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The treatment strategy for non-functioning pituitary adenomas (NFPA) includes surgery, radiotherapy, medical treatment, or follow-up. Prior series of patients with NFPAs followed without intervention include small numbers of patients with macroadenomas. This study investigated the natural history of patients with macroadenomas followed without treatment.Retrospective cohort study included patients18 years, with a diagnosis of NFPA≥10 mm who were naïve to surgery or medical treatment and followed more than 12 months after diagnosis. Patients with chiasmal threat were excluded. Follow-up terminated if the patient underwent surgery, received cabergoline or was lost to follow-up.Data collected included evaluation of tumor characteristics and size by MRI, symptoms including visual disturbances, and hormonal levels. Tumor growth was defined as maximal diameter increase of2 mm.The cohort included 49 patients (30 males, mean age 68.0±12.0 years). At diagnosis, the average tumor size was 17.8±5.9 mm. Mean follow-up time was 4.9±4.9 years. Increase in tumor size occurred in 16 patients (33%), with an average growth of 5.1±4.4 mm. Reduction in tumor size occurred in 10 patients (20%), with a mean decrease of 3.5±1.3 mm. Twenty-three patients remained with stable tumors. Overall, 33 patients (67%) were observed without any intervention; 3 patients were operated and 13 were treated with cabergoline. None of the parameters including age, gender, baseline tumor size, invasiveness, visual disturbances, or hypopituitarism at diagnosis, predicted tumor growth.Observation of NFPAs without surgery or medical therapy is a reasonable approach in selected patients. In our study, no parameter predicted tumor growth. This article is protected by copyright. All rights reserved.

Febrile neutropenia (FN) is a major complication in patients with diffuse large B-Cell lymphoma (DLBCL). Diabetes mellitus (DM) has deleterious effects on the immune system resulting in an increased risk of infections. We evaluated patients with DLBCL who started frontline treatment with R-CHOP, and compared outcomes according to presence of DM comorbidity. Between 2013 and 2018, 218 patients with DLBCL were included. 46 patients (21%) had DM. Rate of admissions for FN was higher for patients with DM (0.7 vs. 0.46 admissions/patient

Purpose:To study the baseline characteristics predicting hypogonadotropic hypogonadism (HH) persistence in men with macroprolactinoma that achieved prolactin normalization.Design:Retrospective cohort study.Methods:Male patients diagnosed with macroprolactinoma and HH that received cabergoline treatment with subsequent prolactin normalization were included: men that achieved eugonadism, and men that remained hypogonadal. Patient’s demographic, clinical and biochemical parameters, sellar imaging and visual fields tests were obtained. Univariate and multivariate models were used to identify predictors of HH persistence.Results:Fifty-eight male patients (age, 49.2±12.6 years) with a median baseline prolactin of 1154 ng/mL (IQR, 478-2763 ng/mL) and adenoma (maximal) diameter of 25.9±14.8 mm were followed for a median of 5.6 years (IQR, 3.0-10.7). Twelve men (21%) suffered from HH persistence at the end of follow-up and 46 men achieved eugonadism. Forty-two out of 46 men (91%) accomplished eugonadism within the first year following prolactin normalization.In a multivariate logistic regression model, hypopituitarism (OR=10.1; 95% CI 1.10 – 101.94), visual field defect (OR=9.9; 95% CI 1.07 – 92.33), and low baseline testosterone levels (OR=0.5; 95% CI 0.29 – 0.93) were independent predictors of HH persistence.Conclusion:In our cohort of men with macroprolactinoma that reached prolactin normalization with cabergoline treatment, 21% had HH persistence. Pituitary hormone deficiency, visual field defects, and low baseline testosterone levels were independently associated with HH persistence. 91% of men achieved eugonadism within the first year following prolactin normalization. These findings may support informed clinical decision-making regarding the initiation of testosterone replacement in men with macroprolactinomas.

Central Diabetes Insipidus (CDI) is mainly associated with structural pathologies of the hypothalamic-pituitary area. Etiologies underlying CDI are identified in most patients, however idiopathic CDI is reported in 13-17% of cases after excluding other etiologies. The Hypopituitarism ENEA Rare Observational Study (HEROS study) retrospectively collected data of patients with idiopathic CDI from 14 pituitary centers in 9 countries.The cohort included 92 patients (59 females), mean age at diagnosis was 35.4±20.7 years, and a mean follow up of 18.2±14.5 years following CDI diagnosis. In 6 women, diagnosis was related to pregnancy. Of 83 patients with available data on pituitary imaging, 40 had normal sellar imaging, and 43 had pathology of the posterior pituitary or the stalk, including loss of the bright spot, posterior pituitary atrophy or stalk enlargement. Anterior pituitary hormone deficiencies at presentation included hypogonadism in 6 patients (5 females), and hypocortisolism in one; during follow-up new anterior pituitary deficiencies developed in 6 patients. Replacement treatment with desmopressin was given to all patients except one, usually with an oral preparation. During follow up, no underlying disease causing CDI was identified in any patient.Conclusions: patients with idiopathic CDI following investigation at baseline are stable with no specific etiology depicted during long-term follow-up.

OBJECTIVE To study the outcome of men with macroprolactinoma following cabergoline treatment based on tumour size. DESIGN Retrospective cohort study. METHODS The study included 94 men, divided into three groups according to adenoma diameter: 10-19 mm (Group A, n = 36); 20-39 mm (Group B, n = 41); or ≥40 mm (Group C, giant prolactinomas, n = 17). Patients were followed for a mean of 7.5 years with sellar magnetic resonance imaging, visual fields and hormone measurements. RESULTS Mean baseline prolactin was 767, 2090 and 24,806 ng/ml in Groups A, B and C, respectively (p

Objective Patients with acromegaly usually present with the classical signs of acromegaly, whereas patients without the specific signs or symptoms are rarely diagnosed. This unique entity can be named "subclinical acromegaly". Methods This was a retrospective study. Our study group consisted of 8 patients (6 females) with incidentally diagnosed acromegaly, most following head MRI for unrelated reasons and without the specific signs of acromegaly. Results Mean age at diagnosis was 50.1 ± 16.3 years. Baseline IGF-1 ranged between 1.27–2.08 x upper limit of normal (ULN). MRI depicted a pituitary microadenoma in 6 patients, one patient presented with an intrasellar macroadenoma and one had no visible pituitary mass. Mean calculated SAGIT clinical score was 4.6. Three patients underwent trans-sphenoidal resection; two achieved hormonal remission and one improved but did not normalize IGF-1 following surgery. Five patients (including one following surgery) were given somatostatin analogs, and three normalized IGF-1. Several patients improved clinically following treatment, reporting improvement in snoring, hypertension, or weight loss, and pituitary adenoma decreased in size in 2 patients that responded to medical treatment. Conclusions we report a series of 8 patients with very mild and subclinical acromegaly. It is uncertain whether all such patients will gain clinical benefit from treatment, but some experienced clinical improvement due to treatment.

Background: dopamine agonists are the recommended treatment for male prolactinomas, but some patients may develop dopamine-agonist-resistant hyperprolactinemia, leading to persistent hypogonadism that requires treatment with testosterone. However, testosterone replacement therapy may be associated with a decrease in the efficacy of dopamine agonists due to the aromatization of testosterone to estradiol, which can stimulate the proliferation and hyperplasia of lactotroph cells in the pituitary, inducing resistance to dopamine agonists. Objective: this paper systematically reviewed the role of aromatase inhibitors for men with prolactinoma and dopamine-agonist-resistant or persistent hypogonadism following treatment. Method: we performed a systematic review of all studies (according to PRISMA guidelines), assessing the role of aromatase inhibitors, including anastrozole and letrozole, for male prolactinoma. An English-language search for relevant studies was conducted on PubMed from its inception to 1 December 2022. The reference lists of the relevant studies were also reviewed. Results: our systematic review identified six articles (nine patients), including five case reports and a single case series, on the use of aromatase inhibitors for male prolactinomas. Reducing estrogen levels with an aromatase inhibitor improved sensitivity to dopamine agonists, as the addition of anastrozole or letrozole improves the control of prolactin levels and may lead to the shrinkage of tumors. Conclusion: aromatase inhibitors are of potential value to patients with dopamine-agonist-resistant prolactinoma, or when hypogonadism persists while using high-dose dopamine agonists.

While obesity is commonly associated with increased morbidity and mortality, in patients with chronic diseases, it has have been associated with a better prognosis, a phenomenon known as the 'obesity paradox'. We investigated the relationship between mortality, length of hospital stay (LOHS), and body mass index (BMI) in patients hospitalized to general surgical wards. We extracted data of patients admitted to the hospital between January 2011 and December 2017. BMI was classified according to the following categories: underweight (

To evaluate current real-life experience with medical treatment for active acromegaly in a large cohort.Data on demographic parameters, blood tests, imaging studies, and treatments were extracted from the medical records.The cohort included 87 patients (43 male) with active acromegaly. The mean age at diagnosis was 40.2±11.4 years, and the mean duration of follow-up was 7.9±5.8 years. Seventy patients presented with a macroadenoma. Mean baseline insulin growth factor 1 (IGF-1) (n = 67) was 3.2±1.9 × upper limit of normal (ULN). Surgery and radiotherapy were performed in 75 and 10 patients, respectively. Currently, 38 subjects receive somatostatin analogues, pegvisomant as a monotherapy is given to 8 patients, pasireotide is given to 17 patients, cabegoline to 4 patients, estrogen to 2 females, and SSAs combined with pegvisomant to 10 patients. Eight patients are not being actively treated, including 4 following radiotherapy. Good biochemical control (IGF-11.3 × ULN) was achieved in 76 patients (87%), and 11 patients (13%) are currently uncontrolled (IGF-11.3 × ULN). Seventy-eight percent of controlled patients are being given 1 medication; 11% are on combination therapy; 4 patients are well controlled after radiotherapy and 2 are partially controlled without any treatment. The main adverse effects of treatment were diabetes mellitus in 7 patients (on pasireotide) and symptomatic cholelithiasis in 5 patients.Active acromegaly can be controlled medically in most patients, with a low rate of adverse effects. This study displays the characteristic variety of treatment options available for active acromegaly.

Background: Reports on clinical and biochemical differences between adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas and macroadenomas are limited and inconsistent. Objective: Compare clinical and biochemical characteristics of patients with corticotroph microadenomas and macroadenomas and assess predictive factors for biochemical response to dynamic testing for Cushing’s disease (CD) in a clinical trial and a systematic review. A second aim was to evaluate differences between macroadenomas with and without cavernous and sphenoid sinus invasion. Methods: Retrospective charts review of patients with CD, treated at Rabin Medical Center between 2000 and 2020 or at Maccabi Healthcare Services in Israel between 2005 and 2017. Clinical and biochemical factors were compared between patients with corticotroph microadenomas and macroadenomas. We have also performed a systematic review of all studies (PRISMA guidelines) comparing corticotroph microadenomas with macroadenomas up to 31 November 2021. Results: The cohort included 105 patients (82 women, 78%; mean age, 41.5 ± 14.5 years), including 80 microadenomas (mean size, 5.2 ± 2.2 mm) and 25 macroadenomas (mean size, 18.0 ± 7.7 mm). Other baseline characteristics were similar between groups. Most common presentation suggestive for hypercortisolemia among patients with both micro- and macroadenomas were weight gain (46.3% vs. 48.0%, p = NS) and Cushingoid features (27.5% vs. 20.0%, p = NS). Mean 24 h urinary free cortisol (5.2 ± 5.4 × ULN vs. 7.8 ± 8.7 × ULN) and serum cortisol following low-dose dexamethasone (372.0 ± 324.5 vs. 487.6 ± 329.8 nmol/L), though higher for macroadenomas, were not significant. Levels of ACTH were greater for macroadenomas (1.9 ± 1.2 × ULN vs. 1.3 ± 0.8 × ULN, respectively, p = 0.01). Rates of recurrent/persistent disease were similar, as were rates of post-operative adrenal insufficiency and duration of post-operative glucocorticoid replacement. Macroadenomas with sphenoid or cavernous sinus invasion were associated with higher ACTH, 24 h free urinary cortisol, and serum cortisol following low-dose dexamethasone, compared with suprasellar or intrasellar macroadenomas. Conclusions: While ACTH-secreting macroadenomas exhibit higher plasma ACTH than microadenomas, there was no association between tumor size with cortisol hypersecretion or clinical features of hypercortisolemia. Though overall rare, increased awareness is needed for patients with CD with tumor extension in the cavernous or sphenoid sinus, which displays increased biochemical burden, highlighting that extent/location of the adenoma may be more important than size per se. Our systematic review, the first on this topic, highlights differences and similarities with our study.

The aim of this study is to assess the benefits of a nurse-led home injection service for somatuline autogel-treated patients with acromegaly, including the adherence to treatment and disease control. Historical prospective data of all patients with acromegaly initiating somatuline autogel between November 14, 2000, and March 9, 2020, who voluntarily enrolled in the nurse-led home injection service between January 1, 2018 and June 30, 2020. Adherence to treatment was calculated as the number of administered injections divided by the number of expected injections during the follow-up period. Excellent adherence to treatment was defined when >90% of scheduled injections were administered, while low adherence was defined when patients received

OBJECTIVES To evaluate the association between admission blood glucose (ABG) and mortality following hospitalization of solid-organ transplant recipients with and without diabetes. STUDY DESIGN Descriptive, retrospective observational data extracted from electronic health records. METHODS Observational data derived from the electronic health records of solid-organ transplant recipients who were hospitalized patients 18 years and older, admitted for any cause between January 2011 and December 2013. ABG levels were classified into categories: 70 to 110 mg/dL (normal), 111 to 140 mg/dL (mildly elevated), 141 to 180 mg/dL (moderately elevated), and greater than 180 mg/dL (markedly elevated). The main outcome was all-cause mortality. RESULTS Our study included 832 patients (median [SD] age = 59 [14] years; 62% male; 68% kidney transplant recipients), 503 (61%) of whom did not have diabetes. Just over half of patients without diabetes had normal ABG (54%), whereas most of those with diabetes had moderately or markedly increased ABG (58%). In patients without diabetes, markedly elevated ABG was associated with increased 30-day mortality risk compared with normal ABG (adjusted odds ratio [aOR], 6.6; 95% CI, 1.9-22.1). The same pattern was evident with investigation of the mortality risk after 1 year (aOR, 5.9; 95% CI, 2.4-14.7) and 3 years (aOR, 10.2; 95% CI, 4.3-24.0). Among patients with diabetes, there was no difference in mortality risk with different ABG. With a competing risk model for 90-day readmission and mortality, there was no association between ABG and risk for readmissions in patients with or without diabetes. CONCLUSIONS In organ transplant recipients admitted for any cause to a general ward, markedly elevated ABG in patients without diabetes was found to be independently associated with higher mortality risk compared with normal ABG levels. In patients with diabetes, there was no association between ABG level and mortality.

Hypocalcemia was reported at low rates (0.05–1.7%) in denosumab-treated postmenopausal women with osteoporosis. This real-life study shows a 7.4% rate of denosumab-induced hypocalcemia in community-dwelling osteoporotic men and women. Pretreatment serum calcium and creatinine levels are major predictors for this complication. Serum-calcium monitoring may help to identify and prevent severe hypocalcemia. RCTs have reported a 0.05–1.7% rate of hypocalcemia in denosumab-treated postmenopausal women with osteoporosis, but long-term real-life data are lacking. We assessed the rate of hypocalcemia in osteoporotic community-dwelling patients treated with denosumab. A retrospective analysis was conducted based on medical records (2010–2018) from a large HMO. An albumin-adjusted serum calcium concentration lower than 8.5 mg/dL was defined as hypocalcemia. We included 2005 patients (93% women, mean age 76 ± 9 years). Hypocalcemia developed during treatment in 149 patients (7.4%; 1% less than 8 mg/dL): in 66 after 0.5–1 years; 48 after 1–2 years; 35 after > 2 years. On comparison of the hypocalcemic and normocalcemic patients, the strongest predictors of hypocalcemia were pretreatment levels of albumin-adjusted serum calcium (9.1 ± 0.4 vs. 9.4 ± 0.5 mg/dL, respectively; p

Background Glucose variability is common among hospitalized patients, but the prognostic implications among patients hospitalized in surgical wards are unknown. The objective of this study was to investigate the association between glucose variability, length of stay, and mortality. Methods Historical prospectively collected data of patients ≥18 years of age, hospitalized in general surgery wards between January 2011 and December 2017. Glucose variability was assessed by coefficient of variance and standard deviation of glucose values during hospitalization. The main outcomes were length of stay and 30-day and end-of-follow-up mortality. Results The cohort included 8,894 patients (mean age 63 ± 19 years, 48% male, mean follow-up 3.0 ± 1.8 years). A total of 2,012 (23%) patients had diabetes mellitus. The mean length of stay was longer with a higher coefficient of variance or standard deviation in patients without and with diabetes mellitus. The 30-day mortality was 6%, associated with a higher versus a lower coefficient of variance (9% vs 3%) and standard deviation (9% vs 3%) in patients without diabetes mellitus and with diabetes mellitus (9% vs 5%; 8% vs 5%, respectively). Mortality at the end of follow-up was increased in patients without diabetes mellitus with a higher coefficient of variance (27% vs 18%) and standard deviation (29% vs 17%) and in patients with diabetes mellitus (33% vs 24% and 32% vs 21%, respectively). Multivariate analysis indicated an increased risk for 30-day and end-of-follow-up mortality, in both groups. Adjustment for glucocorticoid treatment or hypoglycemia did not affect the results. In patients with a high or low coefficient of variance, mortality was higher with median glucose levels during hospitalization ≥180 mg/dl, compared with Conclusion In patients with and without diabetes mellitus hospitalized in general surgery wards, increased glucose variability is associated with longer hospitalization and increased short-term and long-term mortality.

To characterize a cohort of elderly men with prolactinomas and their response to treatment. We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. Mean age at diagnosis was 71.3 ± 5.6 (range 65–86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50–18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to

Objective: Graft-versus-host disease (GVHD) is an immune phenomenon that occurs in 30 to 70% of patients after allogeneic hematopoietic stem cell transplantation (HST). Chronic GVHD is a state of immune dysregulation wherein, depending on the severity and organ involved, patients may require prolonged treatment with additional or higher corticosteroids and other immunosuppressive agents. The objective of this study was to review the endocrine manifestations following HST that can arise as a consequence of the primary disease or its treatment, including chemotherapeutic agents, corticosteroids, radiation, or GVHD. Methods: We performed a narrative review of GVHD after HST. An English-language search for relevant studies was conducted on PubMed from inception to August 1, 2018, using the following search terms: "endocrine complications," "bone marrow transplantation," "graft-versus-host disease," and "GVHD." The reference lists of relevant studies were also reviewed. Results: Chronic GVHD may be associated with considerable pediatric growth impairment and may also contribute to thyroid gland dysfunction and thyroid cancer. These patients may also be at increased risk for low bone mineral density, reduced fertility, metabolic syndrome, and suppression of the pituitary-adrenal axis with adrenal insufficiency. Conclusion: This review indicates the importance of monitoring, diagnosing, and properly treating the endocrine complications in this population. More studies are needed to investigate the independent impact of GVHD on the endocrine system and treatment for complications. Abbreviations: BMD = bone mineral density; GH = growth hormone; GVHD = graft-versus-host disease; HST = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1.

Pasireotide long acting (LAR) can be effective in normalizing insulin-like growth factor (IGF)-1 level in acromegaly patients inadequately controlled by octreotide or lanreotide.Determine the long-term efficacy and safety of pasireotide, including time to biochemical control and time to best response, and risk for diabetes mellitus.A retrospective multicenter study investigating the efficacy and safety of pasireotide LAR treatment in patients with active acromegaly treated for12 months.The study included 19 patients (10 men; mean age ± SD, 48.0 ± 12.9 years) treated with pasireotide for a mean of 50 ± 36 months. During the follow-up, 4 patients discontinued pasireotide treatment. Pasireotide LAR produced a tolerable and long-term significant biochemical response in 15 of 19 patients (79.0%). Mean time to IGF-1 normalization from pasireotide LAR initiation was 13.6 ± 16.9 months with early biochemical normalization (12 months) evident in 11 (64.7%) patients and delayed IGF-1 normalization in 6 (35.2%) patients. Nadir IGF-1 values were recorded within the first 12 months in 6 patients (35.3%), while in 11 patients (64.7%) lowest values were reported after12 months of treatment, including 4 of 11 patients with early IGF-1 normalization. New-onset diabetes was documented in 5 of 7 patients with pre-diabetes and in 1 of 5 patients with normal glucose homeostasis at baseline. Among patients with pre-diabetes or diabetes mellitus prior to initiating pasireotide, mean HbA1c increase was 0.56 ± 1.0%.The results support the long-term efficacy and safety of pasireotide LAR for acromegaly and support the potential delayed effect of treatment on IGF-1 normalization.

Background: The diagnosis of acromegaly still poses a clinical challenge, and prolonged diagnostic delay is common. The most important assays for the biochemical diagnosis and management of acromegaly are growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Objective: Discuss the role of IGF-1, basal serum GH, and nadir GH after oral glucose tolerance test (OGTT) for the diagnosis, management, and treatment of patients with acromegaly. Methods: We performed a narrative review of the published data on the biochemical diagnosis and monitoring of acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 January 2021. The reference lists of relevant studies were also reviewed. Results: Serum IGF-1 levels, basal GH values, and nadir GH after OGTT play a major role in the diagnosis, management, and treatment of patients with acromegaly. Measurement of IGF-1 levels is the key factor in the diagnosis and monitoring of acromegaly, but basal and nadir GH following OGTT are also important. However, several factors may significantly influence the concentrations of these hormones, including assay methods, physiologic and pathologic factors. In some cases, discordant GH and IGF-1 levels may be challenging and usually requires additional data and monitoring. Conclusion: New GH and IGF-1 standards are much more precise and provide more accurate tools to diagnose and monitor patients with acromegaly. However, all these biochemical tools have their limitations, and these should be taken under consideration, along with the history, clinical features and imaging studies, when assessing patients for acromegaly.

The diagnosis of neuroendocrine tumors is based on the recognition of signs and symptoms of the structural and functional effects of these tumors. The structural impact depends on the location of the tumor; in some, such as the pituitary, the structural impact can be significant because of mass effects in a small enclosed and critical area, whereas in others, such as distal pancreas or retroperitoneal sites like adrenal, tumors can grow to be very large without major mass effects. The functional aspects of these tumors involve biochemical confirmation that can be very complex. In this chapter, the various hormone excess syndromes are discussed, along with the specific structural considerations at the common sites of neuroendocrine tumors. The wide array of clinical manifestations of neuroendocrine tumors emphasizes the importance of careful clinical history, sophisticated biochemical investigations, and thoughtful consideration of the potential for germline predisposition syndromes that are common in these disorders.

Neuroendocrine neoplasms arise in tissues of the endocrine system, including pituitary, thyroid, parathyroid, pancreas, respiratory system, gastrointestinal tract, and adrenal glands and rarely in other unusual sites. Surgery is the first line of treatment in many of these cases and can include a complete removal of the organ (i.e., total thyroidectomy or adrenalectomy), partial removal (i.e., hemithyroidectomy or distal pancreatectomy), or removal of only the tumor (i.e., pituitary tumor). Medical treatment is frequently used, and while this is usually reserved as adjuvant treatment to control symptoms or tumor growth in cases of residual disease following surgical intervention, it is sometimes used as a treatment of choice (i.e., prolactinoma), sometimes as neoadjuvant before surgery to improve outcomes (i.e., treatment to control growth hormone or cortisol excess before surgery), or as the sole primary treatment in patients who are poor candidates for surgery. Other treatment options can include radiotherapy and peptide receptor radionuclide therapy (PRRT); in some patients, additional therapies are intended for symptom control. Additional data on the molecular basis of neuroendocrine neoplasms may lead to providing treatment sequences personalized for each patient, based on the tumor biology and molecular and genetic patterns. Immunotherapy with immune checkpoint inhibitors may prove to be a successful option for selected neuroendocrine neoplasms.

Background Diabetic ketoacidosis (DKA) is an acute metabolic complication characterized by hyperglycaemia, ketones in blood or urine, and acidosis. Objective The aim of this study was to characterize features of patients hospitalized for DKA, to identify triggers for DKA and to evaluate the long-term effects of DKA on glycaemic control, complications of diabetes, re-hospitalizations, and mortality. Methods Historical prospectively collected data of patients hospitalized to medical wards for DKA between 2011 and 2017. Data regarding comorbidities, mortality, triggers, and re-hospitalizations for DKA were also collected. Results The cohort consisted of 160 patients (mean age 38 ± 18 years, 43% male). One fifth of the patients (34 patients, 21%) were newly diagnosed with diabetes, and DKA was their first presentation of the disease. Among the 126 patients with pre-existing diabetes, the common identified triggers for DKA were poor compliance to treatment (22%) and infectious diseases (18%). During over 7 years of follow-up, mortality rate was 9% (15 patients), and re-hospitalization for DKA rate was 31% (50 patients). Risk factors for re-hospitalization for DKA included young age (OR = 1.02, 95% CI, 1.00-1.04), pre-existing diabetes compared to DKA as the first presentation (OR = 5.4, 95% CI, 1.7-18), and poorer glycaemic control before initial hospitalization (10.5 ± 2.5% vs. 9.4 ± 2.2%; OR = 0.8, 95% CI [0.68-0.96]) and after discharge (10.3 ± 2.4% vs. 9.0 ± 1.9%; OR = 0.73, 95% CI [0.61-0.87]). Laboratory tests during the initial hospitalization, smoking, alcohol, or comorbidities did not increase the risk for re-hospitalization for DKA. Conclusions The risk for readmission for DKA is higher for young patients with long duration of diabetes, poor compliance of insulin treatment and poorly controlled diabetes.

Medullary thyroid cancer is a rare type of neuroendocrine tumour that arises from the parafollicular cells (C cells) of the thyroid gland. It accounts for 3%&ndash, 5% of thyroid cancer cases. Close to 25% of cases are familial, and 75% are considered sporadic. Familial cases are associated with a germline RET mutation, 43%&ndash, 65% of sporadic cases harbour a somatic event in the gene. Germline RET mutations are associated with the autosomal-dominant inherited multiple endocrine neoplasia (men) 2a and 2b syndromes and the isolated familial medullary thyroid cancer syndrome. More than 100 RET codon mutations have been reported to date, with genotype&ndash, phenotype correlations that include the extent and aggressiveness of the medullary thyroid cancer and the presence of other features of the men2 syndromes. The latter include pheochromocytoma&ndash, paraganglioma, hyperparathyroidism, cutaneous lichen amyloidosis, and Hirschsprung disease.

Objectives Radioactive iodine (RAI) treatment is often indicated after total thyroidectomy in differentiated thyroid cancer (DTC). However, its role in biochemical or locoregional persistent DTC is unclear. We aimed to investigate the effect of a second RAI treatment in patients with incomplete response to initial treatment and no evidence of distant metastases. Methods Patients who underwent at least two RAI treatments over a 20-year period at a tertiary hospital were identified. Thyroglobulin levels and neck imaging were compared before and 1 to 2 years after RAI retreatment and evaluated at the last visit. Results The cohort included 164 patients (103 female; mean age, 46.6 ± 17 years). Of 114 patients retreated without prior reoperation, 53 had structural disease. At 1 to 2 years after RAI retreatment, 10 of the 41 patients with sufficient data had structural progression, 5 resolution/shrinkage, and 26 stable disease. Stimulated thyroglobulin (stTg) measured 93.7.1 ± 108 ng/mL before and 102.2 ± 124 ng/mL after retreatment (P = NS). The other 61 patients had biochemical-only persistence. Their stTg levels decreased from 41.9 ± 56 to 24.6 ± 54 ng/mL (P = 0.003). The 50 patients who underwent neck reoperation before RAI retreatment showed no substantial change in stTg; 21 (42%) still had imaging findings 1 to 2 years later. At final follow-up, despite additional treatment in 63/164 patients (38.4%), only 56/164 (34.1%) had no evidence of disease. Conclusions This comprehensive study showed limited benefit of second RAI treatment in DTC patients with biochemical or locoregional structural persistent disease. Prospective studies are needed to distinguish patients for whom repeated RAI may be indicated to avoid unnecessary exposure.

Context One of the major complications in patients with aggressive lymphoma receiving intensive chemo-immunotherapy is febrile neutropenia (FN). Diabetes mellitus (DM) has deleterious effects on the immune system, resulting in an increased risk for infections, as well as a complicated course of infections. Objectives We aimed to examine whether comorbidity with DM, as well as diabetic control, affects the risk of FN or complicates the course of FN in aggressive lymphoma patients. Design, Setting, and Patients This is a retrospective, single-center study. We included all consecutive patients diagnosed with aggressive large cell lymphoma treated at our institute between 2013 and 2017. Demographics, disease-related outcomes, and laboratory data were extracted from electronic medical records. Categorical variables were compared using the ×2 or the Fisher's exact test, and medians were compared with the Mann–Whitney U test. Results 226 patients with aggressive large cell lymphoma were treated in our medical center. Of these, 49 patients (22%) had type 2 DM. There were 129 hospital admissions due to FN in the entire cohort during lymphoma treatment. Patients with DM had higher mean admission rates due to FN compared to patients without DM (0.88 and 0.51 FN admissions per patient, respectively, P=0.004). The admission rate in patients with DM remained higher after age and gender-matched subgroup analysis (P = 0.005). However, the duration of hospitalizations and number of admissions to the ICU were similar in patients with and without DM. In patients with DM, improved glycemic control during hospitalizations due to FN was associated with shorter hospital stay. However, baseline hemoglobin A1c levels were not associated with increased risk for FN or infectious complications. Use of metformin was associated with an improved overall survival in diabetic patients (overall survival not reached compared to 43 months). Conclusions Patients with aggressive large cell lymphoma and DM had higher rates of hospitalizations due to FN. Furthermore, our data suggest that improved glycemic control during hospitalization is associated with a shorter length of hospitalization for FN. The positive effects of metformin in our study cohort may warrant further investigation.

Distant metastatic spread is the most frequent cause of thyroid cancer-related death. The objective of this study was to evaluate overall and disease-related survival of patients with differentiated thyroid cancer (DTC) and distant metastases (DM) attending a single medical center and to investigate variables predictive of better long-term outcomes.The Rabin Medical Center Thyroid Cancer Registry was searched for patients with DM from DTC.The cohort included 138 patients (58.7% female) diagnosed at age 54.7 ± 19.5 years. Mean primary tumor size was 33.9 ± 26 mm. Most patients (57.7%) were stage T3/T4; 48.7% had extrathyroidal extension; 53.5% had lymph node metastases. Histopathology yielded papillary and follicular thyroid carcinoma in 66.7% and 13.8%, respectively, and intermediate/poorly differentiated carcinoma in 19.6%. All but 2 patients underwent total thyroidectomy, and 133/138 (96.4%) received radioactive iodine (RAI) therapy. DM were synchronous in 55.1%. The mean follow-up was 8.2 years from detection of metastases. The common sites of metastases were the lungs (85.6% of patients), bones (39.9%), brain (5.8%) and liver (3.6%). At last follow-up, resolution was documented in 24.6% of patients, improvement/stable disease in 31.6%, and structurally progressive disease in 43.4%. By the end of the study, 40.6% of patients died, 23.2% of DTC. Improved overall survival and disease progression were associated with younger age, lung-only DM, and metastatic RAI avidity.Patients with DTC and DM treated by standard-of-care approaches frequently achieve favorable long-term outcomes. Novel therapies might be necessary in only a minority of these patients, and the reported prognostic factors can aid in their identification.CR = complete response; DM = distant metastases; DTC = differentiated thyroid cancer; ETE = extra-thyroidal extension; M0 = detected during follow-up; M1 = detected at diagnosis; MSKCC = Memorial Sloan Kettering Cancer Center; NED = no evidence of disease; OS = overall survival; PFS = progression free survival; PTC = papillary thyroid cancer; RAI = radioactive iodine; Tg = thyroglobulin.

The current trend of less aggressive treatment of low-risk differentiated thyroid cancer (DTC) patients was recently challenged by a study reporting10% disease-related mortality (DRM) in low-risk patients ablated with radioiodine activities below 54 mCi. However, this study and others were limited by incomplete data on disease severity at presentation. Whether patients presenting with low-risk disease are at risk for disease-related mortality is crucial for planning current treatment strategies.Patients with documented DRM from DTC were included from the Rabin thyroid cancer registry and the Davidoff Head and Neck cancer service databases. Disease characteristics at presentation, treatments, disease course, and cause of death were analyzed.Of 1374 patients whose charts were reviewed, 56 were confirmed to have died of DTC, and 53 had sufficient data for analysis. Median time from diagnosis to death was 9 years (range 1-36). Cause of death was related to distant metastases in 46 patients and aggressive neck disease in 7 patients. The median age at diagnosis was 62 years (range 22-83, 83% older than 45), and were initially categorized as American Thyroid Association high risk in 89% of cases (in 4 cases due to high thyroglobulin levels), intermediate risk in 6% (3 older patients with N1b disease), misclassification as benign in one case, and none was low risk. Most patients had an advanced disease stage (stage IV, 88%; III, 2%; II, 2%; I, 8%). All patients with stage I disease were45 years, with aggressive features (1 poorly differentiated, 3 gross extrathyroidal extension). One patient with stage II disease was45 years and had distant metastases. Detection of distant metastases occurred within the first year in 25 patients and during subsequent follow-up in 25 patients. Overall, aside from one patient who was misdiagnosed as having a benign follicular adenoma at presentation, all patients had aggressive disease features at presentation.None of the patients with DRM had low-risk features at presentation, supporting the current paradigm of less aggressive approach in the low-risk group. Studies analyzing mortality from thyroid cancer should stratify patients into the various risk categories based on full baseline data, including postoperative thyroglobulin levels.

Context Glucose variability (GV) is common among hospitalized patients, but the prognostic implications are not understood. Objective Investigate the association between GV, hospital length of stay (LOS), and mortality. Methods GV was assessed by coefficient of variance (CV) and standard deviation (SD) of glucose values during hospitalization. Setting Historical prospectively collected data of patients hospitalized between January 2011 and December 2013. Patients Patients ≥18 years old. Main outcome LOS, and in-hospital and mortality at end of follow-up. Results The cohort included 20,303 patients (mean age ± SD, 70 ± 17 years; 51% men; median follow-up, 1022 days), of whom 8565 patients (42%) had diabetes mellitus (DM). Mean LOS was longer with higher CV or SD tertiles in patients without and with DM. In-hospital mortality was 8.2%, associated with higher tertiles of CV (4%, 10%, 19%) and SD (4%, 11%, 21%) in patients without DM and with DM (3%, 5%, 10%; and 2%, 4%, 9%, respectively). Mortality at the end of follow-up was increased in patients without DM with higher CV (28%, 42%, 55%) and SD (28%, 44%, 57%) tertiles and in patients with DM (26%, 35%, 45%; and 25%, 34%, 44%, respectively). Multivariate analysis indicated increased risk for in-hospital and end of follow-up mortality, in both groups. Adjustment for glucocorticoid treatment or hypoglycemia did not affect the results. Glucose levels during hospitalization and GV were two independent factors affecting LOS and in-hospital mortality. In each CV tertile, mortality was higher with median glucose ≥180 mg/dL, compared with Conclusions In hospitalized patients with and without DM, increased GV is associated with longer hospitalization and increased short- and long-term mortality.

Background: The association of blood pressure (BP) variability (BPV) in hospitalized patients, which represents day-to-day variability, with mortality has been extensively reported in patients with stroke, but poorly defined for other medical conditions. Aim and method: To assess the association of day-to-day blood pressure variability in hospitalized patients, 10 BP measurements were obtained in individuals ≥75 years old hospitalized in a geriatric ward. Day-to-day BPV, measured 3 times a day, was calculated in each patient as the coefficient of variation of systolic BP. Patients were stratified by quartiles of coefficient of variation of systolic BP, and 30-day and 1-year mortality data were compared between those in the highest versus the lowest (reference) group. Results: Overall, 469 patients were included in the final analysis. Mean coefficient of variation of systolic BP was 12.1%. 30-day mortality and 1-year mortality occurred in 29/469 (6.2%) and 95/469 (20.2%) individuals respectively. Patients in the highest quartile of BPV were at a significantly higher risk for 30-day mortality (HR =4.12, CI 1.12–15.10) but not for 1-year mortality compared with the lowest BPV quartile (HR =1.61, CI 0.81–3.23). Conclusions: Day-to-day BPV is associated with 30-day, but not with 1-year mortality in hospitalized elderly patients.

Aims Evaluate association between admission blood glucose (ABG) and mortality in patients with or without diabetes mellitus (DM) hospitalized for venous thromboembolism (VTE). Methods Observational data derived from the electronic records of hospitalized patients ≥18years, admitted for VTE (including deep vein thrombosis and pulmonary embolism) between January 2011 and December 2013. ABG levels were classified to categories: ≤70 (low), 70–110 (normal), 111–140 (mildly elevated), 141–180mg/dl (moderately elevated) and>180mg/dl (markedly elevated). Main outcome was all-cause mortality at the end of follow-up. We had complete follow-up data at 12months for all patients; median follow-up time was 1126days. Results Cohort included 567 patients, 137 with (mean age 73, 45% male), and 430 without DM (mean age 65, 40% male). There was a significant interaction between DM, ABG and mortality (p≤0.05). In patients without DM there was a significant association between ABG and mortality: [hazard ratios 1.6, 2.3, and 4.7 respectively for mildly, moderately and markedly elevated ABG (p≤0.01)]. A significant association between ABG and mortality persisted following multivariable analysis only in patients with markedly elevated ABG (HR=2.3 95% CI 1.2–4.5). Similar results were evident in patients with deep vein thrombosis or pulmonary embolism. In patients with DM there was no significant association between ABG and mortality. Conclusion In patients without DM hospitalized for VTE, markedly elevated ABG is associated with increased mortality.

Context Numerous studies investigated the link between hypothyroidism and mortality, but a definite conclusion is hard to reach as these were limited by a number of factors, including age of participants, comorbidities and single measurement of thyroid function. Objective To evaluate the association between TSH and fT4 levels and mortality in patients with levothyroxine-treated hypothyroidism. Design and setting Observational data of hospitalized patients (2011–2014). TSH and fT4 levels obtained between at least 30 days after discharge and until death or end of follow-up were collected. Median TSH and fT4 levels were stratified into categories. Patients In total, 611 patients with treated hypothyroidism, aged 60–80 years (72% females, mean age 71 ± 6 years) were included in the study. Main outcome measure All-cause mortality up to 66 months after discharge, by TSH and fT4 categories. Results During follow-up, the average numbers of TSH and fT4 measurements were 5.5 ± 3.8 and 2.5 ± 4.2 per patient respectively. Mortality rates were 28%, 29% and 54% with median TSH of 0.5–2.5, 2.5–5.0 and 5.0–10.0 IU/L respectively. Adjusted hazard ratios for mortality with median TSH between 5.0 and 10.0 IU/L were 2.3 (95% CI: 1.6–3.4) and 2.2 (95% CI: 1.6–3.2) compared with patients with TSH between 0.5–2.5 IU/L and 2.5–5 IU/L respectively. There was no difference in mortality between patients with median fT4 10–15 or 15–20 pmol/L. Conclusion In treated hypothyroid adult patients and serial measurements of thyroid function tests, median TSH levels of 5–10 IU/L are associated with increased mortality with no effect of fT4 levels. Treatment should aim at achieving euthyroidism to improve survival.

Hypoglycemia is common among hospitalized patients with and without diabetes mellitus.Investigate the association between spontaneous or insulin-related hypoglycemia and mortality in hospitalized patients.Hypoglycemia was defined as blood glucose70 mg/dl (3.9 mmol/l), including moderate (40 to 70 mg/dl, 2.2 to 3.9 mmol/l) and severe hypoglycemia (40 mg/dl, 2.2 mmol/l). Use of insulin during hospitalization defined insulin-related hypoglycemia, thus patients were classified into 6 groups: non-insulin treated (NITC) and insulin-treated controls (ITC), insulin-related hypoglycemia (IH) or severe hypoglycemia (ISH), and non insulin-related hypoglycemia (NIH) and severe hypoglycemia (NISH).Historical prospectively data of patients ≥ 18 years of age, hospitalized in medical wards for any cause between January 2011 and December 2013.All-cause mortality at the end of follow-up.The cohort included 33,675 patients, including 2605 with moderate hypoglycemia (IH, 1011; NIH, 1594) and 342 with severe hypoglycemia (ISH, 201; NISH,141). Overall end-of-follow-up mortality was 31.9% (NITC, 28.0%; ITC, 42.9%; NIH, 50.7%; IH, 55.3%; NISH, 70.9%; ISH, 69.1%). Compared with NITC, unadjusted hazard ratios (95% confidence intervals) for mortality were as follows: ITC, 1.7 (1.6 to 1.8), NIH, 2.2 (2.0 to 2.4), IH, 2.5 (2.2 to 2.7), NISH, 4.2 (3.5 to 5.2), and ISH, 3.8 (3.2 to 4.5); with P0.001. Following multivariate analysis, respective hazard ratios were 1.8, 2.1, 2.4, 3.2, and 3.6 (P0.001). Cause of admission did not affect the association.In hospitalized patients, hypoglycemia, either with insulin use or spontaneous, is associated with increased short- and long-term mortality.

Background: Acromegaly results from a persistent excess in growth hormone with clinical features that may be subtle or severe. The most common cause of acromegaly is a pituitary tumor that causes excessive production of growth hormone (GH), and rare cases are due to an excess of the GH-releasing hormone (GHRH) or the ectopic production of GH. Objective: Discuss the different diseases that present with manifestations of GH excess and clinical acromegaly, emphasizing the distinct clinical and radiological characteristics of the different pathological entities. Methods: We performed a narrative review of the published clinicopathological information about acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 August 2019. The reference lists of relevant studies were also reviewed. Results: Pituitary tumors that cause GH excess have several variants, including pure somatotroph tumors that can be densely or sparsely granulated, or plurihormonal tumors that include mammosomatotroph, mixed somatotroph-lactotroph tumors and mature plurihomonal Pit1-lineage tumors, acidophil stem cell tumors and poorly-differentiated Pit1-lineage tumors. Each tumor type has a distinct pathophysiology, resulting in variations in clinical manifestations, imaging and responses to therapies. Conclusion: Detailed clinicopathological information will be useful in the era of precision medicine, in which physicians tailor the correct treatment modality to each patient.

The management of pancreatic neuroendocrine tumors (PanNETs) involves classification into non-functional or functional PanNET, and as localized or metastatic PanNET. In addition, while most PanNETs are sporadic, these endocrine neoplasms can also be manifestations of genetic syndromes. All these factors may assist in forming a risk stratification system permitting a tailored management approach. Most PanNETs are classified as non-functional because they are not associated with clinical sequelae of hormone excess. They are characterized by non-specific symptoms, such as abdominal pain or weight loss, resulting from mass effect related to the pancreatic tumor or secondary to distant metastases. Accurate staging of the disease is essential for determining the appropriate approach to therapy. As cure is only potentially possible with surgical resection of the tumor, it is recommended to remove all localized and limited metastatic disease. However, many patients present with metastatic and/or advanced local disease. In such instances, the goal of therapy is to control tumor growth and/or decrease tumor burden, lengthen survival, and palliate local symptoms and those of hormone excess. This typically requires a multimodal approach, including surgery, liver-directed treatment, and systemic medical therapy.

Previous studies have reported conflicting results on the association between hypoalbuminaemia and morbidity and mortality in hospitalised patients.To investigate the association of albumin levels on admission and change in levels during hospitalisation of patients in general surgery wards with hospitalisation outcomes.Historical prospective data of patients hospitalised between January 2011 and December 2017. Albumin levels were classified as follows: marked hypoalbuminaemia (2.5 mg/dL), mild hypoalbuminaemia (2.5-3.5 mg/dL), normal albumin (3.5-4.5 mg/dL) and hyperalbuminaemia (4.5 mg/dL). Main outcomes were length of hospitalisation, 30-days and long-term mortality.The cohort included 17 930 patients (mean age 58 ± 20 years, 49% male). Most had normal albumin levels on admission (n = 11 087, 62%), 16% had mild hypoalbuminaemia (n = 2824) and 3% had marked hypoalbuminaemia (n = 529). Hyperalbuminaemia on admission was evident in 20% of the patients (n = 3490). Follow-up time was up to 7.2 years (median ± SD = 3 ± 2 years). Compared to 30-day mortality with normal albumin on admission (2%), mortality was higher with mild (9%) and marked hypoalbuminaemia (22%) and lower with hyperalbuminaemia (0.4%). The mortality rate at the end of follow up was 14% with normal albumin levels, and 35% and 58% with mild and marked hypoalbuminaemia respectively. Patients with hyperalbuminaemia on admission and before discharge had the best short- and long-term survival. This pattern was similar when analysed separately in different age groups. In patients with hypoalbuminaemia on admission, normalisation of albumin levels before discharge was associated with lower short- (12% vs 1%) and long-term mortality risk (42% vs 17%).Low albumin levels on admission to general surgery wards are associated with increased short- and long-term mortality. Normalisation of albumin levels before discharge was associated with lower mortality, compared to hypoalbuminaemia before discharge.