Laurence Katznelson, MD

All Publications

• Optimizing Care Teams by Leveraging Advanced Practice Providers Through Strategic Workforce Planning. The Journal of nursing administration Kuriakose, C., Stringer, M., Ziegler, A., Hsieh, C., Atashroo, M., Hendershott, J., Tippett, V., Shah, D., Cianfichi, L., Katznelson, L., Mahoney, M. 2022; 52 (9): 474-478

  Abstract

  INTRODUCTION: Advanced practice providers (APPs) are integral members of the healthcare delivery team. However, there has been a lack of standardization and uniformity in how they are utilized across inpatient, ambulatory, and procedural settings.METHODS: A multidisciplinary workforce planning committee was formed in March 2021 to evaluate all new and replacement full-time equivalent APP positions at Stanford Health Care (SHC), an academic medical center of more than 600 APPs, to optimize and standardize the role of APPs as per national benchmarks.RESULTS: Six months since the launch of the committee, there has been a 10% increase in the number of visits and procedures performed by APPs providing better access for patients. In addition, there has been a 38.7% improvement in ambulatory APPs meeting their productivity target, 19.4% improvement in ambulatory APPs meeting utilization targets, and 36.8% improvement in ambulatory APPs meeting the 50th percentile and above as per the relative value unit benchmark published by the Medical Group Management Association for Academic Medical Centers. For inpatient APPs, there has been a 38.8% improvement in APPs meeting the average daily census target.DISCUSSION: APP utilization is an important topic that has not been consistently addressed in the literature. Inappropriate utilization and lack of top of licensure practice have been associated with increased turnover, decreased job satisfaction, and professional development. By developing a multidisciplinary workforce planning committee, full-time employee positions are evaluated with a goal of optimizing and standardizing the role of APPs at SHC.

  View details for DOI 10.1097/NNA.0000000000001185

  View details for PubMedID 35994601

• Prospective intraoperative and histologic evaluation of cavernous sinus medial wall invasion by pituitary adenomas and its implications for acromegaly remission outcomes. Scientific reports Mohyeldin, A., Katznelson, L. J., Hoffman, A. R., Asmaro, K., Ahmadian, S. S., Eltobgy, M. M., Nayak, J. V., Patel, Z. M., Hwang, P. H., Fernandez-Miranda, J. C. 2022; 12 (1): 9919

  Abstract

  Recurrence and biochemical remission rates vary widely among different histological subtypes of pituitary adenoma. In this prospective study, we evaluated 107 consecutive primary pituitary adenomas operated on by a single neurosurgeon including 28 corticotroph, 27 gonadotroph, 24 somatotroph, 17 lactotroph, 5 null-cell and 6 plurihormonal. In each case, we performed direct endoscopic intraoperative inspection of the medial wall of the cavernous sinus, which was surgically removed when invasion was visualized. This was performed irrespective of tumor functional status. Medial wall resection was performed in 47% of pituitary adenomas, and 39/50 walls confirmed pathologic evidence of invasion, rendering a positive predictive value of intraoperative evaluation of medial wall invasion of 78%. We show for the first-time dramatic disparities in the frequency of medial wall invasion among pathological subtypes. Somatotroph tumors invaded the medial wall much more often than other adenoma subtypes, 81% intraoperatively and 69% histologically, followed by plurihormonal tumors (40%) and gonadotroph cell tumors (33%), both with intraoperative positive predictive value of 100%. The least likely to invade were corticotroph adenomas, at a rate of 32% intraoperatively and 21% histologically, and null-cell adenomas at 0%. Removal of the cavernous sinus medial wall was not associated with permanent cranial nerve morbidity nor carotid artery injury, although 4 patients (all Knosp 3-4) experienced transient diplopia. Medial wall resection in acromegaly resulted in the highest potential for biochemical remission ever reported, with an average postoperative day 1 GH levels of 0.96 ug/L and surgical remission rates of 92% based on normalization of IGF-1 levels after surgery (mean = 15.56 months; range 3-30 months). Our findings suggest that tumor invasion of the medial wall of the cavernous sinus may explain the relatively low biochemical remission rates currently seen for acromegaly and illustrate the relevance of advanced intradural surgical approaches for successful and durable outcomes in endonasal pituitary surgery for functional adenomas.

  View details for DOI 10.1038/s41598-022-12980-1

  View details for PubMedID 35705579

• Acromegaly: An Endocrine Society Clinical Practice Guideline JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Katznelson, L., Laws, E. R., Melmed, S., Molitch, M. E., Murad, M. H., Utz, A., Wass, J. A. 2014; 99 (11): 3933-3951

  Abstract

  The aim was to formulate clinical practice guidelines for acromegaly.The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology.This evidence-based guideline 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. The Task Force reviewed primary evidence and commissioned two additional systematic reviews.One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines.Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.

  View details for DOI 10.1210/jc.2014-2700

  View details for Web of Science ID 000346743100001

  View details for PubMedID 25356808

• Surgical Interventions and Medical Treatments in Treatment-Naive Patients With Acromegaly: Systematic Review and Meta-Analysis JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Abu Dabrh, A. M., Mohammed, K., Asi, N., Farah, W. H., Wang, Z., Farah, M. H., Prokop, L. J., Katznelson, L., Murad, M. H. 2014; 99 (11): 4003-4014

  Abstract

  Acromegaly is usually treated with surgery as a first-line treatment, although medical therapy has also been used as an alternative primary treatment.We conducted a systematic review and meta-analysis to synthesize the existing evidence comparing these two approaches in treatment-naïve patients with acromegaly.This study performed a comprehensive search in multiple databases, including Medline, EMBASE, and Scopus from early inception through April 2014.The study used original controlled and uncontrolled studies that enrolled patients with acromegaly to receive either surgical treatment or medical treatment as their first-line treatment.Reviewers extracted data independently and in duplicates. Because of the noncomparative nature of the available studies, we modified the Newcastle-Ottawa Scale to assess the quality of included studies. Outcomes evaluated were biochemical remission and change in IGF-1 or GH levels. We pooled outcomes using the random-effects model.The final search yielded 35 studies enrolling 2629 patients. Studies were noncomparative series with a follow-up range of 6-360 months. Compared with medical therapy, surgery was associated with a higher remission rate (67% vs 45%; P = .02). Surgery had higher remission rates at longer follow-up periods (≥ 24 mo) (66% vs 44%; P = .04) but not the shorter follow-up periods (≤ 6 mo) (53% vs 26%; P = .02). Surgery had higher remission rates in the follow-up levels of GH (65% vs 46%; P = .05). In one study, the IGF-1 level was reduced more with surgery compared with medical treatment (-731 μg/L vs -251 μg/L; P = .04). Studies in which surgery was performed by a single operator reported a higher remission rate than those with multiple operators (71% vs 47%; P = .002).Surgery may be associated with higher remission rate; however, the confidence in such evidence is very low due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

  View details for DOI 10.1210/jc.2014-2900

  View details for Web of Science ID 000346743100013

  View details for PubMedID 25356809

• Utility of Adrenocorticotropic Hormone in Assessing the Response to Transsphenoidal Surgery for Cushing's Disease. Endocrine practice Salmon, P. M., Loftus, P. D., Dodd, R. L., Harsh, G., Chu, O. S., Katznelson, L. 2014; 20 (11): 1159-1164

  Abstract

  To compare adrenocorticotrophic hormone (ACTH) and cortisol dynamics in subjects with Cushing's disease (CD) following transsphenoidal surgery (TSS) and to determine the value of early postoperative ACTH levels in predicting subsequent hypocortisolemia.Following TSS for CD, serum cortisol and plasma ACTH were measured every 6 hours in the absence of empiric glucocorticoid coverage.A total of 26 subjects (25 female) underwent 28 operations. Hypocortisolemia was achieved in 21 (81%) subjects after the initial TSS. Repeat TSS was performed in 2 subjects, resulting in hypocortisolemia in 1. Subjects who achieved hypocortisolemia had significantly lower ACTH levels by 19 hours postoperatively (P = .007). Plasma ACTH fell to <30 pg/mL in 86% and <20 pg/mL in 82% of subjects who subsequently achieved hypocortisolemia. Plasma ACTH declined to <30 pg/mL by a mean of 10 hours and to <20 pg/mL by 13 hours prior to hypocortisolemia. Follow-up data were available on 25 patients for a median of 23 months. Three subjects who achieved initial surgical remission had disease recurrence at 19, 24, and 36 months; all of these subjects had a postoperative nadir serum cortisol levels <3 μg/dL and plasma ACTH <20 pg/mL.Following TSS for CD, plasma ACTH declined prior to achievement of hypocortisolemia in most subjects. In the majority, the ACTH level reached a nadir of <20 pg/mL. Low early postoperative ACTH levels predict early hypocortisolemia but may not accurately predict long-term remission.

  View details for DOI 10.4158/EP14140.OR

  View details for PubMedID 24936567

• Global clinical response in Cushing's syndrome patients treated with mifepristone. Clinical endocrinology Katznelson, L., Loriaux, D. L., Feldman, D., Braunstein, G. D., Schteingart, D. E., Gross, C. 2014; 80 (4): 562-569

  Abstract

  Mifepristone, a glucocorticoid receptor antagonist, improves clinical status in patients with Cushing's syndrome (CS). We examined the pattern, reliability and correlates of global clinical response (GCR) assessments during a 6-month clinical trial of mifepristone in CS.Post hoc analysis of secondary end-point data from a 24-week multicentre, open-label trial of mifepristone (300-1200 mg daily) in CS. Intraclass correlation coefficient (ICC) was used to examine rater concordance, and drivers of clinical improvement were determined by multivariate regression analysis.Forty-six adult patients with refractory CS along with diabetes mellitus type 2 or impaired glucose tolerance, and/or a diagnosis of hypertension.Global clinical assessment made by three independent reviewers using a three-point ordinal scale (+1 = improvement; 0 = no change; -1 = worsening) based on eight broad clinical categories including glucose control, lipids, blood pressure, body composition, clinical appearance, strength, psychiatric/cognitive symptoms and quality of life at Weeks 6, 10, 16, and 24.Positive GCR increased progressively over time with 88% of patients having improved at Week 24 (P < 0·001). The full concordance among reviewers occurred in 76·6% of evaluations resulting in an ICC of 0·652 (P < 0·001). Changes in body weight (P < 0·0001), diastolic blood pressure (P < 0·0001), two-hour postoral glucose challenge glucose concentration (P = 0·0003), and Cushingoid appearance (P = 0·022) were strong correlates of GCR.Mifepristone treatment for CS results in progressive clinical improvement. Overall agreement among clinical reviewers was substantial and determinants of positive GCR included change in weight, blood pressure, glucose levels and appearance.

  View details for DOI 10.1111/cen.12332

  View details for PubMedID 24102404

• Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults PITUITARY Yuen, K. C., Biller, B. M., Katznelson, L., Rhoads, S. A., Gurel, M. H., Chu, O., Corazzini, V., Spiller, K., Gordon, M. B., Salvatori, R., Cook, D. M. 2013; 16 (2): 220-230

  Abstract

  Weight-based (WB: 0.03 mg/kg) and fixed dose (FD: 1-1.5 mg) regimens of the glucagon stimulation test (GST) have been used to evaluate GH and cortisol secretion in children and adults, respectively. However, experience of the WB regimen in assessing GH and cortisol secretion in adults are limited. We describe a multicenter experience using WB and FD regimens in evaluating GH and cortisol secretion in adults suspected of GH deficiency and central adrenal insufficiency. Retrospective case series of GSTs (n = 515) performed at five tertiary centers. Peak and nadir glucose, and peak GH and peak cortisol responses occurred later with WB (mean dose: 2.77 mg) compared to FD (mean dose: 1.20 mg) regimens. Main side-effects were nausea and vomiting, particularly in younger females. Nausea was comparable but vomiting was more frequent in the WB regimen (WB: 10.0 % vs FD: 2.4 %; P < 0.05). Peak and nadir glucose, ΔGH, and peak and Δcortisol were higher in the WB regimen. In both regimens, age correlated negatively with peak cortisol levels, and body mass index (BMI), fasting, peak and nadir glucose correlated negatively with peak GH levels. WB and FD regimens can induce adult GH and cortisol secretion, but peak responses occur later in the WB regimen. Both regimens are relatively safe, and vomiting was more prevalent in the WB regimen. As age, BMI, and glucose tolerance negatively correlated with peak GH and cortisol levels, the WB regimen may be more effective than the FD regimen in older overweight glucose intolerant patients.

  View details for DOI 10.1007/s11102-012-0407-7

  View details for PubMedID 22806554

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND TREATMENT OF ACROMEGALY-2011 UPDATE: EXECUTIVE SUMMARY ENDOCRINE PRACTICE Katznelson, L., Atkinson, J. L., Cook, D. M., Ezzat, S. Z., Hamrahian, A. H., Miller, K. K. 2011; 17 (4): 636-646

  View details for Web of Science ID 000294276000014

  View details for PubMedID 21846619

• Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Freda, P. U., Beckers, A. M., Katznelson, L., Molitch, M. E., Montori, V. M., Post, K. D., Vance, M. L. 2011; 96 (4): 894-904

  Abstract

  The aim was to formulate practice guidelines for endocrine evaluation and treatment of pituitary incidentalomas.Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails and one in-person meeting.We recommend that patients with a pituitary incidentaloma undergo a complete history and physical examination, laboratory evaluations screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm. We recommend that patients with incidentalomas not meeting criteria for surgical removal be followed with clinical assessments, neuroimaging (magnetic resonance imaging at 6 months for macroincidentalomas, 1 yr for a microincidentaloma, and thereafter progressively less frequently if unchanged in size), visual field examinations for incidentalomas that abut or compress the optic nerve and chiasm (6 months and yearly), and endocrine testing for macroincidentalomas (6 months and yearly) after the initial evaluations. We recommend that patients with a pituitary incidentaloma be referred for surgery if they have a visual field deficit; signs of compression by the tumor leading to other visual abnormalities, such as ophthalmoplegia, or neurological compromise due to compression by the lesion; a lesion abutting the optic nerves or chiasm; pituitary apoplexy with visual disturbance; or if the incidentaloma is a hypersecreting tumor other than a prolactinoma.

  View details for DOI 10.1210/jc.2010-1048

  View details for Web of Science ID 000289242800027

  View details for PubMedID 21474686

• Fatigue after traumatic brain injury: Association with neuroendocrine, sleep, depression and other factors BRAIN INJURY Englander, J., Bushnik, T., Oggins, J., Katznelson, L. 2010; 24 (12): 1379-1388

  Abstract

  Define associations between post-traumatic brain injury (TBI) fatigue and abnormalities in neuroendocrine axes, sleep, mood, cognition and physical functioning.Survey.Large community hospital-based rehabilitation centre.Convenience sample of 119 individuals at least 1 year post-TBI.Multidimensional Assessment of Fatigue (MAF); Fatigue Severity Scale (FSS); neuroendocrine assessments-growth hormone (GH) reserve, thyroid, cortisol and testosterone levels; visual analogue pain rating; Pittsburgh Sleep Quality Index; Beck Depression Inventory-II; Disability Rating Scale; Craig Handicap Assessment and Reporting Technique; Neurobehavioural Functioning Inventory.Fifty-three per cent reported fatigue on the MAF and one-third on the FSS; 65% were found to have moderate/severe GH deficiency; 64% had adrenal insufficiency (low fasting cortisol); 12% had central hypothyroidism; and 15% of men had testosterone deficiency. Pituitary dysfunction did not correlate with fatigue or other symptoms. Predictors of MAF total scores were female gender, depression, pain and self-assessed memory deficits. Predictors of FSS scores were depression, self-assessed motor deficits and anti-depressant usage.Robust correlates of fatigue were gender, depression, pain and memory and motor dysfunction. Investigation of post-TBI fatigue should include screening for depression, pain and sleep disturbance. There was no correlation between pituitary dysfunction and fatigue; however, the relatively high prevalence of hypothyroidism and adrenal dysfunction suggests screening for these hormone deficiencies.

  View details for DOI 10.3109/02699052.2010.523041

  View details for Web of Science ID 000283200800001

  View details for PubMedID 20961172

• Fatigue after TBI: Association with neuroendocrine abnormalities BRAIN INJURY Bushnik, T., Englander, J., Katznelson, L. 2007; 21 (6): 559-566

  Abstract

  Evaluate the association between neuroendocrine findings and fatigue after traumatic brain injury (TBI) Research design: Prospective, observational.Sixty-four individuals at least 1 year post-TBI underwent neuroendocrine testing including thyroid, adrenal, gonadal axes and growth hormone (GH) after glucagon stimulation with assessment of fatigue using the Global Fatigue Index (GFI) and the Fatigue Severity Scale (FSS).GFI and FSS scores were significantly higher within this sample compared to published control data. At least one pituitary axis was abnormal in 90% of participants. Higher GH levels were significantly associated with higher FSS scores. There was a noted trend between lower basal cortisol and higher scores on both the FSS and GFI.The association between higher GH levels and greater fatigue contradicted the prevailing hypothesis that post-acute TBI fatigue is associated with GH deficiency. The association between lower basal cortisol and greater fatigue was in the expected direction. While no other trends were noted, the fatigue derived from neuroendocrine abnormalities alone may be masked by fatigue induced by other factors commonly experienced following TBI. Given the high prevalence of pituitary abnormalities, screening for hypopituitarism after TBI is a reasonable recommendation. The contribution of GH deficiency to diminished quality of life post-TBI remains unclear.

  View details for DOI 10.1080/02699050701426915

  View details for Web of Science ID 000248204100002

  View details for PubMedID 17577706

• Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nature reviews. Endocrinology Petersenn, S., Fleseriu, M., Casanueva, F. F., Giustina, A., Biermasz, N., Biller, B. M., Bronstein, M., Chanson, P., Fukuoka, H., Gadelha, M., Greenman, Y., Gurnell, M., Ho, K. K., Honegger, J., Ioachimescu, A. G., Kaiser, U. B., Karavitaki, N., Katznelson, L., Lodish, M., Maiter, D., Marcus, H. J., McCormack, A., Molitch, M., Muir, C. A., Neggers, S., Pereira, A. M., Pivonello, R., Post, K., Raverot, G., Salvatori, R., Samson, S. L., Shimon, I., Spencer-Segal, J., Vila, G., Wass, J., Melmed, S. 2023

  Abstract

  This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant andaggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

  View details for DOI 10.1038/s41574-023-00886-5

  View details for PubMedID 37670148

• Patient handoffs and multi-specialty trainee perspectives across an institution: informing recommendations for health systems and an expanded conceptual framework for handoffs. BMC medical education Williams, S. R., Sebok-Syer, S. S., Caretta-Weyer, H., Katznelson, L., Dohn, A. M., Park, Y. S., Gisondi, M. A., Tekian, A. 2023; 23 (1): 434

  Abstract

  Safe and effective physician-to-physician patient handoffs are integral to patient safety. Unfortunately, poor handoffs continue to be a major cause of medical errors. Developing a better understanding of challenges faced by health care providers is critical to address this continued patient safety threat. This study addresses the gap in the literature exploring broad, cross-specialty trainee perspectives around handoffs and provides a set of trainee-informed recommendations for both training programs and institutions.Using a constructivist paradigm, the authors conducted a concurrent/embedded mixed method study to investigate trainees' experiences with patient handoffs across Stanford University Hospital, a large academic medical center. The authors designed and administered a survey instrument including Likert-style and open-ended questions to solicit information about trainee experiences from multiple specialties. The authors performed a thematic analysis of open-ended responses.687/1138 (60.4%) of residents and fellows responded to the survey, representing 46 training programs and over 30 specialties. There was wide variability in handoff content and process, most notably code status not being consistently mentioned a third of the time for patients who were not full code. Supervision and feedback about handoffs were inconsistently provided. Trainees identified multiple health-systems level issues that complicated handoffs and suggested solutions to these threats. Our thematic analysis identified five important aspects of handoffs: (1) handoff elements, (2) health-systems-level factors, (3) impact of the handoff, (4) agency (duty), and (5) blame and shame.Health systems, interpersonal, and intrapersonal issues affect handoff communication. The authors propose an expanded theoretical framework for effective patient handoffs and provide a set of trainee-informed recommendations for training programs and sponsoring institutions. Cultural and health-systems issues must be prioritized and addressed, as an undercurrent of blame and shame permeates the clinical environment.

  View details for DOI 10.1186/s12909-023-04355-5

  View details for PubMedID 37312085

• Cytodifferentiation of pituitary tumors influences pathogenesis and cavernous sinus invasion. Journal of neurosurgery Asmaro, K., Zhang, M., Rodrigues, A. J., Mohyeldin, A., Vigo, V., Nernekli, K., Vogel, H., Born, D. E., Katznelson, L., Fernandez-Miranda, J. C. 2023: 1-9

  Abstract

  Pituitary tumors (PTs) continue to present unique challenges given their proximity to the cavernous sinus, whereby invasive behavior can limit the extent of resection and surgical outcome, especially in functional tumors. The aim of this study was to elucidate patterns of cavernoinvasive behavior by PT subtype.A total of 169 consecutive first-time surgeries for PTs were analyzed; 45% of the tumors were functional. There were 64 pituitary transcription factor-1 (PIT-1)-expressing, 62 steroidogenic factor-1 (SF-1)-expressing, 38 T-box transcription factor (TPIT)-expressing, and 5 nonstaining PTs. The gold standard for cavernous sinus invasion (CSI) was based on histopathological examination of the cavernous sinus medial wall and intraoperative exploration.Cavernous sinus disease was present in 33% of patients. Of the Knosp grade 3 and 4 tumors, 12 (19%) expressed PIT-1, 7 (11%) expressed SF-1, 8 (21%) expressed TPIT, and 2 (40%), were nonstaining (p = 0.36). PIT-1 tumors had a significantly higher predilection for CSI: 53% versus 24% and 18% for TPIT and SF-1 tumors, respectively (OR 6.08, 95% CI 2.86-13.55; p < 0.001). Microscopic CSI-defined as Knosp grade 0-2 tumors with confirmed invasion-was present in 44% of PIT-1 tumors compared with 7% and 13% of TPIT and SF-1 tumors, respectively (OR 11.72, 95% CI 4.35-35.50; p < 0.001). Using the transcavernous approach to excise cavernous sinus disease, surgical biochemical remission rates for patients with acromegaly, prolactinoma, and Cushing disease were 88%, 87%, and 100%, respectively. The granule density of PIT-1 tumors and corticotroph functional status did not influence CSI.The likelihood of CSI differed by transcription factor expression; PIT-1-expressing tumors had a higher predilection for invading the cavernous sinus, particularly microscopically, compared with the other tumor subtypes. This elucidates a unique cavernoinvasive behavior absent in cells from other lineages. Innovative surgical techniques, however, can mitigate tumor behavior and achieve robust, reproducible biochemical remission and gross-total resection rates. These findings can have considerable implications on the surgical management and study of PT biology and behavior.

  View details for DOI 10.3171/2023.3.JNS221949

  View details for PubMedID 37119095

• Socio-behavioral dysfunction in disorders of hypothalamic-pituitary involvement: The potential role of disease-induced oxytocin and vasopressin signaling deficits. Neuroscience and biobehavioral reviews Clarke, L., Zyga, O., Pineo-Cavanaugh, P. L., Jeng, M., Fischbein, N. J., Partap, S., Katznelson, L., Parker, K. J. 2022: 104770

  Abstract

  Disorders involving hypothalamic and pituitary (HPIT) structures-including craniopharyngioma, Langerhans cell histiocytosis, and intracranial germ cell tumors-can disrupt brain and endocrine function. An area of emerging clinical concern in patients with these disorders is the co-occurring socio-behavioral dysfunction that persists after standard hormone replacement therapy. Although the two neuropeptides most implicated in mammalian social functioning (oxytocin and arginine vasopressin) are of hypothalamic origin, little is known about how disease-induced damage to HPIT structures may disrupt neuropeptide signaling and, in turn, impact patients' socio-behavioral functioning. Here we provide a clinical primer on disorders of HPIT involvement and a review of neuropeptide signaling and socio-behavioral functioning in relevant animal models and patient populations. This collective evidence suggests that neuropeptide signaling disruptions contribute to socio-behavioral deficits experienced by patients with disorders of HPIT involvement. A better understanding of the biological underpinnings of patients' socio-behavioral symptoms is now needed to enable the development of the first targeted pharmacological strategies by which to manage patients' socio-behavioral dysfunction.

  View details for DOI 10.1016/j.neubiorev.2022.104770

  View details for PubMedID 35803395

• Role of Radiation in the treatment of Cushing Disease. Pituitary Katznelson, L. 2022

  Abstract

  In Cushing disease (CD), radiation therapy (RT) is mostly used in the adjuvant setting in patients who have failed transsphenoidal surgery or have recurrent CD. Stereotactic radiotherapy (SRT) is administered as either single or several sessions, and the most commonly used modalities include photon source (Gamma Knife, CyberKnife, and LINAC) or heavy particles (protons). In multicenter studies, Gamma Knife SRT can lead to biochemical control in 80%, with medial time to remission approximately 15 mos, and 70% recurrence free at 10 years. Conventional RT (CRT) consists of administration of small daily fractions over six weeks, with cumulative dose of 45-50Gy. Biochemical control is achieved in up to 64% of patients with CRT. Choice of radiation modality includes convenience for patients (SRT is more convenient) and proximity to critical structures. Both forms of RT can result in hypopituitarism. RT remains an important modality for the treatment of patients with CD.

  View details for DOI 10.1007/s11102-022-01234-y

  View details for PubMedID 35687214

• The role of growth hormone for fertility in women with hypopituitarism. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society Chen, J., Katznelson, L. 2022; 63: 101458

  Abstract

  Growth hormone (GH) is an important regulator of the female reproductive system. In vitro and non-human in vivo studies demonstrate a role of GH in steroidogenesis, folliculogenesis, and post-fertilization development. Given its ability to modulate the reproductive system and potentiate the effects of gonadotropins, a beneficial role of GH replacement therapy to optimize fertility has been suggested. Women with hypopituitarism have lower pregnancy and live birth rates. Limited data suggest a role of GH in enhancing fertility management in women with hypopituitarism. GH replacement therapy may be especially relevant in women with hypopituitarism as well as in women considered poor ovarian responders and require assisted reproductive techniques.

  View details for DOI 10.1016/j.ghir.2022.101458

  View details for PubMedID 35398725

• ITALIAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS (AME) AND INTERNATIONAL CHAPTER OF CLINICAL ENDOCRINOLOGY (ICCE). POSITION STATEMENT FOR CLINICAL PRACTICE: PROLACTIN-SECRETING TUMORS. European journal of endocrinology Cozzi, R., Ambrosio, M. R., Attanasio, R., Battista, C., Bozzao, A., Caputo, M., Ciccarelli, E., De Marinis, L., De Menis, E., Faustini-Fustini, M., Grimaldi, F., Lania, A., Lasio, G., Logoluso, F., Losa, M., Maffei, P., Milani, D., Poggi, M., Zini, M., Katznelson, L., Luger, A., Poiana, C. 1800

  Abstract

  Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century prolactinomas represented the paradigm of pituitary tumors for whom the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

  View details for DOI 10.1530/EJE-21-0977

  View details for PubMedID 35000899

• Performance Nutrition for Physician Trainees Working Overnight Shifts: A Randomized Controlled Trial. Academic medicine : journal of the Association of American Medical Colleges Makowski, M. S., Trockel, M. T., Menon, N. K., Wang, H., Katznelson, L., Shanafelt, T. D. 2021

  Abstract

  PURPOSE: To compare acute effects of 2 dietary interventions with usual dietary habits on physician trainees' alertness during overnight shifts.METHOD: This registered, controlled, block-randomized crossover trial (NCT03698123) was conducted between October 2018 and May 2019 at Stanford Medicine. Physician trainees working at least 3 overnight shifts during a 1-week period were recruited. During the first overnight shift, participants followed their usual dietary habits. During the intervention nights (low carbohydrate-to-protein ratio and high carbohydrate-to-protein ratio interventions), participants received healthy dinners, snacks, water, and, upon request, caffeinated beverages, at the beginning of their shifts and were instructed to eat meals before 10 p.m. The sequence of interventions on the second and third nights were block-randomized across study weeks. Outcome measures (a priori) were overnight changes in validated measures of specific neurobehavioral dimensions: psychomotor vigilance, sensory-motor speed, working memory, and risk decision-making, as well as self-reported sleepiness and work exhaustion.RESULTS: Sixty-one physician trainees participated in this study. Compared to usual dietary habits, overnight changes in psychomotor vigilance scores (scale 0-1,000) improved by 51.02 points (95% confidence interval [CI]: 12.08, 89.96); sleepiness (scale 1-7) improved by 0.69 points (95% CI: 0.33, 1.05) under the low carbohydrate-to-protein ratio intervention. Compared to usual dietary habits, overnight changes in sleepiness (scale 1-7) improved by 0.61 points (95% CI: 0.25, 0.96) under the high carbohydrate-to-protein ratio intervention. Neither intervention had beneficial effects relative to usual dietary habits with respect to sensory-motor speed, working memory, risk decision-making, or work exhaustion. There were no differences in outcomes between low carbohydrate-to-protein ratio and high carbohydrate-to-protein ratio interventions.CONCLUSIONS: Dietary interventions may mitigate negative effects of physician trainee sleep deprivation during overnight shifts. Future studies are warranted to further examine the effectiveness of nutritional strategies on physician alertness during overnight shifts.

  View details for DOI 10.1097/ACM.0000000000004509

  View details for PubMedID 34753859

• A pilot, randomized controlled trial of telementorship: A useful tool during social distancing. Journal of clinical and translational research Prionas, N. D., Kung, T. H., Dohn, A., Piro, N., von Eyben, R., Katznelson, L., Caruso, T. J. 2021; 7 (1): 66-71

  Abstract

  Background: During social distancing, resident mentorship may be an unmet need. Telementorship, mentorship through video conferencing software, presents a unique approach to overcome these challenges.Aims: This study evaluated whether telementorship through video conference increased access to mentorship encounters and decreased perceived barriers to access, factors that determine likelihood to maintain mentor relationships, and quality of mentorship.Methods: A year-long randomized, prospective cohort study was conducted in 2016-2017 with pairs of resident mentors from seven different training programs and medical student mentees, randomized to telementorship or in-person mentorship. The number of quarterly encounters was monitored and demographic predictors of meeting were determined. Likert scale survey responses were analyzed with linear regression.Results: Forty-three of 46 (93.5%) volunteer mentor-mentee pairs participated. Telementorship did not alter likelihood of meeting or attitudes toward mentorship barriers (time and distance). Mentee satisfaction increased from 42.5% to 65.4% (P<0.05) throughout the year. Operating room-based practice (P<0.05) and higher postgraduate level (P=0.02) decreased the likelihood of meeting.Conclusion: Telementorship provided an equal number of encounters compared to the pairs who were asked to meet in-person. Telementorship may serve as an adjunct modality for flexible communication.Relevance for Patients: Medical mentorship is a key component to medical education. Effective mentorship increases academic research productivity, job satisfaction, and advancement of clinical skills, which translate to improved patient care.

  View details for PubMedID 34104809

• Glucocorticoid use in patients with adrenal insufficiency following administration of the COVID-19 vaccine: a pituitary society statement. Pituitary Katznelson, L., Gadelha, M. 2021

  Abstract

  PURPOSE: Side effects of the coronavirus disease 2019 (COVID-19) vaccines include pain at the injection site, fatigue, headache, myalgias, arthralgias, chills, and fever, all of which can be early indicators of an increased need for glucocorticoid replacement in patients with adrenal insufficiency. The Pituitary Society surveyed its membership to understand planned approaches to glucocorticoid management in patients with adrenal insufficiency who will receive a COVID-19 vaccine.METHODS: Members were asked to complete up to 3 questions regarding their planned approach for use of glucocorticoid replacement in patients with proven adrenal insufficiency.RESULTS: Surveys were sent to 273 members and 103 responded. Thirty-six percent plan to recommend that patients automatically increase glucocorticoid dosage with administration of the first vaccine injection. Of these, 84% plan to increase glucocorticoid dose on the day of vaccination, and 49% plan to increase glucocorticoid dose prior to vaccination. Of the 64% who do not plan to recommend automatic glucocorticoid dose increase with vaccine administration, 88% plan to increase the dose if the patient develops a fever, and 47% plan to increase the dose if myalgias and arthralgias occur.CONCLUSIONS: Most clinicians plan to maintain the current glucocorticoid dose with vaccine administration. The vast majority plan and to increase glucocorticoid dose in case of fever, and just under half in case of arthralgias and myalgias. These survey results offer suggested management guidance for glucocorticoid management in patients with adrenal insufficiency.

  View details for DOI 10.1007/s11102-021-01130-x

  View details for PubMedID 33564969

• Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time? Journal of the Endocrine Society Ho, K. n., Fleseriu, M. n., Kaiser, U. n., Salvatori, R. n., Brue, T. n., Lopes, M. B., Kunz, P. n., Molitch, M. n., Camper, S. A., Gadelha, M. n., Syro, L. V., Laws, E. n., Reincke, M. n., Nishioka, H. n., Grossman, A. n., Barkan, A. n., Casanueva, F. n., Wass, J. n., Mamelak, A. n., Katznelson, L. n., van der Lely, A. J., Radovick, S. n., Bidlingmaier, M. n., Boguszewski, M. n., Bollerslev, J. n., Hoffman, A. R., Oyesiku, N. n., Raverot, G. n., Ben-Shlomo, A. n., Fowkes, R. n., Shimon, I. n., Fukuoka, H. n., Pereira, A. M., Greenman, Y. n., Heaney, A. P., Gurnell, M. n., Johannsson, G. n., Osamura, R. Y., Buchfelder, M. n., Zatelli, M. C., Korbonits, M. n., Chanson, P. n., Biermasz, N. n., Clemmons, D. R., Karavitaki, N. n., Bronstein, M. D., Trainer, P. n., Melmed, S. n. 2021; 5 (3): bvaa205

  Abstract

  The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

  View details for DOI 10.1210/jendso/bvaa205

  View details for PubMedID 33604494

  View details for PubMedCentralID PMC7874572

• Consensus on diagnosis and management of Cushing's disease: a guideline update. The lancet. Diabetes & endocrinology Fleseriu, M., Auchus, R., Bancos, I., Ben-Shlomo, A., Bertherat, J., Biermasz, N. R., Boguszewski, C. L., Bronstein, M. D., Buchfelder, M., Carmichael, J. D., Casanueva, F. F., Castinetti, F., Chanson, P., Findling, J., Gadelha, M., Geer, E. B., Giustina, A., Grossman, A., Gurnell, M., Ho, K., Ioachimescu, A. G., Kaiser, U. B., Karavitaki, N., Katznelson, L., Kelly, D. F., Lacroix, A., McCormack, A., Melmed, S., Molitch, M., Mortini, P., Newell-Price, J., Nieman, L., Pereira, A. M., Petersenn, S., Pivonello, R., Raff, H., Reincke, M., Salvatori, R., Scaroni, C., Shimon, I., Stratakis, C. A., Swearingen, B., Tabarin, A., Takahashi, Y., Theodoropoulou, M., Tsagarakis, S., Valassi, E., Varlamov, E. V., Vila, G., Wass, J., Webb, S. M., Zatelli, M. C., Biller, B. M. 2021

  Abstract

  Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.

  View details for DOI 10.1016/S2213-8587(21)00235-7

  View details for PubMedID 34687601

• A Pituitary Society update to acromegaly management guidelines. Pituitary Fleseriu, M., Biller, B. M., Freda, P. U., Gadelha, M. R., Giustina, A., Katznelson, L., Molitch, M. E., Samson, S. L., Strasburger, C. J., van der Lely, A. J., Melmed, S. 2020

  Abstract

  Guidelines and consensus statements ensure that physicians managing acromegaly patients have access to current information on evidence-based treatments to optimize outcomes. Given significant novel recent advances in understanding acromegaly natural history and individualized therapies, the Pituitary Society invited acromegaly experts to critically review the current literature in the context of Endocrine Society guidelines and Acromegaly Consensus Group statements. This update focuses on how recent key advances affect treatment decision-making and outcomes, and also highlights the likely role of recently FDA-approved therapies as well as novel combination therapies within the treatment armamentarium.

  View details for DOI 10.1007/s11102-020-01091-7

  View details for PubMedID 33079318

• Managing complications of endoscopic transsphenoidal surgery in pituitary adenomas. Expert review of endocrinology & metabolism Abhinav, K., Tyler, M., Dale, O. T., Mohyeldin, A., Fernandez-Miranda, J. C., Katznelson, L. 2020: 1–9

  Abstract

  INTRODUCTION: Over the last two decades there has been a gradual shift from the traditional microscopic approach toward the use of endoscopic endonasal approach for resection of pituitary adenomas. Multiple medical and surgical complications can occur following endoscopic transsphenoidal resection of adenomas.AREAS COVERED: We discuss the evolution of the surgical practice from the use of the 'microscope' to the 'endoscope' in the resection of pituitary adenomas. We present a comprehensive review of the medical and surgical complications following surgery with particular emphasis on both the prevention and management of electrolyte disturbance, cerebrospinal fluid leak and the rare but dreaded complication of internal carotid injury (ICA). We also searched the PubMed database to identify relevant literature between 1984 and 2019.EXPERT OPINION: Use of endoscope compared with microscope may be associated with better preservation of pituitary gland function with similar extent of resection. Overall medical and surgical complications can be safely managed in high volume centers in association with endocrinologists and skull base trained otolaryngologists. Understanding of anatomico-technical nuances and meticulous surgical technique are important toward preventing ICA injury. Ongoing surgical and technical developments coupled with imaging advances will likely lead to better future outcomes for patients with functioning and nonfunctioning adenomas.

  View details for DOI 10.1080/17446651.2020.1800452

  View details for PubMedID 32744080

• RNA Expression Profiles of Pituitary Adenomas Using Laser Capture Microdissection and Smart-3SEQ Lavezo, J., Zhu, C., Vennam, S., Reveron-Thornton, R., Toland, A., Katznelson, L., Vogel, H., West, R. OXFORD UNIV PRESS INC. 2020: 713

  View details for Web of Science ID 000538796100242

• Italian Association Of Clinical Endocrinologists (Ame) And Italian Aace Chapter Position Statement For Clinical Practice: Acromegaly - Part 2: Therapeutic Issues. Endocrine, metabolic & immune disorders drug targets Cozzi, R., Ambrosio, M. R., Attanasio, R., Bozzao, A., De Marinis, L., De Menis, E., Guastamacchia, E., Lania, A., Lasio, G., Logoluso, F., Maffei, P., Poggi, M., Toscano, V., Zini, M., Chanson, P., Katznelson, L. 2020

  Abstract

  Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas. The therapeutic management of acromegaly always requires a personalized strategy. Normal age-matched IGF-I values are the treatment goal. Transsphenoidal surgery by an expert neurosurgeon is the primary treatment modality for most patients, especially if there are neurological complications. In patients with poor clinical conditions or who refuse surgery, primary medical treatment should be offered, firstly with somatostatin analogs (SSAs). In patients who do not reach hormonal targets with first generation depot SSAs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with SSA) should be offered. Irradiation could be proposed to patients with surgical remnants who would like to be free from long-term medical therapies or those with persistent disease activity or tumor growth despite surgery or medical therapy. Since the therapeutic tools available enable therapeutic targets to be achieved in most cases, the challenge is to focus more on the quality of life.

  View details for DOI 10.2174/1871530320666200129113328

  View details for PubMedID 31995025

• ITALIAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS (AME) and ITALIAN AACE CHAPTER POSITION STATEMENT FOR CLINICAL PRACTICE: ACROMEGALY - PART 1: DIAGNOSTIC AND CLINICAL ISSUES. Endocrine, metabolic & immune disorders drug targets Cozzi, R. n., Ambrosio, M. R., Attanasio, R. n., Bozzao, A. n., De Marinis, L. n., De Menis, E. n., Guastamacchia, E. n., Lania, A. n., Lasio, G. n., Logoluso, F. n., Maffei, P. n., Poggi, M. n., Toscano, V. n., Zini, M. n., Chanson, P. n., Katznelson, L. n. 2020

  Abstract

  Acromegaly is a rare disease. Improvements in lifespan in these patients have recently been reported due to transsphenoidal surgery (TSS), advances in medical therapy, and tighter criteria for defining disease remission. This document reports the opinions of a group of Italian experts who have gathered together their prolonged clinical experience in the diagnostic and therapeutic challenges of acromegaly patients. Both GH and IGF-I (only IGF-I in those treated with Pegvisomant - PegV) are needed in the diagnosis and follow-up. Comorbidities (cardio-cerebrovascular disease, sleep apnea, metabolic derangement, neoplasms, and bone/joint disease) should be specifically addressed. Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas.

  View details for DOI 10.2174/1871530320666200127103320

  View details for PubMedID 31985386

• The New USMLE Step 1 Paradigm: An Opportunity to Cultivate Diversity of Excellence. Academic medicine : journal of the Association of American Medical Colleges Pershing, S. n., Co, J. P., Katznelson, L. n. 2020

  Abstract

  The February 2020 announcement that United States Medical Licensing Examination (USMLE) Step 1 results will be reported as pass/fail instead of numerical scores has been controversial. Step 1 scores have played a key role in residency selection, including screening for interviews. Although Step 1 scores are viewed as an objective criterion, they have been shown to disadvantage female and underrepresented minority applicants, cause student anxiety and financial burden, and affect student well-being. Furthermore, Step 1 scores incompletely predict applicants' overall residency performance. With this paradigm shift in Step 1 score reporting, residency programs will have fewer objective, standardized metrics for selection decisions, which may lead to greater emphasis on USMLE Step 2 Clinical Knowledge scores or yield unintended consequences such as shifting weight to metrics such as medical school reputation).Yet, greater breadth in residency selection metrics will better serve both applicants and programs. Some students excel in coursework, others in research or leadership. All factors should be recognized, and broader metrics should be implemented to promote and recognize diversity of excellence. Given the need for metrics for residency selection as well as for a more holistic approach to evaluating residency applicants, assessment during medical school should be revisited and made more meaningful. Another opportunity may involve use of situational judgement tests to predict professionalism and performance on other competencies. It will be important to evaluate the impact of the new Step 1 paradigm and related initiatives going forward. Residency application overload must also be addressed.

  View details for DOI 10.1097/ACM.0000000000003512

  View details for PubMedID 32433311

• A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update. The Journal of clinical endocrinology and metabolism Giustina, A., Barkan, A., Beckers, A., Biermasz, N., Biller, B. M., Boguszewski, C., Bolanowski, M., Bonert, V., Bronstein, M. D., Casanueva, F. F., Clemmons, D., Colao, A., Ferone, D., Fleseriu, M., Frara, S., Gadelha, M. R., Ghigo, E., Gurnell, M., Heaney, A. P., Ho, K., Ioachimescu, A., Katznelson, L., Kelestimur, F., Kopchick, J., Krsek, M., Lamberts, S., Losa, M., Luger, A., Maffei, P., Marazuela, M., Mazziotti, G., Mercado, M., Mortini, P., Neggers, S., Pereira, A. M., Petersenn, S., Puig-Domingo, M., Salvatori, R., Shimon, I., Strasburger, C., Tsagarakis, S., van der Lely, A. J., Wass, J., Zatelli, M. C., Melmed, S. 2019

  Abstract

  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.

  View details for DOI 10.1210/clinem/dgz096

  View details for PubMedID 31606735

• Beyond duty hours: leveraging large-scale paging data to monitor resident workload NPJ DIGITAL MEDICINE Kaushal, A., Katznelson, L., Harrington, R. A. 2019; 2: 87

  Abstract

  Monitoring and managing resident workload is a cornerstone of policy in graduate medical education, and the duty hours metric is the backbone of current regulations. While the duty hours metric measures hours worked, it does not capture differences in intensity of work completed during those hours, which may independently contribute to fatigue and burnout. Few such metrics exist. Digital data streams generated during the usual course of hospital operations can serve as a novel source of insight into workload intensity by providing high-resolution, minute-by-minute data at the individual level; however, study and use of these data streams for workload monitoring has been limited to date. Paging data is one such data stream. In this work, we analyze over 500,000 pages-two full years of pages in an academic internal medicine residency program-to characterize paging patterns among housestaff. We demonstrate technical feasibility, validity, and utility of paging burden as a metric to provide insight into resident workload beyond duty hours alone, and illustrate a general framework for evaluation and incorporation of novel digital data streams into resident workload monitoring.

  View details for DOI 10.1038/s41746-019-0165-2

  View details for Web of Science ID 000484610000001

  View details for PubMedID 31531394

  View details for PubMedCentralID PMC6733865

• A protected time policy to improve dental health among resident physicians JOURNAL OF THE AMERICAN DENTAL ASSOCIATION Jun, T., Liebert, C., Esquivel, M., Cox, J., Trockel, M., Katznelson, L. 2019; 150 (5): 362-+

  Abstract

  Resident physicians underuse preventive dental health services. The authors assessed the barriers to and need for oral health care among residents and piloted a program to enhance dental health care among house staff.Participants from 5 residency programs received 2 hours of protected time during business hours for visits to a nearby dental office. The authors surveyed participating residents before and after the visits about barriers to seeking oral health care and their experiences with the program. The authors recorded dental findings for each participant.A total of 35 of 243 eligible residents (14.4%) participated in the study; 71.4% reported delaying or skipping preventive dental examinations during residency. Lack of time and norms and peer perceptions were important barriers; 28.6% of residents had dental findings requiring further management.Residents neglect preventive oral health care because of work obligations. More than one-quarter of residents had clinically significant dental findings. Providing protected time addressed common barriers and was well received.Resident physicians have unmet oral health care needs. Collaborations between residency programs and dental practices to provide protected time for residents to seek oral health care could address common barriers to care.

  View details for DOI 10.1016/j.adaj.2018.12.016

  View details for Web of Science ID 000465431400024

  View details for PubMedID 31029211

• Authors' response. Journal of the American Dental Association (1939) Jun, T. W., Liebert, C. A., Esquivel, M. n., Cox, J. A., Trockel, M. n., Katznelson, L. n. 2019; 150 (7): 568–69

  View details for DOI 10.1016/j.adaj.2019.05.010

  View details for PubMedID 31248480

• Psychological effects of Dopamine Agonist Treatment in Patients with Hyperprolactinemia and Prolactin Secreting Adenomas. European journal of endocrinology Ioachimescu, A. G., Fleseriu, M., Hoffman, A. R., Vaughan Iii, T. B., Katznelson, L. 2018

  Abstract

  BACKGROUND: Dopamine agonists (DAs) are the main treatment for patients with hyperprolactinemia and prolactinomas. Recently, an increasing number of reports emphasized DAs' psychological side effects, either de- novo or as exacerbations of prior psychiatric disease.METHODS: Review of prospective and retrospective studies (PubMed 1976- September 2018) evaluating the psychological profile of DAs-treated patients with hyperprolactinemia and prolactinomas. Case -series and case reports of psychiatric complications were also reviewed.RESULTS: Most studies were cross-sectional and had a control group of healthy volunteers or patients with nonfunctioning pituitary adenomas. There were few prospective studies, with/without control group, that included small numbers of patients. Compared with controls, patients with hyperprolactinemia generally had worse quality of life, anxiety, depression and certain personality traits. Patients receiving DAs had higher impulsivity scores than normoprolactinemic controls. Impulse control disorders (ICDs) were reported in both genders, with hypersexuality mostly in men. Multiple ICDs were sometimes reported in the same patient, usually reversible after DA discontinuation. In case reports, DA therapy was temporally associated with severe depression, manic episodes or psychosis, which improved after discontinuation and administration of psychiatric medications. Gender type of DA, dose and duration of therapy didn't correlate with occurrence of psychiatric pathology.CONCLUSION: Patients with hyperprolactinemia receiving DAs may develop changes in mood and behavior regardless of prior psychiatric history. Increased awareness for ICDs, depression, mania and other types of psychosis is needed by all physicians who prescribe DAs. Larger prospective controlled clinical studies are needed to delineate prevalence, risk stratification and management.

  View details for PubMedID 30400048

• Natural history of Rathke's cleft cysts: A retrospective analysis of a two centres experience CLINICAL ENDOCRINOLOGY Sala, E., Moore, J. M., Amorin, A., Carosi, G., Martinez, H., Harsh, G. R., Arosio, M., Mantovani, G., Katznelson, L. 2018; 89 (2): 178–86

  Abstract

  Rathke's cleft cyst (RCC) is a common sellar lesion which may cause visual impairment, hypopituitarism and headaches from mass effect. The natural history of these lesions is currently unclear. We investigated the natural history of RCCs and compared surgically treated patients with those treated conservatively.We performed a retrospective cohort study of patients diagnosed with a RCC between 1996 and 2016 at Stanford University and Ospedale Maggiore Policlinico di Milano.Patients were divided into 2 cohorts: Group A, 72 subjects who underwent surgical resection of a symptomatic RCC, and Group B, 62 subjects managed conservatively. Compared to Group B, Group A subjects had larger RCCs (79% vs 22% had a largest diameter >10 mm, P < .001) and were more likely (41.5% vs 16%, P < .001) to present with hypopituitarism and diabetes insipidus (DI) (18% vs 1.6%, P = .002). In Group A, after a mean follow-up of 53.7 months, 12.5% of patients had recurrence and a second surgery. After surgery, 35% of patients recovered pituitary function. Hyperprolactinemia (26.6%) and hypogonadism (66.6%) resolved more commonly that did DI (20.1%). New pituitary deficits appeared in 16.6% of patients after surgery. In Group B, with a mean follow-up of 41 months, only 6.4% had cyst enlargement, none underwent surgery, and none developed a pituitary deficit.Our data offer guidance in decision-making regarding the management of RCC patients and confirm the safety of conservative treatment in asymptomatic patients.

  View details for PubMedID 29781512

• Clinical and Immunohistochemical Analysis of Clinically Non-functional Pituitary Neuroendocrine Tumors Lavezo, J., Frankel, M., Balliu, B., Pan, J., Hoffman, A., Dodd, R., Harsh, G., Katznelson, L., Vogel, H. OXFORD UNIV PRESS INC. 2018: 518

  View details for Web of Science ID 000434064400162

• CyberKnife robotic radiosurgery in the multimodal management of acromegaly patients with invasive macroadenoma: a single center's experience JOURNAL OF NEURO-ONCOLOGY Sala, E., Moore, J. M., Amorin, A., Martinez, H., Bhowmik, A. C., Lamsam, L., Chang, S., Soltys, S. G., Katznelson, L., Harsh, G. R. 2018; 138 (2): 291–98

  Abstract

  Surgery is the primary treatment for acromegaly. However, surgery may not be curative of some tumors, particularly invasive macroadenomas. Adjuvant radiation, specifically robotic stereotactic radiosurgery (rSRS), may improve the endocrine outcome. We retrospectively reviewed hormonal and radiological data of 22 acromegalic patients with invasive macroadenomas treated with rSRS at Stanford University Medical Center between 2000 and 2016. Prior to treatment, the tumor's median maximal diameter was 19 mm (2.5-50 mm). Cavernous sinus invasion occurred in 19 patients (86.3%) and compression of the optic chiasm in 2 (9.0%). At last follow up, with an average follow up of 43.2 months, all patients had a reduction in their IGF-1 levels (median IGF-1% upper limit of normal (ULN) baseline: 136% vs last follow up: 97%; p = 0.05); 9 patients (40.9%) were cured, and 4 (18.1%) others demonstrated biochemical control of acromegaly. The median time to cure was 50 months and the mean interval to cure or biochemical control was 30.3 months (± 24 months, range 6-84 months). Hypopituitarism was present in 8 patients (36.3%) and new pituitary deficits occurred in 6 patients with a median latency of 31.6 ± 14.5 months. At final radiologic follow-up, 3 tumors (13.6%) were smaller and 19 were stable in size. The mean biologically effective dose (BED) was higher in subjects cured compared to those with persistent disease, 163 Gy3 (± 47) versus 111 Gy3 (± 43), respectively (p = 0.01). No patient suffered visual deterioration. Robotic SRS is a safe and effective treatment for acromegaly: radiation-induced visual complications and hypopituitarism is rare.

  View details for PubMedID 29429125

• Nurse Telephonic Triage Service for After-hour Patient Calls in Neurosurgery. Annals of surgery Escobedo-Wu, E. L., Dhebar, F., Harsh, G., Steinberg, G., Vyas, A., Katznelson, L., Ho, A. L., Pendharkar, A. V., Sussman, E. S., Rohatgi, N. 2018; 267 (4): e67–e68

  Abstract

  OBJECTIVE: The aim of this study was to report the utilization and experience of the nurse telephonic triage service for after-hour patient calls in Neurosurgery.BACKGROUND: It is challenging for patients to reach their clinicians after-hours in a timely manner. This may result in worse health outcomes for the patients, or inappropriate utilization of emergency rooms and urgent care facilities. Physicians continue to remain overwhelmed with frequent after-hours calls in addition to other clinical responsibilities while on-call.METHODS: In August 2015, our institution launched the Clinical Advice Service (CAS) to provide a patient-centric, nurse-run telephone triage service for after-hour calls from Neurosurgery patients. Clinical protocols were created for use by CAS staff by Neurosurgery clinicians.RESULTS: Between July 2016 and June 2017, CAS has accepted 1021 after-hours calls from Neurosurgery patients. A total of 71.4% of these calls were clinical, and the remaining nonclinical (directions, appointments, general information). CAS escalated 37.3% of the calls to the on-call Neurosurgery physician; 4.8% Neurosurgery patients were triaged to the emergency room by CAS.CONCLUSION: CAS has been able to provide well-coordinated care to Neurosurgery patients while reducing physician workload.

  View details for PubMedID 29064895

• Adrenal Axis Insufficiency After Endoscopic Transsphenoidal Resection of Pituitary Adenomas WORLD NEUROSURGERY Ajlan, A., Almufawez, K. A., Albakr, A., Katznelson, L., Harsh, G. R. 2018; 112: E869–E875

  Abstract

  Hormonal insufficiency of 1 or more pituitary axes can appear after pituitary surgery. Adrenal axis impairment after surgery can lead to serious consequences if not identified and treated.Assess early and late postoperative adrenal insufficiency (AI) and identify the risk factors predicting their occurrence after endoscopic transsphenoidal resection of pituitary adenomas.Retrospective review identified 176 pituitary adenomas resected using an endoscopic transsphenoidal approach. Patients taking steroids preoperatively, Cushing disease patients, and patients with incomplete records were excluded. Sixty-nine patients were excluded according to our exclusion criteria.The study group thus included 107 patients (total of 111 operations). The median age was 50 years (range, 18-89 years). The median duration of follow-up was 30 months (range, 6-74 months). Eighty-three patients (74.7%) had macroadenomas, and 89 (59.3%) had nonfunctional adenomas. Of the 111 procedures, 61 patients (55%) had early AI. Of the 61 patients, 48 patients (79%) were not taking steroids in long-term follow-up, and only 13 (21%) required long-term replacement. Sixteen of the patients undergoing 111 procedures (14.4%) had AI on long-term follow-up. Of those 16 patients, 13 were already taking steroids and 3 had new diagnoses of AI. Age, male gender, and cerebrospinal fluid (CSF) leaks were associated with persistent postoperative AI (P = 0.018, P = 0.001, P = 0.007, respectively).Hypothalamic pituitary adrenal axis insufficiency is common after endoscopic transsphenoidal surgery. Male gender, age greater than 50 years, visual impairment, and intraoperative CSF leak were correlated with late postoperative AI. More than two thirds of patients in whom early AI developed did not require steroids in the long term.

  View details for PubMedID 29421453

• Diabetes Insipidus following Endoscopic Transsphenoidal Surgery for Pituitary Adenoma JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Ajlan, A. M., Bin Abdulqader, S., Achrol, A. S., Aljamaan, Y., Feroze, A. H., Katznelson, L., Harsh, G. R. 2018; 79 (2): 117–22

  Abstract

  Objectives  Pituitary adenoma (PA), among the most commonly encountered sellar pathologies, accounts for 10% of primary intracranial tumors. The reported incidence of postoperative diabetes insipidus (DI) is highly variable. In this study, we report our experience with DI following endoscopic transsphenoidal surgery (TSS) for PAs, elucidating the risk factors of postoperative DI, the likelihood of long-term DI, and the impact of DI on the length of stay (LOS). Methods  The study included 178 patients who underwent endoscopic resection of PAs. Early DI was defined as that occurring within the first postoperative week. The mean follow-up was 36 months. Long-term DI was considered as DI apparent in the last follow-up visit. Results  Of the 178 patients included in the study, 77% of the tumors were macroadenomas. Forty-seven patients (26%) developed early DI. Long-term DI was observed in 18 (10.1%) of the full cohort. Age younger than 50 years was significantly associated with a higher incidence of long-term DI ( p  = 0.02). Macroadenoma and gross total resection were significantly associated with higher incidence of early DI ( p  = 0.05 and p  = 0.04, respectively). The mean LOS was 4 days for patients with early postoperative DI and 3 days for those without it. Conclusion  The reported incidence of postoperative DI is significantly variable. We identified age younger than 50 years a risk factor for developing long-term postoperative DI. Gross total surgical resection and tumor size (> 1 cm) were associated with development of early DI. Early DI increased the LOS on average by 1 day.

  View details for PubMedID 29868315

  View details for PubMedCentralID PMC5978855

• CyberKnife Radiosurgery in the Multimodal Management of Patients with Cushing Disease WORLD NEUROSURGERY Moore, J. M., Sala, E., Amorin, A., Martinez, H., Bhowmik, A. C., Chang, S. D., Soltys, S. G., Harsh, G. R., Katznelson, L. 2018; 112: E425–E430

  Abstract

  Surgery is the primary treatment for Cushing disease. When surgery is unsuccessful in normalizing hypercortisolism, adjuvant radiation, such as stereotactic radiosurgery, may be useful to improve biochemical control.This retrospective study included a cohort of consecutive patients treated with CyberKnife (CK) radiosurgery for active Cushing disease at Stanford Hospital and Clinics.As first-line treatment, all patients underwent transsphenoidal surgery with histologic demonstration of an adrenocorticotropic hormone-producing pituitary adenoma. CK was performed as adjuvant therapy for persistent or recurrent disease. The median time between surgery and CK was 14 ± 34 months. Before CK, median maximal diameter of tumors was 9 mm (range, 7-32 mm), with cavernous sinus invasion in all patients (100%) and abutment of the optic chiasm in 1 patient (14.2%). With an average follow-up of 55.4 months, normalization of hypercortisolism was achieved in 4 patients (57.1%): 2 patients (28.5%) achieved normalization of the hypothalamic-pituitary-adrenal axis without glucocorticoid replacement, and 2 patients developed hypoadrenalism (28.5%). The median time to biochemical remission was 12.5 months. Hypopituitarism occurred in only 1 patient (14.2%), and no patients had visual complications. Time between surgery and radiotherapy of <14 months was associated with a significantly improved biochemical remission rate (P = 0.02).In a cohort of patients with Cushing disease, we demonstrate that CK is an effective treatment with rare complications.

  View details for PubMedID 29355797

• Utility of Pit-1 Immunostaining in Distinguishing Pituitary Adenomas of Primitive Differentiation from Null Cell Adenomas ENDOCRINE PATHOLOGY Lee, J. C., Pekmezci, M., Lavezo, J. L., Vogel, H., Katznelson, L., Fraenkel, M., Harsh, G., Dulai, M., Perry, A., Tihan, T. 2017; 28 (4): 287–92

  Abstract

  Pit-1 immunostaining is not routinely used in the characterization of pituitary adenomas, and its utility in distinguishing adenomas dedicated towards the lactotroph, somatotroph, and thyrotroph lineage from null cell adenomas warrants further evaluation. Pituitary adenomas that were negative for expression of a basic panel of hormonal markers (ACTH, prolactin, and growth hormone) were further evaluated for TSH, SF-1, and Pit-1 expression using a tissue microarray. Among the 147 identified pituitary adenomas that were negative for ACTH, prolactin, growth hormone, and TSH, expression of SF-1 was present in 68 cases (46%). Of the remaining 72 cases with sufficient tissue for further analysis, four were Pit-1 positive (6% of the adenomas negative for ACTH, prolactin, growth hormone, TSH, and SF-1); the remaining 68 were potentially null cell adenomas. Two of the Pit-1-positive adenomas displayed a paranuclear CAM 5.2 staining pattern suggestive of a sparsely granulated somatotroph adenoma; however, only one case contained fibrous bodies within a majority of the adenoma cells. Our data suggests that Pit-1 can be utilized as a second tier immunostain in cases of clinically non-functioning adenomas that are immunonegative for ACTH, prolactin, growth hormone, TSH, and SF-1 in order to further segregate rare cases of Pit-1-positive adenomas from null cell adenomas. Pit-1 immunostaining can recognize rare cases of sparsely granulated somatotroph adenomas that appear immunonegative for growth hormone, as well as rare cases of other Pit-1-positive adenomas that are negative for Pit-1 lineage hormones. Overall, pituitary adenomas of the Pit-1 lineage that do not produce prolactin, growth hormone, or TSH are rare, with only four cases identified in the current study.

  View details for PubMedID 28994039

• Encouraging Mindfulness in Medical House Staff via Smartphone App: A Pilot Study. Academic psychiatry : the journal of the American Association of Directors of Psychiatric Residency Training and the Association for Academic Psychiatry Wen, L., Sweeney, T. E., Welton, L., Trockel, M., Katznelson, L. 2017; 41 (5): 646-650

  Abstract

  Stress and burnout are increasingly recognized as urgent issues among resident physicians, especially given the concerning implications of burnout on physician well-being and patient care outcomes.The authors assessed how a mindfulness and meditation practice among residents, supported via a self-guided, smartphone-based mindfulness app, affects wellness as measured by prevalidated surveys.Residents in the departments of general surgery, anesthesia, and obstetrics and gynecology were recruited for participation in this survey-based, four-week, single-arm study. All participants used the app (Headspace) on a self-guided basis, and took surveys at enrollment, at 2 weeks, and at 4 weeks. The Positive and Negative Affect Schedule (PANAS) assessed mood, and the Freiburg Mindfulness Inventory (FMI) measured mindfulness.Forty-three residents enrolled in this study from April 2015 to August 2016; 30 residents (90% female) completed two or more surveys, and so were included for further analysis. In a comparison of baseline scores to week four scores, there was a significant increase in FMI at week four (36.88 ± 7.00; Cohen's d = 0.77, p = 0.005), a trend toward increase in the positive affect score (PAS) (31.73 ± 6.07; Cohen's d = 0.38, p = 0.08), and no change in negative affect score (NAS) (21.62 ± 7.85; Cohen's d = -0.15, p = NS). In mixed-effect multivariate modeling, both the PAS and the FMI scores showed significant positive change with increasing use of the smartphone app (PAS, 0.31 (95% CI 0.03-0.57); FMI, 0.38 (95% CI 0.11-0.66)), while the NAS did not show significant change.Study limitations include self-guided app usage, a homogenous study subject population, insufficient study subjects to perform stratified analysis of the impact of specialty on the findings, lack of control group, and possible influence from the Hawthorne effect. This study suggests the feasibility and efficacy of a short mindfulness intervention delivered by a smartphone app to improve mindfulness and associated resident physician wellness parameters.

  View details for DOI 10.1007/s40596-017-0768-3

  View details for PubMedID 28795335

• Follow-up intervals in patients with Cushing's disease: recommendations from a panel of experienced pituitary clinicians. Pituitary Geer, E. B., Ayala, A., Bonert, V., Carmichael, J. D., Gordon, M. B., Katznelson, L., Manuylova, E., Shafiq, I., Surampudi, V., Swerdloff, R. S., Broder, M. S., Cherepanov, D., Eagan, M., Lee, J., Said, Q., Neary, M. P., Biller, B. M. 2017

  Abstract

  Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing's disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course.The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after ("second round") an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: "agreement" if no more than two responses were outside a 2 week window around the median response; "disagreement" if more than two responses were outside a 2 week window around the median response. Recommendations were developed based on second round results.Panel agreement was 65.9% before and 88.6% after the in-person discussion. The panel recommended follow-up within 8 weeks for patients in remission on glucocorticoid replacement and within 1 year of surgery; within 4 weeks for patients with uncontrolled persistent or recurrent disease; within 8-24 weeks in post-radiotherapy patients controlled on medical therapy; and within 24 weeks in asymptomatic patients with stable plasma ACTH concentrations after bilateral adrenalectomy.With a high level of consensus using the Delphi process, panelists recommended regular follow-up in most patient scenarios for this chronic condition. These recommendations may be useful for assessment of CD care both in research and clinical practice.

  View details for DOI 10.1007/s11102-017-0801-2

  View details for PubMedID 28275992

• Practice transition in graduate medical education. The clinical teacher Shaffer, R., Piro, N., Katznelson, L., Gephart, M. H. 2017

  Abstract

  Debt repayment, professional negotiation and practice management skills are vital to a successful medical practice, yet are undervalued and seldom taught in graduate medical education. Medical residents need additional training to confidently transition to independent practice, requiring the development of novel curricula. Medical residents need additional training to confidently transition to independent practice METHODS: We developed a trial practice management curriculum to educate senior residents and fellows through voluntary workshops. Topics discussed in the workshops included debt repayment, billing compliance, medical malpractice, contract negotiations, and lifestyle and financial management. Resident self-confidence was assessed, and feedback was obtained through voluntary survey responses before and after attendance at a workshop, scored using a Likert scale.Twenty-five residents from 20 specialties attended a 1-day session incorporating all lectures; 53 residents from 17 specialties attended a re-designed quarterly session with one or two topics per session. Survey evaluations completed before and after the workshop demonstrated an improvement in residents' self-assessment of confidence in contract negotiations (p < 0.001) and their first year in practice (p < 0.001): after the curriculum, 94 per cent (n = 42) of respondents felt confident participating in contract negotiations, and 93 per cent (n = 38) of respondents felt confident about their first year in practice. One hundred per cent of respondents agreed that the presentation objectives were relevant to their needs as residents.Participant responses indicated a need for structured education in practice management for senior trainees. Senior residents and fellows will benefit most from curricula, but have high familial and professional demands on their schedules.

  View details for DOI 10.1111/tct.12593

  View details for PubMedID 28164441

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: DIAGNOSIS OF RECURRENCE IN CUSHING DISEASE ENDOCRINE PRACTICE Fleseriu, M., Hamrahian, A. H., Hoffman, A. R., Kelly, D. F., Katznelson, L. 2016; 22 (12): 1436-1448

  Abstract

  Recurrence of hypercortisolemia after initial treatment of Cushing disease (CD) is more common than previously thought, with a third of patients suffering a recurrence over their lifetime. Awareness of this high rate and delayed timeline (sometimes decades) of potential recurrence is critical and patients with CD should be monitored at regular intervals throughout their lives. In this manuscript, we review the complex evaluation needed for defining CD remission versus persistent disease after surgery, and focus on challenges in diagnosing early recurrent hypercortisolemia. Late night salivary cortisol appears to be an earlier predictor of recurrence when compared with urinary free cortisol (UFC) excretion. We also review the criteria suggested to define recurrence of hypercortisolemia in patients treated with medical therapy. Further research is needed to determine the optimal way to evaluate a patient with CD recurrence as well as the riskbenefit ratio of treatment in early, mild recurrent disease.ACTH = adrenocorticotropic hormone AI = adrenal insufficiency CD = Cushing disease CDDT = coupled dexamethasone desmopressin test CR = circadian rhythm CRH = corticotropin-releasing hormone GC = glucocorticoid GCR = global clinical response HPA = hypothalamic-pituitary-adrenal LDDST = low-dose dexamethasone suppression test LNSC = late-night salivary cortisol ODST = overnight dexamethasone suppression test TSS = trans-sphenoidal surgery.

  View details for DOI 10.4158/EP161512.DSCR

  View details for Web of Science ID 000389843300011

  View details for PubMedID 27643842

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: UPDATE ON GROWTH HORMONE STIMULATION TESTING AND PROPOSED REVISED CUT-POINT FOR THE GLUCAGON STIMULATION TEST IN THE DIAGNOSIS OF ADULT GROWTH HORMONE DEFICIENCY ENDOCRINE PRACTICE Yuen, K. C., Tritos, N. A., Samson, S. L., Hoffman, A. R., Katznelson, L. 2016; 22 (10): 1235-1244

  Abstract

  The clinical features of adult GH deficiency (GHD) are nonspecific, and GH stimulation testing is often required to confirm the diagnosis. However, diagnosing adult GHD can be challenging due to the episodic and pulsatile GH secretion, concurrently modified by age, gender, and body mass index (BMI).PubMed searches were conducted to identify published data since 2009 on GH stimulation tests used to diagnose adult GHD. Relevant articles in English language were identified and considered for inclusion in the present document.Testing for confirmation of adult GHD should only be considered if there is a high pretest probability, and the intent to treat if the diagnosis is confirmed. The insulin tolerance test (ITT) and glucagon stimulation test (GST) are the two main tests used in the United States. While the ITT has been accepted as the gold-standard test, its safety concerns hamper wider use. Previously, the GH-releasing hormone-arginine test, and more recently the GST, are accepted alternatives to the ITT. However, several recent studies have questioned the diagnostic accuracy of the GST when the GH cut-point of 3 μg/L is used and have suggested that a lower GH cut-point of 1 μg/L improved the sensitivity and specificity of this test in overweight/obese patients and in those with glucose intolerance.Until a potent, safe, and reliable test becomes available, the GST should remain as the alternative to the ITT in the United States. In order to reduce over-diagnosing adult GHD in overweight/obese patients with the GST, we propose utilizing a lower GH cut-point of 1 μg/L in these subjects. However, this lower GH cut-point still needs further evaluation for diagnostic accuracy in larger patient populations with varying BMIs and degrees of glucose tolerance.AACE = American Association of Clinical Endocrinologists BMI = body mass index GH = growth hormone GHD = GH deficiency GHRH = GH-releasing hormone GHS = GH secretagogue GST = glucagon stimulation test IGF = insulin-like growth factor IGFBP-3 = IGF-binding protein 3 ITT = insulin tolerance test ROC = receiver operating characteristic WB-GST = weight-based GST.

  View details for DOI 10.4158/EP161407.DSCR

  View details for Web of Science ID 000389842700012

  View details for PubMedID 27409821

• UTILITY OF A GLUCOCORTICOID SPARING STRATEGY IN THE MANAGEMENT OF PATIENTS FOLLOWING TRANSSPHENOIDAL SURGERY ENDOCRINE PRACTICE Jia, X., Pendharkar, A. V., Loftus, P., Dodd, R. L., Chu, O., Fraenkel, M., Katznelson, L. 2016; 22 (9): 1033-1039

  Abstract

  Following transsphenoidal surgery (TSS), it is important to assess for and manage adrenal insufficiency (AI). The goal of this study is to assess the efficacy and safety of a glucocorticoid (GC) sparing protocol to limit GC exposure in patients undergoing TSS.Adult patients undergoing TSS (excluding Cushing disease) with adequate adrenal function prior to surgery underwent TSS without perioperative GC coverage. Following TSS, daily morning fasting serum cortisol levels were tested. GCs were administered at stress doses for serum cortisol <5 mcg/dL, between 5 and 12 mcg/dL in the presence of clinically significant symptoms of AI, or >12 mcg/dL with severe headache, nausea or vomiting, fatigue, anorexia, or hyponatremia. The primary endpoint was the use of GCs in the immediate postoperative period.Of 178 subjects, GCs were administered to 80 (45%) patients for the following indications: 31.3% for serum cortisol <5 mcg/dL; 36.3% for cortisol between 5 and 12 mcg/dL accompanied by symptoms or signs of AI; 8.8% for moderate to severe postoperative hyponatremia; and 7.5% for severe headache, nausea and vomiting, fatigue, or anorexia with cortisol >12 mcg/dL. Logistic regression analysis showed that longer length of hospital stay (odds ratio [OR] 1.22, confidence interval [CI] 1.02-1.45) and the presence of new postoperative anterior pituitary hormone deficiency (OR 3.3, CI 1.26-8.67) were associated with postoperative GC use. By 12 weeks, only 14% of subjects remained on GCs. There were no adverse events related to withholding GCs.Our protocol for managing GC replacement is both safe and effective for limiting GC exposure in patients undergoing TSS.AI = adrenal insufficiency CI = confidence interval FSH = follicle-stimulating hormone GC = glucocorticoid GH = growth hormone IGF-1 = insulin-like growth factor-1 IV = intravenous LH = luteinizing hormone LOS = length of hospital stay OR = odds ratio TSS = transsphenoidal surgery.

  View details for DOI 10.4158/EP161256.OR

  View details for Web of Science ID 000384279900001

  View details for PubMedID 27124693

• Safety analysis of long-term budesonide nasal irrigations in patients with chronic rhinosinusitis post endoscopic sinus surgery INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Soudry, E., Wang, J., Vaezeafshar, R., Katznelson, L., Hwang, P. H. 2016; 6 (6): 568-572

  Abstract

  Although the safety of topical nasal steroids is well established for nasal spray forms, data regarding the safety of steroid irrigations is limited. We studied the effect of long-term budesonide nasal irrigations (>6 months) on hypothalamic-pituitary-adrenal axis (HPAA) function and intraocular pressure (IOP) in patients post-endoscopic sinus surgery.This was retrospective case series. Adrenal function was assessed by using the high-dose cosyntropin stimulation test.A total of 48 patients were assessed, with a mean duration of budesonide irrigations of 22 months. Stimulated cortisol levels were abnormally low in 11 patients (23%). None reported to have symptoms of adrenal suppression. Three of 4 patients who repeated the study being off budesonide for at least 1 month returned to near normal levels. Logistic regression analysis revealed that concomitant use of both nasal steroid sprays and pulmonary steroid inhalers was significantly associated with HPAA suppression (p = 0.024). Patients with low stimulated cortisol levels were able to continue budesonide irrigations under the supervision of an endocrinologist without frank clinical manifestations of adrenal insufficiency. IOP was within normal limits in all patients.Long-term use of budesonide nasal irrigations is generally safe, but asymptomatic HPAA suppression may occur in selected patients. Concomitant use of both nasal steroid sprays and pulmonary steroid inhalers while using daily budesonide nasal irrigations is associated with an increased risk. Rhinologists should be alerted to the potential risks of long-term use of budesonide nasal irrigations, and monitoring for HPAA suppression may be warranted in patients receiving long-term budesonide irrigation therapy.

  View details for DOI 10.1002/alr.21724

  View details for Web of Science ID 000379700700003

  View details for PubMedID 26879335

• Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations EUROPEAN JOURNAL OF ENDOCRINOLOGY Christiansen, J. S., Backeljauw, P. F., Bidlingmaier, M., Biller, B. M., Boguszewski, M. C., Casanueva, F. F., Chanson, P., Chatelain, P., Choong, C. S., Clemmons, D. R., Cohen, L. E., Cohen, P., Frystyk, J., Grimberg, A., Hasegawa, Y., Haymond, M. W., Ho, K., Hoffman, A. R., Holly, J. M., Horikawa, R., Hoeybye, C., Jorgensen, J. O., Johannsson, G., Juul, A., Katznelson, L., Kopchick, J. J., Lee, K. O., Lee, K., Luo, X., Melmed, S., Miller, B. S., Misra, M., Popovic, V., Rosenfeld, R. G., Ross, J., Ross, R. J., Saenger, P., Strasburger, C. J., Thorner, M. O., Werner, H., Yuen, K. 2016; 174 (6): C1-C8

  Abstract

  The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH).A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry.Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues.Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors.LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.

  View details for DOI 10.1530/EJE-16-0111

  View details for PubMedID 27009113

• Giant Prolactinoma Presenting with Neck Pain and Structural Compromise of the Occipital Condyles. Journal of neurological surgery reports Yecies, D., Ajlan, A., Ratliff, J., Ziskin, J., Hwang, P., Vogel, H., Katznelson, L., Harsh, G. 2015; 76 (2): e297-301

  Abstract

  Prolactinomas are the most common form of endocrinologically active pituitary adenoma; they account for ∼ 45% of pituitary adenomas encountered in clinical practice. Giant adenomas are those > 4 cm in diameter. Less than 0.5% of pituitary adenomas encountered in neurosurgical practice are giant prolactinomas. Patients with giant prolactinomas typically present with highly elevated prolactin levels, endocrinologic disturbances, and neurologic symptoms from mass-induced pressure. Described here is an unusual case of a giant prolactinoma presenting with neck pain and structural compromise of the occipital condyles. Transnasal biopsy of the nasopharyngeal portion of the mass obtained tissue consistent with an atypical prolactinoma with p53 reactivity and a high Ki-67 index of 5%. Despite the size and invasiveness of the tumor, the patient had resolution of his clinical symptoms, dramatic reduction of his hyperprolactinemia, and near-complete disappearance of his tumor following medical treatment.

  View details for DOI 10.1055/s-0035-1566124

  View details for PubMedID 26623246

• Mifepristone Treatment of Cushing's Syndrome in a Pediatric Patient PEDIATRICS Banerjee, R. R., Marina, N., Katznelson, L., Feldman, B. J. 2015; 136 (5): E1377-E1381

  Abstract

  Cushing's syndrome (CS) in the pediatric population is challenging to diagnose and treat. Although next-generation medical therapies are emerging for adults with CS, none are currently approved or used in children. Here we describe the first use of mifepristone, a glucocorticoid receptor antagonist, to treat CS in a pediatric subject. The patient, a 14-year-old girl with an 18-month history of metastatic neuroendocrine carcinoma, suffered from fatigue, profound myopathy, irritability, and depression. She was found to have hypertension, hypokalemia, and worsening control of her preexisting type 1 diabetes. In this report, we detail our clinical evaluation that confirmed CS caused by an ectopic adrenocorticotropic hormone secreting tumor. Surgical and radiation therapies were not pursued because of her poor functional status and limited life expectancy, and medical treatment of CS was indicated for symptom relief. Mifepristone treatment provided rapid improvement in glycemic control, insulin resistance, and hypertension as well as significant diminishment of her myopathy and fatigue. Hypokalemia was managed with an oral potassium replacement and dose escalation of spironolactone; no other significant adverse effects were observed. Despite successful palliation of Cushing's signs and symptoms, the patient died of progression of her cancer. This case demonstrates the safety and efficacy of mifepristone treatment in a pediatric patient with symptomatic, ectopic CS. We conclude that, in appropriate pediatric patients with CS, glucocorticoid receptor antagonism with mifepristone should be considered to control the effects of hypercortisolism and to improve quality of life.

  View details for DOI 10.1542/peds.2015-0684

  View details for Web of Science ID 000363969600027

  View details for PubMedID 26459648

• RADIOTHERAPY VERSUS RADIOSURGERY IN TREATING PATIENTS WITH ACROMEGALY: A SYSTEMATIC REVIEW AND META-ANALYSIS. Endocrine practice Abu Dabrh, A. M., Asi, N., Farah, W. H., Mohammed, K., Wang, Z., Farah, M. H., Prokop, L. J., Katznelson, L., Murad, M. H. 2015; 21 (8): 943-956

  Abstract

  When patients with acromegaly have residual disease following surgery, adjuvant radiation therapy is considered. Both stereotactic radiosurgery (SRS) and conventional fractionated radiotherapy (RT) are utilized. We conducted a systematic review and meta-analysis to synthesize the existing evidence and compare outcomes for SRS and RT in patients with acromegaly.We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through April 2014 for studies in which SRS or RT were used in patients with acromegaly. Outcomes evaluated were serum insulin-like growth factor-I (IGF-I) and growth hormone (GH) levels, biochemical remission, all-cause mortality, hypopituitarism, headaches, and secondary malignancies. We pooled outcomes using a random-effects model.The final search yielded 30 eligible studies assessing 2,464 patients. Compared to RT, SRS was associated with a nonsignificant increase in remission rate at the latest follow-up period (52% vs. 36%; P = .14) and a significantly lower follow-up IGF-I level (-409.72 μg/L vs. -102 μg/L, P = .002). SRS had a lower incidence of hypopituitarism than RT; however, the difference was not statistically significant (32% vs. 51%, respectively; P = .05).SRS may be associated with better biochemical remission, and it had a lower risk of hypopituitarism with at least 1 deficient axis when compared with RT; however, the confidence in such evidence is very low due to the noncomparative nature of the studies, high heterogeneity, and imprecision.GH = growth hormone GKRS = gamma-knife radio-surgery IGF-I = insulin-like growth factor-I LINAC = linear accelerator RT = conventional radiotherapy SRS = stereotactic radiosurgery.

  View details for DOI 10.4158/EP14574.OR

  View details for PubMedID 26247235

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: POSTOPERATIVE MANAGEMENT FOLLOWING PITUITARY SURGERY ENDOCRINE PRACTICE Woodmansee, W. W., Carmichael, J., Kelly, D., Katznelson, L. 2015; 21 (7): 832-838

  Abstract

  Pituitary lesions are common in the general population. Patients can present with a wide range of signs and symptoms that can be related to tumor mass effects or pituitary hormonal alterations. Evaluation involves assessing patients for the extent of tumor burden and pituitary hyper- or hypofunction and includes clinical exams, hormonal testing, and brain imaging. Preoperative diagnosis and treatment planning generally require a multidisciplinary team approach with expertise from endocrinologists, neurosurgeons, neuro-ophthalmologists, and neuroradiologists. This review will outline considerations for the evaluation and management of patients with pituitary masses at each stage in their treatment including the pre-, peri- and postoperative phases.

  View details for DOI 10.4158/EP14541.DSCR

  View details for Web of Science ID 000377964500015

  View details for PubMedID 26172128

• Nelson Syndrome: Update on Therapeutic Approaches WORLD NEUROSURGERY Azad, T. D., Veeravagu, A., Kumar, S., Katznelson, L. 2015; 83 (6): 1135-1140

  Abstract

  To review the pathophysiology and therapeutic modalities availble for Nelson syndrome.We reviewed the current literature including managment for Nelson syndrome.For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS.An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome.

  View details for DOI 10.1016/j.wneu.2015.01.038

  View details for Web of Science ID 000356138800052

• Nelson Syndrome: Update on Therapeutic Approaches. World neurosurgery Azad, T. D., Veeravagu, A., Kumar, S., Katznelson, L. 2015; 83 (6): 1135-1140

  Abstract

  To review the pathophysiology and therapeutic modalities availble for Nelson syndrome.We reviewed the current literature including managment for Nelson syndrome.For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS.An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome.

  View details for DOI 10.1016/j.wneu.2015.01.038

  View details for PubMedID 25683128

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: MANAGEMENT OF ACROMEGALY PATIENTS: WHAT IS THE ROLE OF PRE-OPERATIVE MEDICAL THERAPY? Endocrine practice Fleseriu, M., Hoffman, A. R., Katznelson, L. 2015; 21 (6): 668-673

  Abstract

  Acromegaly is a complex disease characterized by growth hormone (GH) excess originating in most cases from a pituitary tumor. The goals of treatment include removing the tumor or reducing tumor burden, normalizing GH secretion and insulin-like growth factor 1 levels, and preserving normal pituitary function if possible. Surgery by an experienced neurosurgeon is still considered first-line therapy, especially in cases with small tumors. In the last few decades, significant progress in the development of selective pharmacologic agents has greatly facilitated the management of active acromegaly, with agents such as somatostatin-receptor ligands (SRLs), GH-receptor antagonists, and dopamine agonists. In addition to adjuvant treatment, pre-operative medical therapy and primary therapy in de novo patients are increasingly employed.A United States National Library of Medicine PubMed search (through July 2014) was conducted for the following terms: acromegaly, pre-operative medical therapy, somatostatin-receptor ligands, and somatostatin analogs. Articles not in English and those not in peer-reviewed journals were excluded. In reviewing pertinent articles, focus was placed on biochemical and other postoperative outcomes of medical therapy.An analysis of the full effect of pre-operative use of SRLs on surgical outcomes (remission rates and peri-operative complications) is limited by heterogeneity of methodology, low overall surgical cure rates, and different study designs. The assumption that SRL use prior to surgery reduces peri-operative surgical risk has yet to be proven. A variable degree of tumor shrinkage with preoperative SRLs is observed. Likewise, SRL treatment 3 months before surgery may improve surgical remission rates in the short term; however, positive results do not persist in the long term.We consider that medical therapy before surgery could play a role in carefully selected patients, but treatment should be individualized. Primary medical therapy with a SRL may be considered in patients with macroadenomas without local mass effects on the optic chiasm, as SRLs have been shown to reduce tumor size and control GH hypersecretion. However, the data are insufficient to support general use of a SRL prior to surgery in order to improve post-surgery biochemical outcomes. Theoretically, patients with severe cardiac and respiratory complications due to acromegaly could potentially benefit from pre-operative SRLs in order to reduce peri-operative morbidity. Further investigation and investment in large randomized long-term clinical trials are needed to define the precise role and duration of pre-surgical medical treatment in acromegaly patients.GH = growth hormone IGF-1 = insulin-like growth factor 1 MRI = magnetic resonance imaging SRL = somatostatin-receptor ligand.

  View details for DOI 10.4158/EP14575.DSCR

  View details for PubMedID 26135961

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: MANAGEMENT OF ACROMEGALY PATIENTS: MANAGEMENT OF ACROMEGALY PATIENTS: WHAT IS THE ROLE OF PRE-OPERATIVE MEDICAL THERAPY? ENDOCRINE PRACTICE Fleseriu, M., Hoffman, A. R., Katznelson, L. 2015; 21 (6): 668-673

  View details for DOI 10.4158/EP14575.DSCR

  View details for Web of Science ID 000357732000013

• AACE/ACE DISEASE STATE CLINICAL REVIEW: DIAGNOSIS AND MANAGEMENT OF MIDGUT CARCINOIDS ENDOCRINE PRACTICE Liu, E. H., Solorzano, C. C., Katznelson, L., Vinik, A. I., Wong, R., Randolph, G., AACE Endocrine Surg Sci Committee, Neuroendocrine Carcinoid Subgrp 2015; 21 (5): 534–45

  Abstract

  Neuroendocrine tumors (NETs) are a collection of complex tumors that arise from the diffuse endocrine system, primarily from the digestive tract. Carcinoid tumors most commonly originate from the small intestine. These tumors are either referred to as small intestinal neuroendocrine tumors or midgut carcinoids (MGCs). The purpose of this review article is to survey the diagnostic and therapeutic pathways for patients with MGC and provide an overview of the complex multidisciplinary care involved in improving their quality of life, treatment outcomes, and survival.The current literature regarding the diagnosis and management of MGCs was reviewed.Dry flushing and secretory diarrhea are the hallmarks of the clinical syndrome of MGC. Managing MGC requires attention to the overall symptom complex, including the physical effects of the tumor and biomarker levels. The somatostatin analogs (SAs) octreotide and lanreotide are highly efficacious for symptomatic improvement. MGCs require resection to encompass the primary tumor and mesenteric lymph node metastases and should include cholecystectomy if the patient is likely to receive SA therapy. Debulking of liver metastasis by resection in combination with ablative therapies and other liver-directed modalities may help palliate symptoms and hormonal overproduction in carefully selected patients. Quality of life is an important measure of patients' perception of the burden of their disease and impact of treatment modalities and may be a useful guide in deciding changes in therapy to alter apparent health status.MGC is a challenging malignancy that requires the input of a multidisciplinary team to develop the best treatment plan. Consultation with expert centers that specialize in NETs may also be indicated for complex cases. With expert care, patients can be cured or live with the disease and enjoy good quality of life.

  View details for PubMedID 25962092

  View details for PubMedCentralID PMC4987303

• Bilateral adrenalectomy for Cushing's disease PITUITARY Katznelson, L. 2015; 18 (2): 269-273

  Abstract

  Review the indications, outcomes, and consequences of bilateral adrenalectomy (BLA) in patients with Cushing's disease.A literature review was performed.The primary therapy for Cushing's disease is surgery, with medical therapy and radiation therapy relegated to an adjuvant role. BLA is indicated in cases of persistent disease following pituitary surgery or in situations where rapid normalization of hypercortisolism is required. When performed via the laparoscopic approach, BLA is associated with a significantly reduced morbidity compared to the traditional, open approach. Following BLA, patients are at risk for adrenal crisis and the concern of Nelson's syndrome. However, BLA leads to a rapid resolution of the signs and symptoms of CS and leads to an improved long-term quality of life.BLA should be considered in the treatment algorithm for patients with persistent CD after failed pituitary surgery, especially in patients who have severe consequences of hypercortisolism or desire pregnancy.

  View details for DOI 10.1007/s11102-014-0633-2

  View details for Web of Science ID 000351565500015

  View details for PubMedID 25566751

• Radiotherapy vs. Radiosurgery in Treating Patients with Acromegaly: Systematic Review and Meta-Analysis. Endocrine practice Abu Dabrh, A., Asi, N., Farah, W., Mohammed, K., Wang, Z., Farah, M., Prokop, L., Katznelson, L., Murad, M. 2015: 1-33

  Abstract

  When patients with acromegaly have residual disease following surgery, adjuvant radiation therapy is considered. Both stereotactic radiosurgery (SRS) and conventional fractionated radiotherapy (RT) are utilized. We conducted a systematic review and meta-analysis to synthesize the existing evidence to compare outcomes with SRS and RT in patients with acromegaly.We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through April 2014 for studies in which SRS or RT were used in patients with acromegaly. Outcomes evaluated were serum IGF-1 and GH levels, biochemical remission, all-cause mortality, hypopituitarism, headaches and secondary malignancies. We pooled outcomes using the random-effects model.The final search yielded 30 eligible studies enrolling 2464 patients. When compared to RT, SRS was associated with a non-significant increase in remission rate at the latest follow-up period (52% vs. 36%; p = 0.14), and a significantly lower follow-up IGF-1 level (decline of - 409.72 μg/1 vs. -102 μg/1; p = 0.002). SRS was associated with lower incidence of hypopituitarism than RT; however the difference was not statistically significant [(32% vs.51%, respectively; p = 0.05).SRS may be associated with better biochemical remission and lower risk of hypopituitarism with at least one deficient axis when compared with RT; however, the confidence in such evidence is very low due to the non-comparative nature of the studies, high heterogeneity, and imprecision.

  View details for PubMedID 25786558

• Long-term efficacy and safety of pegvisomant therapy in acromegaly. Endocrine practice Yuen, K. C., Katznelson, L. 2015; 21 (3): 296-298

  View details for DOI 10.4158/EP14566.CO

  View details for PubMedID 25667381

• Cushing's disease: predicting long-term remission after surgical treatment NEUROSURGICAL FOCUS Pendharkar, A. V., Sussman, E. S., Ho, A. L., Gephart, M. G., Katznelson, L. 2015; 38 (2)

  Abstract

  Cushing's disease (CD) is a state of excess glucocorticoid production resulting from an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The gold-standard treatment for CD is transsphenoidal adenomectomy. In the hands of an experienced neurosurgeon, gross-total resection is possible in the majority of ACTH-secreting pituitary adenomas, with early postoperative remission rates ranging from 67% to 95%. In contrast to the strong data in support of resection, the clinical course of postsurgical persistent or recurrent disease remains unclear. There is significant variability in recurrence rates, with reports as high as 36% with a mean time to recurrence of 15-50 months. It is therefore important to develop biochemical criteria that define postsurgical remission and that may provide prognosis for long-term recurrence. Despite the use of a number of biochemical assessments, there is debate regarding the accuracy of these tests in predicting recurrence. Here, the authors review the various biochemical criteria and assess their utility in predicting CD recurrence after resection.

  View details for DOI 10.3171/2014.10.FOCUS14682

  View details for Web of Science ID 000349263300013

  View details for PubMedID 25639315

• Limits to Scholarship: How Can We Enhance the Program Director's Role? Academic psychiatry De Golia, S. G., Katznelson, L. 2015; 39 (1): 70-72

  View details for DOI 10.1007/s40596-014-0255-z

  View details for PubMedID 25467936

• Pharmacokinetics, Pharmacodynamics, and Safety of Pasireotide LAR in Patients With Acromegaly: A Randomized, Multicenter, Open-Label, Phase I Study JOURNAL OF CLINICAL PHARMACOLOGY Petersenn, S., Bollerslev, J., Arafat, A. M., Schopohl, J., Serri, O., Katznelson, L., Lasher, J., Hughes, G., Hu, K., Shen, G., Resendiz, K. H., Giannone, V., Beckers, A. 2014; 54 (11): 1308-1317

  View details for DOI 10.1002/jcph.326

  View details for Web of Science ID 000344051600014

• Pharmacokinetics, pharmacodynamics, and safety of pasireotide LAR in patients with acromegaly: a randomized, multicenter, open-label, phase I study. Journal of clinical pharmacology Petersenn, S., Bollerslev, J., Arafat, A. M., Schopohl, J., Serri, O., Katznelson, L., Lasher, J., Hughes, G., Hu, K., Shen, G., Reséndiz, K. H., Giannone, V., Beckers, A. 2014; 54 (11): 1308-1317

  Abstract

  Pasireotide (SOM230), a multireceptor-targeted somatostatin analogue, has exhibited favorable safety/tolerability in several clinical studies. A long-acting-release (LAR) formulation of pasireotide may offer advantages over the subcutaneous formulation. This randomized, open-label, Phase I study evaluated the safety, PK, and PD of pasireotide LAR 20, 40, or 60 mg/month in patients with acromegaly. Safety assessments and blood samples for PK and PD were taken at designated time points. Thirty-five patients were randomized and completed the study. Steady-state pasireotide concentrations were achieved following three monthly injections. Trough pasireotide concentrations (ng/mL) 28 days after each injection were: 2.48, 4.16, and 3.10 (20 mg group); 6.42, 6.62, and 7.12 (40 mg group); and 9.51, 11.7, and 13.0 (60 mg group). At study end, 51% and 57% of patients achieved GH levels ≤2.5 μg/L and IGF-1 levels below ULN, respectively. Compared with baseline, fasting blood glucose and HbA1c levels increased, whereas fasting blood insulin levels decreased. Acromegaly symptoms were generally improved. Adverse events were mostly gastrointestinal and mild/moderate. Pasireotide LAR was generally well tolerated. Steady-state PK was achieved after three monthly doses; exposures were approximately dose proportional. Control of GH, IGF-1, and symptoms improved, suggesting that pasireotide LAR may be an effective treatment for acromegaly.

  View details for DOI 10.1002/jcph.326

  View details for PubMedID 24800725

• Treatments, complications, and healthcare utilization associated with acromegaly: a study in two large United States databases PITUITARY Broder, M. S., Neary, M. P., Chang, E., Cherepanov, D., Katznelson, L. 2014; 17 (4): 333-341

  Abstract

  The economic burden of acromegaly in the US has been largely unknown. We describe the prevalence of treatment patterns, complication rates, and associated healthcare utilization and costs of acromegaly in the US. Patients were identified between 1/1/2002 and 12/31/2009 in claims databases. During 1-year after each continuously-enrolled patient's first acromegaly claim, pharmacy and medical claims were used to estimate outcomes. Regression models were used to adjust outcomes. There were 2,171 acromegaly patients (mean age: 45.3 years; 49.7% female); 77.8% received the majority of their care from non-endocrinologists. Pharmacologic treatment was used by 30.8% of patients: octreotide-LAR in 18.6%, dopamine agonists in 9.8%, short-acting octreotide in 4.7%, pegvisomant in 4.1%, and lanreotide in 1.2%; 56% had biochemical monitoring. Comorbidities were common, ranging from 6.6% (colon neoplasms) to 25.6% (musculoskeletal abnormalities). Mean healthcare costs were $24,900. Adjusted analyses indicated comorbidities increased the odds of hospitalization: by 76% for musculoskeletal abnormalities; 193% for cardiovascular abnormalities; and 56% for sleep apnea (p < 0.05). Odds of emergency department visits increased by 87% (musculoskeletal) and 132% (cardiovascular abnormalities) (p < 0.01). After adjustments, colon neoplasms were associated with $8,401 mean increase in costs; musculoskeletal abnormalities with $7,502, cardiovascular abnormalities with $13,331, sleep apnea with $10,453, and hypopituitarism with $6,742 (p < 0.01). Complications are common and increase utilization and cost in acromegaly patients. Cardiovascular complications nearly tripled the odds of hospitalization (OR 2.93) and increased annual mean cost by $13,331. Adequate management of this disease may be able to reduce health care utilization and cost associated with these complications and with acromegaly in general.

  View details for DOI 10.1007/s11102-013-0506-0

  View details for Web of Science ID 000339347100005

  View details for PubMedID 24037646

• In reply. Neurosurgery McLaughlin, N., Laws, E. R., Oyesiku, N. M., Katznelson, L., Kelly, D. F. 2014; 74 (1): E143-4

  View details for DOI 10.1227/NEU.0000000000000160

  View details for PubMedID 24030177

• Clinical characteristics and pituitary dysfunction in patients with metastatic cancer to the sella. Endocrine practice Ariel, D., Sung, H., Coghlan, N., Dodd, R., Gibbs, I. C., Katznelson, L. 2013; 19 (6): 914-919

  Abstract

  Objective: Metastatic disease to the sella is uncommon and there are limited available data regarding the clinical aspects of this disease. We sought to characterize the clinical demographics of sellar metastases.Methods: Retrospective chart review of adults at Stanford University Medical Center from 1980 to 2011 with metastatic disease to the sella.Results: 13 subjects were identified (9 F). The mean age at diagnosis was 55 years (range: 25-73 y). 6 (46%) had breast carcinoma, 3 (23%) had renal cell carcinoma, 2 (15%) had squamous cell carcinoma of the head and neck, 1 had bronchoalveolar carcinoma of the lung, and 1 had nodular sclerosing Hodgkin's lymphoma. The most common presenting signs and symptoms were headache (58%), followed by fatigue (50%), polyuria (50%), visual field defects (42%), and ophthalmoplegia (42%). 75% presented with at least one pituitary hormone insufficiency, including 6 (50%) with diabetes insipidus (DI). 8 (67%) subjects had secondary hypothyroidism, and 5 (45%) had secondary adrenal insufficiency. Of the patients with stalk involvement, 86% had DI. All patients had a prior diagnosis of malignancy for a mean duration of 95 months.Conclusion: In this retrospective review, the most common neoplastic sources to the sella were breast and renal cell carcinoma. Secondary hypothyroidism was the most common endocrine abnormality, followed by DI, and adrenal insufficiency. New onset central hypothyroidism and diabetes insipidus along with known malignancy in a patient with a sellar lesion should raise the suspicion of a metastatic source.

  View details for DOI 10.4158/EP12407.OR

  View details for PubMedID 23757610

• In reply. Neurosurgery McLaughlin, N., Laws, E. R., Oyesiku, N. M., Katznelson, L., Kelly, D. F. 2013; 73 (3): E557-8

  View details for DOI 10.1227/NEU.0000000000000020

  View details for PubMedID 23756738

• Sustained Improvements in Plasma ACTH and Clinical Status in a Patient With Nelson's Syndrome Treated With Pasireotide LAR, a Multireceptor Somatostatin Analog. journal of clinical endocrinology & metabolism Katznelson, L. 2013; 98 (5): 1803-1807

  Abstract

  Context: Nelson's syndrome refers to aggressive pituitary corticotroph adenoma growth after bilateral adrenalectomy for treatment of Cushing's disease (CD). Pasireotide, a novel somatostatin analog, has been effective in treating CD. Here, the first case report of a patient with Nelson's syndrome treated with pasireotide is presented. Case Presentation: A 55-year-old female was diagnosed with CD in 1973 at age 15 years and underwent bilateral adrenalectomy 1 year later. She subsequently developed Nelson's syndrome and underwent multiple surgeries and radiotherapy for adenoma growth. After presentation with ocular pain, third cranial nerve palsy, and a finding of suprasellar tumor enlargement with hemorrhage, she began pasireotide long-acting release 60 mg/28 days im. At baseline, fasting plasma ACTH was 42 710 pg/mL (normal, 5-27 pg/mL), and fasting plasma glucose was 98 mg/dL. After 1 month, ACTH declined to 4272 pg/mL, and it has remained stable over 19 months of follow-up. Hyperpigmentation progressively improved. Magnetic resonance imaging scans show reduction in the suprasellar component. Fasting plasma glucose increased to 124 mg/dL, and the patient underwent diabetes management. Evidence Acquisition and Synthesis: In this clinical case seminar, the current understanding of the treatment of Nelson's syndrome and the use of pasireotide in CD are summarized. Conclusion: A case of Nelson's syndrome with clinically significant and dramatic biochemical and clinical responses to pasireotide administration is reported. Hyperglycemia was noted after pasireotide administration. Pasireotide may represent a useful tool in the medical management of Nelson's syndrome. Further study of the potential benefits and risks of pasireotide in this population is necessary.

  View details for DOI 10.1210/jc.2013-1497

  View details for PubMedID 23539733

• Pituitary Centers of Excellence NEUROSURGERY McLaughlin, N., Laws, E. R., Oyesiku, N. M., Katznelson, L., Kelly, D. F. 2012; 71 (5): 916-924

  Abstract

  Pituitary tumors and associated neuroendocrine disorders pose significant challenges in diagnostic and therapeutic management. Optimal care of the "pituitary patient" is best provided in a multidisciplinary collaborative environment that includes not only experienced pituitary practitioners in neurosurgery and endocrinology, but also in otorhinolaryngological surgery, radiation oncology, medical oncology, neuro-ophthalmology, diagnostic and interventional neuroradiology, and neuropathology. We provide the background and rationale for recognizing pituitary centers of excellence and suggest a voluntary verification process, similar to that used by the American College of Surgeons for Trauma Center verification. We propose that pituitary centers of excellence should fulfill 3 key missions: (1) provide comprehensive care and support to patients with pituitary disorders; (2) provide residency training, fellowship training, and/or continuing medical education in the management of pituitary and neuroendocrine disease; and (3) contribute to research in pituitary disorders. As this is a preliminary proposal, we recognize several issues that warrant further consideration including center and surgeon practice volume as well as oversight of the verification process.

  View details for DOI 10.1227/NEU.0b013e31826d5d06

  View details for Web of Science ID 000310360300016

  View details for PubMedID 22902334

• The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing's disease PITUITARY Srinivasan, L., Laws, E. R., Dodd, R. L., Monita, M. M., Tannenbaum, C. E., Kirkeby, K. M., Chu, O. S., Harsh, G. R., Katznelson, L. 2011; 14 (4): 312-317

  Abstract

  Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post-operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined.

  View details for DOI 10.1007/s11102-011-0295-2

  View details for Web of Science ID 000300349800003

  View details for PubMedID 21298507

• American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 update. Endocrine practice Katznelson, L., Atkinson, J. L., Cook, D. M., Ezzat, S. Z., Hamrahian, A. H., Miller, K. K. 2011; 17: 1-44

  View details for PubMedID 21846616

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND TREATMENT OF ACROMEGALY-2011 UPDATE ENDOCRINE PRACTICE Katznelson, L., Atkinson, J. L., Cook, D. M., Ezzat, S. Z., Hamrahian, A. H., Miller, K. K. 2011; 17: 1-?

  View details for Web of Science ID 000208716100001

• The Hormone Foundation's Patient guide to pituitary incidentaloma assessment and treatment. journal of clinical endocrinology and metabolism Freda, P., Katznelson, L., Molitch, M. 2011; 96 (4): 35A-6A

  View details for PubMedID 21474684

• ECTOPIC ACROMEGALY DUE TO A PANCREATIC NEUROENDOCRINE TUMOR PRODUCING GROWTH HORMONE-RELEASING HORMONE ENDOCRINE PRACTICE Weiss, D. E., Vogel, H., Lopes, M. B., Chang, S. D., Katznelson, L. 2011; 17 (1): 79-84

  Abstract

  To present a case of acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion from a pancreatic neuroendocrine tumor in the context of multiple endocrine neoplasia type 1 (MEN 1).We describe the clinical, imaging, and pathologic findings of the study patient.A 46-year-old woman presented with clinical and biochemical findings diagnostic of acromegaly. Magnetic resonance imaging showed a 1.2-cm sellar mass. Following resection of the macroadenoma, serum insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels remained unchanged. Pathologic examination revealed adenomatous changes, including a nonsecretory focus and a prolactin immunopositive area (GH stain negative in both). Octreotide long-acting release was ineffective. Search for an ectopic tumor included normal octreoscan and abdominal computed tomography. GHRH was greater than 1000 pg/mL. Repeated abdominal computed tomography documented a 6.2-cm mass in the tail and body of the pancreas. Distal pancreatectomy revealed a pancreatic neuroendocrine tumor that stained positive for GHRH. Postoperatively, serum GHRH and IGF-1 normalized. Re-evaluation of the initial pituitary pathologic specimen revealed additional somatotroph hyperplasia of the adjacent, normal pituitary gland. Primary hyperparathyroidism was diagnosed, and multigland parathyroid hyperplasia was noted at surgery. Genetic testing was positive for a mutation in the MEN1 gene.This patient's acromegaly was resistant to somatostatin analogue therapy, reflecting the negative octreoscan imaging. In addition, this case is novel because the patient presented with pituitary adenomatous changes, which were presumably associated with MEN 1 and/or possibly the elevated GHRH levels.

  View details for DOI 10.4158/EP10165.CR

  View details for PubMedID 20713338

• Retrosellar intracranial extracerebral glioneuronal heterotopion: case report CLINICAL NEUROPATHOLOGY Karamchandani, J., Fischbein, N., Harsh, G., Katznelson, L., Vogel, H. 2010; 29 (5): 297-300

  Abstract

  We report the case of an 18-year-old woman with an intradural retroclival retrosellar glioneuronal heterotopion. At the time of surgery, a well circumscribed pale-tan mass was identified posterior to and distinct from the posterior pituitary. Pathologic examination showed disorganized, non-neoplastic glial tissue characteristic of glioneuronal heterotopia. To our knowledge, this is the first report of such a lesion in this location.

  View details for Web of Science ID 000281967000004

  View details for PubMedID 20860892

• Approach to the Patient with Persistent Acromegaly after Pituitary Surgery JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Katznelson, L. 2010; 95 (9): 4114-4123

  Abstract

  The approach to a patient with acromegaly and persistent disease after surgery requires a complex diagnostic assessment. Acromegaly is a chronic and insidious disease that is associated with multisystem comorbidities, including cardiovascular disease, hypertension, sleep apnea syndrome, colon polyposis, arthropathy, and metabolic complications including glucose intolerance and type 2 diabetes mellitus. Patients also have a variety of signs and symptoms, including headache, arthralgias, carpal tunnel syndrome, sweating, fatigue, and psychological issues that impact significantly on quality of life. The recommended approach to the evaluation of the postoperative patient includes a biochemical assessment, with measurement of serum IGF-I along with a glucose-suppressed GH value, radiological assessment to determine location of residual tumor and presence of mass effects, a physical examination for evidence of skeletal and soft tissue overgrowth and related signs of acromegaly, and a thorough clinical assessment for the presence of comorbidities. Repeat surgery is indicated if there is residual tumor that is surgically accessible and there may be a chance for surgical cure, or if there are persistent mass effects upon the optic chiasm. Otherwise, medical therapy is indicated, utilizing somatostatin analogs, dopamine agonists, and pegvisomant, a GH receptor antagonist. Radiation therapy is usually relegated to situations where medical therapy is ineffective or poorly tolerated or where patients would prefer not to sustain the cost of long-term medical therapy. The choice of therapy requires close dialog among endocrinologists, neurosurgeons, radiation therapists, and neuroophthalmologists for optimal care of patients.

  View details for DOI 10.1210/jc.2010-0670

  View details for PubMedID 20823464

• Clinical Characteristics of the Glucagon Stimulation Test (GST) in the Evaluation of Growth Hormone (GH) Reserve and Hypothalamic-Pituitary-Adrenal (HPA) Axis in Adults: A Multi-Centered US Experience 92nd Meeting and Expo of the Endocrine Society (ENDO 2010) Yuen, K. C., Biller, B. M., Legg, S. E., Rhoads, S. A., Dillard, T. H., Gurel, M. H., Chu, O., Uwaifo, G. I., Koch, C., Katznelson, L., Cook, D. M. ENDOCRINE SOC. 2010: S1694–S1694

  View details for Web of Science ID 000281989400147

• Ectopic Acromegaly due to a Growth Hormone Releasing Hormone Producing Pancreatic NET. 92nd Meeting and Expo of the Endocrine Society (ENDO 2010) Weiss, D. E., Lopes, B. S., Katznelson, L. ENDOCRINE SOC. 2010

  View details for Web of Science ID 000281989401084

• A NOVEL PRKAR1A MUTATION ASSOCIATED WITH PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE AND THE CARNEY COMPLEX ENDOCRINE PRACTICE Peck, M. C., Visser, B. C., Norton, J. A., Pasche, L., Katznelson, L. 2010; 16 (2): 198-204

  Abstract

  To delineate the genetic and phenotypic features of Carney complex in a family with multiple cases of primary pigmented nodular adrenocortical disease (PPNAD).Detailed clinical, laboratory, genetic, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed.A 17-year-old girl presented with symptoms and physical findings suggestive of hypercortisolemia, in addition to facial lentigines. She was found to have adrenocorticotropic hormone (ACTH)-independent Cushing syndrome. The adrenal glands appeared normal on computed tomographic scanning. Bilateral surgical adrenalectomy revealed PPNAD. Evaluation of her 14-year-old sister revealed ACTH-independent Cushing syndrome as well as facial lentigines, and adrenalectomy revealed PPNAD as well. Genetic testing of the 2 sisters and their mother (who also had multiple facial lentigines but did not have Cushing syndrome) revealed a novel mutation in the PRKAR1A gene.We describe a novel mutation in the PRKAR1A gene in a family with Carney complex and multiple members with PPNAD. PPNAD should be suspected in cases of ACTH-independent Cushing syndrome, and screening for Carney complex and its complications is recommended in all cases of PPNAD, including first-degree relatives.

  View details for DOI 10.4158/EP09245.OR

  View details for PubMedID 19833579

• Prevalence and clinical demographics of cerebral salt wasting in patients with aneurysmal subarachnoid hemorrhage PITUITARY Kao, L., Al-Lawati, Z., Vavao, J., Steinberg, G. K., Katznelson, L. 2009; 12 (4): 347-351

  Abstract

  Hyponatremia is a frequent complication following subarachnoid hemorrhage (SAH), and is commonly attributed either to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting syndrome (CSW). The object of this study is to elucidate the clinical demographics and sequelae of hyponatremia due to CSW in subjects with aneurysmal SAH. Retrospective chart review of patients >18 years with aneurysmal SAH admitted between January 2004 and July 2007 was performed. Subjects with moderate to severe hyponatremia (serum sodium <130 mmol l(-1)) were divided into groups consistent with CSW and SIADH based on urine output, fluid balance, natriuresis, and response to saline infusion. Clinical demographics were compared. Of 316 subjects identified, hyponatremia (serum sodium <135 mmol l(-1)) was detected in 187 (59.2%) subjects and moderate to severe hyponatremia in 48 (15.2%). Of the latter group, 35.4% were categorized with SIADH and 22.9% with CSW. Compared to eunatremic subjects, hyponatremia was associated with significantly longer hospital stay (15.7 +/- 1.9 vs. 9.6 +/- 1.1 days, p < 0.001). Subjects with CSW had similar mortality and duration of hospital stay vs. those with SIADH. Though less common than SIADH, CSW was detected in approximately 23% of patients with history of aneurysmal SAH and was not clearly associated with enhanced morbidity and mortality compared to subjects with SIADH. Further studies regarding the pathogenesis and management, along with the medical consequences, of CSW are important.

  View details for DOI 10.1007/s11102-009-0188-9

  View details for Web of Science ID 000270977600011

  View details for PubMedID 19462244

• Lanreotide promotes apoptosis and is not radioprotective in GH3 cells ENDOCRINE-RELATED CANCER Ning, S., Knox, S. J., Harsh, G. R., Culler, M. D., Katznelson, L. 2009; 16 (3): 1045-1055

  Abstract

  Somatostatin analogs are a mainstay of medical therapy in patients with GH producing human pituitary tumors, and it has been suggested that somatostatin analogs may be radioprotective. We utilized GH secreting rat GH3 cells to investigate whether a somatostatin analog may limit the effects of radiation on proliferation and apoptosis in vitro and on tumor growth in vivo. Treatment with lanreotide alone at doses of either 100 or 1000 nM for 48 h reduced clonogenic survival by 5-10%. Radiation alone produced a dose-dependent survival curve with a SF2 of 48-55%, and lanreotide had no effect on this curve. The addition of lanreotide resulted in a 23% increase in the proportion of apoptotic sub-G1 cells following irradiation (P<0.01). In a mouse GH3 tumor xenograft model, lanreotide 10 mg/kg moderately inhibited the growth of GH3 tumors, with a 4x tumor growth delay (TGD) time that ranged from 4.5 to 8.3 days. Fractionated local tumor radiation alone significantly inhibited tumor growth and produced a TGD of 35.1+/-5.7 days for 250 cGy fractions. The combination of lanreotide, either antecedent to or concurrent, with radiation of 250, 200 or 150 cGy/fraction for 5 days inhibited tumor growth and produced the TGD times that were similar to radiation alone (P>0.05). Pretreatment with lanreotide had the most significant radiosensitizing effect. These studies demonstrate that the somatostatin analog lanreotide is not radioprotective in GH3 cells, and further studies are necessary to determine the impact of lanreotide on apoptosis.

  View details for DOI 10.1677/ERC-09-0003

  View details for Web of Science ID 000272670300027

  View details for PubMedID 19528243

• Non-surgical management of hormone-secreting pituitary tumors JOURNAL OF CLINICAL NEUROSCIENCE Patil, C. G., Hayden, M., Katznelson, L., Chang, S. D. 2009; 16 (8): 985-993

  Abstract

  Hormone-secreting pituitary tumors account for about 30% of all pituitary tumors. Successful long-term management of patients with these tumors frequently requires a multimodality team approach. Given that the role and efficacy of neurosurgical resection of hormone-secreting pituitary tumors is well described, we focus this review on the other important treatment modalities that are becoming increasingly crucial in the management of acromegaly, Cushing's disease and prolactinomas. Medical management with standard and novel drugs as well as the role and effectiveness of radiation therapy and radiosurgery are discussed in detail.

  View details for DOI 10.1016/j.jocn.2008.11.001

  View details for Web of Science ID 000268608000001

  View details for PubMedID 19443220

• The impact of hypopituitarism on function and performance in subjects with recent history of traumatic brain injury and aneurysmal subarachnoid haemorrhage. Brain injury Srinivasan, L., Roberts, B., Bushnik, T., Englander, J., Spain, D. A., Steinberg, G. K., Ren, L., Sandel, M. E., Al-Lawati, Z., Teraoka, J., Hoffman, A. R., Katznelson, L. 2009; 23 (7): 639-648

  Abstract

  To correlate deficient pituitary function with life satisfaction and functional performance in subjects with a recent history of traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH).Cross-sectional study.Eighteen subjects with TBI and 16 subjects with SAH underwent pituitary hormonal and functional assessments 5-12 months following the event. Adrenal reserve was assessed with a 1 mcg cosyntropin stimulation test and growth hormone deficiency (GHD) was diagnosed by insufficient GH response to GHRH-Arginine stimulation. Assessments of life satisfaction and performance-function included the Satisfaction with Life Scale (SWLS), Craig Handicap Assessment and Reporting Technique (CHART) and the Mayo Portland Adaptability Inventory-4 (MPAI-4).Hypopituitarism was present in 20 (58.8%) subjects, including 50% with adrenal insufficiency. Hypothyroidism correlated with worse performance on SWLS and CHART measures. GHD was associated with poorer performance on CHART and MPAI-4 scale.In this series of subjects with history of TBI and SAH, hypothyroidism and GHD were associated with diminished life satisfaction and performance-function on multiple assessments. Further studies are necessary to determine the appropriate testing of adrenal reserve in this population and to determine the benefit of pituitary hormone replacement therapy on function following brain injury.

  View details for DOI 10.1080/02699050902970778

  View details for PubMedID 19557567

• Alterations in body composition in acromegaly PITUITARY Katznelson, L. 2009; 12 (2): 136-142

  Abstract

  Acromegaly is a condition characterized by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) hypersecretion, and is associated with boney overgrowth, and soft tissue abnormalities due to anabolic, lipolytic, and sodium retaining actions of GH. GH and IGF-1 excess is associated with alterations in body composition, including an increase in body water and lean body mass, and a reduction in body fat. Achievement of biochemical control of the disease results in a reduction in body water and fat-free mass, and an increase in body fat. BMD is generally increased in acromegaly, though the anabolic effect of GH excess on bone is reduced, if not negated, by the presence of hypogonadism, particularly with regard to the trabecular compartment. Further studies are necessary to determine the effect of long-term biochemical control on bone density in subjects with acromegaly.

  View details for DOI 10.1007/s11102-008-0104-8

  View details for Web of Science ID 000264629800006

  View details for PubMedID 18369725

• Endogenous NIS Expression in Triple-Negative Breast Cancers ANNALS OF SURGICAL ONCOLOGY Renier, C., Yao, C., Goris, M., Ghosh, M., Katznelson, L., Nowles, K., Gambhir, S. S., Wapnir, I. 2009; 16 (4): 962-968

  Abstract

  The sodium iodide symporter (NIS) mediates iodide transport into cells and has been identified in approximately 70% of breast cancers. Functional NIS expression raises the possibility of using (131)I for therapeutic targeting of tumor cells. Treatment of triple-negative breast cancers [estrogen/progesterone receptor-negative and HER2-negative (ER-/PR-/HER2-)] is primarily limited to chemotherapy. Our aim was to characterize NIS expression in this subset of tumors.Archival tissue sections from 23 women with triple-negative breast cancer were analyzed for NIS expression using immunohistochemical methods and an anti-human NIS antibody. Tumors were evaluated for the presence of plasma membrane immunoreactivity. One patient with a NIS-expressing positive tumor underwent (123)I scintigraphic imaging with dosimetric analysis.Fifteen cases (65.2%) demonstrated NIS-positivity with 11 tumors (47.8%) exhibiting strong expression. Plasma membrane immunoreactivity was observed in four breast cancers and was equivocal in another four tumors. Tumor-specific radioiodide uptake was demonstrated by (123)I scintigraphy in a patient with a large primary breast cancer unresponsive to neoadjuvant therapy. The tumor concentrated 2.05, 1.53, and 1.96 times more isotope than normal breast tissue at 1, 5, and 21 h. The relative increased uptake is consistent with positive NIS expression in the tumor on definitive surgery; however, the cumulative concentration in the tumor was not sufficient to achieve a therapeutic effect, had the isotope been (131)I.NIS is strongly expressed in a significant proportion of triple-negative breast cancer cells, suggesting a potential role for NIS-directed (131)I-radioablative strategies in this patient population.

  View details for DOI 10.1245/s10434-008-0280-9

  View details for PubMedID 19184238

• The impact of hypopituitarism on function and performance in subjects with recent history of traumatic brain injury and aneurysmal subarachnoid haemorrhage BRAIN INJURY Srinivasan, L., Roberts, B., Bushnik, T., Englander, J., Spain, D. A., Steinberg, G. K., Ren, L., Sandel, M. E., Al-Lawati, Z., Teraoka, J., Hoffman, A. R., Katznelson, L. 2009; 23 (7-8): 639-648

  Abstract

  To correlate deficient pituitary function with life satisfaction and functional performance in subjects with a recent history of traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH).Cross-sectional study.Eighteen subjects with TBI and 16 subjects with SAH underwent pituitary hormonal and functional assessments 5-12 months following the event. Adrenal reserve was assessed with a 1 mcg cosyntropin stimulation test and growth hormone deficiency (GHD) was diagnosed by insufficient GH response to GHRH-Arginine stimulation. Assessments of life satisfaction and performance-function included the Satisfaction with Life Scale (SWLS), Craig Handicap Assessment and Reporting Technique (CHART) and the Mayo Portland Adaptability Inventory-4 (MPAI-4).Hypopituitarism was present in 20 (58.8%) subjects, including 50% with adrenal insufficiency. Hypothyroidism correlated with worse performance on SWLS and CHART measures. GHD was associated with poorer performance on CHART and MPAI-4 scale.In this series of subjects with history of TBI and SAH, hypothyroidism and GHD were associated with diminished life satisfaction and performance-function on multiple assessments. Further studies are necessary to determine the appropriate testing of adrenal reserve in this population and to determine the benefit of pituitary hormone replacement therapy on function following brain injury.

  View details for DOI 10.1080/02699050902970778

  View details for Web of Science ID 000267370600008

• Use of high-dose oral bisphosphonate therapy for symptomatic fibrous dysplasia of the skull JOURNAL OF NEUROSURGERY Chao, K., Katznelson, L. 2008; 109 (5): 889-892

  Abstract

  Fibrous dysplasia of the bone in adults is a rare anomaly of skeletal development caused by a defect in differentiation of osteoblasts. This condition is associated with bone pain, bone deformity, and an increased incidence of fracture. Involvement of the skull is associated with headache along with dysmorphic features. Until recently, the principal treatment has been resection or fracture repair, although the latter is often palliative at best. However, new insight into the molecular mechanism of fibrous dysplasia has led to the use of bisphosphonates to treat this disease. The authors examined the effects of high-dose oral alendronate (40 mg daily) for 6 months on 3 adult patients with intractable headache due to fibrous dysplasia of the skull. Each patient had disease processes not amenable to surgery. The patients underwent clinical follow-up at 1, 3, and 6 months. Their pain levels were documented at each visit by using a visual analog scale. All 3 patients demonstrated a significant decrease in pain levels and became independent of scheduled analgesics. Tumor bulk did not progress during this interval in any patient. Overall, alendronate was tolerated well, although in 1 patient it was discontinued early due to esophagitis. High-dose oral bisphosphonate therapy is an alternative therapeutic option for the palliative treatment of patients with fibrous dysplasia of the skull.

  View details for DOI 10.3171/JNS/2008/109/11/0889

  View details for Web of Science ID 000260362100014

  View details for PubMedID 18976079

• An update on treatment strategies for acromegaly EXPERT OPINION ON PHARMACOTHERAPY Katznelson, L. 2008; 9 (13): 2273-2280

  Abstract

  Acromegaly is an insidious disease due to growth hormone (GH) hypersecretion from a pituitary adenoma, and is associated with multiple comorbidities and risk of premature mortality.To review the therapeutic goals and options for acromegaly.Literature review.Surgery is the mainstay of therapy, but a role for primary medical therapy using somatostatin analogs is described as well. Somatostatin analogs are the mainstay for medical therapy, largely in an adjuvant setting. The GH receptor antagonist is also used and may be considered in addition to the somatostatin analogs, or as second line therapy. Based on these multiple modalities of therapy, it should be possible to achieve biochemical control in almost all patients.

  View details for DOI 10.1517/14656560802358277

  View details for Web of Science ID 000259105400006

  View details for PubMedID 18710352

• Outcomes after repeat transsphenoidal surgery for recurrent Cushing's disease NEUROSURGERY Patil, C. G., Veeravagu, A., Prevedello, D. A., Katznelson, L., Vance, M. L., Laws, E. R., Kelly, D. F., Oyesiku, N. M., Post, K. D., Esposito, F., Cappabianca, P. 2008; 63 (2): 266-271

  Abstract

  To systematically analyze patient outcomes after repeat transsphenoidal (TS) surgery for recurrent Cushing's disease.We retrospectively reviewed records of all patients with recurrent Cushing's disease who underwent repeat TS surgery for resection of a pituitary corticotroph adenoma at the University of Virginia Medical Center from 1992 to 2006. Remission at follow-up was defined as a normal postoperative 24-hour urine free cortisol, or continued need for glucocorticoid replacement after repeat TS surgery. Recurrence of the disease was defined as an elevated 24-hour urine free cortisol with clinical symptoms consistent with Cushing's disease while not receiving glucocorticoid replacement. Multivariate logistic regression was performed to evaluate the effect of potential predictors on remission. Recurrence rates, subsequent treatments, and the final endocrine status of the patients are presented.We identified 36 patients who underwent repeat TS surgery for recurrent Cushing's disease. The mean age of the patients was 40.3 years (range, 17.1-63.0 yr), and 26 were women. The median time to recurrence after initial successful TS surgery was 36 months (range, 4 mo-16 yr). Remission after repeat TS surgery was observed in 22 (61%) of the 36 patients. During the same time period, of the 338 patients who underwent first-time TS surgery for Cushing's disease, remission was achieved in 289 (85.5%). The odds of failure (to achieve remission) for patients with repeat TS surgery for recurrent Cushing's disease were 3.7 times that of patients undergoing first-time TS surgery (odds ratio, 3.7; 95% confidence interval, 1.8-7.8). Two of the 22 patients with successful repeat TS surgery had a second recurrence at 6 and 11 months, respectively. Complete biochemical and clinical remission after stereotactic radiosurgery, adrenalectomy, and ongoing ketoconazole therapy was achieved in 30 (83.3%) of the 36 patients, and active disease continued in 6 patients (16.7%).Although the success of repeat TS surgery for recurrence of Cushing's disease is less than that of initial surgery, a second procedure offers a reasonable possibility of immediate remission. If the operation is not successful, other treatments, including pituitary radiation, medical therapy, and even bilateral adrenalectomy, are required.

  View details for DOI 10.1227/01.NEU.0000313117.35824.9F

  View details for Web of Science ID 000258944100017

  View details for PubMedID 18797356

• Late recurrences of Cushing's disease after initial successful transsphenoidal surgery JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Patil, C. G., Prevedello, D. M., Lad, S. P., Vance, M. L., Thorner, M. O., Katznelson, L., Laws, E. R. 2008; 93 (2): 358-362

  Abstract

  Few studies have systematically analyzed the long-term recurrence rates of Cushing's disease after initial successful transsphenoidal surgery.This was a retrospective review of patients treated at the University of Virginia Medical Center.A total of 215 subjects with Cushing's disease who underwent initial transsphenoidal surgery for resection of a presumed pituitary microadenoma from 1992-2006 were included.Remission and recurrence rates of Cushing's disease were examined. Recurrence was defined as an elevated 24-h urine free cortisol with clinical symptoms consistent with Cushing's disease.Of the 215 patients who underwent transsphenoidal surgery for Cushing's disease, surgical remission was achieved in 184 (85.6%). The mean length of follow-up was 45 months. Actuarial recurrence rates of Cushing's disease after initially successful transsphenoidal surgery at 1, 2, 3, and 5 yr were 0.5, 6.7, 10.8, and 25.5%, respectively. Among the 184 patients who achieved remission, 32 (17.4%) patients followed for more than 6 months ultimately had a recurrence of Cushing's disease. The median time to recurrence was 39 months. Immediate postoperative hypocortisolemia (serum cortisol < or = 2 microg/dl within 72-h surgery) was achieved in 97 (45.1%) patients. Patients who had postoperative serum cortisol of more than 2 microg/dl were 2.5 times more likely to have a recurrence than patients who had serum cortisol less than or equal to 2 microg/dl (odds ratio = 2.5; 95% confidence interval 1.12-5.52; P = 0.022).A quarter of the patients with Cushing's disease who achieve surgical remission after transsphenoidal surgery, recur with long-term follow-up. This finding emphasizes the need for continued biochemical and clinical follow-up to ensure remission after surgery.

  View details for DOI 10.1210/jc.2007-2013

  View details for Web of Science ID 000253165800005

  View details for PubMedID 18056770

• Reninoma: case report and literature review JOURNAL OF HYPERTENSION Wonga, L., Hsu, T. H., Perlroth, M. G., Hofmann, L. V., Haynes, C. M., Katznelson, L. 2008; 26 (2): 368-373

  Abstract

  Reninoma is a tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia via hypersecretion of renin. We describe a case of reninoma and provide a review of the literature, with a discussion emphasizing the diagnostic evaluation for such patients. The subject had persistent elevation of both plasma renin activity (PRA) and aldosterone. Imaging studies revealed the presence of a lesion in the renal cortex, which was further identified as a renin-producing lesion via selective venous catheterization following administration of an angiotensin-converting enzyme inhibitor (ACE-I). Following partial nephrectomy, the PRA and plasma aldosterone levels declined rapidly and the blood pressure and potassium supplementation requirements normalized. This case demonstrates the utility of both appropriate imaging studies and selective venous catheterization following provocative administration of an ACE-I for diagnosis.

  View details for Web of Science ID 000252778100030

  View details for PubMedID 18192852

• Current thinking on the management of the acromegalic patient. Current opinion in endocrinology, diabetes, and obesity Katznelson, L. 2007; 14 (4): 311-316

  Abstract

  Although the concept that acromegaly is associated with heightened cardiovascular risk is not new, it has become apparent that there are a number of risk factors associated with this disease and that specific therapeutic modalities may have variable effects on these risk factors. In addition, it is important to understand the medical therapies available for acromegaly and their role in acromegaly management.Acromegaly is associated with heightened cardiovascular risk, including derangements in glucose homeostasis and lipids, but also in markers of vascular function. Recent studies have demonstrated treatment-specific effects on these markers. In addition, recent studies have detailed further the efficacy and safety of various therapeutic options, in particular that of pegvisomant, the growth hormone receptor antagonist. A role for medical therapy as primary, de-novo therapy has been considered and recent studies support such use.The goals of acromegaly therapy are to control excess growth hormone secretion and limit, if not reverse, the long-term medical consequences and risk of premature mortality associated with acromegaly. It is critical to control both the growth hormone hypersecretion and associated cardiovascular risk factors to prevent the associated risks of cardiovascular disease and enhanced mortality. Medical therapy has an important adjuvant role in the management of acromegaly and use of somatostatin analogs as first-line therapy for specific groups of patients should be considered.

  View details for PubMedID 17940458

• Pegvisomant for the treatment of acromegaly-translation of clinical trials into clinical practice NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM Katznelson, L. 2007; 3 (7): 514-515

  View details for DOI 10.1038/ncpendmet0533

  View details for Web of Science ID 000247376700008

  View details for PubMedID 17519915

• Approach to the evaluation of the GH/IGF-axis in patients with pituitary disease: Which test to order PITUITARY Roberts, B., Katznelson, L. 2007; 10 (2): 205-211

  Abstract

  The diagnosis of adult growth hormone deficiency (AGHD) and acromegaly involves assessment of serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations. The diagnosis of AGHD typically requires a provocative test of GH reserve, but is supported by demonstration of low-serum IGF-1 levels. Therapeutic monitoring of rhGH replacement is performed utilizing measurement of serum IGF-1 concentrations. In patients with suspected acromegaly, the diagnosis is confirmed by elevated serum IGF-1 levels and further validated by the presence of elevated GH levels both before and following an oral glucose load. A goal of acromegaly therapy is to normalize IGF-1 concentrations, and, depending on the therapeutic modality, GH levels as well. Using case based clinical scenarios, we have presented a standard approach to the biochemical diagnosis and therapeutic monitoring of these disorders.

  View details for DOI 10.1007/s11102-007-0026-x

  View details for Web of Science ID 000252303800013

  View details for PubMedID 17429594

• Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary Roberts, B. K., Ouyang, D. L., Lad, S. P., Chang, S. D., Harsh, G. R., Adler, J. R., Soltys, S. G., Gibbs, I. C., Remedios, L., Katznelson, L. 2007; 10 (1): 17

  View details for DOI 10.1007/s11102-007-0024-z

  View details for PubMedID 27519534

• The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing's disease. Neurosurgical focus Lad, S. P., Patil, C. G., Laws, E. R., Katznelson, L. 2007; 23 (3): E2-?

  Abstract

  Cushing's syndrome can present a complex problem of differential diagnosis. Of cases in which hypercortisolemia results from an adrenocorticotropic hormone (ACTH)-dependent process, approximately 80% are due to a pituitary adenoma (Cushing's disease [CD]), 10% are due to adrenal lesions, and the remaining 10% are secondary to ectopic ACTH secretion. For patients with CD, surgical removal of the pituitary adenoma is the treatment of choice. Thus, localization of the source of ACTH secretion is critical in guiding timely treatment decisions. Inferior petrosal sinus sampling (IPSS) is considered to be the gold standard for confirming the origin of ACTH secretion in patients with Cushing's syndrome. The authors present an overview of IPSS--both the technique and its interpretation--as well as a summary of recent studies. A number of other techniques are discussed including sampling from the cavernous sinus, the jugular vein, and multiple sites to aid the diagnosis and lateralization of ACTH-producing pituitary adenomas. Management is best undertaken by a comprehensive multidisciplinary team taking into account the results of all the biochemical and imaging studies available, to provide the best advice in patient treatment decisions.

  View details for PubMedID 17961020

• Brain atrophy and cognitive deficits in Cushing's disease. Neurosurgical focus Patil, C. G., Lad, S. P., Katznelson, L., Laws, E. R. 2007; 23 (3): E11-?

  Abstract

  Cushing's disease is associated with brain atrophy and cognitive deficits. Excess glucocorticoids cause retraction and simplification of dendrites in the hippocampus, and this morphological change probably accounts for the hippocampal volume loss. Mechanisms by which glucocorticoids affect the brain include decreased neurogenesis and synthesis of neurotrophic factors, impaired glucose utilization, and increased actions of excitatory amino acids. In this review, the timing, pathology, and pathophysiology of the brain atrophy in Cushing's disease are discussed. The correlation of atrophy with cognitive deficits and its reversibility is also reviewed.

  View details for PubMedID 17961025

• Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary Roberts, B. K., Ouyang, D. L., Lad, S. P., Chang, S. D., Harsh, G. R., Adler, J. R., Soltys, S. G., Gibbs, I. C., Remedios, L., Katznelson, L. 2007; 10 (1): 19-25

  Abstract

  Acromegaly is a disease characterized by GH hypersecretion, and is typically caused by a pituitary somatotroph adenoma. The primary mode of therapy is surgery, and radiotherapy is utilized as an adjuvant strategy to treat persistent disease. The aim of this study was to determine the efficacy and tolerability of CyberKnife stereotactic radiosurgery in acromegaly.A retrospective review of biochemical and imaging data for subjects with acromegaly treated with CyberKnife stereotactic radiosurgery between 1998 and 2005 at Stanford University Hospital.Nine patients with active acromegaly were treated with radiosurgery using the CyberKnife (CK).Biochemical response based on serum insulin-like growth factor-1 (IGF-1), anterior pituitary hormone function, and tumor size with MRI scans were analyzed.After a mean follow up of 25.4 months (range, 6-53 months), CK radiosurgery resulted in complete biochemical remission in 4 (44.4%) subjects, and in biochemical control with the concomitant use of a somatostatin analog in an additional subject. Smaller tumor size was predictive of treatment success: baseline tumor volume was 1.28 cc (+/- 0.81, SD) vs. 3.93 cc (+/- 1.54) in subjects with a normal IGF-1 vs. those with persistent, active disease, respectively (P = 0.02). The mean biologically effective dose (BED) was higher in subjects who achieved a normal IGF-1 vs. those with persistent, active disease, 172 Gy(3) (+/-28) vs. 94 Gy(3) (+/-17), respectively (P < 0.01). At least one new anterior pituitary hormone deficiency was observed after CK in 3 (33%) patients: two developed hypogonadism, and one developed panhypopituitarism.CK radiosurgery may be a valuable adjuvant therapy for the management of acromegaly.

  View details for PubMedID 17273921

• Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men EUROPEAN JOURNAL OF ENDOCRINOLOGY Katznelson, L., Robinson, M. W., Coyle, C. L., Lee, H., Farrell, C. E. 2006; 155 (6): 867-875

  Abstract

  One of the factors that may promote deterioration in quality of life and body composition in elderly men is the relative decline in serum testosterone levels with aging. In this study, we assessed the effects of modest doses of testosterone and a home-based strengthening program on quality of life and body composition in elderly men with relative testosterone insufficiency.Double-blind, placebo-controlled randomized study (testosterone), and additional randomization to a resistance exercise program or no additional exercise for 12 weeks in men between ages of 65 and 85 years with relative testosterone insufficiency.Seventy sedentary, community dwelling men were randomized to a 5 mg testoderm transdermal system applied daily vs placebo system, and additionally randomized to a home-based resistance exercise program. Subjects were randomized to Group 1 (testosterone plus exercise), Group 2 (testosterone plus no exercise), Group 3 (placebo plus exercise), and Group 4 (placebo plus no exercise). Endpoints included quality of life (assessed by the short form-36 questionnaire) and body composition (measured by dual x-ray absorptiometry scan).Serum testosterone increased by a mean of 10.0 +/- 1.9, 6.6 +/- 1.6, 0.52 +/- 0.6, and 0.5 +/- 0.6 nmol/l in Groups 1, 2, 3, and 4 respectively. There was a significant interaction of testosterone and exercise on quality of life in the domains of physical functioning (P = 0.03), role physical (P = 0.01), general health (P = 0.049), and social functioning (P = 0.04). There were no effects of testosterone or exercise on quality of life alone, nor in body composition parameters.Modest testosterone supplementation to elderly men with relative testosterone insufficiency improved quality of life when accompanied by an exercise program. The combination of testosterone and exercise may be an important strategy in the elderly, though further studies are necessary to determine the long-term impact on body composition and function and for analysis of risk/benefit ratios as well.

  View details for DOI 10.1530/eje.1.02291

  View details for Web of Science ID 000243357300014

  View details for PubMedID 17132757

• Isolated Langerhans cell histiocytosis in an adult with central diabetes insipidus: case report and review of literature. Endocrine practice Ouyang, D. L., Roberts, B. K., Gibbs, I. C., Katznelson, L. 2006; 12 (6): 660-663

  Abstract

  To report a case of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) in a patient with two distinct neuroendocrine tumors and to highlight the difficulties of establishing the differential diagnosis of EAS.We describe the clinical presentation of the current case, discuss its management, and report the results of molecular studies undertaken to determine whether the two tumors had a common origin.A 52-year-old woman presented with obvious features of Cushing's syndrome. Findings on hormonal evaluation were consistent with EAS. Pituitary magnetic resonance imaging revealed normal findings. Computed tomographic imaging disclosed two masses, one in the lung and one in the pancreas. Somatostatin receptor scintigraphy showed uptake only in the pancreatic mass, which was surgically removed. It was a well-differentiated neuroendocrine tumor, with negative immunostaining for ACTH. Hypercortisolemia did not resolve after removal of the pancreatic tumor. The lung mass was subsequently excised, and pathology examination showed a carcinoid tumor with immunostaining for ACTH. Thereafter, plasma ACTH became immeasurable. The two tumors had similar patterns of X-chromosome inactivation; thus, whether they arose independently could be neither confirmed nor excluded.This case demonstrates that, in the presence of more than one neuroendocrine tumor, somatostatin receptor scintigraphy may misguide the decision regarding the appropriate surgical course in patients with EAS, and it highlights the need for accurate studies to determine the source of ACTH in patients with EAS.

  View details for PubMedID 17229663

• Drug Insight: primary medical therapy of acromegaly NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM Katznelson, L. 2006; 2 (2): 109-117

  Abstract

  Acromegaly is an insidious disease that, in most cases, is a result of a pituitary adenoma that hypersecretes growth hormone (GH). The goals of therapy are to control excess GH secretion and limit, if not reverse, the long-term medical consequences and risk of premature mortality associated with acromegaly. Surgery is currently the preferred primary therapeutic option because it can lead to rapid reductions in GH levels and prevent mass effects from local tumor growth. Medical therapy is used most often in an adjuvant, secondary role for patients in whom surgery has been unsuccessful. Radiation therapy is most commonly recommended in the setting of failed surgery and lack of adequate control with medical therapy. A role of primary medical therapy for patients de novo has been proposed, particularly with regard to somatostatin analogues. These analogues may control GH levels and reduce tumor volume in up to 50% of subjects, suggesting that they may be efficacious in this context. The use of somatostatin analogues to improve surgical outcome has also been proposed, but there is a lack of randomized trials available to address this issue. Primary medical therapy is well tolerated and further studies are necessary to identify patients who should be targeted for such therapy.

  View details for DOI 10.1038/ncpendmet0096

  View details for Web of Science ID 000235552100006

  View details for PubMedID 16932265

• Long-acting somatostatin analog therapy of acromegaly: A meta- analysis JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Freda, P. U., Katznelson, L., van der Lely, A. J., Reyes, C. M., Zhao, S. H., Rabinowitz, D. 2005; 90 (8): 4465-4473

  Abstract

  Although considerable data exist on the use of long-acting somatostatin analogs to treat acromegaly, their reported efficacy differs substantially among trials.We conducted a meta-analysis to derive definitive estimates of their efficacy for biochemical control and tumor shrinkage.A search of literature was conducted through 2003, primarily via PubMed.Inclusion criteria, met in 44 trials, included at least 3 months of secondary octreotide long-acting release (LAR) or lanreotide slow release (SR) therapy or of primary octreotide LAR, lanreotide SR, or sc octreotide therapy and clearly reported data on biochemical efficacy and/or tumor shrinkage. Fifty other trials screened did not meet analysis inclusion criteria.Data were extracted by three independent observers.Among subjects not selected for somatostatin analog responsiveness before study entry, both GH efficacy criteria and IGF-I normalization were met in a greater proportion of those treated with octreotide LAR vs. lanreotide SR (GH: B = 0.2310, P = 0.016; IGF-I: B = 0.2325, P = 0.007). Prestudy selection for somatostatin analog responsiveness was not a significant predictor of meeting GH efficacy criteria (B = 0.0992; P = 0.12). Preselection was a positive predictor of IGF-I normalization rate (B = 0.1213; P = 0.04), which was greater among preselected than unselected subjects (B = 0.1472; P = 0.0475). IGF-I normalization occurred in a greater proportion of secondary octreotide LAR- vs. primary octreotide-treated subjects (B = 0.2056; P = 0.009). The odds of tumor shrinkage more than 10% were lower in the unselected vs. preselected subjects. However, the effect of drug type was an important predictor of shrinkage; such that regardless of preselection or not, the odds of shrinkage with lanreotide SR were lower than with octreotide LAR (P = 0.003). Shrinkage greater than 10% occurred in a higher percentage of primary octreotide LAR-treated vs. primary octreotide sc-treated subjects (odds ratio = 9.4; P < 0.0001). The overall rate of tumor increase was 1.4%.In this meta-analysis, we have shown that the efficacy of octreotide LAR is greater than lanreotide SR among subjects unselected for prior somatostatin analog responsiveness. Preselection is a significant positive predictor of IGF-I normalization and is associated with increased odds of tumor shrinkage, which is also greatest with octreotide LAR. Biochemical efficacy is similar, but tumor shrinkage is greater when these drugs are given as primary vs. secondary therapy.

  View details for DOI 10.1210/jc.2005-0260

  View details for Web of Science ID 000231068500007

  View details for PubMedID 15886238

• Diagnosis and treatment of acromegaly 18th Annual National Cooperative Growth Study/5th Annual National Cooperative Somatropin Surveillance Investigator Meeting Katznelson, L. CHURCHILL LIVINGSTONE. 2005: S31–S35

  Abstract

  Acromegaly is an insidious disease that occurs, in the majority of cases, as a result of a pituitary adenoma that hypersecretes growth hormone (GH). The clinical consequences of acromegaly are a function of excess GH secretion and mass effect of the pituitary tumor. The involvement of multiple organ systems may lead to significant morbidity and mortality, prompting the need for rapid and accurate disease recognition and treatment. This brief review will describe current recommendations for management of this uncommon, but debilitating, endocrine disorder.

  View details for Web of Science ID 000231443900008

  View details for PubMedID 16023876

• Diagnostic errors after inferior petrosal sinus sampling JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Swearingen, B., Katznelson, L., Miller, K., Grinspoon, S., Waltman, A., Dorer, D. J., Klibanski, A., Biller, B. M. 2004; 89 (8): 3752-3763

  Abstract

  Although inferior petrosal sinus sampling (IPSS) is useful in the evaluation of Cushing's syndrome, false negative cases have been described, and many patients presumed to have ectopic tumors based upon negative IPSS remain without a final diagnosis. These patients are often managed as if they have as yet undiscovered ectopic tumors. To test this assumption, we conducted a retrospective review of our results to determine the ultimate diagnoses after IPSS. Between 1986 and 2002, 179 patients underwent 185 IPSS procedures as part of their evaluation for Cushing's syndrome. Confirmed diagnoses were available for 149 patients (83%): 139 patients had pituitary adenomas (94%), eight had bronchial carcinoids (5%), and two had adrenal tumors (1%). Threshold criteria for a pituitary source were defined as an inferior petrosal sinus to peripheral (IPS:P) basal ratio of 2:1 or greater without CRH or an IPS:P ratio of 3:1 or greater after CRH stimulation. There were nine patients in whom the IPS:P ratio failed to meet threshold criteria after successful sampling, but were nonetheless found to have pituitary tumors after transsphenoidal exploration (false negatives). Eight of these had received CRH and had a significant rise (>35%) in peripheral ACTH levels after CRH treatment, even though the IPS:P ratio did not reach the threshold. There were two patients in whom the IPS:P ratio reached threshold criteria, and ectopic tumors were demonstrated as the source of ACTH overproduction (false positives). The sensitivity after CRH stimulation was 90% (95% confidence interval, 80.8-95.5%) with a specificity of 67% (95% confidence interval, 11.4-94.5%). The positive and negative predictive values were 99 and 20%, respectively. Our data show that patients with an IPS:P ratio suggestive of a nonpituitary source of ACTH overproduction may still have Cushing's disease. Analyzing the CRH-stimulated peripheral ACTH levels in addition to the standard IPS:P ratios may provide improved diagnostic accuracy. Transsphenoidal exploration should be considered in all cases of unsuccessful sampling and in those cases for which no ectopic source can be identified after further body imaging, even if the IPSS is negative, and especially if peripheral ACTH levels rise significantly with CRH stimulation.

  View details for DOI 10.1210/jc.2003-032249

  View details for Web of Science ID 000223072400023

  View details for PubMedID 15292301

• AACE Medical Guidelines for Clinical Practice for the diagnosis and treatment of acromegaly. Endocrine practice Cook, D. M., Ezzat, S., Katznelson, L., Kleinberg, D. L., Laws, E. R., Nippoldt, T. B., Swearingen, B., Vance, M. L. 2004; 10 (3): 213-225

  View details for PubMedID 15382339

• Effects of growth hormone secretion on body composition in patients with Crohn's disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Katznelson, L., Fairfield, W. P., Zeizafoun, N., Sands, B. E., Peppercorn, M. A., Rosenthal, D. I., Klibanski, A. 2003; 88 (11): 5468-5472

  Abstract

  Crohn's disease is a multisystem disorder characterized by chronic intestinal inflammation. Accumulation of mesenteric fat occurs in patients with Crohn's disease, although the mechanisms underlying site-specific changes in adipose deposition are unclear. To investigate whether there are alterations in site-specific adipose deposition in patients with Crohn's disease and to determine hormonal influences that may underlie such changes, we investigated body composition and serum hormone levels in 20 men with Crohn's disease (mean age, 45 +/- 2 yr) and 20 age-, gender-, and body mass index-matched normal controls (mean age, 43 +/- 3 yr). None of the Crohn's patients was receiving glucocorticoid therapy. Subjects underwent hourly GH sampling for 12 h beginning at 2000 h and fasting serum IGF-I and testosterone measurements. Body composition was assessed by quantitative computed tomography of the abdomen and bioelectrical impedance analysis. In the Crohn's disease and control subjects, mean serum GH levels were 1.07 +/- 0.2 and 1.7 +/- 0.2 ng/ml (P = 0.06), serum IGF-I levels were 162.7 +/- 10.5 and 194.8 +/- 15.7 ng/ml (P = 0.1), and serum testosterone levels were 489 +/- 33 and 514 +/- 38 ng/ml (P = NS), respectively. Percentage body fat was significantly higher in the Crohn's patients (21 +/- 0.8% vs. 17.7 +/- 0.9%, respectively; P = 0.013). Intraabdominal fat (IAF) was significantly higher in the Crohn's subjects vs. controls (115 +/- 11 vs. 69 +/- 7 cm(2), respectively; P = 0.001). The ratio of intraabdominal to total body fat was higher in the Crohn's subjects than in the controls (0.4 +/- 0.1 vs. 0.3 +/- 0.1, respectively; P = 0.025). Subcutaneous fat area was similar in the two groups. IAF was higher in Crohn's patients even when controlling for testosterone and mean serum GH. Mean serum GH contributed independently to the differences in IAF (P = 0.001). The ratio of IAF to total body fat remained higher in the Crohn's subjects when controlling for serum testosterone, but was no longer significant in a model that also included IGF-I and mean serum GH. GH levels contributed independently to the differences in the intraabdominal to total body fat ratio (P = 0.02). In the Crohn's patients, serum GH correlated negatively with intraabdominal and total body fat and the ratio of intraabdominal to total body fat. Crohn's disease is associated with an increase in central fat accumulation, with more IAF and a higher ratio of intraabdominal to total body fat compared with controls. Although serum GH levels were similar in the two groups, GH contributed significantly to the abdominal fat measurements. These data show that GH has an important role in modulating visceral fat distribution in patients with Crohn's disease.

  View details for DOI 10.1210/jc.2003-030608

  View details for Web of Science ID 000186393900064

  View details for PubMedID 14602791

• Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Sesmilo, G., Fairfield, W. P., Katznelson, L., Pulaski, K., Freda, P. U., Bonert, V., Dimaraki, E., Stavrou, S., Vance, M. L., Hayden, D., Klibanski, A. 2002; 87 (4): 1692-1699

  Abstract

  Acromegaly is associated with premature cardiovascular mortality. GH replacement therapy decreases inflammatory markers of cardiovascular risk, but little is known about these markers in patients with acromegaly. The GH receptor antagonist, pegvisomant, reduces IGF-I levels in 98% of patients treated. We investigated the effects of GH receptor blockade on inflammatory and other cardiovascular risk markers in active acromegaly. Forty-eight patients with acromegaly and 47 age- and body mass index-matched controls were included. The study consisted of 3 parts: a cross-sectional study, a prospective randomized 12-wk placebo-controlled study, and a longitudinal open-label study of up to 18 months of pegvisomant treatment. After baseline evaluation, patients with acromegaly were randomized to placebo (n = 14), 10 mg (n = 12), 15 mg (n = 10), or 20 mg (n = 12) daily pegvisomant for 12 wk. Subsequently, all patients received at least 10 mg pegvisomant daily for up to 18 months, with dose adjustments to achieve a normal IGF-I level. Anthropometry, GH, IGF-I, and pegvisomant levels were measured monthly. C-reactive protein (CRP), IL-6, homocysteine, lipoprotein(a), glucose, insulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were determined at baseline, 4 and 12 wk in the placebo-controlled study and at 3-month intervals (during which IGF-I levels were normal) in the longitudinal study. In the cross-sectional study, patients had lower CRP than did controls [median, 0.3 (range, 0.2-0.8) vs. 2.0 (0.6-3.7) mg/liter; P < 0.0001] and had higher insulin [78.6 (55.8-130.2) vs. 54.5 (36.6-77.5) pM, P = 0.0051]. IL-6, homocysteine, triglycerides, lipoprotein(a), LDL cholesterol and HDL cholesterol were not different between groups. In the placebo-controlled study, CRP increased in patients treated with 20 mg pegvisomant, compared with placebo (mean +/- SEM, 13.7 +/- 3.6 vs. 0.5 +/- 3.3 mg/liter; P = 0.010). There were no significant differences in IL-6, homocysteine, glucose, insulin, triglyceride, total cholesterol, LDL cholesterol and HDL cholesterol levels. In the longitudinal open-label study (median duration, 15.6 months), CRP increased by 2.0 +/- 0.5 mg/liter (P = 0.0002). Total cholesterol and triglycerides increased (0.22 +/- 0.11 mM, P = 0.050; and 0.25 +/- 0.09 mM, P = 0.007, respectively), whereas lipoprotein(a) decreased (-70 +/- 33 mg/liter, P = 0.039). Glucose, insulin, homocysteine, HDL cholesterol, and IL-6 did not change. We conclude that patients with active acromegaly have lower CRP and higher insulin levels than healthy controls. Administration of pegvisomant increases CRP levels. We propose that GH secretory status is an important determinant of serum CRP levels, although additional studies are needed to determine the mechanism and significance of this finding.

  View details for Web of Science ID 000174963100042

  View details for PubMedID 11932303

• Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist LANCET van der Lely, A. J., Hutson, R. K., Trainer, P. J., Besser, G. M., Barkan, A. L., Katznelson, L., Klibanski, A., Herman-Bonert, V., Melmed, S., Vance, M. L., Freda, P. U., Stewart, P. M., Friend, K. E., Clemmons, D. R., Johannsson, G., Stavrou, S., Cook, D. M., Phillips, L. S., Strasburger, C. J., Hacker, S., Zib, K. A., Davis, R. J., Scarlett, J. A., Thorner, M. 2001; 358 (9295): 1754-1759

  Abstract

  Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days.Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis.Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353).Pegvisomant is an effective medical treatment for acromegaly.

  View details for Web of Science ID 000172385100009

  View details for PubMedID 11734231

• Somatostatin receptor-specific analogs: Effects on cell proliferation and growth hormone secretion in human somatotroph tumors JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Danila, D. C., Haidar, J. N., Zhang, X., Katznelson, L., Culler, M. D., Klibanski, A. 2001; 86 (7): 2976-2981

  Abstract

  Somatostatin (SST) acts through a family of seven transmembrane domain G protein-coupled receptors to inhibit hormone secretion and cell proliferation in a variety of neuroendocrine tissues. In normal and neoplastic human pituitary somatotroph cells, SST-specific receptor types (SSTR) 1, 2, 3, and 5 are prevalently expressed, and SST and its analogs have been shown to inhibit GH secretion. However, in somatotroph adenomas, little is known regarding: 1) effects of SST and its analogs on pituitary tumor proliferation; 2) the relationship between the effects of SST analogs on GH secretion and tumor cell proliferation; and 3) whether SSTR expression predicts the antiproliferative effects of SST analogs in human somatotroph tumors. We investigated the effects of SST-14, lanreotide, and SSTR 2 (BIM-23190) and SSTR 5 (BIM-23268) specific analogs in 18 somatotroph pituitary adenomas in primary culture. Our results showed that cell proliferation was significantly inhibited by SST-14, lanreotide, BIM-23190, and BIM-23268 in 4, 7, 3, and 4 tumors, respectively (range of proliferation suppression 5-60%; median, 16%). Tumors that were responsive to SSTR 2- and 5-specific analogs were also responsive to lanreotide. SST-14 inhibited GH secretion in 8 of 13 tumors; lanreotide, BIM-23190, and BIM-23268 inhibited GH secretion in six tumors each (range of GH secretion inhibition 23-43%; median 33%). SSTR 2 and 5 messenger RNA was expressed in all tumors investigated, whereas SSTR 1 and 3 messenger RNA was expressed in 11 and 12 tumors, respectively. We observed a dissociation between the in vitro effects of SST-14 or lanreotide on tumor cell proliferation and the effects on GH secretion in human somatotroph tumors. Although differences in receptor concentration and the presence of other SST receptor subtypes may play a role, the presence of SSTR 2 and/or 5 did not have a predictive value. These data suggest that inhibition of cell proliferation occurs independently of effects on GH secretory pathways. Further studies are needed to clarify the mechanism of SST induced antiproliferative effects.

  View details for Web of Science ID 000169838300011

  View details for PubMedID 11443154

• Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: Demonstration of a dose-effect relationship using dose-volume histogram analysis 41st Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO 99) Pai, H. H., Thornton, A., Katznelson, L., Finkelstein, D. M., Adams, J. A., Fullerton, B. C., Loeffler, J. S., Leibsch, N. J., Klibanski, A., Munzenrider, J. E. ELSEVIER SCIENCE INC. 2001: 1079–92

  Abstract

  To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored.Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion.The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction.Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.

  View details for Web of Science ID 000167327200020

  View details for PubMedID 11240250

• Hypogonadism in patients with acromegaly: data from the multi-centre acromegaly registry pilot study CLINICAL ENDOCRINOLOGY Katznelson, L., Kleinberg, D., Vance, M. L., Stravou, S., Pulaski, K. J., Schoenfeld, D. A., Hayden, D. L., Wright, M. E., Woodburn, C. J., Klibanski, A. 2001; 54 (2): 183-188

  Abstract

  Because acromegaly is an uncommon disorder, epidemiological data regarding the demographics of the disease such as the prevalence of hypogonadism have been limited. In order to derive clinical and epidemiological information, including underlying hormonal factors, regarding hypogonadism in patients with acromegaly, we performed a pilot study designed to develop a multi-centre acromegaly patient registry.Medical records of patients with acromegaly seen between 1976 and 1996 at three Institutions were reviewed, and data were entered into a database using a secure internet website. Hypogonadism was defined as amenorrhoea in women and testosterone deficiency in men. Subanalysis was performed in patients with microadenomas and women less than 50 years of age, to include women of reproductive age.Information was available on 363 patients, of whom 54% were women. The mean age at diagnosis was 41 +/- 13 years. In subjects less than 50 years of age, hypogonadism was present in 59%. Hyperprolactinaemia was present in 45% and 21% of hypogonadal and eugonadal patients of reproductive age, respectively (P = 0.0003). GH levels were higher in patients with hypogonadism (P = 0.03). In patients < 50 years of age with microadenomas, hypogonadism was present in nine of the 22 (41%) patients, including 55% of the women and 27% of the men (P = ns). Hyperprolactinaemia was present in three of the 10 and four of the 14 of microadenoma patients with hypogonadism and eugonadism, respectively.We developed a web-based acromegaly patient registry and used it to show that hypogonadism is a frequent consequence of acromegaly, even in patients with microadenomas, who are not at risk from hypopituitarism due to local mass effects. We also demonstrated that prolactin and GH hypersecretion contribute to the pathogenesis of hypogonadism in acromegaly, and that hypogonadism may occur in microadenoma patients even in the absence of hyperprolactinaemia.

  View details for Web of Science ID 000166984800007

  View details for PubMedID 11207632

• Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant NEW ENGLAND JOURNAL OF MEDICINE Trainer, P. J., Drake, W. M., Katznelson, L., Freda, P. U., Herman-Bonert, V., van der Lely, A. J., Dimaraki, E. V., Stewart, P. M., Friend, K. E., Vance, M. L., Besser, G. M., Scarlett, J. A., Thorner, M. O., Parkinson, C., Klibanski, A., Powell, J. S., Barkan, A. L., Sheppard, M. C., Maldonado, M., Rose, D. R., Clemmons, D. R., Johannson, G., Bengtsson, B. A., Stavrou, S., Kleinberg, D. L., Cook, D. M., Phillips, L. S., Bidlingmaier, M., Strasburger, C. J., Hackett, S., Zib, K., Bennett, W. F., Davis, R. J. 2000; 342 (16): 1171-1177

  Abstract

  Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone.We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly.The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups.On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

  View details for Web of Science ID 000086523700004

  View details for PubMedID 10770982

• Acromegalic heart disease ENDOCRINOLOGIST Pinzone, J. J., Katznelson, L., Klibanski, A. 1998; 8 (4): 273-278

  View details for Web of Science ID 000075246400007

• Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Katznelson, L., Bogan, J. S., Trob, J. R., Schoenfeld, D. A., Hedley-Whyte, E. T., Hsu, D. W., Zervas, N. T., Swearingen, B., Sleeper, M., Klibanski, A. 1998; 83 (5): 1619-1623

  Abstract

  The majority of cases of Cushing's disease are due to an underlying pituitary corticotroph microadenoma (< or = 10 mm). Corticotroph macroadenomas (> 10 mm) are a less common cause of Cushing's disease, and little is known about specific clinical and biochemical findings in such patients. To define further the clinical characteristics of patients with corticotroph macroadenomas, we performed a retrospective review of Cushing's disease due to macroadenomas seen at Massachusetts General Hospital between 1979 and 1995. Of 531 patients identified with a diagnostic code of Cushing's syndrome, 20 were determined to have Cushing's disease due to a macroadenoma based on radiographic evidence of pituitary adenoma greater than 10 mm and pathological confirmation of a pituitary adenoma. A comparison review of charts of 24 patients with Cushing's disease due to corticotroph microadenomas identified on the basis of radiographic evidence of a normal pituitary gland or a pituitary adenoma 10 mm or less in diameter was also performed. The mean ages of the patients (+/- SD) with macroadenomas and microadenomas were similar (39 +/- 12 and 38 +/- 14 yr, respectively). The baseline median 24-h urine free cortisol (UFC) excretion was 1341 nmol/day (range, 304-69,033 nmol/day) and 877 nmol/day (range, 293-2,558 nmol/day) for macroadenoma and microadenoma patients, respectively (P = 0.058). After the 48-h high dose dexamethasone suppression test, UFC decreased by 77 +/- 19% (mean +/- SD) and 91 +/- 7% in macroadenoma and microadenoma subjects, respectively (P = 0.04). Fifty-six percent of macroadenoma patients and 92% of microadenoma patients had greater than 80% suppression of UFC after high dose dexamethasone administration (P = 0.03). The baseline median 24-h urinary 17-hydroxysteroid (17-OHCS) excretion was 52 mumol/day (range, 25-786 mumol/day) and 44 mumol/day (range, 17-86 mumol/day) for macroadenoma and microadenoma subjects, respectively (P = 0.09). After the standard high dose dexamethasone suppression test, 17-OHCS excretion decreased by 46 +/- 33% and 72 +/- 22% for macroadenoma and microadenoma subjects, respectively (P = 0.02). Fifty-three percent of patients with macroadenomas and 86% of patients with microadenomas had greater than 50% suppression of 17-OHCS after high dose dexamethasone administration (P = 0.02). Baseline plasma ACTH values were above the normal range in 83.3% of macroadenoma patients and in 45% of microadenoma subjects (P = 0.05). Tumors were immunostained with the MIB-1 antibody for Ki-67 to investigate proliferation in the adenomas. There was a trend for a higher Ki-67 labeling index in corticotroph macroadenomas, and seven (44%) macroadenomas vs. three (18%) microadenomas had labeling indexes greater than 3%, but this was not statistically significant. In summary, corticotroph macroadenomas are often associated with less glucocorticoid suppressibility than the more frequently occurring microadenomas. Therefore, the lack of suppression of UFC or 17-OHCS after the administration of high dose dexamethasone in a patient with Cushing's disease does not necessarily imply the presence of ACTH-independent Cushing's syndrome and is more commonly seen in patients with corticotroph macroadenomas than in those with microadenomas. Increased plasma ACTH concentrations are typical of patients with corticotroph macroadenomas and may be a more sensitive indicator of neoplastic corticotrophs than the UFC or 17-OHCS response to standard high dose dexamethasone testing.

  View details for Web of Science ID 000073535300039

  View details for PubMedID 9589666

• CHARACTERIZATION OF GLYCOPROTEIN HORMONE AND FREE-SUBUNIT PRODUCTION IN PITUITARY-TUMORS 5TH EUROPEAN WORKSHOP ON PITUITARY ADENOMAS Katznelson, L., Klibanski, A. ELSEVIER SCIENCE PUBL B V. 1991: 207–214

  View details for Web of Science ID A1991BU75B00023