High mortality within 90 days of diagnosis in patients with Cushing's syndrome: results from the ERCUSYN registry.

OBJECTIVE: Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. METHODS: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2-5.5) years. RESULTS: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. CONCLUSION: Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.

Clinical, pathologic, and imaging characteristics of pituitary null cell adenomas as defined according to the 2017 World Health Organization criteria: a case series from two pituitary centers.

PURPOSE: The 2017 World Health Organization classification of pituitary tumors redefined pituitary null cell adenomas (NCAs) by restricting this diagnostic category to pituitary tumors that are negative for pituitary transcription factors and adenohypophyseal hormones. The clinical behavior of this redefined entity has not been widely studied, and this is a major shortcoming of the classification. This study evaluated the imaging and clinical features of NCAs from two pituitary centers and compared them with those of gonadotroph adenomas (GAs). METHODS: Imaging, pathologic, and clinical characteristics of NCAs and GAs were retrospectively reviewed. Tumor immunohistochemistry was performed to confirm absence of adenohypophyseal hormones and pituitary transcription factor expression. RESULTS: Thirty-one NCAs were compared with 38 GAs. NCAs were more likely to invade the cavernous sinus (15/31 [48%] vs. 5/38 [13%], P = .003) and had a higher proliferative index (i.e., MIB-1 > 3%, 11/31 [35%] vs. 5/38 [13%], P = .04). Gross total resection was less likely in the NCA group (19/31 [61%] vs. 33/38 [87], P = .02). Progression-free survival was worse in the NCA cohort (5-year progression-free survival, 0.70 vs. 1.00; P = .011, by log-rank test). CONCLUSIONS: Compared with GAs, NCAs are more invasive at the time of presentation and have a more aggressive clinical course. This study provides evidence that NCAs represent a distinct clinicopathologic entity with behavior that differs adversely from that of GAs. This may inform clinical decision-making, including frequency of postoperative tumor surveillance and timing of adjunctive treatments.

Characteristics and relative numbers of lethal snake bite cases in medicolegal practice in central Myanmar - A five year study.

Clinical and pathological case files of lethal snakebites were reviewed from the Magway Region General Hospital, Magway, Myanmar, over a five-year period (January 2013 December 2017). A total of 2069 postmortem examinations were performed which included 84 cases of lethal snake bite (4.1%). The annual numbers ranged from 10 out of a total of 268 autopsies in 2013 (3.7%), to 31 out of a total of 501 autopsies in 2016 (6.2%). There were 54 males (64%) and 30 females (36%) (M:F = 1.9:1; age range 5-75yrs, mean 33yrs). The most common time for lethal envenomation was August (16/84-19%), the middle of the monsoon season. 45/84 (54%) had acute renal failure, 27/84 (32%) were shocked, and the remaining 12/84 (14%) had disseminated intravascular coagulation. Twenty cases (24%) died within 24 h after envenomation. Fang marks were identified on the legs (either right or left) in 73/84 cases (87%) and on the arms in five cases (6%). The predominant findings at autopsy were of acute renal injury (82/84-98%), pituitary haemorrhage/necrosis (36/84-43%), and adrenal gland haemorrhage (30/84-36%). Despite the reduction in fatalities over the years snakebite from Russell's viper in particular remains an important contributor to mortality in central Myanmar despite the availability of antivenom.

Treatment of adult growth hormone deficiency with human recombinant growth hormone: an update on current evidence and critical review of advantages and pitfalls.

Adult-onset growth-hormone (GH) deficiency (GHD) is a rare disorder, which most commonly results from pituitary or peripituitary tumors and their treatment, and is characterized by alterations in body composition, carbohydrate and lipid metabolism, bone mineral density, cardiovascular risk profile and quality of life, all of which may contribute to an increased morbidity and mortality. Since recombinant human GH (rhGH) became available in 1985, several studies have provided evidence of its beneficial effects, despite the potential risk of developing adverse effects, and much clinical experience has been accumulated. However, in adults, the precise therapeutic role of GH replacement therapy and the individual response to it remains highly variable and is still a matter of debate. In this article, we present a critical review of the available evidence on rhGH replacement therapy in GHD adults, emphasizing the pitfalls clinicians encounter in the diagnosis of GHD and monitoring of rhGH replacement therapy. We will cover all the relevant aspects regarding the potential usefulness of GH treatment, including the hot topic of mortality.

What's New in Old Horses? Postmortem Diagnoses in Mature and Aged Equids.

Postmortem findings in 241 equids admitted to a teaching hospital that were at least 15 years old at autopsy were reviewed (1) to determine disease prevalence, (2) to compare the cause of death (or euthanasia) in equids 15 to 19 years of age (n = 116) with that in equids ≥20 years of age (n = 125), and (3) to catalog coexisting lesions in equids with pituitary pars intermedia dysfunction (PPID). Breed and sex were evenly distributed between the age groups. Death or euthanasia was attributed to disease of the digestive system (41.5%), pituitary gland (12.9%), locomotor system (10.0%), nervous system (7.9%), cardiovascular system (4.6%), urinary system (4.6%), reproductive system (4.2%), respiratory system (4.2%), integumentary system (4.2%), lymphoid system (2.5%), liver (2.5%), or systemic neoplasia (1.2%). Nervous system disease was more common in the 15- to 19-year group; urinary tract disease was more common in the ≥20-year group. Neoplastic disease, regardless of systemic location, was the basis for death or euthanasia in 18.7% of all equids. Squamous cell carcinoma, lymphoma, and melanoma were the most common malignant neoplasms. PPID was the most common specific diagnosis, based on the postmortem presence of hyperplasia or adenoma, and was the reason for euthanasia in 47.7% of 65 equids with PPID. The most common nonpituitary causes for death or euthanasia in equids with PPID were colic, lameness, cancer, and spinal cord disease. Coexisting conditions in equids with PPID that were not considered the basis for euthanasia included neoplasms, infections, lameness, and recurrent airway obstruction.

Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study.

PURPOSE: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS). EXPERIMENTAL DESIGN: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan-Meier. RESULTS: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms. CONCLUSION: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given.

Pituitary disease mortality: is it fiction?

During the last 20 years a tremendous improvement in the care of patients with pituitary tumors and of hypopituitarism has been achieved. If we resolve most of the possible causes of the increased cardiovascular disease and stroke mortality a normal survival is expected in these patients. Recently, a large population based study showed a decline in the risk of non-fatal stroke and of non-fatal cardiac events in GH deficient patients. This improvement was achieved by complete hormone replacement, including long term GH replacement, together with prescription of cardio protective drugs. If we follow the latest achievements in pituitary imaging, surgery techniques, hormone substitutions, cardio protective medications, we would expect a normal longevity in these patients. This review will focus on; (1) pituitary insufficiencies and hormone substitutions, (2) modes of cranial radiotherapy, and (3) new techniques in the surgery of a pituitary adenoma.

Mortality and pituitary disease.

Outcome data from large series confirm increased mortality of patients with pituitary tumours, predominantly due to vascular disease. Control of cortisol secretion and growth hormone (GH) hypersecretion (together with cardiovascular risk factor reduction) is key in the normalisation of mortality rates in patients with Cushing's disease and acromegaly, respectively, though some excess mortality may persist even in "cured" patients.

Mortality in patients with pituitary disease.

Pituitary disease is associated with increased mortality predominantly due to vascular disease. Control of cortisol secretion and GH hypersecretion (and cardiovascular risk factor reduction) is key in the reduction of mortality in patients with Cushing's disease and acromegaly, retrospectively. For patients with acromegaly, the role of IGF-I is less clear-cut. Confounding pituitary hormone deficiencies such as gonadotropins and particularly ACTH deficiency (with higher doses of hydrocortisone replacement) may have a detrimental effect on outcome in patients with pituitary disease. Pituitary radiotherapy is a further factor that has been associated with increased mortality (particularly cerebrovascular). Although standardized mortality ratios in pituitary disease are falling due to improved treatment, mortality for many conditions are still elevated above that of the general population, and therefore further measures are needed. Craniopharyngioma patients have a particularly increased risk of mortality as a result of the tumor itself and treatment to control tumor growth; this is a key area for future research in order to optimize the outcome for these patients.

Excess mortality in women with pituitary disease: a meta-analysis.

BACKGROUND: Increased mortality has been reported in patients with pituitary disease, with some studies showing higher standard mortality rates (SMR) in women than in men. OBJECTIVE: To assess overall SMR for men and women with benign pituitary disease without excessive ATCH or GH secretion and to investigate associations between SMR and time period of diagnosis. DESIGN: From searches in PubMed, Embase and Web of Science databases, and reference lists of major reviews and original articles, we included original studies providing SMR values and 95% confidence intervals (CI) for men and women separately. Thirty articles were studied in detail. Six studies were eligible for the meta-analysis of sex-specific mortality, and seven for the analysis of association between SMR and diagnosis period. RESULTS: Individual studies (total 5412 patients) reported total SMR values (men and women together) ranging from 1.21 to 3.80. SMR varied from 0.98 to 3.36 in men and from 2.11 to 4.54 in women. Weighted SMR values were significantly higher in women (2.80; CI 2.59-3.02) than in men (2.06; CI 1.94-2 20) (P < 0.0001). SMR was negatively correlated with first year of diagnosis in individual studies (partial correlation analysis controlling for sex, P = 0.017), and approached normal in recent studies in men but not in women. CONCLUSIONS: In our meta-analysis of patients with pituitary disease without ACTH or GH excess, SMR was significantly higher in women than in men. SMR reached normal levels in men treated in recent decades, but remained elevated in women.

Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis.

BACKGROUND: Permanent consequences in Langerhans cell histiocytosis (LCH) are irreversible late sequelae related to the disease that may severely impair the quality of life of survivors. The frequency and pattern of permanent consequences affecting the central nervous system (CNS) remains to be determined. PROCEDURE: In this single center study, 25 LCH patients observed for a median time of 10 years 3 months underwent a uniform thorough follow-up program including neuropsychological testing and electrophysiological evaluation. RESULTS: Overall permanent consequences were seen in 9 of 25 patients. Intracranial abnormalities were the most frequent including diabetes insipidus (DI) in seven patients, anterior pituitary deficiencies in five patients, and neurodegenerative CNS disease in five patients. No patient had overt neurological symptoms upon neurological evaluation, but psychological testing revealed subtle deficits in short-term auditory memory (STAM) in 14 patients. Brain stem evoked potentials showed abnormalities in four of nine tested patients, all of these four had neurodegeneration on MRI. CONCLUSION: Psychoneuroendocrine sequelae were found in an unexpectedly high number of patients in this single center study. Long-term follow-up focusing on such sequelae are important in LCH survivors, in order to detect early deficits, to monitor the evolution of the disease, and to provide specific support.

Pituitary hypoplasia and respiratory distress syndrome in Prop1 knockout mice.

Mutations in Prophet of PIT1 (Prop1), one of several homeodomain transcription factors that are required for the development of the anterior pituitary gland, are the predominant cause of MPHD (multiple pituitary hormone deficiency) in humans. We show that deletion of Prop1 in mice causes severe pituitary hypoplasia with failure of the entire Pit1 lineage and delayed gonadotrope development. The pituitary hormone deficiencies cause secondary endocrine problems and a high rate of perinatal mortality due to respiratory distress. Lung atelectasis in mutants correlates with reduced levels of NKX2.1 and surfactant. Lethality of mice homozygous for either the null allele or a spontaneous hypomorphic allele is strongly influenced by genetic background. Prop1-null mice are an excellent model for MPHD and may be useful for testing the efficacy of pharmaceutical intervention for neonatal respiratory distress.