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Seminars in Oncology Dec 2023Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies,... (Review)
Review
Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.
Topics: Humans; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological; Neoplasms; Addison Disease; Antibodies, Monoclonal
PubMed: 38151399
DOI: 10.1053/j.seminoncol.2023.11.003 -
Biomolecules Nov 2023BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivatives have attracted attention as probes in applications like imaging and sensing due to their unique... (Review)
Review
BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivatives have attracted attention as probes in applications like imaging and sensing due to their unique properties like (1) strong absorption and emission in the visible and near-infrared regions of the electromagnetic spectrum, (2) strong fluorescence and (3) supreme photostability. They have also been employed in areas like photodynamic therapy. Over the last decade, BODIPY-based molecules have even emerged as candidates for cancer treatments. Cancer remains a significant health issue world-wide, necessitating a continuing search for novel therapeutic options. BODIPY is a flexible fluorophore with distinct photophysical characteristics and is a fascinating drug development platform. This review provides a comprehensive overview of the most recent breakthroughs in BODIPY-based small molecules for cancer or disease detection and therapy, including their functional potential.
Topics: Boron Compounds; Photochemotherapy; Fluorescence; Fluorescent Dyes
PubMed: 38136594
DOI: 10.3390/biom13121723 -
Current Atherosclerosis Reports Feb 2024To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral,... (Review)
Review
PURPOSE OF REVIEW
To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD).
RECENT FINDINGS
Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C. Phase 3 pivotal registration trials including a cardiovascular outcomes trial are underway. Obicetrapib has an excellent safety and tolerability profile and robustly lowers atherogenic lipoproteins and raises HDL-C. As such, obicetrapib may be a promising agent for the treatment of ASCVD.
Topics: Humans; Cholesterol Ester Transfer Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Cholesterol, HDL; Atherosclerosis; Lipoproteins; Ezetimibe
PubMed: 38133847
DOI: 10.1007/s11883-023-01184-1 -
Diseases (Basel, Switzerland) Dec 2023Alzheimer's disease is the sixth most common cause of death in the United States (U.S.), with one in three adults 65 years of age and older dying of the disease each... (Review)
Review
UNLABELLED
Alzheimer's disease is the sixth most common cause of death in the United States (U.S.), with one in three adults 65 years of age and older dying of the disease each year. Deaths from Alzheimer's have more than doubled between 2000 and 2019, killing more adults than both breast cancer and prostate cancer. In 2021, Alzheimer's disease resulted in 36 deaths per 100,000 in the U.S. In Mississippi, deaths from Alzheimer's have almost doubled between 2011 and 2021, resulting in 52.9 deaths per 100,000. Women have a higher mortality rate from Alzheimer's than men. Alzheimer's is a progressive disease that develops through seven stages. There are effective strategies to prevent the onset of Alzheimer's.
METHODS
This paper reviews the risk factors, mortality trends, etiology, and prognosis of Alzheimer's in Mississippi with a focus on prevention.
RESULTS
The southern diet with foods high in sugar and sodium, along with sedentary and poor lifestyle choices, increases mortality risk from Alzheimer's disease for women in Mississippi, specifically due to women over 65 having higher rates of obesity and hypertension.
CONCLUSION
Understanding the epidemiology and risk factors of Alzheimer's in Mississippi will help inform communities, policies, and programs to prevent disease occurrence.
PubMed: 38131985
DOI: 10.3390/diseases11040179 -
Journal of Clinical Medicine Nov 2023(1) Background: Patients with primary adrenal insufficiency (PAI) suffer from a reduced quality of life. However, clinical factors associated with this impairment remain...
(1) Background: Patients with primary adrenal insufficiency (PAI) suffer from a reduced quality of life. However, clinical factors associated with this impairment remain unclear. The aim of this study was to assess the health-related quality of life (HRQoL) and to evaluate the associations with clinical and hormonal parameters in a group of patients with PAI. (2) Methods: The study included 32 patients with autoimmune PAI, who answered the quality of life in Addison's disease questionnaire (AddiQoL). Clinical data and hormonal measurements were collected from the patients. (3) Results: The total AddiQoL score of males was significantly higher than that of females ( = 0.011). Furthermore, males reached significantly higher scores in each of the four subscales (fatigue- = 0.013, emotional sphere- = 0.048, adrenal insufficiency symptoms- = 0.039, and miscellaneous questions- = 0.034). There was a negative correlation between HRQoL and gonadotropin levels (FSH and fatigue r = (-)0.38, = 0.032; FSH and emotional sphere r = (-)0.416, = 0.018). This study found no significant associations between AddiQoL scores and the presence of autoimmune comorbidities; only fatigue scores were worse in the presence of autoimmune thyroiditis ( = 0.034). The doses of hydrocortisone and fludrocortisone in the replacement therapy were not associated with AddiQoL scores. AddiQoL scores correlated negatively with the age of diagnosis ( = 0.015). (4) Conclusions: Female sex, higher gonadotropins level, and older age at diagnosis were associated with impaired HRQoL in the studied group of patients with PAI.
PubMed: 38068288
DOI: 10.3390/jcm12237237 -
Frontiers in Endocrinology 2023Adrenal insufficiency encompasses a group of congenital and acquired disorders that lead to inadequate steroid production by the adrenal glands, mainly glucocorticoids,... (Review)
Review
Adrenal insufficiency encompasses a group of congenital and acquired disorders that lead to inadequate steroid production by the adrenal glands, mainly glucocorticoids, mineralocorticoids and androgens. These may be associated with other hormone deficiencies. Adrenal insufficiency may be primary, affecting the adrenal gland's ability to produce cortisol directly; secondary, affecting the pituitary gland's ability to produce adrenocorticotrophic hormone (ACTH); or tertiary, affecting corticotrophin-releasing hormone (CRH) production at the level of the hypothalamus. Congenital causes of adrenal insufficiency include the subtypes of Congenital Adrenal Hyperplasia, Adrenal Hypoplasia, genetic causes of Isolated ACTH deficiency or Combined Pituitary Hormone Deficiencies, usually caused by mutations in essential transcription factors. The most commonly inherited primary cause of adrenal insufficiency is Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency; with the classical form affecting 1 in 10,000 to 15,000 cases per year. Acquired causes of adrenal insufficiency can be subtyped into autoimmune (Addison's Disease), traumatic (including haemorrhage or infarction), infective (e.g. Tuberculosis), infiltrative (e.g. neuroblastoma) and iatrogenic. Iatrogenic acquired causes include the use of prolonged exogenous steroids and post-surgical causes, such as the excision of a hypothalamic-pituitary tumour or adrenalectomy. Clinical features of adrenal insufficiency vary with age and with aetiology. They are often non-specific and may sometimes become apparent only in times of illness. Features range from those related to hypoglycaemia such as drowsiness, collapse, jitteriness, hypothermia and seizures. Features may also include signs of hypotension such as significant electrolyte imbalances and shock. Recognition of hypoglycaemia as a symptom of adrenal insufficiency is important to prevent treatable causes of sudden deaths. Cortisol has a key role in glucose homeostasis, particularly in the counter-regulatory mechanisms to prevent hypoglycaemia in times of biological stress. Affected neonates particularly appear susceptible to the compromise of these counter-regulatory mechanisms but it is recognised that affected older children and adults remain at risk of hypoglycaemia. In this review, we summarise the pathogenesis of hypoglycaemia in the context of adrenal insufficiency. We further explore the clinical features of hypoglycaemia based on different age groups and the burden of the disease, focusing on hypoglycaemic-related events in the various aetiologies of adrenal insufficiency. Finally, we sum up strategies from published literature for improved recognition and early prevention of hypoglycaemia in adrenal insufficiency, such as the use of continuous glucose monitoring or modifying glucocorticoid replacement.
Topics: Child; Adult; Infant, Newborn; Humans; Adolescent; Hydrocortisone; Adrenal Hyperplasia, Congenital; Blood Glucose Self-Monitoring; Blood Glucose; Adrenal Insufficiency; Glucocorticoids; Adrenocorticotropic Hormone; Hypoglycemia; Iatrogenic Disease
PubMed: 38053731
DOI: 10.3389/fendo.2023.1198519 -
Journal of Veterinary Internal Medicine 2024Dogs with eunatremic, eukalemic hypoadrenocorticism (EEH) typically show signs of chronic gastrointestinal disease (CGD). Previous glucocorticoid administration (PGA)...
Prevalence of eunatremic, eukalemic hypoadrenocorticism in dogs with signs of chronic gastrointestinal disease and risk of misdiagnosis after previous glucocorticoid administration.
BACKGROUND
Dogs with eunatremic, eukalemic hypoadrenocorticism (EEH) typically show signs of chronic gastrointestinal disease (CGD). Previous glucocorticoid administration (PGA) can give false-positive results on the ACTH stimulation test (ACTHst).
HYPOTHESIS/OBJECTIVES
To determine the prevalence of EEH in dogs with signs of CGD, and to identify clinical and clinicopathological features for EEH and PGA.
ANIMALS
One hundred twelve dogs with CGD (101 non-PGA and 11 PGA), 20 dogs with EEH.
METHODS
Multicenter prospective cohort study. Basal serum cortisol (BSC) concentration was measured in dogs with signs of CGD. When BSC was <2 μg/dL and in PGA dogs, ACTHst plus measurement of endogenous ACTH (eACTH) were performed. Records of dogs with EEH from 2009 to 2021 were reviewed.
RESULTS
The BSC concentration was <2 μg/dL in 48/101 (47.5%) non-PGA and in 9/11 (82%) PGA dogs. EEH was diagnosed in 1/112 dog (prevalence 0.9%; 95% CI, 0.1%-4.8%); the ACTHst provided false-positive results in 2/11 PGA dogs. PGA dogs showed lower C-reactive protein-to-haptoglobin ratio (median 0.01, range 0.003-0.08; P = .01), and higher haptoglobin (140, 26-285 mg/dL; P = .002) than non-PGA dogs (0.04, 0.007-1.5; 38.5, 1-246 mg/dL, respectively). eACTH was higher (P = .03) in EEH (396, 5->1250 pg/mL) than in non-PGA dogs (13.5, 7.3-46.6 pg/mL). Cortisol-to-ACTH ratio was lower (P < .0001 and P = .01, respectively) in EEH (0.002, 0.0002-0.2) than in non-PGA (0.1, 0.02-0.2) and PGA dogs (0.1, 0.02-0.2).
CONCLUSIONS AND CLINICAL IMPORTANCE
The prevalence of EEH in dogs with signs of CGD was lower than previously reported. The clinical and clinicopathological features herein identified could increase the index of suspicion for EEH or PGA in dogs with an unclear history of glucocorticoid administration.
Topics: Humans; Dogs; Animals; Hydrocortisone; Glucocorticoids; Prospective Studies; Haptoglobins; Prevalence; Dog Diseases; Adrenal Insufficiency; Adrenocorticotropic Hormone; Diagnostic Errors; Gastrointestinal Diseases
PubMed: 38053513
DOI: 10.1111/jvim.16921 -
AACE Clinical Case Reports 2023Infiltrative fungal infections are an unusual cause of primary adrenal insufficiency (AI). Our objective is to present a long-term follow-up of a patient with AI due to...
BACKGROUND/OBJECTIVE
Infiltrative fungal infections are an unusual cause of primary adrenal insufficiency (AI). Our objective is to present a long-term follow-up of a patient with AI due to cryptococcal adrenalitis.
CASE REPORT
A 47-year-old woman presented in January 2004, with 50-lb weight loss, nausea, emesis, and headache with diplopia. During the 6 months prior to her presentation the patient had multiple admissions for evaluation of recurrent nausea and emesis. Prior to the most recent of these admissions, the patient developed a headache; evaluation of her cerebrospinal fluid revealed the presence of , and she was treated with a 2-week course of amphotericin B. Physical examination demonstrated a temperature of 101.1 °F, heart rate of 110 bpm, and blood pressure of 94/65 mm Hg. She appeared ill and was underweight with dry mucous membranes and photophobia. Laboratory tests revealed random cortisol of 0.5 μg per dL. CT imaging showed bilateral adrenal gland enlargement and fine needle aspiration of the adrenal gland revealed encapsulated budding yeast. Stress dose intravenous glucocorticoids were administered and switched to oral hydrocortisone and fludrocortisone because the patient clinically improved with a second course of amphotericin B. Further evaluation in 2017 revealed persistently enlarged adrenal glands, positive cryptococcus antigen, and low IgG levels.
DISCUSSION
Our literature review noted few publications of AI caused by disseminated cryptococcus with no long-term follow-up of these cases beyond a 1- to 4-year time frame.
CONCLUSION
Patients with AI due to disseminated fungal infection need long-term follow-up to assess for resolution of adrenal enlargement and evaluation of immunocompromised status.
PubMed: 38045798
DOI: 10.1016/j.aace.2023.09.002 -
Frontiers in Immunology 2023Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have...
INTRODUCTION
Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency.
METHODS
This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated.
RESULTS
The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected.
DISCUSSION
In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.
Topics: Humans; Addison Disease; Cross-Sectional Studies; Leukocytes, Mononuclear; Cushing Syndrome; Glucocorticoids; Hydrocortisone; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency
PubMed: 38045693
DOI: 10.3389/fimmu.2023.1275828 -
Cureus Oct 2023We describe a case of a 28-year-old male who presented with general malaise, fatigue, anorexia, occasional epigastric pain, and vomiting a few days after a mild severe...
We describe a case of a 28-year-old male who presented with general malaise, fatigue, anorexia, occasional epigastric pain, and vomiting a few days after a mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Clinical evolution led to weight loss (6 kg in six months) and craving for salty foods. Physical examination revealed dehydration, hypotension, and hyperpigmentation of the skin and mucosal surfaces. Laboratory tests demonstrated normocytic normochromic anemia, acute kidney injury, hyperkalemia, hyponatremia, and compensated metabolic acidosis. Adrenal workup allowed us to establish a diagnosis of adrenal insufficiency (AI) due to autoimmune adrenalitis, considering findings of a low cortisol and positive 21-hydroxylase antibodies (21OH-Abs), as well as high serum renin and adrenocorticotropic hormone (ACTH). Atypical presentations and comorbidities may appear regarding coronavirus disease 2019 (COVID-19), such as the association between COVID-19 and the hypothalamic-pituitary-adrenal (HPA) axis, which may be affected in any patient with SARS-CoV-2 infection, thus making adrenal insufficiency a diagnosis to consider.
PubMed: 38034146
DOI: 10.7759/cureus.47920