify factors associated with NS. Kaplan-Meier estimates used to assess survival. RESULTS: Two thousand-seventy patients with Stage I-III ACC were identified, of which 17.5% were NS. 85.9% of NS patients were not offered surgery; 69.9% of NS patients did not receive chemotherapy or radiation therapy. NS were older and less likely to receive care at an Academic center or high volume center (≥5 cases during the study period). NS patients were more likely to have advanced T stage and N1 disease. On multivariate regression, factors associated with lower odds of surgery include older age (OR 1.03, 95% CI 1.02-1.06), T4 disease (OR 3.34, 95% CI 1.05-10.68), and treatment at a community center (OR 2.92, 95% CI 1.58-5.40). Overall median survival was significantly poorer for NS patients (50.4 versus 78.4 months, P < 0.01). CONCLUSION: Patients with locally advanced ACC are less likely to undergo an operation, while those treated at centers with more operative experience or Academic facilities are more likely to undergo an operation. As the surgery-first approach is the current standard of care for resectable ACC, these patients may be best served at high volume Academic facilities.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Growth hormone is permissive for neoplastic colon growth.

Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)(-/-) mice exhibited induced colon p53 levels, and cross-breeding them with Apc(min+/-) mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear ß-catenin accumulation, and increased epithelial-mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the "field change" milieu permissive for neoplastic colon growth.

Silent corticotroph adenomas.

PURPOSE: Silent corticotroph adenomas (SCAs) present clinically as non-functioning adenomas (NFAs) but are immunopositive for adrenocorticotrophic hormone (ACTH) without biochemical and clinical manifestation of hypercortisolism. Pathologic examination of resected NFAs that demonstrate positive ACTH and/or TPIT expression confirms its corticotroph lineage. SCAs comprise up to 20% of NFAs and exhibit a higher rate of recurrence. Studies of molecular mechanisms have generated multiple hypotheses on SCA tumorigenesis, pathophysiology, and growth that as yet remain to be proven. An improved understanding of their pathologic and clinical characteristics is needed. METHODS: A literature review was performed using PubMed to identify research reports and clinical case series on SCAs. RESULTS: Up to date findings regarding epidemiology, mechanisms of pathogenesis, differentiation, progression, and growth, as well as clinical presentation, postoperative course, and treatment options for patients with SCAs are presented. Pooled results demonstrate that 25-40% of cases show cavernous sinus invasion, preoperative hypopituitarism, new-onset hypopituitarism, and recurrence. CONCLUSION: This article reviews the incidence, molecular pathology, and clinical behavior of these unique non-functioning pituitary corticotroph adenomas, and highlights the need for rigorous monitoring for recurrences and hypopituitarism in patients with SCAs.

Consensus-driven in-hospital cortisol assessment after ACTH-secreting pituitary adenoma resection.

PURPOSE: Remission from Cushing disease (CD) after pituitary adenoma resection may be predicted by a postoperative reduction in serum cortisol level. A 2008 consensus statement recommends assessing morning cortisol levels during the first postoperative week, and replacing glucocorticoid (GC) if cortisol nadir of < 2 or < 5 µg/dL is achieved. We sought to evaluate adherence to consensus recommendations following adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma resection at our tertiary medical center, and assess time to cortisol nadir to better define the window for assessment and intervention. METHODS: We retrospectively analyzed data extracted from in-hospital electronic medical records for CD surgeries between January 1991 and September 2015. We compared cortisol levels and collection times, ACTH measurement, and postoperative and discharge GC treatment before and after consensus statement publication in July 2008. RESULTS: 107 surgeries were performed in 92 patients with CD. After 2008, more surgeries had at least one cortisol value assessed (67.9% before vs. 91.3% after, p = 0.033), with median initial cortisol measurement at 14 h post-surgery. However, ACTH measurement remained unchanged (42.9% vs. 43.5%; p > 0.99). Cortisol collection during GC treatment tended to increase (32.7% vs. 57.1%; p = 0.068). Of surgeries performed without prior GC treatment, 31.7 and 55.0% had a cortisol nadir of < 2 and < 5 µg/dL, respectively, within 72 h postoperative. CONCLUSIONS: Our physicians were more diligent in measuring in-hospital postoperative cortisol levels consistent with 2008 consensus recommendations. Better management of cortisol measurements and their timing is an opportunity for improvement.

Somatostatin and dopamine receptor regulation of pituitary somatotroph adenomas.

Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands octreotide, lanreotide, and pasireotide, and to a lesser extent, dopamine and the dopamine analogs bromocriptine and cabergoline, suppress growth hormone (GH) secretion from a GH-secreting pituitary somatotroph adenoma. Somatostatin and dopamine receptors are Gαi-protein coupled that inhibit adenylate cyclase activity and cAMP production and reduce intracellular calcium concentration and calcium flux oscillations. Although their main action on somatotroph cells is acute inhibition of GH secretion, they also may inhibit GH production and possibly somatotroph proliferation. These receptors have been reported to create complexes that exhibit functions distinct from that of receptor monomers. Somatostatin suppression of GH is mediated mainly by somatostatin receptor subtype 2 and to a lesser extent by SST5. Human somatostatin receptor subtype 5 has also been shown to harbor mutations associated with GH levels, somatotroph tumor behavior, and somatostatin receptor ligand (SRL) responsiveness. Reviewing current knowledge of somatostatin and dopamine receptor expression and signaling in normal and tumoral somatotroph cells offers insights into mechanisms underlying SRL and dopamine agonist effectiveness in patients with acromegaly.

Enhanced cosyntropin stimulation test performance enabled by electronic medical record.

PURPOSE: To improve performance of the cosyntropin stimulation test (CST) used for diagnosis of adrenal-cortisol insufficiency by implementing an electronic medical record (EMR) system protocol. METHODS: We implemented a SmartForm protocol of the validated CST in our EMR system (CS-Link™, EPIC) system and compared medical staff test performance before and after protocol implementation. RESULTS: Correct performance of the CST improved significantly after EMR implementation. The number of correctly performed CSTs increased from 16.1 % before to 53.5 % after implementation (p < 0.0001) while those performed incorrectly and were uninterpretable decreased from 36.2 to 7.1 % (p < 0.0001). This performance improvement result in a calculated cost savings of $50,414 for every 100 tests performed. CONCLUSIONS: The EMR system is useful for guiding medical staff to accurately perform the CST, reduce the number of wasted tests, and maximize staff time and resources.

Growth hormone is a cellular senescence target in pituitary and nonpituitary cells.

Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin-induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence.

Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor.

Cushing disease caused by adrenocorticotropin (ACTH)-secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity, and increased mortality. There is no effective pituitary targeted pharmacotherapy for Cushing disease. Here, we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene (PTTG/securin) targeted to the adenohypophyseal proopiomelanocortin (POMC) lineage, which recapitulated early features pathognomonic of corticotroph adenomas, including corticotroph expansion and partial glucocorticoid resistance. Adult Tg:Pomc-Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up-regulation, as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease. Early development of corticotroph pathologies in Tg:Pomc-Pttg embryos facilitated drug testing in vivo. We identified a pharmacologic CDK2/cyclin E inhibitor, R-roscovitine (seliciclib; CYC202), which specifically reversed corticotroph expansion in live Tg:Pomc-Pttg embryos. We further validated that orally administered R-roscovitine suppresses ACTH and corticosterone levels, and also restrained tumor growth in a mouse model of ACTH-secreting pituitary adenomas. Molecular analyses in vitro and in vivo showed that R-roscovitine suppresses ACTH expression, induces corticotroph tumor cell senescence and cell cycle exit by up-regulating p27, p21 and p57, and downregulates cyclin E expression. The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion.

The effect of hormonal secretion on survival in adrenocortical carcinoma: A multi-center study.

BACKGROUND: Current evidence suggests that cortisol secreting adrenocortical carcinoma has worse prognosis compared to non-secreting adrenocortical carcinoma. However, the effect of other secretory subtypes is unknown. METHODS: This multicenter study within the American-Australian-Asian Adrenal Alliance included adults with adrenocortical carcinoma (1997-2020). We compared overall survival and disease-free survival among cortisol secreting, mixed cortisol/androgen secreting, androgen secreting, and non-secreting adrenocortical carcinoma. RESULTS: Of the 807 patients (mean age 50), 719 included in the secretory subtype analysis: 24.5% were cortisol secreting, 13% androgen secreting, 28% mixed cortisol/androgen, 32.5% non-secreting, and 2% were mineralocorticoid secreting. Median overall survival and disease-free survival for the entire cohort were 60 and 9 months, respectively. Median overall survival was 36 months for cortisol, 30 for mixed, 60 for androgen secreting, and 115 for non-secreting adrenocortical carcinoma, P < .01. Median disease-free survival was 7 months for cortisol, 8 for mixed, 10 for androgen, and 12 for non-secreting adrenocortical carcinoma, P = .06. On multivariable analysis of age, sex, Ki67%, secretory subtype, stage, resection, and adjuvant therapy, predictors of worse overall survival were older age, higher Ki67%, stage IV, mixed secreting, R1, and no adjuvant therapy, P < .05. On subgroup analysis of R0 resection, predictors of worse overall survival included older age and higher Ki67%. Ki67% ≥40, stage III and cortisol secretion were associated with worse disease-free survival. CONCLUSION: Mixed cortisol/androgen secreting adrenocortical carcinoma was associated with worse overall survival, while cortisol or androgen secreting alone were not. Notably, among patients after R0 resection, secretory subtype did not affect overall survival. Cortisol secreting adrenocortical carcinoma demonstrated worse disease-free survival. Ki67% remained a strong predictor of worse overall survival and disease-free survival independent of stage.

Opioid-induced adrenal insufficiency: diagnostic and management considerations.

The dramatic rise in opioid use over the last two decades has led to a surge in their harmful health effects. Lesser known among clinicians is the impact of opioids on the endocrine system, especially with regard to cortisol. Opioids can suppress the hypothalamus-pituitary-adrenal (HPA) axis and may result in clinically significant adrenal insufficiency, especially in those treated at higher doses and for a longer time. A high clinical suspicion is necessary in this population for early diagnosis of opioid-induced adrenal insufficiency (OAI). Diagnosis of OAI is challenging, as the symptoms are often vague and overlap with those due to opioid use or the underlying pain disorder. Traditional assays to diagnose adrenal insufficiency have not been widely studied in this population, and more investigation is needed to determine how opioids might affect assay results. Once a diagnosis of adrenal insufficiency has been made, glucocorticoid replacement in the form of hydrocortisone is likely the mainstay of treatment, and effort should be made to taper down opioids where possible. Cortisol levels should be retested periodically, with the goal of stopping glucocorticoid replacement once the HPA axis has recovered. In this review, we provide context for diagnostic challenges in OAI, suggest diagnostic tools for this population based on available data, and offer recommendations for the management of this disorder. There is a paucity of literature in this field; given the widespread use of opioids in the general population, more investigation into the effects of opioids on the HPA axis is sorely needed.

Generation of isogenic and homozygous MEN1 mutant cell lines from patient-derived iPSCs using CRISPR/Cas9.

MEN1, an autosomal dominant disorder caused by mutations in the tumor suppressor gene MEN1, manifests with co-occurrence of multiple endocrine/neuroendocrine neoplasms. An iPSC line derived from an index patient carrying the mutation c.1273C>T (p.Arg465*) was edited using a single multiplex CRISPR/Cas approach to create an isogenic control non-mutated line and a homozygous double mutant line. These cell lines will be useful for elucidating subcellular MEN1 pathophysiology and for screening to identify potential MEN1 therapeutic targets.

Fluid Restriction Reduces Delayed Hyponatremia and Hospital Readmissions After Transsphenoidal Surgery.

CONTEXT: Postoperative hyponatremia leads to prolonged hospital length of stay and readmission within 30 days. OBJECTIVE: To assess 3 strategies for reducing rates of postoperative hyponatremia and analyze risk factors for hyponatremia. DESIGN: Two retrospective analyses and 1 prospective study. SETTING: Tertiary referral hospital. PATIENTS: Patients undergoing transsphenoidal surgery for pituitary adenomas and other sellar and parasellar pathologies. INTERVENTION(S): Phase 1: no intervention. Phase 2: postoperative day (POD) 7 sodium testing and patient education. Phase 3: fluid restriction to 1 L/day on discharge in addition to phase 2 interventions. MAIN OUTCOME MEASURES: Rates of early and delayed hyponatremia and readmissions. Secondary outcomes were risk factors for hyponatremia and readmission costs. RESULTS: In phase 1, 296 patients underwent transsphenoidal surgery. Twenty percent developed early and 28% delayed hyponatremia. Thirty-eight percent underwent POD 7 sodium testing. Readmission rates were 15% overall and 4.3% for hyponatremia. In phase 2 (n = 316), 22% developed early and 25% delayed hyponatremia. Eighty-nine percent complied with POD 7 sodium testing. Readmissions were unchanged although severity of hyponatremia was reduced by 60%. In phase 3 (n = 110), delayed hyponatremia was reduced 2-fold [12.7%, relative risk (RR) = 0.52] and readmissions 3-fold [4.6%, RR = 0.30 (0.12-0.73)]; readmissions for hyponatremia were markedly reduced. Hyponatremia readmission increased costs by 30%. CONCLUSIONS: Restricting fluid to 1 L/day on discharge decreases rates of delayed hyponatremia and readmissions by 50%. Standardized patient education and POD 7 sodium testing decreases severity of hyponatremia but does not impact readmission rates. These protocols should be considered standard practice for patients undergoing transsphenoidal surgery.

Treatment of Cushing Disease With Pituitary-Targeting Seliciclib.

CONTEXT: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. OBJECTIVE: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). METHODS: Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥ 50% reduction in UFC from baseline to study end. RESULTS: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥ 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients who achieved ≥ 48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation. CONCLUSION: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.

Adrenal Cushing's Syndrome Treated With Preoperative Osilodrostat and Adrenalectomy.

Background/Objective: Reducing severity of Cushing's syndrome caused by an adrenal adenoma (adrenal Cushing's syndrome [ACS]) might decrease morbidity and mortality risk in adrenalectomy. We used off-label osilodrostat, approved in the United States for pituitary Cushing's disease, to reduce cortisol levels and disease severity before adrenalectomy 3 weeks later. Case Report: A 48-year-old woman with a 6-year history of obesity, depression, and anxiety and 3-year history of diabetes and hypertension was admitted with vomiting and lumbar back pain. Facial plethora and hirsutism, posterior cervicothoracic fat pad, and truncal obesity coupled with morning serum cortisol >13 µg/dL after 1 mg oral dexamethasone suppression, urinary free cortisol 1324 µg/24hr (4.0-50.0 µg/24 h), and adrenocorticotropin <5 pg/mL (6-50 pg/mL) confirmed ACS. Computed tomography with contrast revealed a 3.4-cm right adrenal mass. Osilodrostat 2 mg twice daily initiated at discharge was increased to 4 mg twice daily on day 6. Three days later, she reported nausea, vomiting, and fatigue. Despite 7.2 µg/dL morning cortisol, adrenal insufficiency was suspected; osilodrostat was reduced to 2 mg twice daily and maintenance oral hydrocortisone 20 mg daily was added with symptom resolution. Prior to adrenalectomy, morning cortisol was 5.1 µg/dL, fasting glucose was 122 mg/dL, and she self-discontinued diabetes medications. Hypertension remained unchanged (149/100 vs 151/94 mmHg). Adrenalectomy revealed a 3.4-cm focally pigmented adrenocortical adenoma. Discussion: Three-week treatment of overt ACS with off-label osilodrostat reduced cortisol and glucose levels before curative adrenalectomy. Abrupt cortisol reduction led to suspected adrenal insufficiency managed with maintenance hydrocortisone. Conclusion: Osilodrostat might help reduce ACS severity before adrenalectomy. Adrenal insufficiency is a risk but can be safely managed with hydrocortisone.

p21(Cip1) restrains pituitary tumor growth.

As commonly encountered, pituitary adenomas are invariably benign. We therefore studied protective pituitary proliferative mechanisms. Pituitary tumor transforming gene (Pttg) deletion results in pituitary p21 induction and abrogates tumor development in Rb(+/-)Pttg(-/-) mice. p21 disruption restores attenuated Rb(+/-)Pttg(-/-) pituitary proliferation rates and enables high penetrance of pituitary, but not thyroid, tumor growth in triple mutant animals (88% of Rb(+/-) and 72% of Rb(+/-)Pttg(-/-)p21(-/-) vs. 30% of Rb(+/-)Pttg(-/-) mice developed pituitary tumors, P < 0.001). p21 deletion also accelerated S-phase entry and enhanced transformation rates in triple mutant MEFs. Intranuclear p21 accumulates in Pttg-null aneuploid GH-secreting cells, and GH(3) rat pituitary tumor cells overexpressing PTTG also exhibited increased levels of mRNA for both p21 (18-fold, P < 0.01) and ATM (9-fold, P < 0.01). PTTG is abundantly expressed in human pituitary tumors, and in 23 of 26 GH-producing pituitary adenomas with high PTTG levels, senescence was evidenced by increased p21 and SA-beta-galactosidase. Thus, either deletion or overexpression of Pttg promotes pituitary cell aneuploidy and p53/p21-dependent senescence, particularly in GH-secreting cells. Aneuploid pituitary cell p21 may constrain pituitary tumor growth, thus accounting for the very low incidence of pituitary carcinomas.