Pituitary Complications of Checkpoint Inhibitor Use.

Immune checkpoint inhibitors have revolutionized cancer therapy but are associated with a risk of endocrine immune-related adverse events, including pituitary complications. Autoimmune hypophysitis, traditionally a rare diagnosis, has become a more frequently encountered clinical entity with the emergence of antitumor immunotherapy. This mini-review aims to consolidate current knowledge, encompassing the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of pituitary complications of immune checkpoint inhibitor use.

Pre-Existing Autoimmune Disease Increases the Risk of Cardiovascular and Noncardiovascular Events After Immunotherapy.

Background: The use of immune checkpoint inhibitors (ICI) is associated with cardiovascular (CV) events, and patients with pre-existing autoimmune disease are at increased CV risk.

Objectives: The aim of this study was to characterize the risk for CV events in patients with pre-existing autoimmune disease post-ICI.

Methods: This was a retrospective study of 6,683 patients treated with ICIs within an academic network.

Bone marrow adipose tissue is associated with fracture history in anorexia nervosa.

Unlabelled: Although bone mineral density (BMD) is decreased and fracture risk increased in anorexia nervosa, BMD does not predict fracture history in this disorder. We assessed BMD, bone microarchitecture, and bone marrow adipose tissue (BMAT) in women with anorexia nervosa and found that only BMAT was associated with fracture history.

Introduction: Anorexia nervosa (AN) is a psychiatric disorder characterized by low body weight, low BMD, and increased risk of fracture.

Sprouting Angiogenesis in Human Pituitary Adenomas.

Introduction: Angiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors.

Materials And Methods: 219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR.

The Prolactin per Unit Tumor Volume Ratio Accurately Distinguishes Prolactinomas From Secondary Hyperprolactinemia due to Stalk Effect.

Objective: The prolactin levels alone are insufficient to distinguish between some cases of prolactinomas and stalk effect. We aimed to formally characterize the relationship between serum prolactin and prolactinoma volume, determine a cutoff for prolactin/mm that accurately distinguishes prolactinomas from stalk effect, and validate this cutoff in a cohort selected to include ambiguous prolactin values ranging from 50 to 150 ng/mL.

Methods: We used the Research Patient Data Registry and transsphenoidal surgery database in our institution to retrospectively identify adult patients with clinically nonfunctioning (NF) tumors (primary analysis, n = 279; validation cohort, n = 10) and prolactinomas (primary analysis, n = 94; validation cohort, n = 18).

The Upregulation of Molecules Related to Tumor Immune Escape in Human Pituitary Adenomas.

Human pituitary adenomas are one of the most common intracranial neoplasms. Although most of these tumors are benign and can be treated medically or by transsphenoidal surgery, a subset of these tumors are fast-growing, aggressive, recur, and remain a therapeutic dilemma. Because antibodies against immune checkpoint receptors PD-1 and CLTA-4 are now routinely used for cancer treatment, we quantified the expression of mRNA coding for PD-1, CLTA-4, and their ligands, PD-L1, PD-L2, CD80, and CD86 in human pituitary adenomas and normal pituitary glands, with the ultimate goal of exploiting immune checkpoint therapy in aggressive pituitary adenomas.

Effect of a multidisciplinary Severe Immunotherapy Complications Service on outcomes for patients receiving immune checkpoint inhibitor therapy for cancer.

Background: In 2017, Massachusetts General Hospital implemented the Severe Immunotherapy Complications (SIC) Service, a multidisciplinary care team for patients hospitalized with immune-related adverse events (irAEs), a unique spectrum of toxicities associated with immune checkpoint inhibitors (ICIs). This study's objectives were to evaluate the intervention's (1) effect on patient outcomes and healthcare utilization, and (2) ability to collect biological samples via a central infrastructure, in order to study the mechanisms responsible for irAEs.

Methods: A hospital database was used to identify patients who received ICIs for a malignancy and were hospitalized with severe irAEs, before (April 2, 2016-October 3, 2017) and after (October 3, 2017-October 24, 2018) SIC Service initiation.

The dynamics of human bone marrow adipose tissue in response to feeding and fasting.

BACKGROUNDAdipocytes were long considered inert components of the bone marrow niche, but mouse and human models suggest bone marrow adipose tissue (BMAT) is dynamic and responsive to hormonal and nutrient cues.METHODSIn this study of healthy volunteers, we investigated how BMAT responds to acute nutrient changes, including analyses of endocrine determinants and paracrine factors from marrow aspirates. Study participants underwent a 10-day high-calorie protocol, followed by a 10-day fast.

Temporal Trends and Outcomes Among Patients Admitted for Immune-Related Adverse Events: A Single-Center Retrospective Cohort Study from 2011 to 2018.

Background: The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death.

Methods: Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed.

Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors.

Background: Hyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined the risk and predictors of hyponatremia and other electrolyte abnormalities in a 'real-world' sample of patients receiving ICIs to treat advanced malignancies.

Methods: This was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018.

Chronic lymphocytic leukemia, a rare cause of pituitary stalk thickening.

This case highlights a rare presentation of chronic lymphocytic leukemia (CLL). CNS involvement by CLL is rare, and only 5 cases with pituitary or hypothalamic involvement have previously been reported. Unfamiliarity with this disease complication may lead to a delay in diagnosis and treatment.

Immune-Related Adverse Events in the Setting of PD-1/L1 Inhibitor Combination Therapy.

In 2018, a multi‐disciplinary workshop was held at the Massachusetts General Hospital to discuss challenges in defining, diagnosing, and treating immune‐related adverse events (irAE), including those that occur in patients administered PD‐1/L1 inhibitor combination therapy. In this commentary, the workshop participants present a clinical case that illustrates the complexity of irAE diagnosis and management in a patient receiving PD‐1/L1 combination therapy, summarize the current state of PD‐1/L1 combination therapy, and discuss challenges and opportunities for the evaluation of irAEs as these combinations become more widely used to treat patients with cancer.

Red and White Blood Cell Counts Are Associated With Bone Marrow Adipose Tissue, Bone Mineral Density, and Bone Microarchitecture in Premenopausal Women.

Bone marrow adipose tissue (BMAT) resides within the bone marrow microenvironment where its function remains poorly understood. BMAT is elevated in anorexia nervosa, a disease model of chronic starvation, despite depletion of other fat depots. In addition to BMAT, the marrow microenvironment also consists of osteoblast and hematopoietic progenitors.

Biochemical Control in Acromegaly With Multimodality Therapies: Outcomes From a Pituitary Center and Changes Over Time.

Purpose: To determine the prevalence of insulin-like growth factor-1 (IGF-1) normalization with long-term multimodality therapy in a pituitary center and to assess changes over time.

Methods: Patients with acromegaly (N = 409), with ≥1 year of data after surgery and at least 2 subsequent clinic visits were included in long-term analysis (N = 266). Biochemical data, clinical characteristics, and therapeutic interventions were reviewed retrospectively.

IGF-1 is associated with estimated bone strength in anorexia nervosa.

Unlabelled: IGF-1 and leptin are two nutritionally dependent hormones associated with low bone mass in women with anorexia nervosa. Using finite element analysis, we estimated bone strength in women with anorexia nervosa and found that IGF-1 but not leptin correlated significantly with estimated bone strength in both the radius and tibia.

Purpose: Women with anorexia nervosa, a psychiatric disorder characterized by self-induced starvation and low body weight, have impaired bone formation, low bone mass, and an increased risk of fracture.

Differences in Trabecular Plate and Rod Structure in Premenopausal Women Across the Weight Spectrum.

Context: Premenopausal women with anorexia nervosa (AN) and obesity (OB) have elevated fracture risk. More plate-like and axially aligned trabecular bone, assessed by individual trabeculae segmentation (ITS), is associated with higher estimated bone strength. Trabecular plate and rod structure has not been reported across the weight spectrum.

Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis.

Objective: Little has been published describing hypophysitis after nivolumab or pembrolizumab treatment. We aimed to (i) assess the risk of hypophysitis following nivolumab or pembrolizumab treatment, (ii) characterize the clinical presentation and outcomes in these patients and (iii) compare these patients to hypophysitis following ipilimumab and ipilimumab plus nivolumab (combo). We hypothesized that headaches, pituitary enlargement on MRI and multiple anterior pituitary hormone deficiencies would occur less often in the nivolumab/pembrolizumab group versus ipilimumab or combo hypophysitis patients.

Low Plasma Oxytocin Levels and Increased Psychopathology in Hypopituitary Men With Diabetes Insipidus.

Context: Oxytocin (OT) and vasopressin share anatomical pathways of synthesis and secretion, and patients with central diabetes insipidus (CDI) presumably are at risk for OT deficiency. However, an OT-deficient state in hypopituitary patients has not been established.

Objectives: We hypothesized that men with CDI compared to patients with similar anterior pituitary deficiencies (APD) but no CDI and healthy controls (HC) of similar age and body mass index, would have lower plasma OT levels, associated with increased psychopathology.

Changes in marrow adipose tissue with short-term changes in weight in premenopausal women with anorexia nervosa.

Objective: In anorexia nervosa, a psychiatric disease characterized by self-induced starvation and a model of chronic undernutrition, levels of subcutaneous (SAT) and visceral (VAT) adipose tissue are low, whereas marrow adipose tissue (MAT) levels are elevated compared to normal-weight women. The reason for this paradoxical elevation of an adipose tissue depot in starvation is not known. We sought to understand changes in MAT in response to subacute changes in weight and to compare these changes with those of other fat depots and body composition parameters.

High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma.

Background: It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune-related adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses.

Methods: In total, 98 patients with melanoma who had ipilimumab-induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool.

Treatment With a Ghrelin Agonist in Outpatient Women With Anorexia Nervosa: A Randomized Clinical Trial.

Objective: To assess the effects of relamorelin-an agonist of the appetite-stimulating hormone ghrelin, which has effects on gastric emptying-on (1) weight gain and (2) gastric emptying in women with anorexia nervosa.

Methods: In a randomized, double-blind, placebo-controlled design, the effects of the ghrelin agonist relamorelin were studied in 22 outpatient women with anorexia nervosa, diagnosed using DSM-5 criteria. The study was conducted at the Massachusetts General Hospital Clinical Research Center between March 11, 2013, and February 26, 2015.

Hypophysitis: Evaluation and Management.

Hypophysitis is the acute or chronic inflammation of the pituitary gland. The spectrum of hypophysitis has expanded in recent years with the addition of two histologic subtypes and recognition as a complication of treatment with immune checkpoint inhibitors. Despite the increased number of published cases, the pathogenesis of hypophysitis is poorly understood, and treatment strategies are diverse and controversial.

Bone density, body composition, and psychopathology of anorexia nervosa spectrum disorders in DSM-IV vs DSM-5.

Objective: DSM-5 revised the diagnostic criteria for anorexia nervosa (AN) by eliminating the amenorrhea requirement, liberalizing weight and psychological criteria, and adding the formal diagnosis of "atypical AN" for individuals with AN psychological symptoms without low weight. We sought to determine whether bone density (BMD) is impaired in women diagnosed with AN using the new, more liberal, DSM-5 criteria.

Method: Cross-sectional study of 168 women, 18 - 45y: (1) AN by DSM-IV (DSM-IV AN) (n = 37), (2) AN by DSM-5 but not DSM-IV criteria (DSM-5 AN) (n = 33), (3) atypical AN (ATYPICAL AN) (n = 77), (4) healthy comparison group (HC) (n = 21).