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1.
J Endocrinol Invest ; 44(1): 195-203, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32449093

ABSTRACT

PURPOSE: Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. METHODS: A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. RESULTS AND CONCLUSIONS: Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis.


Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Biomarkers/blood , Hypophysitis/pathology , Ipilimumab/adverse effects , Melanoma/drug therapy , Thyrotropin/blood , Thyroxine/blood , Adult , Aged , Female , Follow-Up Studies , Humans , Hypophysitis/blood , Hypophysitis/chemically induced , Male , Melanoma/pathology , Middle Aged , Prognosis , Retrospective Studies
2.
Br Dent J ; 229(7): 398, 2020 10.
Article in English | MEDLINE | ID: mdl-33037335
3.
Endocr Connect ; 7(7): G1-G7, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29930025

ABSTRACT

Immunotherapy treatment with checkpoint inhibitors (CPI) (CTLA-4 and PD-1 inhibitors) significantly improves survival in a number of cancers. Treatment can be limited by immune-mediated adverse effects including endocrinopathies such as hypophysitis, adrenalitis, thyroiditis and diabetes mellitus. If endocrinopathies (particularly hypocortisolemia) are not recognized early, they can be fatal. The diagnosis and management of endocrinopathies can be complicated by simultaneous multi-organ immune adverse effects. Here, we present Endocrine Emergency Guidance for the acute management of the endocrine complications of checkpoint inhibitor therapy, the first specialty-specific guidance with Endocrinology, Oncology and Acute Medicine input and endorsed by the Society for Endocrinology Clinical Committee. We present algorithms for management: endocrine assessment and management of patients in the first 24 hours who present life-threateningly unwell (CTCAE grade 3-4) and the appropriate management of mild-moderately unwell patients (CTCAE grade 1-2) presenting with features compatible with an endocrinopathy. Other important considerations in relation to hypohysitis and the maintenance of glucocorticoid therapy are discussed.

4.
Clin Endocrinol (Oxf) ; 86(4): 614-620, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28028828

ABSTRACT

CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. OBJECTIVE: To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. RESULTS: Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13·0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22·2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13·0% treated with a PD-1 inhibitor, 15·9% following a PD-1 inhibitor, and 22·2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23·0% following ipilimumab, 39·1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.


Subject(s)
CTLA-4 Antigen/therapeutic use , Melanoma/complications , Melanoma/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Thyroid Diseases/physiopathology , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Female , Humans , Ipilimumab , Male , Middle Aged , Nivolumab , Thyroid Diseases/chemically induced , Thyroid Function Tests
5.
Eur Radiol ; 19(10): 2467-73, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19597822

ABSTRACT

Insulinomas, although rare, cause considerable morbidity but are frequently amenable to surgical cure. Laparoscopic surgery can now be considered if the tumour is localised pre-operatively, but the optimal imaging approach has not been determined. The objective of this study was to evaluate the ability of different imaging investigations, including CT, MRI, endoscopic ultrasound, octreotide scintigraphy and arterial stimulation with simultaneous venous sampling (ASVS), to localise insulinomas. All patients with biochemically proven insulinoma at our institution underwent ASVS along with other imaging investigations as part of their routine investigation. The results of these investigations were compared with histological findings. Twenty-eight patients with biochemically proven insulinoma confirmed by histology were identified. Ultimately ASVS localised a lesion in all patients. Seventeen patients (61%) had laparoscopic surgery. Tumor-detection rates for other imaging investigations included 43.5% of cases using CT, 71% using MRI, 86% using endoscopic ultrasound and 33% using octreotide scintigraphy. In four patients, the ASVS was the only test to correctly localise the lesion. ASVS should be considered routinely before surgery to ensure accurate localisation of insulinomas.


Subject(s)
Calcium Gluconate , Hepatic Veins/metabolism , Insulin/blood , Insulinoma/diagnosis , Magnetic Resonance Imaging/methods , Pancreatic Neoplasms/diagnosis , Tomography, X-Ray Computed/methods , Adolescent , Adult , Aged , Aged, 80 and over , Anatomy, Cross-Sectional/methods , Calcium Gluconate/administration & dosage , Contrast Media , Female , Humans , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Injections, Intra-Arterial , Insulinoma/blood , Male , Middle Aged , Pancreatic Neoplasms/blood , Reproducibility of Results , Sensitivity and Specificity , Young Adult
6.
J Lipid Res ; 49(3): 679-85, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18046046

ABSTRACT

This study describes a novel approach to generate conditionally immortalized preadipocyte cell lines from white adipose tissue (IMWAT) that can be induced to differentiate into white adipocytes even after expansion in culture. Such adipocytes express markers of white fat such as peroxisome proliferator-activated receptor gamma and aP2 but not brown fat markers, have an intact insulin signaling pathway, and express proinflammatory cytokines. They can be readily transduced with adenoviral vectors, allowing them to be used to investigate the consequences of the depletion of specific adipocyte factors using short hairpin RNA. This approach has been used to study the effect of reduced expression of the nuclear receptor corepressor receptor interacting protein 140 (RIP140), a regulator of adipocyte function. The depletion of RIP140 results in changes in metabolic gene expression that resemble those in adipose tissue of the RIP140 null mouse. Thus, IMWAT cells provide a novel model for adipocytes that are derived from preadipocytes rather than fibroblasts and provide an alternative system to primary preadipocytes for the investigation of adipocyte function.


Subject(s)
Adipocytes, White/cytology , Cell Line , Adaptor Proteins, Signal Transducing/deficiency , Animals , Cell Culture Techniques , Cell Differentiation , Mice , Mice, Transgenic , Nuclear Proteins/deficiency , Nuclear Receptor Interacting Protein 1 , Transduction, Genetic
10.
Prev Med ; 17(3): 295-309, 1988 May.
Article in English | MEDLINE | ID: mdl-3405986

ABSTRACT

The role of caffeine or coffee in causing or promoting the incidence of serious disease is equivocal. Two design factors may account for the discrepancies in reported findings on the effects of coffee drinking: (a) imprecision of measurement and (b) confounding variables. A study of 2,714 white U.S. adults disclosed that, of 32 risk factors analyzed by linear and logistic regression, only sex and cigarette smoking were found to be important potential confounders of caffeine and coffee intake. Partial R2 values of the other 30 risk factors were relatively small and were inconsistent for each sex. It is unlikely that any of these factors could explain any of the reported associations between caffeine or coffee consumption and certain diseases. However, certain weak associations with caffeine or coffee intake should be included in the study design when they are known to be risk factors of a disease under investigation. These factors for men are dietary fat intake, vitamin C intake, and body mass index; and for women are vitamin use, alcohol intake, stress, and perceived health status.


Subject(s)
Caffeine/adverse effects , Coffee/adverse effects , Disease Susceptibility/etiology , Drinking Behavior , Research Design/standards , Adult , Aged , Coronary Disease/etiology , Female , Humans , Male , Middle Aged , Neoplasms/etiology , Random Allocation , Risk Factors , Self Disclosure , Sex Factors
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