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Objective This extended evaluation (EE) of the SONICS study assessed the effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing's syndrome. Design/Methods SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at months 9 and 12 (relative to the start of maintenance). For pituitary MRI in patients with Cushing's disease, a threshold of ≥2 mm denoted change from baseline in the largest tumor diameter. Results Sixty patients entered EE at month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, BMI, abdominal girth, hirsutism, CushingQoL, and Beck Depression Inventory-II scores improved from the study baseline at months 9 and 12. Forty-six patients completed month 12; four (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal, Fridericia-corrected QT interval >460 ms, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and month 12 or follow-up, the largest tumor diameter was stable in 27 (87%) patients, decreased in one, and increased in three (largest increase 4 mm). Conclusion In the first long-term levoketoconazole study, continued treatment through a 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

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.

The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often repeated surgical, medical, and radiation treatment. Herein, we summarize the currently known somatic and genetic mutations and other molecular factors that influence the pathogenesis of these tumors and discuss currently available therapies. Although recent molecular studies have advanced our understanding of the pathogenesis and behavior of these refractory corticotroph adenomas, these insights do not reliably guide treatment choices at present. Development of additional diagnostic tools and novel tumor-directed therapies that offer efficacious treatment choices for patients with refractory corticotroph adenomas are needed.

Objectives The aim of this study was to identify the reasons for patient messages, phone calls, and emergency department (ED) visits prior to the first postoperative visit following discharge after endoscopic transnasal transsphenoidal (eTNTS) surgery. Design This is a retrospective review of patients at a tertiary care academic center who underwent eTNTS for resection of a sellar region tumor between May 2020 and August 2021. Patient, tumor, and surgical characteristics were collected, along with postoperative, postdischarge, and readmission information. Regression analyses were performed to investigate risk factors associated with postdischarge phone calls, messages, ED visits, and readmissions. Main Outcome Measures The main outcomes were the number of and reasons for phone calls, patient messages, and ED visits between hospital discharge and the first postoperative visit. We additionally determined whether these reasons were addressed in each patient's discharge instructions. Results A total of 98 patients underwent eTNTS during the study period. The median length of hospital stay was 2 days (interquartile range [IQR]: 1–4 days), at which point most patients (82%) were provided with eTNTS-specific discharge instructions. First postoperative visit took place 9 days after discharge (IQR: 7–10 days). Within that time, 54% of patients made at least one phone call or sent at least electronic message and 17% presented to the ED. Most common reasons for call/message were nasal care, appointment scheduling, and symptom and medication questions. Conclusion Through this work, we highlight the most common reasons for resource utilization via patient phone calls, messages, and ED visits among our cohort to better understand any shortfall or gap in the discharge process that may reduce these events.

Context Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks’ open-label osilodrostat). Results Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P Conclusion Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.

Objective This study aimed to evaluate the impact of endoscopic anterior cranial base (ACB) surgery on sinonasal symptoms in the pediatric population utilizing the Sino-Nasal Outcome Test (SNOT)-22 questionnaire. Design This is a retrospective review. Setting The study was conducted at a tertiary academic medical center. Participants Thirty-four consecutive patients, age 6 to 17 years, M:F 14:20, who underwent endoscopic ACB surgery from July 2008 to August 2019. Ten patients had baseline and a minimum of two subsequent postoperative SNOT-22 questionnaires available for analysis. Main Outcome Measures Baseline and postoperative SNOT-22 scores were compared. The mean change from baseline sinonasal symptom scores in the pediatric and historical adult cohorts was compared. Results The mean baseline SNOT-22 score for our 10 patient cohort was 0.46 out of 5 for each of the first 10 sinonasal-specific questions. This worsened to 1.69 at 1 month and returned to near baseline, 0.7, at 3 months postoperatively. The mean quality-of-life score improved to 0.91 at 1 month and 0.6 at 3 months postoperatively. The mean change from baseline for the following items: need to blow nose, runny nose, postnasal discharge, thick nasal discharge, wake up at night, reduced concentration, and frustrated/restless/irritable were similar to those in our historical adult cohort at 3 months postoperatively. Conclusion Endoscopic ACB surgery in the pediatric population results in increased sinonasal symptom morbidity in the early postoperative period; however, symptoms return to near baseline by ∼3 months, and quality-of-life scores progressively improve in the postoperative period. These trends were similar to those seen in our historic adult cohort.

Background Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid and sustained normalization of mean urinary free cortisol (mUFC) in patients with Cushing's disease (CD) during the 48-week (W) core period of LINC 4 (NCT02697734), and was well tolerated. We report long-term efficacy and safety results from the LINC 4 core and extension phases combined. Methods 73 adults with CD and mUFC >1.3× the upper limit of normal (ULN) were enrolled. LINC 4 comprised a 12W, randomized, double-blind, placebo-controlled period followed by 36W of open-label osilodrostat. At W48, patients could enter an optional extension. Dose adjustments were permitted based on efficacy/tolerability (range during open-label treatment 1–30 mg bid). LINC 4 ended when all patients transitioned to a separate long-term safety study (not reported) or discontinued treatment. Efficacy/safety are reported for all patients unless otherwise stated, and excludes data collected during W1–12 for placebo recipients. Results Of the 65 patients who completed the core phase, 60 entered the extension. Median (range) osilodrostat exposure from core baseline to study end was 87.1 (2–127) W; median average (IQR) dose was 4.6 (3.7–9.2) mg/day. 15 patients discontinued osilodrostat; 7 after W48 (6 because of adverse events [AEs]). The proportion of patients with normal mUFC (≤138 nmol/24h [50 µg/24h]) was 68.5% (n=50/73) at W48, 61.5% (n=40/65) at W72 and 72.4% (n=42/58) at the end-of-treatment extension (EOT) visit. Median mUFC decreased from 2.5×ULN (core baseline) to 0.5×ULN (W48 and W72), to 0.4×ULN (EOT). Median late-night salivary cortisol decreased from 2.8×ULN (core baseline) to 1.2×ULN (W48 and W72), to 1.1×ULN (EOT).The most common AEs during the entire study were decreased appetite (46.6%), arthralgia (45.2%), fatigue (39.7%), nausea (37.0%), headache (34.2%) and dizziness (30.1%). Hypocortisolism- and adrenal-hormone-precursor-accumulation-related AEs occurred in 28.8% (21/73) and 61.6% (45/73) of patients during the entire study, less frequently in the extension than the core. Most were grade 1/2 and resolved with dose reduction/interruption and/or concomitant medication. During the extension, hirsutism and acne were reported as AEs by 1 and 0 patients, respectively.Median ACTH increased from 1.1×ULN (core baseline) to 3.0×ULN (W48), to 3.6×ULN (W72), to 3.5×ULN (EOT). Median change (95% CI) in pituitary tumor volume (assessed by MRI) from core baseline to last available assessment was 4.0 mm3 (−24.1–169.8); pituitary-tumor-enlargement-related AEs led to drug discontinuation in 2 and 0 patients during the core and extension, respectively. No trend was observed between tumor volume change and osilodrostat dose. Conclusion Osilodrostat provided long-term control of cortisol production during LINC 4. Fewer AEs related to hypocortisolism and accumulation of adrenal-hormone-precursors occurred during the extension than during the core. Osilodrostat is an effective and well-tolerated long-term treatment option for CD patients. Presentation: Tuesday, June 14, 2022 10:15 a.m. - 10:30 a.m.

Objective Quality of life (QoL) outcomes following endoscopic endonasal transphenoidal surgery (EETS) across a variety of reconstructive methods improve by 2 to 6 months. An option for sellar reconstruction, in the absence of a significant intraoperative cerebrospinal fluid (CSF) leak, is a free mucosal graft (FMG) from the posterior septum. We analyze sinonasal QoL outcomes in patients undergoing EETS with FMG reconstruction. Study Design This study was a retrospective review. Setting This study was conducted at tertiary care academic center. Participants This study group consisted of patients undergoing EETS for pituitary adenomas from 2013 to 2018. Main Outcome Measures Tumor and surgical factors were included, along with postoperative complications. Patients completed Sinonasal Outcome Test-22 (SNOT-22) questionnaires. Pre- and postoperative scores were compared among the entire cohort using linear multilevel regression. A subcohort analysis was performed among patients who completed questionnaires during the preoperative visit and two postoperative visits (within 1 month and between 2 and 3 months, respectively); pre- and postoperative total and individual domain SNOT-22 scores were compared using paired t-tests. Results A total of 243 patients underwent EETS with FMG reconstruction. Four patients (1.6%) developed a postoperative CSF leak requiring reoperation. Among the entire cohort, SNOT-22 scores increased at the first postoperative visit (p Conclusion Posterior septum FMG reconstruction of sellar defects is an effective option, demonstrating early recovery of baseline sinonasal QoL by 2 to 3 months.

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%)., Extracellular vesicles (EVs) are present in circulation at relatively early stages of disease, providing potential opportunities for early cancer diagnosis. Here, the authors report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific EV purification system for early detection of HCC by performing digital scoring on the purified EVs.

Objective: Immune checkpoint inhibitors are approved to treat multiple cancers. We report life-threatening hepatic failure in 2 consecutive patients with Cushing syndrome that were treated with ketoconazole (KTZ) in combination with 2 different programmed cell death protein 1 (PD-1) inhibitors, Nivolumab and Pembrolizumab. Methods: The first patient suffered from corticotroph pituitary carcinoma and the second from metastatic adrenal cortical carcinoma. They were both treated with KTZ for tumor-associated hypercortisolism. Results: Hepatic function was normal on KTZ prior to initiation of PD-1 inhibitors, after which they rapidly developed severe hepatic dysfunction. In both cases, liver biopsy was consistent with drug-induced hepatic injury. Liver function fully recovered on discontinuing KTZ and the PD-1 inhibitors along with methylprednisone therapy. Conclusion: Antifungal azole therapy is commonly used in oncology patients who may be co-treated with PD-1 inhibitors. Although the specific combination of KTZ and PD-1 inhibitors to treat Cushing syndrome may be relatively uncommon, we recommend careful monitoring of hepatic function using a combination PD-1 inhibitors and azole antifungal agents, especially KTZ, due to the potential of life-threatening hepatic failure. Abbreviations: ACTH adrenocorticotropic hormone CS Cushing syndrome ICI immune checkpoint inhibitor KTZ ketoconazole MRI magnetic resonance imaging PD-1 programmed cell death protein 1

Objective: Acromegaly results from the excessive production of growth hormone and insulin-like growth factor-1. While there is up to a 2-fold increased prevalence of thyroid nodules in patients with acromegaly, the incidence of thyroid cancer in this population varies from 1.6 to 10.6% in several European studies. The goal of our study was to determine the prevalence of thyroid nodules and thyroid cancer among patients with acromegaly at a large urban academic medical center in the United States (U.S.). Methods: A retrospective chart review was performed of all patients with acromegaly between 2006-2015 within the University of California, Los Angeles health system. Data were collected regarding patient demographics, thyroid ultrasounds, thyroid nodule fine needle aspiration (FNA) biopsy cytology, and thyroid surgical pathology. Results: In this cohort (n = 221, 49.3% women, mean age 53.8 ± 15.2 [SD] years, 55.2% Caucasian), 102 patients (46.2%) underwent a thyroid ultrasound, from which 71 patients (52.1% women, mean age 52.9 ± 15.2 [SD] years, 56.3% Caucasian) were found to have a thyroid nodule. Seventeen patients underwent a thyroid nodule FNA biopsy and the results revealed 12 benign biopsies, 1 follicular neoplasm, 3 suspicious for malignancy, and 1 papillary thyroid cancer (PTC), from which 6 underwent thyroidectomy; PTC was confirmed by surgical pathology for all cases (8.5% of all nodules observed). Conclusion: In this sample, the prevalence of thyroid cancer in patients with acromegaly and coexisting thyroid nodules is similar to that reported in the general U.S. population with thyroid nodules (7 to 15%). These findings suggest that there is no benefit of dedicated thyroid nodule screening in patients newly diagnosed with acromegaly. Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; DTC = differentiated thyroid cancer; FNA = fine needle aspiration; GH = growth hormone; IGF-1 = insulin-like growth factor-1; PTC = papillary thyroid cancer; U.S. = United States.

Background The literature on opiate use after endoscopic endonasal transsphenoidal surgery (EETS) is limited. Objective To determine the risk factors for higher opiate use following EETS and the quantity of opiates used after discharge. Methods A retrospective review of 144 patients undergoing EETS from July 2018 to July 2020 was conducted. Patient, tumor, and surgical factors were documented. Pain scores and medications used on postoperative days (POD) 0 and 1, and discharge prescriptions, were recorded. Opiate use was quantified using morphine milligram equivalents (MME) dose. Multiple linear regression determined risk factors independently associated with POD0 to 1 opiate use. Results On POD 0 to 1, mean pain score was 4.9/10 (standard deviation [SD] ± 2.0). Mean acetaminophen use was 3.4 tablets (SD ± 1.6; 650 mg per tablet). Mean opiate use was 35.6 MME (SD ± 36.3), equivalent to 4.7 tablets (SD ± 4.8) of oxycodone 5 mg. Multiple linear regression showed that current smokers required an additional 37.1 MME ( P = .011), and patients with grade 3 intraoperative cerebrospinal fluid leaks required an additional 36.7 MME ( P = .046) on POD0 to 1. On discharge, mean opiate prescription was 117.7 MME (SD ± 102.1), equivalent to 15.7 tablets (SD ± 13.6) of oxycodone 5 mg. Thirty-nine patients (27.1%) did not require prescriptions. Only 10 patients (6.9%) required opiate refill(s) within 30 days after surgery. Conclusion Patients undergoing EETS have higher opiate needs compared to those undergoing endoscopic sinus surgery, although the overall requirements are still considered low. Independent risk factors associated with higher opiate use in the immediate postoperative period included current smokers and grade 3 intraoperative cerebrospinal fluid leaks.

Background Cushing's disease (CD) is a serious disorder associated with increased cardiovascular morbidity and mortality, and reduced patient quality of life (QoL), because of hypercortisolism. We report long-term effects of osilodrostat, a potent 11β-hydroxylase inhibitor, on cardiovascular/metabolic-related risk factors, physical features of hypercortisolism and QoL in CD patients following the core and extension phases of the LINC 4 study (NCT02697734). Methods LINC 4 comprised a 12-week (W), randomized, double-blind, placebo-controlled period, 36W of open-label osilodrostat, and an optional extension phase in adults with CD and mUFC >1.3xULN. Dose adjustments were permitted based on efficacy/tolerability (range during open-label treatment 1–30 mg bid). LINC 4 ended when all patients transitioned to a separate long-term safety study or discontinued treatment. Cardiovascular/metabolic-related parameters, physical features of hypercortisolism (rating: 0=absent; 1=mild; 2=moderate; 3=severe), and CushingQoL score were evaluated at core baseline, every 2, 4, 12 or 24W (depending on study phase/parameter) and at the end-of-treatment extension (EOT) visit. Change from baseline is provided for patients with assessments at core baseline, W48 and EOT. Results Of the 65 patients completing W48, 60 entered the extension. Median (range) osilodrostat exposure from core baseline to study end: 87.1 (2–127) W; median (IQR) average dose: 4.6 (3.7‍–‍9.2) mg/day. Mean changes (95% CI) in cardiovascular/metabolic-related parameters from core baseline to W48 and EOT, respectively, included decreases in systolic (−9.7 [−14.9, −4.6] mmHg; −12.4 [−17.4, −7.4] mmHg; baseline: 131.5 mmHg) and diastolic (−4.2 [−7.3, −1.2] mmHg; −5.6 [−8.9, −2.4] mmHg; baseline 87.5 mmHg) blood pressure, fasting plasma glucose (−3.1 [−6.8, 0.6] mg/dL; −3.5 [−8.5, 1.4] mg/dL; baseline: 95.3 mg/dL) and cholesterol (−0.5 [−0.8, −0.2] mmol/L; −0.6 [−0.9, −0.3] mmol/L; baseline: 5.5 mmol/L). Improvements (mean change [95% CI]) from core baseline to W48 and EOT also occurred for weight (–4.3 [–5.9, –2.6] kg; –6.8 [–8.8, –4.8] kg; baseline: 78.3 kg) and waist circumference (–4.5 [–6.0, –3.1] cm; –7.6 [–9.6, –5.6] cm; baseline: 102.8 cm). Physical features of hypercortisolism improved (severity reduced) or remained stable from core baseline to EOT in most patients (respectively): ecchymosis (21% [n=10/48]; 79% [n=38/48]), striae (26%; n=12/46; 72% [n=33/46]), hirsutism in females (29% [n=11/38]; 61% [n=23/38]), muscle weakness (33% [n=16/49]; 61% [n=30/49]), facial rubor (48% [n=23/48]; 46% [n=22/48]), central obesity (55% [n=27/49]; 37% [n=18/49]), and fat pads (dorsal: 58% [n=28/48]; 31% [n=15/48]; supraclavicular: 65% [n=32/49]; 35% [n=17/49]). CushingQoL score improved from core baseline to W48 and EOT (mean change [95% CI]: 12.0 [8.2, 15.9]; 17.1 [12.5, 21.7]; baseline: 51.8). Conclusion Most cardiovascular/metabolic-related parameters continued to improve during long-term osilodrostat treatment. Additionally, most physical features of hypercortisolism, including hirsutism, either improved or remained stable, and CushingQoL score improved. Osilodrostat is an effective treatment that may alleviate disease burden for many patients with CD. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Circulating tumor cell (CTC) clusters are present in cancer patients with severe metastasis, resulting in poor clinical outcomes. However, CTC clusters have not been studied as extensively as single CTCs, and the clinical utility of CTC clusters remains largely unknown. In this study, we aim sought to explore the feasibility of NanoVelcro Chips to simultaneously detect both single CTCs and CTC clusters with negligible perturbation to their intrinsic properties in neuroendocrine tumors (NETs). We discovered frequent CTC clusters in patients with advanced NETs and examined their potential roles, together with single NET CTCs, as novel biomarkers of patient response following peptide receptor radionuclide therapy (PRRT). We observed dynamic changes in both total NET CTCs and NET CTC cluster counts in NET patients undergoing PRRT which correlated with clinical outcome. These preliminary findings suggest that CTC clusters, along with single CTCs, offer a potential non-invasive option to monitor the treatment response in NET patients undergoing PRRT.

Context Glucocorticoids act through the glucocorticoid receptor (GR) encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene. Objective This study aimed to examine the function of NR3C1 variants and their possible pathogenic role in Cushing disease (CD). Methods Next-generation sequencing was conducted in 49 CD patients. Corticotroph tumor GR protein expression was examined by immunohistochemistry (IHC). Constructs harboring the 3 NR3C1-mutant and wild-type (WT) GR were transfected into the murine corticotropic adenoma cell line (AtT-20), and GR protein expression was quantified by Western blot. Translocation activity was assessed by immunofluorescence and effects of the GR mutants on corticotroph tumor proliferation, pro-opiomelanocortin (POMC) transcription, and ACTH secretion were tested. Results Clinical features were similar in patients harboring the NR3C1 mutations and WT GR. Recurrent adenomas showed higher GR IHC scores than nonrecurrent tumors. In vitro studies demonstrated that the p.R469X mutant generated a truncated GR protein, and the p.D590G and p.Y693D GR mutants resulted in lower GR expression. Dexamethasone (DEX) treatment of AtT-20 cells demonstrated decreased DEX-induced nuclear translocation, increased cell proliferation, and attenuated suppression of POMC transcription of 3 GR mutants. Interestingly, the p.R469X GR mutant resulted in increased murine corticotroph tumor ACTH secretion compared to WT GR. Conclusion Our findings identify 3/49 (6.1%) consecutive human corticotroph tumors harboring GR mutations. Further findings demonstrate the role NR3C1 plays in CD pathogenesis and offer insights into a novel treatment approach in this patient subset.

Introduction Improved evidence-based guidelines on the optimal type and duration of antibiotics for patients undergoing endoscopic endonasal transsphenoidal surgery (EETS) are needed. We analyze the infectious complications among a large cohort of EETS patients undergoing a standardized regimen of cefazolin for 24 hours, followed by cephalexin for 7 days after surgery (clindamycin if penicillin/cephalosporin allergic). Methods A retrospective review of 132 EETS patients from 2018 to 2020 was conducted. Patient, tumor, and surgical characteristics were collected, along with infection rates. Multivariate logistic regression determined the variable(s) independently associated with infectious outcomes. Results Nearly all patients (99%) received postoperative antibiotics with 78% receiving cefazolin, 17% receiving cephalexin, 3% receiving clindamycin, and 2% receiving other antibiotics. Fifty-three patients (40%) had an intraoperative cerebrospinal fluid (CSF) leak, and three patients (2%) developed a postoperative CSF leak requiring surgical repair. Within 30 days, no patients developed meningitis. Five patients (4%) developed sinusitis, two patients (3%) developed pneumonia, and one patient (1%) developed cellulitis at a peripheral intravenous line. Two patients (2%) developed an allergy to cephalexin, requiring conservative management. After adjustment for comorbidities and operative factors, presence of postoperative infectious complications was independently associated with increased LOS (β = 3.7 days; p = 0.001). Conclusion Compared with reported findings in the literature, we report low rates of infectious complications and antibiotic intolerance, despite presence of a heavy burden of comorbidities and high intraoperative CSF leak rates among our cohort. These findings support our standardized 7-day perioperative antibiotic regimen.

Background Corticotroph tumor progression (CTP) leading to Nelson’s syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing’s disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. Methods A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. Results Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). Conclusions We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2–4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension

Introduction The association between Cushing syndrome and a hypercoagulable state has been demonstrated in the literature. A standard venous thromboembolism (VTE) prophylaxis regimen has yet to be established for patients undergoing surgery for Cushing disease. Here we present outcomes associated with VTE prophylaxis in patients with Cushing disease undergoing endoscopic transsphenoidal surgery for pituitary tumor resection. Methods A review of Cushing disease patients undergoing endoscopic transsphenoidal pituitary surgery between January 2010 and June 2020 was performed. Administration and type of VTE prophylaxis was recorded, and comparison was made between VTE and hemorrhagic complications before and after institution of a VTE prophylaxis protocol. Results A total of 65 patients were identified, 98.5% of which underwent VTE prophylaxis with either 5,000 units of subcutaneous heparin twice daily (n = 44) or 40 mg enoxaparin nightly (n = 20). VTE complications were not significantly different between the subcutaneous heparin and enoxaparin cohorts (4.5% v 0%; p = 0.61). The overall incidence of hemorrhagic complications requiring blood transfusion was 1.5%, and there was no significant difference in hemorrhagic complications between heparin and enoxaparin cohorts (0% v 5%; p = 0.32). Conclusion VTE prophylaxis in addition to sequential compression devices and early ambulation are critical in reducing VTE complications in patients with hypercortisolism from Cushing disease. Pharmacologic prophylaxis can be safely instituted in these patients with low risk of hemorrhagic complications.

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.

Serotonin (5-HT) is an important hormonal modulator and neurotransmitter, and 5-HT has been demonstrated in pituitary tissue from several species. Previous responses to 5-HT antagonists have been reported in some patients with Cushing disease although this effect was unsustained, and ACTH and cortisol levels actually increased in some patients. To better understand the role of serotonin in the regulation of corticotroph tumor growth and ACTH secretion, we first measured serotonin levels in supernatants (SNs) derived from murine corticotroph tumor AtT20 cells. We demonstrated that AtT20 cells secrete serotonin (2±0.05ng/105cells/24h) which was ~50% of the levels secreted by the serotonin secreting mid-gut carcinoid BON-1 cell-line (4.2±0.05ng/105cells/24h). In contrast, serotonin secretion was not detected in rat pituitary tumor lactotroph (GH3) or human embryonic kidney (HEK293) cell SNs, or in our Ham’s F12 medium control. Immunocytochemical staining using serotonin specific antibodies demonstrated that serotonin was diffusively present in AtT20 cell cytoplasm, suggesting that serotonin was endogenously generated in the AtT20 cells. Using real-time PCR, we demonstrated that both serotonin synthesis enzymes, tyrosine hydroxylase-1 (THP1) and -2 (THP2) are expressed in AtT20 cells with higher relative THP1 expression, confirming endogenous corticotroph pituitary tumor serotonin production. We further demonstrated that the synthetic glucocorticoid Dexamethasone (100nM x 24h) suppressed TPH1 expression and inhibited corticotroph tumor serotonin secretion. We next evaluated the actions of serotonin and various serotonin antagonists on corticotroph tumor cell proliferation and ACTH secretion. Ritanserin (10-5M) inhibited murine corticotroph tumor proliferation by 5% and inhibited ACTH secretion by ~25%. In contrast, metergoline (10-5M) and the orally administered TPH inhibitor, telotristat etiprate (10-5M for 1-3 days), inhibited ACTH secretion by 50% and 30% respectively but did not reduce cell proliferation, suggesting that Metergoline and telotristat may regulate ACTH secretion independently of their anti-proliferative effect. Addition of serotonin (10-4~10-5M) to corticotroph tumor cells cultured in reduced serum (OptiMEM) or no serum conditions, resulted in an 80% increase in cell proliferation but had little effect on ACTH secretion with a 1-4% increase. In summary, we have demonstrated that serotonin is synthesized in and secreted from corticotroph tumor cells and that serotonin plays a role in regulation of corticotroph tumor proliferation and ACTH secretion in vitro. Our findings using inhibitors of serotonin action indicate potential for targeting this pathway as a novel treatment for patients with CD.

Neuroendocrine tumors (NETs) comprise a group of complex heterogeneous and increasingly prevalent neoplasms. They arise from diverse body regions, share derivation from primitive neuronal stem cells, secrete various bioactive peptides and exhibit a wide spectrum of tumor behavior from relatively indolent to rapidly progressive. Pituitary tumors represent 20% of intracranial tumors and share some features of NET histo-pathologic morphology, their excess hormone production and some have proposed re-naming pituitary tumors as PitNETs. However there has been no precise cell type composition comparison at the whole genome level in these two types of tumors. To explore intratumoral heterogeneity at a single cell resolution in pituitary and pancreatic NETs, we employed single cell RNA sequencing (scRNA-seq) to analyze in parallel cell populations from surgically resected pituitary tumors (n=4) and pancreatic NETs (pNET, n=2) using a 10x Genomics platform (v3). Using Cell Ranger pipeline for alignment and mapping, we obtained an average of 8,306±2,519 cells/sample with 1,516±822 genes/cell (mean reads/cell 67.9±30K). Seurat v3 was then used for read pre-filtering, normalization, and cluster identification. We identified 5 genes commonly expressed in both pNET and pituitary tumor populations, namely CALY (clathrin light chain binding GO:0032051), SPINT (peptidase inhibitor activity GO:0030414), CHGB (hormone activity GO:0005179), SCG5 (GTP binding GO:0005525) and SEZ6L2. As proof of their oral epidermal embryonic origin, the commonly expressed genes in 4 pituitary tumor samples include pituitary tissue restricted transcription factors (POU1F1, BEX1/2 GO:0033613), GNAS (G-protein beta/gamma-subunit complex binding GO:0031683), NLRP1 (peptidase activator activity involved in apoptotic process GO:0016505), PTN (protein phosphatase regulator activity GO:0019888) and ATP6V1G1 (ATPase binding GO:0051117). In parallel, 71 genes were present at high levels in pNET and involved in molecular functions such as calcium ion binding (HSPA5; ENPP2; C2CD4B; CALR; HSP90B1 GO:0005509) and endopeptidase inhibitor activity (PCSK1N; WFDC2 GO:0004866). Although our exploratory findings are limited to 6 samples, the robust commonly expressed genes within each tumor type clearly separated pituitary and pancreatic neuroendocrine tumors into distinct entities. We did observe conservation of chromogranins and prohormone convertases in these two tumor types, but it only represented a very small portion of overlap in transcriptome in pNETs. In summary, our findings suggest that pituitary and neuroendocrine tumors have only limited common molecular features, and by and large they stand as separate biologic populations. Our observations may begin to provide insight into the differences in tumor progression that are encountered clinically between pituitary tumors and pancreatic NETs.

The hypothalamic–pituitary–adrenal (HPA) axis plays a critical role in adaptive stress responses and maintaining organism homeostasis. The pituitary corticotroph is the central player in the HPA axis and is regulated by a plethora of hormonal and stress related factors that synergistically interact to activate and temper pro-opiomelanocortin (POMC) transcription, to either increase or decrease adrenocorticotropic hormone (ACTH) production and secretion as needed. Nuclear receptors are a family of highly conserved transcription factors that can also be induced by various physiologic signals, and they mediate their responses via multiple targets to regulate metabolism and homeostasis. In this review, we summarize the modulatory roles of nuclear receptors on pituitary corticotroph cell POMC transcription, describe the unique and complex role these factors play in hypothalamic–pituitary–adrenal axis (HPA) regulation and discuss potential therapeutic targets in disease states.

Cushing Disease (CD) is a life-threatening condition with suboptimal medical treatment. To identify drugs that not only inhibit ACTH secretion to attain eucortisolemia but also inhibit tumor growth, we conducted a high throughput screen employing a novel “gain of signal” ACTH AlphaLISA assay. From a kinase inhibitor library containing 430 compounds, we identified the dual PI3K/HDAC inhibitor, CUDC-907, as a potent inhibitor of both in vitro and in vivo corticotroph tumor ACTH secretion and growth. By stepwise comparison of CUDC-907 with mono-functional PI3K and HDAC inhibitors, we demonstrated that CUDC-907 exerts its inhibitory effect on ACTH secretion primarily through its inhibition of HDAC activity at the POMC transcriptional level; while PI3K-mediated inhibition of corticotroph cell viability further contributes to reduced ACTH secretion. We also used RNA-seq to characterize the global transcriptiome changes associated with CUDC-907 treatment. Hierarchical clustering showed that 1432 differentially expressed genes (DEGs, p≤0.05 and fold-change≥1.5) were altered by CUDC-907 treatment in comparison to the vehicle-treated control cells. Gene ontology (GO) analysis of 456 downregulated and 976 upregulated DEGs revealed that the most enriched biological processes were cholesterol biosynthesis (GO:0006695, p=1.977e-17) and the type I interferon signaling pathway (GO: 0060337, p=4.928e-7) respectively. Further analysis demonstrated downregulation of the membrane-bound transcription factor sterol regulatory element binding proteins (SREBPs). Downregulation of SREBP-2 by CUDC-907 as well as the several other target enzymes in the cholesterol biosynthesis and uptake pathway including IDI2, NSDHL, MVD, and HMGCR, was confirmed by real-time PCR. To further characterize a role for SREBP-2 in regulation of corticotroph tumor ACTH secretion and proliferation, we employed siRNA targeting endogenous SREBP-2 (SREBP-2 mRNA, Control vs. siRNA 1±0.03 vs. 0.6±0.08, p

Objective The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013. Participants The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration. Evidence This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities. Consensus Process Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system. Conclusions Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.

Neuroendocrine tumors, including carcinoids, are rare and insidiously growing tumors. Related to their site of origin, tumors can be functional, causing various forms of the carcinoid syndrome, owing to the overproduction of serotonin, histamine, or other bioactive substances. They often invade adjacent structures or metastasize to the liver and elsewhere. Treatment includes multimodal approaches, including cytoreductive surgery, locoregional embolization, cytotoxic therapy, peptide receptor radionuclide therapy, and various targeted therapies with goals of symptom relief and control of tumor growth. This article summarizes current and emerging approaches to management and reviews several promising future therapies.

Pituitary tumors are the second most common intracranial tumors, however, pituitary carcinoma is a rare clinical entity which represents only 0.1–0.2% of all pituitary tumors. Diagnosis of pituitary carcinoma requires the presence of metastasis. Early identification of pituitary carcinoma is difficult, and only recently have guidelines been published for the treatment of aggressive pituitary tumors. We present two cases from our institution, with a review of other cases available in literature in order to better characterize this rare disease. A retrospective review of two patients with pituitary carcinoma treated at a tertiary medical center was performed. The MEDLINE database was searched for all cases of pituitary carcinoma. Information for age at diagnosis, sex, pituitary tumor type, latency period from pituitary tumor to presentation of carcinoma, sites of metastasis, number of surgical therapies, radiation and chemotherapy, and survival after diagnosis were collected. A total of 69 studies were available for review for a total of 72 unique cases. The average age at diagnosis was 46.3 years. The most common tumors were ACTH-secreting (34.7%), Prolactin-secreting (23.6%), and Null Cell (15.3%). The average latency period from pituitary tumor diagnosis to metastasis was 9 years. All patients underwent surgical therapy during their treatment, with an average of 2.76 procedures. The mortality rate was 54.8% with average time to death after diagnosis of approximately 10 months. Pituitary carcinoma is a rare disease with high mortality rate and is a diagnostic and treatment challenge. Further study is required but is difficult due to its low incidence.

Silent pituitary corticotroph tumors derive from the Tpit (aka TBX19) pituitary lineage. Accounting for ~ 30% of corticotroph tumors, they are not infrequently clinically aggressive and invade locally into adjacent sellar structures, making complete surgical resection challenging and contributing to their higher recurrence rates. How silent and active corticotroph tumor subtypes differ is not clear although some studies reported that silent corticotroph tumors exhibit reduced PC1 expression causing impaired POMC processing. We used single cell RNAseq to compare the transcriptome between silent (n = 2) and active (n = 4) corticotroph tumors at the single cell level. We obtained an average of 265 million reads, and 24,682 genes per patient with an average of 1,240 genes expressed and 3,5442 unique molecular identifiers (UMIs) detected per cell. We further defined 5 distinct cell populations from a total of 23,269 cells, namely tumor cells (62%), stromal cells (25%), immune cells (7%), progenitor cells (5%), and a minor population of erythrocytes (1%). Tumor cells clustered in an origin-dependent manner and all expressed POMC and TBX19. However, the gene signatures of silent and active corticotroph tumors differed in 3 major aspects. Firstly, and supporting prior studies, a series of hormone processing peptidase genes, including PC1 (aka PCSK1), PDIA3, SEC11C, SPCS1 and CTSB, were reduced in silent corticotroph tumors (p=5.54e-5) compared to active corticotroph tumors. Secondly, genes involved in organization of secretory vesicles such as SCG5, TIMP1, VGF, SYT17, LGALS3 and CALY were also reduced in silent corticotroph tumors, which could further compound their inability to secrete ACTH. Thirdly, the silent corticotroph tumors exhibited several features of endothelial-to-mesenchymal transition (EMT), including increased expression of the mesenchymal genes CDH2 (aka NCAD), COL1A1, PCDH9, FGF5, ID2 (p=8.4e-3), and loss of EPCAM, which regulate cell migration and movement. Upstream analysis suggested that aberrant STAT3 activation may be related to these changes. Consequently, we noted that the stromal content was higher in silent corticotroph tumors (47.5% vs. 18.13%), concordant with the observed EMT de-differentiation of tumor cells. In summary, our scRNAseq analysis provides an unprecedented precise investigation of the transcriptomic features of thousands of heterogenous corticotroph tumor cells simultaneously. We demonstrate that although silent corticotroph tumor cells still express the pituitary lineage markers PITX1 and TBX19, they exhibit EMT, potentially affording increased migratory capacity at the cost of reduced neuroendocrine function with inability to produce and secrete mature ACTH. Our findings provide novel insights into the pathogenesis of silent versus active corticotroph tumor, but may reveal novel molecular targets for treatment of these challenging tumors.

Background: In a prior Phase III, randomized-withdrawal study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid and sustained normalization of mean urinary free cortisol (mUFC) in most patients (pts) with CD. Now, we report efficacy and safety results from another Phase III study of osilodrostat in pts with CD that included an upfront, double-blind, randomized, placebo-controlled phase (LINC 4: NCT02697734). Methods: Adults with CD with mUFC >1.3 x ULN were randomized 2:1 to osilodrostat 2 mg bid or matching placebo for a 12-week (W) double-blind period, with dose adjustments at W2, 5 and 8 (range 1-20 mg bid) based on efficacy and tolerability; dose matching and adjustments were managed by independent endocrinologists. From W12 to W48, all pts received open-label osilodrostat, with dose adjustments permitted (range 1-30 mg bid). At W48, pts could enter an optional extension. Primary endpoint: proportion of randomized pts in each arm who received ≥1 treatment dose with mUFC ≤ULN at W12. Results: 73 pts were randomized and received osilodrostat (n=48) or matching placebo (n=25; baseline median [range] mUFC 2.5 x ULN [0.7-12.5] vs 2.2 x ULN [0.2-18.9]). 77% of osilodrostat recipients achieved mUFC ≤ULN at W12 vs 8% of placebo recipients (OR 43.4; 95% CI 7.1-343.2; P Conclusion: Osilodrostat was superior to placebo at normalizing mUFC levels at W12 (77% vs 8%). Improvements in mUFC levels were sustained at W36. Few pts discontinued because of AEs; hypocortisolism-related AEs were infrequent and manageable. We conclude that osilodrostat is a highly effective and well-tolerated treatment for pts with CD.

Somatostatin receptor positron emission tomography (SSTR-PET) is an imaging modality for patients with neuroendocrine tumors (NETs) that has demonstrated a significant improvement over conventional imaging (CI). SSTR-PET should replace In-111 pentetreotide scintigraphy (OctreoScan) in all indications in which SSTR scintigraphy is currently being used. These appropriate use criteria (AUC) are intended to aid referring medical practitioners in the appropriate use of SSTR-PET for imaging of patients with NETs, and the indications were evaluated in well-differentiated NETs. Of the 12 clinical scenarios evaluated, nine were graded as appropriate: initial staging after the histologic diagnosis of NET, evaluation of an unknown primary, evaluation of a mass suggestive of NET not amenable to endoscopic or percutaneous biopsy, staging of NET prior to planned surgery, monitoring of NET seen predominantly on SSTR-PET, evaluation of patients with biochemical evidence and symptoms of a NET, evaluation of patients with biochemical evidence of a NET without evidence on CI or a prior histologic diagnosis, restaging at time of clinical or laboratory progression without progression on CI, and new indeterminate lesion on CI with unclear progression. Representatives from the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the American College of Radiology (ACR), the American Society of Clinical Oncology (ASCO), the North American Neuroendocrine Tumor Society (NANETS), the European Association of Nuclear Medicine (EANM), the Endocrine Society, the Society of Surgical Oncology, the National Comprehensive Cancer Network (NCCN), the American College of Physicians (ACP), the American Gastroenterological Association (AGA), and the World Conference on Interventional Oncology (WCIO) assembled under the auspices of an autonomous workgroup to develop the following AUC.

Objective We evaluated tumor recurrence and regrowth rates following endoscopic transnasal transsphenoidal (TNTS) surgical removal in a consecutive series of clinically nonfunctioning pituitary adenomas (CNFTs). Design Retrospective chart review of clinical, biochemical, and sellar MRI findings in all TNTS surgeries in patients with CNFT, performed by a single surgeon, between 2008 and 2015 (n = 280). Patients Ninety-three patients met eligibility criteria, with complete clinical, biochemical, and imaging follow-up for a 3-year minimum. Results Of 85 patients who were not irradiated, 3-month postsurgical MRI demonstrated no residual tumor in 58 of 85 (68.2%), equivocal findings in 12 of 85 (14.1%), and definite residual tumor in 15 of 85 (17.6%) patients. Six of 85 (7.1%) demonstrated tumor regrowth by 3 years, and 2 further patients demonstrated true tumor recurrence at 3 and 6 years after surgery, respectively, for a total recurrence rate of 9.4% (8 of 85). Eight of the 93 patients were irradiated between 3 months and 4 years after pituitary surgery. In 3 patients with tumor regrowth, 2 exhibited residual tumor and 1 had no residual findings at the 3-month postoperative imaging. Overall, Ki-67 labeling index or Knosp grading did not predict recurrence. Conclusion Tumor recurrence at 3 years was low (1 of 58; 1.7%) if the 3-month postoperative MRI showed no residual tumor. The findings support a less frequent imaging schedule for this group. Patients with definite residual tumor visible at 3 months harbor the greatest risk for tumor growth, but regrowth does not occur in all patients (6 of 15; 40%).