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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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

Effects of future expansion/intensification of irrigated agriculture on groundwater and surface water levels and availability in a semi-arid watershed were evaluated using an integrated hydrologic model (MIKE SHE/MIKE 11) in conjunction with biophysical measurements. Improved water use efficiency, water storage, and energy policy options were evaluated for their ability to sustain the future (2035) increased groundwater withdrawals. Three future withdrawal scenarios (low = 20, medium = 30, high = 50 wells/100 km2/year) based on the historical rate of growth of irrigation wells were formulated. While well drying from falling groundwater levels was limited to drought and consecutive below average rainfall years, under the current (2015) withdrawals, significant increases in frequency and duration (17–97 days/year) of well drying along with 13–26% (19–37 mm) reductions in surface flows were predicted under the future withdrawals. Higher (27–108%) energy demands of existing irrigation pumps due to declining groundwater levels and reduced hydroelectric generation due to decreased surface flows would create a vicious water-food-energy nexus in the future. Crop failure, one of the main causes of farmers’ emotional distress and death in the region, is predicted to exacerbate under the future withdrawal scenarios. Shift to negative net recharge (−63 mm) and early and prolonged drying of wells under the high scenario will reduce the groundwater availability and negatively affect crop production in more than 60% and 90% of cropped areas in the Rabi (November–February) and summer (March–May) seasons, respectively during a drought year. Individual and combined demand (drip irrigation and reduced farm electricity subsidy) and supply (water storage) management options improved groundwater levels and reduced well drying by 55–97 days/year compared to business-as-usual management under the high scenario. The combined management (50% drip conversion, 50% reduction in subsidy, and enhanced water storage) mitigated well drying even during drought and consecutive below average rainfall years under the high scenario. A conservative economic evaluation for management options under the high scenario showed increases in crop production and per farmer annual profits by $987–$1397 during a drought year (average household income = $1520/year). A scale-up of results showed that diverting 50% state power subsidy ($6 billion for 3–6 years) can almost entirely fund the conversion to drip irrigation ($4.2 billion) and water storage structures ($2.9 billion) and help meet the water supply demand of a 50% increase in irrigated area under the high scenario. Converting flood to drip irrigation in 50% of irrigated area under the high scenario can reduce the electric energy consumption (7 × 106Mwh/year) and carbon footprint (6000 Mt/year) of groundwater irrigation by 24% in the state. Management options considered can potentially create a sustainable water-food-energy nexus in the larger semi-arid hard rock region. Reducing the power subsidy will require a strong political will since it has been used as a tool to win the elections in India. Considering future agricultural intensification, timely interventions are needed to ensure the livelihood and well-being of millions of small- and medium-scale farmers that rely on low storage, hard rock aquifers in the semi-arid regions of the world.

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%).

BACKGROUND Unplanned readmissions within 30 days of discharge is a quality measure introduced by the Centers for Medicare Services. This measure has been used to rate hospital quality and also to penalize hospitals for excess readmissions. It has been hypothesized that shorter hospital stays and fewer readmissions are associated with endoscopic skull base procedures. In this study we analyze endoscopic skull base procedures performed at our institution over a 10-year period to identify rates and factors associated with readmissions after endoscopic skull base surgery. METHODS A retrospective chart review was performed at a tertiary care academic medical center identifying patients who underwent endoscopic skull base surgery over the past 10 years. Data on patient demographics and tumor variables, as well as patient variables such as body mass index (BMI), revision surgery, history of skull base radiation, medical comorbidities, intraoperative cerebrospinal fluid (CSF) leaks, and postoperative CSF leaks, were recorded. RESULTS Eight hundred thirty-three patients were included in our study. Sixty-one patients (7.3%) were readmitted a total of 66 times within 30 days. The most common reasons were as follows: hyponatremia (n = 18); CSF leak (n = 17); epistaxis (n = 3); diabetes insipidus (n = 3); rhinorrhea (n = 3); as well as other reasons. Statistical analysis revealed that the presence of intraoperative CSF leak was the only statistically significant variable associated with increased rate of readmissions within 30 days of discharge (p < 0.001). CONCLUSION Presence of intraoperative CSF leak was the only statistically significant variable associated with an increased risk for readmission after surgery. Other tumor and patient variables were not associated with an increased risk of readmission within 30 days.

Lack of an immortalized or long-term hormone-secreting human pituitary tumor in vitro cell line has significantly hampered studies of etiopathogenesis and development of targeted therapies for pituitary tumors. Various media, vessels, substrates and additives have been explored to optimize primary cultures. Some methods have prolonged cell survival time but maintaining hormone secretion is still a major challenge. We have recently developed methodology to maintain robust hormone secretion in human prolactinoma, somatotroph and corticotroph tumors in vitro for up to 9 months. To gain insight into the changes in gene expression profiles that occurred prior to/coincident with loss of hormone secretion during in vitro human pituitary tumor cultures, we compared the global transcriptiome landscape in serial passages from two human prolactinoma primary cultures. We obtained 27.1 million quality filtered reads per sample of which ~90% were exonic reads detecting an average of 16,000 genes. 3D principal component analysis identified 3 distinct clusters, with close similarity between cell passages 1-2, those beyond passage 4-5 and a stand-alone passage 3. Analysis of differential gene expression (DEG) over time using DAVID knowledgebase and hierarchical clustering demonstrated that most changes in gene expression occurred in the first 1-2 weeks in in vitro culture. During the first week of in vitro culture, although the cells maintained robust PRL secretion, reduced activation of angiogenesis and growth signal pathways (PI-3K, MAPK pathways, cell adhesion, GTPase activity, cell proliferation and cell-cell junction assembly) was observed. In the following 1-2 weeks, the cell population maintained PRL secretion but exhibited continued loss of survival signals, with increased expression of extracellular matrix (ECM) and surface adhesion molecules consistent with development of a fibroblastic phenotype that dominated later stage cultures. Based on our findings, we propose that the molecular events underpinning loss of hormone production in primary pituitary tumor cultures represent transition from endocrine cells to pituitary specific fibroblastic folliculo-stellate cell likely selected by the in vitro culture conditions. Our data further reveal that underexpression of several GPCRs and resultant downregulation of the PKA pathway may lead to loss of hormone production in parallel with loss of cell survival signals. In summary, our study defines a temporal progressive transcriptome transition signature to explain loss of hormone secretion and morphological alterations observed during human pituitary tumor in vitro culture and may provide molecular targets to further optimize our culture methodology to attain “immortalized” hormone-producing human pituitary tumor cell-lines.

Cushing Disease (CD), caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, leads to excess production of adrenal-derived cortisol. Current medical treatments for CD include adrenal steroidogenesis inhibitors (Ketoconazole, Metyrapone), the somatostatin receptor ligand Pasireotide, and the glucocorticoid receptor antagonist (Korlym). Although Pasireotide is tumor directed, its effect on tumor growth is modest, and it frequently causes hyperglycemia. Additionally, long-term compliance with these drugs is < 30% - either due to escape from control caused by increased tumor-derived ACTH or drug side effects. Clearly there is a large unmet need for improved medical treatments for CD. We hypothesize that an ideal drug would act on the tumor itself, potently and selectively inhibit corticotroph tumor-derived ACTH production to attain sustained eucorticolism and inhibit corticotroph tumor growth. Using our recently developed ACTH quantification assay (ACTH AlphaLISA), we screened an annotated kinase inhibitor library (KIL, n=430) at 10μM, 1μM and 100nM doses. The KIL contains inhibitors of PI3K/AKT/mTOR (n=95), protein tyrosine kinases (n=87), MAPK (n=45), angiogenesis (n=44), cell cycle (n=44), JAK/STAT (n=26), and others (n=89). Out of 430 compounds screened, 6, 20 and 115 compounds exhibited >50% ACTH AlphaLISA inhibition and 36, 105 and 263 compounds exhibited >50% nuclei inhibition in murine corticotroph tumor AtT20 cells at 100nM, 1μM and 10μM respectively. Three out of the 6 compounds that exhibited efficacy >50% at 100nM are currently being evaluated in Phase II clinical trials in a variety of solid tumors. Given the involvement of PI3K/AKT pathway in pituitary tumor pathogenesis and recent findings of aberrant USP8 mutant-associated EGFR activation in corticotroph tumors, we have thus far performed dose-response curves for one of the PI3K inhibitors using two separate assays of ACTH secretion (AlphaLISA and ELISA) and cell proliferation (Hoechst nuclei staining and CellTilter Glow assay). Both demonstrated comparable inhibition rates with an EC50 of 246nM for ACTH inhibition determined by AlphaLISA assay, and LC50 of 18 nM for cytotoxicity. Experiments to elucidate the mode of action of the PI3K inhibitor on ACTH synthesis and/or secretion, demonstrated it inhibited POMC mRNA expression by 40% at 300nM and 87% at 1μM (p

Background Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models. Methods To characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures. Findings scRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months. Interpretation Our human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD. Funding This work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation.

We recently demonstrated that the orphan nuclear receptor testicular receptor 4 (TR4) is a potent regulator of corticotroph tumor growth and hormone secretion. The Ras/Raf/MEK/ERK pathway is commonly overactivated in human tumors and we have demonstrated that corticotroph tumor TR4 is activated by ERK1/2-mediated phosphorylation. We evaluated effects of MEK-162, a selective, non-ATP-competitive allosteric inhibitor of MEK1/2, on murine and human in vitro and in vivo corticotroph tumor proliferation and adrenocorticotrophic hormone (ACTH) secretion. MEK-162 treatment dose-dependently inhibited corticotroph tumor proliferation, induced apoptosis, reduced pro-opiomelanocortin (POMC) mRNA levels and inhibited ACTH secretion in vitro. Similar findings were obtained in human corticotroph tumor primary cultures (n = 5). These actions of MEK-162 were augmented in the presence of TR4 overexpression, suggesting that TR4 levels may serve as a predictive biomarker of MEK-162 corticotroph tumor responsiveness. Additionally, MEK-162 treatment reduced TR4 protein expression and blocked recruitment of TR4 to bind its consensus site on the POMC promoter (-854bp to -637bp), elucidating multiple mechanisms to control TR4 corticotroph tumor actions. In a murine corticotroph tumor in vivo model of Cushing's disease, MEK-162 treatment inhibited tumor growth and reduced tumor-derived circulating plasma ACTH, and corticosterone levels. These results demonstrate the potent actions of MEK-162 to inhibit corticotroph tumor growth and hormone secretion in vitro and in vivo via TR4-dependent and independent mechanisms, and raise the possibility of MEK-162 as a novel therapy for Cushing's disease.

Aggressive prolactinomas (PRL-omas) and carcinomas comprise a rare but challenging subset of pituitary tumors. Firstly, the holistic definition that reliably identifies these tumors in a prospective manner remains elusive. Although comprehensive evaluation of patient gender, age, local invasiveness, treatment responses, and histopathological features may be informative to assess the potential for PRL-oma aggressiveness, a definitive diagnosis cannot be made until disease progression is observed despite standard therapy, which typically includes medical and surgical therapy. The failed early diagnosis of these aggressive PRL-omas may delay the initiation of intensive stepwise multimodal treatments and lessen ultimate therapeutic outcomes. Secondly, even though current therapeutic options for aggressive prolactinomas are suboptimal in some cases, due to the rarity of this disease entity, large-scale clinic trials and prospective studies are impractical. Most novel therapies in this subset of tumors are based on case reports or small series, which greatly reduces their validity and limits recommendations. Randomized prospective multicenter studies would be a major advantage to identify reliable predictive diagnostic biomarkers and explore novel efficacious treatment options for these tumors. These could perhaps be conducted on a global basis though funding such an effort is a limiting factor. This chapter provides an overview of current knowledge regarding the various tools used to diagnose aggressive prolactin-secreting tumors and discusses both established and emerging therapeutic options.

CONTEXT Aggressive prolactin (PRL)-secreting pituitary adenomas that are resistant to conventional therapy with dopamine agonists, surgery, and radiation pose a therapeutic challenge. The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved to treat neuroendocrine tumors (NETs), and cotreatment with the somatostatin receptor ligand octreotide improved median progression-free survival in patients with metastatic pancreatic NETs. PATIENT, INTERVENTION, AND RESULTS We describe off-label everolimus treatment of a prolactinoma (PRLoma) refractory to cabergoline, repeat surgical resection, and radiation therapy. Addition of everolimus to cabergoline led to decreased PRL levels and tumor regression after 5 months. Tumor size remained stable for 12 months, and although PRL levels rose, they remained below pretreatment levels. Immunohistochemical (IHC) evaluation of expression of key mTOR pathway drivers of cell proliferation revealed elevated phosphorylated (p-)AKT, p-4EBP1, and p-S6 in the index patient's tumor. IHC analysis of seven additional PRLomas demonstrated increased expression of nuclear p-AKT, cytoplasmic p-S6, and globally increased p-4EBP1 in the PRLomas compared with 11 autopsy-derived normal pituitary tissues. In in vitro studies in murine mammosomatotroph tumor GH3 cells, we observed that both the dopamine agonist cabergoline and the mTOR inhibitor everolimus inhibited GH3 cell proliferation and PRL secretion as single agents, and the synergistic effect was noted with combination treatment only on inhibition of PRL secretion but not proliferation. CONCLUSIONS In summary, our findings demonstrate that the mTOR pathway is activated in PRLomas and that everolimus exhibits antiproliferative actions in vitro. We suggest that everolimus may be a novel therapeutic option for some aggressive PRL-secreting tumors unresponsive to conventional treatments.

CONTEXT Neurocytoma (NC) is a rare, low-grade tumor of the central nervous system, with a 10-year survival rate of 90% and local control rate of 74%. However, 25% of NCs will be atypical, with an elevated Ki-67 labeling index >2%, and will exhibit a more aggressive course, with a high propensity for local recurrence and/or craniospinal dissemination. Although no standard treatment regimen exists for these atypical cases, adjuvant stereotactic or conventional radiotherapy and/or chemotherapy have been typically offered but have yielded inconsistent results. CASE DESCRIPTION We have described the case of a patient with a vasopressin-secreting atypical NC of the sellar and cavernous sinus region. After subtotal resection via endoscopic transsphenoidal surgery, the residual tumor showed increased fluorodeoxyglucose uptake and high somatostatin receptor (SSTR) expression on a 68Ga-DOTA-TATE positron emission tomography/CT scan. Somatostatin receptor ligand (SRL) therapy with lanreotide (120 mg every 28 days) was initiated. Four years later, the residual tumor was stable with decreased fluorodeoxyglucose tumor uptake. Immunocytochemical SSTR2 and SSTR5 expression >80% was further confirmed in a series of NC tissues. CONCLUSIONS To the best of our knowledge, we have described the first use of SRL therapy for an atypical NC. Our results support consideration of adjuvant SRL therapy for NC refractory to surgical removal. Our findings further raise the possibility of SSTR-directed peptide receptor radionuclide therapy as NC therapy.

Tumors of hypothalamic neurons that produce vasopressin are rare. We retrieved all cases of vasopressin-positive tumors in the sellar region from the database of the Department of Pathology. Five cases fulfilled the selection criteria, representing the first series of such tumors. Clinical, radiologic, and pathologic features were reviewed. Four tumors classified as neurocytomas were identified in 3 females and 1 male patient; the ages at onset of symptoms ranged from 17 to 40 years. All were large sellar masses with suprasellar extension and/or invasion of the parasellar sinuses. Three patients had the syndrome of inappropriate antidiuresis; in one of these, a 6-year history was initially considered to be idiopathic. One patient died of progressive disease; 3 had incomplete resections and are being followed. In contrast to these patients with neurocytoma, a 65-year-old woman had Cushing disease and a 0.8 cm mass that was completely resected at transsphenoidal surgery; this tumor was a gangliocytoma producing vasopressin associated with corticotroph hyperplasia. We postulate that the small amount of vasopressin secreted by this mature gangliocytic tumor was locally bound to corticotrophs, resulting in hyperplasia and Cushing disease, without sufficient overproduction to cause systemic effects of vasopressin excess. Hypothalamic neurocytoma is a tumor that can mimic pituitary neuroendocrine tumors and olfactory neuroblastoma but is distinguished by positivity for neurofilaments, NeuN, and TTF-1 and negative staining for adenohypophysial biomarkers. Our cases illustrate that neurocytoma and gangliocytoma are 2 variants of tumors of hypothalamic neurons that can produce vasopressin. The morphologic and proliferative features of these 2 tumor types represent 2 ends of a spectrum; their function also can result in divergent clinical manifestations, one characterized by reduced urine output and the other by the more insidious features of glucocorticoid excess.

Background Higher serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with a lower risk of multiple cancer types across a range of 25(OH)D concentrations. Objectives To investigate whether the previously reported inverse association between 25(OH)D and cancer risk could be replicated, and if a 25(OH)D response region could be identified among women aged 55 years and older across a broad range of 25(OH)D concentrations. Methods Data from two cohorts representing different median 25(OH)D concentrations were pooled to afford a broader range of 25(OH)D concentrations than either cohort alone: the Lappe cohort (N = 1,169), a randomized clinical trial cohort (median 25(OH)D = 30 ng/ml) and the GrassrootsHealth cohort (N = 1,135), a prospective cohort (median 25(OH)D = 48 ng/ml). Cancer incidence over a multi-year period (median: 3.9 years) was compared according to 25(OH)D concentration. Kaplan-Meier plots were developed and the association between 25(OH)D and cancer risk was examined with multivariate Cox regression using multiple 25(OH)D measurements and spline functions. The study included all invasive cancers excluding skin cancer. Results Age-adjusted cancer incidence across the combined cohort (N = 2,304) was 840 cases per 100,000 person-years (1,020 per 100,000 person-years in the Lappe cohort and 722 per 100,000 person-years in the GrassrootsHealth cohort). Incidence was lower at higher concentrations of 25(OH)D. Women with 25(OH)D concentrations ≥40 ng/ml had a 67% lower risk of cancer than women with concentrations

Background: Higher serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with a lower risk of multiple cancer types across a range of 25(OH)D concentrations. Objectives: To investigate whether the previously reported inverse association between 25(OH)D and cancer risk could be replicated, and if a 25(OH)D response region could be identified among women aged 55 years and older across a broad range of 25(OH)D concentrations. Methods: Data from two cohorts representing different median 25(OH)D concentrations were pooled to afford a broader range of 25(OH)D concentrations than either cohort alone: the Lappe cohort (N=1,169), a randomized clinical trial cohort (median 25(OH)D=30 ng/ml) and the GrassrootsHealth cohort (N=1,135), a prospective cohort (median 25(OH)D=48 ng/ml). Cancer incidence over a multi-year period (median: 3.9 years) was compared according to 25(OH)D concentration. Kaplan-Meier plots were developed and the association between 25(OH)D and cancer risk was examined with multivariate Cox regression using multiple 25(OH)D measurements and spline functions. The study included all invasive cancers excluding skin cancer. Results: Age-adjusted cancer incidence across the combined cohort (N=2,304) was 840 cases per 100,000 person-years (1,020 per 100,000 person-years in the Lappe cohort and 722 per 100,000 person-years in the GrassrootsHealth cohort). Incidence was lower at higher concentrations of 25(OH)D. Women with 25(OH)D concentrations ≥40 ng/ml had a 67% lower risk of cancer than women with concentrations Conclusions: 25(OH)D concentrations ≥40 ng/ml were associated with substantial reduction in risk of all invasive cancers combined.

In 1986, David Barker, a British epidemiologist, noted a connection between small infant birth size and risk of heart disease later in adult life.1 The theory that certain adult-onset diseases might have their roots in nutritional insults sustained in the perinatal period (either in utero or in the early months of infancy—or perhaps both) has since been known as “the Barker hypothesis” or sometimes “The Fetal Origins Hypothesis.” The original association between undernutrition in utero and late-life heart disease has been difficult to confirm, but the idea that early-life influences can have important downstream consequences is intuitively attractive and is supported by such concrete instances as perinatal thyroid function (and, its cognate, adequate dietary iodine), which is absolutely essential for early-life brain development and maturation. Perinatal iodine deficiency and hypothyroidism from any cause are recognized as important contributors worldwide to mental retardation and learning disabilities during childhood and adult life. In this example, iodine deficiency and its consequences certainly qualify as an outspoken instance of the Barker hypothesis in operation. A critical feature of diseases occurring by way of the Barker hypothesis is the nutritional irreversibility of the long-latency disorders that result. Beyond certain critical points in development, full nutrient repletion is not able to offset or reverse the early inadequacy. This irreversibility is the major stimulus for the better elucidation of these disorders, leading to emphasis on the imperative of early-life preventive nutrition. The Barker hypothesis has been elaborated and evaluated in several reviews,2–4 but to the best of my knowledge, there has been no attempt to evaluate the hypothesis specifically for vitamin D. Thus, what I propose to explore in this very brief review is the evidence relating unrecognized, perinatal vitamin D inadequacy to increased risk of certain chronic diseases later in life, that is, to ascertain whether any such effects might be an instance of the “Barker hypothesis.” I deliberately avoid use of labels such as “deficient” or “insufficient” in characterizing vitamin D status, as these terms are often linked to specific values for serum 25-hydroxyvitamin D [25(OH)D], about which there is considerable controversy. Instead, I use terms such as “low” or “inadequate,” referencing in each such use prevailing values for vitamin D status or input relative to values found in those individuals who do not manifest the disorders concerned. I defer until the end of this review consideration of the actual, numerical range of vitamin D status values that appears to permit avoidance of the Barker effect if it is present. Also, it is important to be clear that I am not including in this exploration the well-known downstream skeletal effects of classic rickets, for example, the pelvic deformation that is considered to have been a major factor in the evolution of pale skin for populations living in, or migrating to, high latitudes. Rickets in childhood is a serious disorder and fortunately is evident and both preventable and treatable. Instead, where I focus here is on the nonskeletal consequences both of untreated rickets and of lesser degrees of vitamin D inadequacy, often not clinically apparent and occurring at critical periods during maturation, in some instances well before the life stages when rickets is typically manifest. For most of the disorders concerned, etiology is almost always multi-factorial. The relation to vitamin D inadequacy should be understood simply as just one of the conditions that, when met, together lead to expression of the diseases concerned. Removing that single factor will not usually be expected completely to eradicate the disease of interest, but will reduce its expression at a population level. For the handful of diseases discussed in what follows, the extent of that risk reduction appears to be large enough to demand serious attention, including more research.

Higher serum 25–hydroxyvitamin D [25(OH)D] concentrations have been associated with lower risk of type 2 diabetes. This study compared incidence rates of type 2 diabetes among participants aged ≥20 years in two U.S. cohorts with markedly different median 25(OH)D concentrations. The median 25(OH)D concentration in the GrassrootsHealth (GRH) cohort was 41ng/ml (N=4933) while in the 2005–6 National Health and Nutrition Examination Survey (NHANES) it was 22ng/ml (N=4078) (P

The World Health Organization's International Agency for Research on Cancer recommends avoiding outdoor activities at midday, wearing clothing to cover the whole body, and daily use of sunscreen on usually exposed skin [1]. The American Cancer Society advocates Slip! Slop! Slap! and Wrap! to make sure skin is covered in clothing or sunscreen and to avoid exposure to the sun between 10 am and 4 pm [2]. The U.S. Surgeon General has issued a Call to Action focused on reducing ultraviolet (UV) exposure, whether from indoor UV or from the sun [3]. Though these recommendations, all focused on reduction of skin cancer, are accompanied by brief acknowledgement of the importance of vitamin D for health, they persist in urging avoidance of the sun at the precise times when vitamin D can be synthesized in the skin—the hours between 10 am and 3 pm—and suggest that all necessary vitamin D can be obtained through food and dietary supplements. These recommendations are understandable from the viewpoint of preventing the 3.5 million new cases of and 2000 deaths from nonmelanoma skin cancer in the United States each year [4], but they neglect the fact that we have a long cultural history of appreciation of the sun and use of UV radiation for healing purposes. Moreover, they neglect that we have evolved with physiological adaptations to help protect the skin from the sun [5] when we are mindful of our exposure and do not burn. They neglect the fact that increased sun exposure, based on latitude, has been associated with protection from several different types of cancer [6–15], type 1 diabetes [16], multiple sclerosis [17,18], and other diseases [19–23]. They also neglect the fact that exposure to the sun induces beneficial physiological changes beyond the production of vitamin D. Though adherence to the current sun-protective recommendations would likely result in the reduction of nonmelanoma skin cancer, that reduction would likely be overshadowed by the potential reduction in deaths from other cancers and from cardiovascular disease, which could be achieved by doubling average blood concentrations of 25-hydroxyvitamin D (25(OH)D) to 40 ng/mL through a combination of sun exposure and supplements [24]. The potential harm of sun avoidance and the neglect of its positive effects on human health led to a seminar, Vitamin D for Public Health: Integrating Sunshine, Supplements and Measurement for Optimal Health, presented by GrassrootsHealth at the University of California San Diego to inform and to help initiate an action plan to restore a more balanced approach to solar radiation based on input by the conference speakers.

The aim of this study is to demonstrate the importance of considering Cushing’s syndrome (CS) as a potential etiology for weight gain and metabolic complications in patients undergoing bariatric surgery (BS). This is a retrospective chart review case series of patients (n = 16) with CS from five tertiary care centers in the USA who had BS. Median age at BS surgery was 35.5 years (median 2.5 years between BS and CS surgery). CS was not identified in 12 patients prior to BS. Four patients had CS surgery prior to BS, without recognition of recurrent or persistent CS until after BS. Median body mass index (BMI) values before BS, nadir after BS, prior to surgery for CS, and after surgery for CS were 47, 31, 38, and 35 kg/m2, respectively. Prior to BS, 55 % of patients had hypertension and 55 % had diabetes mellitus. Only 17 % had resolution of hypertension or diabetes mellitus after BS. CS may be under-recognized in patients undergoing BS. Testing for CS should be performed prior to BS in patients with features of CS and in post-operative BS patients with persistent hypertension, diabetes mellitus, or excessive weight regain. Studies should be conducted to determine the role of prospective testing for CS in subjects considering BS.

A 52-year old male with a history of insulin treated T2DM complicated by end stage renal disease (ESRD requiring hemodialysis and prior gastric bypass surgery presented with severe recurrent hypoglycemia with seizures. A 72 hour fast demonstrated hyperinsulinemic hypoglycemia. Abdominal CT scan and endoscopic ultrasound guided biopsy demonstrated a pancreatic neuroendocrine tumor (pNET). Symptoms persisted despite pNET resection and on further testing he was found to have a highly specific insulin antibody resulting in insulin autoimmune syndrome. He responded well to prednisone therapy with resolution of hypoglycemia and decline in the insulin autoantibody titers. This study concludes that autoimmune forms of hypoglycemia are uncommon and interpretation of tests can be challenging. However, insulin autoimmune syndrome (IAS) should be considered in a patient with both fasting and postprandial hypoglycemia in setting of very high insulin levels with associated anti-insulin antibodies and elevated insulin to C peptide molar ratio.

BACKGROUND: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. METHODS: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mgevery 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to

There have been significant developments in diagnostic and therapeutic options for patients with neuroendocrine tumors. Key phase III studies include the CLARINET trial which evaluated lanreotide in patients with non-functioning enteropancreatic NETs, the RADIANT 2 and RADIANT 4 studies, which evaluated everolimus in functioning and non-functioning NETs of the GI tract and lungs, the TELESTAR study which evaluated telotristat ethyl in patients with refractory carcinoid syndrome, and the NETTER-1 trial which evaluated 177Lutetium-dotatate in NETs of the small intestine and proximal colon (midgut). Based on these and other advances, the North American Neuroendocrine Tumor Society (NANETS) convened a multidisciplinary panel of experts with the goal of updating consensus-based guidelines for evaluation and treatment of midgut NETs. The medical aspects of these guidelines (focusing on systemic treatment, nonsurgical liver-directed therapy, and post-operative surveillance) are summarized in this manuscript. Surgical guidelines are described in a companion manuscript.

Objectives. Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. We used GrassrootsHealth data to examine the relationship between vitamin D status and kidney stone incidence. Methods. The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones. Results. We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3). Conclusions. We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.

The 2013 Santa Fe Bone Symposium included plenary sessions on new developments in the fields of osteoporosis and metabolic bone disease, oral presentations of abstracts, and faculty panel discussions of common clinical conundrums: scenarios of perplexing circumstances where treatment decisions are not clearly defined by current medical evidence and clinical practice guidelines. Controversial issues in the care of osteoporosis were reviewed and discussed by faculty and participants. This is a review of the proceedings of the Santa Fe Bone Symposium, constituting in its entirety an update of advances in the understanding of selected bone disease topics of interest and the implications for managing patients in clinical practice. Topics included the associations of diabetes and obesity with skeletal fragility, the complexities and pitfalls in assessing the benefits and potential adverse effects of nutrients for treatment of osteoporosis, uses of dual-energy X-ray absorptiometry beyond measurement of bone mineral density, challenges in the care of osteoporosis in the very elderly, new findings on the role of osteocytes in regulating bone remodeling, and current concepts on the use of bone turnover markers in managing patients with chronic kidney disease who are at high risk for fracture.

An effective urban water demand management program can greatly influence both peak and average demand and therefore long-term water supply and infrastructure planning. Although a theoretical framework for evaluating residential indoor demand management has been well established, little has been done to evaluate other water use sectors such as residential irrigation in a compatible manner for integrating these results into an overall solution. This paper presents a systematic procedure to evaluate the optimal blend of single family residential irrigation demand management strategies to achieve a specified goal based on performance functions derived from parcel level tax assessor's data linked to customer level monthly water billing data. This framework is then generalized to apply to any urban water sector, as exponential functions can be fit to all resulting cumulative water savings functions. Two alternative formulations are presented: maximize net benefits, or minimize total costs subject to satisfying a target water savings. Explicit analytical solutions are presented for both formulations based on appropriate exponential best fits of performance functions. A direct result of this solution is the dual variable which represents the marginal cost of water saved at a specified target water savings goal. A case study of 16,303 single family irrigators in Gainesville Regional Utilities utilizing high quality tax assessor and monthly billing data along with parcel level GIS data provide an illustrative example of these techniques. Spatial clustering of targeted homes can be easily performed in GIS to identify priority demand management areas.

Recently Veugelers and Ekwaru published data [1] indicating that, in its dietary reference intakes for calcium and vitamin D, the Institute of Medicine (IOM) had made a serious calculation error [2]. Using the same data set as had the IOM panel, these investigators showed that the Recommended Dietary Allowance (RDA) for vitamin D had been underestimated by an order of magnitude. Veugelers and Ekwaru, using the IOM’s data, calculated an RDA of 8895 IU per day. They noted that there was some uncertainty in that estimate, inasmuch as this value required an extrapolation from the available data, which did not include individuals receiving daily vitamin D inputs above 2400 IU/day.[...]