Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas.

PURPOSE: The pathogenesis of pituitary adenomas (PA) is complex. Ki-67, pituitary tumour transforming gene (PTTG), vascular endothelial growth factor (VEGF), cyclin D1, c-MYC and pituitary adenylate cyclase-activating peptide (PACAP) protein expression were analysed and correlated with tumour and patient characteristics. METHODS: 74 pituitary tumour samples (48 non-functional PA, 26 functional PAs); Immunohistochemical analysis of protein expression, retrospective analysis of MR images and in vitro analysis of octreotide treatment was carried out on GH3 cells. RESULTS: PTTG expression was negatively associated with age and positively with PA size, regrowth and Ki-67 index. Cyclin D1 correlated with Ki-67 and tumour size. c-MYC negatively correlated with size of tumour and age; and correlated with PTTG expression. Somatostatin analogue treatment was associated with lower Ki-67, PTTG and Cyclin D1 expression while T2 hypointense PAs were associated with lower PTTG, cyclin D1, c-MYC and Ki-67. In vitro analyses confirmed the effect of somatostatin analogue treatment on Pttg and Cyclin D1 expression. CONCLUSIONS: Interesting and novel observations on the differences in expression of tumour markers studied are reported. Correlation between Ki-67 expression, PTTG nuclear expression and recurrence/regrowth of PAs, emphasizes the role that Ki-67 and PTTG expression have as markers of increased proliferation. c-MYC and PTTG nuclear expression levels were correlated providing evidence that PTTG induces c-MYC expression in PAs and we propose that c-MYC might principally have a role in early pituitary tumorigenesis. Evidence is shown that the anti-proliferative effect of somatostatin analogue treatment in vivo occurs through regulation of the cell cycle.

Epidemiology and radiological geometric assessment of pituitary macroadenomas: population-based study.

CONTEXT: Pituitary adenomas are relatively common tumours with diverse clinical features. Epidemiological data are important to help quantify health burden. OBJECTIVE: To provide in-depth epidemiological data on macroadenomas and radiologically characterize macroadenomas. DESIGN: Population-based retrospective analysis, Prevalence as at 2014; Incidence based on data from 2000 to 2014, Retrospective analysis of baseline MRI. SETTING: The Maltese islands. PATIENTS: 173/136 patients with macroadenomas for prevalence/incidence estimates respectively, 122 baseline MRI for radiological characterization. MAIN OUTCOME MEASURES: Prevalence rates, Standardized Incidence rates (SIR), MRI findings. RESULTS: The prevalence for macroadenomas was 40·67/100 000 people and the SIR was 1·90/100 000/year. Giant pituitary adenomas (>40 mm) constituted 4·8% of the whole cohort of PAs and the SIR was 0·18/100 000/year. Giant prolactinomas constituted 4·7% of all the prolactinomas and the SIR was 0·07/100 000/year, while giant NFPA constituted 6·0% of all NFPA and the SIR was 0·12/100 000/year. There was a statistically significant difference in the degree of suprasellar extension (P < 0·001) and infrasellar extension (P = 0·028) between the different macroadenoma subtypes and in the vertical extension indices (median vertical extension index NFPA 3·0 mm; PRLoma -7·7 mm; GH-secreting PA -1·7 mm; P < 0·001). Pituitary macroadenomas with cavernous sinus invasion were statistically significantly larger than those without cavernous sinus invasion (P < 0·001). NFPA had predominantly a superior extension into the cavernous sinus (63·6%) compared to the functional PAs which had predominantly an inferior extension into the cavernous sinus (59·1%) (P = 0·032). CONCLUSIONS: The various macroadenoma subtypes' epidemiological data are presented and differences between growth patterns among the various subtypes are highlighted.

High Population Frequency of GNRHR p.Q106R in Malta: An Evaluation of Fertility and Hormone Profiles in Heterozygotes.

Context: The gonadotropin-releasing hormone receptor variant GNRHR p.Q106R (rs104893836) in homozygosity, compound heterozygosity, or single heterozygosity is often reported as the causative variant in idiopathic hypogonadotropic hypogonadism (IHH) patients with GnRH deficiency. Genotyping of a Maltese newborn cord-blood collection yielded a minor allele frequency (MAF) 10 times higher (MAF = 0.029; n = 493) than that of the global population (MAF = 0.003). Objective: To determine whether GNRHR p.Q106R in heterozygosity influences profiles of endogenous hormones belonging to the hypothalamic-pituitary axis and the onset of puberty and fertility in adult men (n = 739) and women (n = 239). Design Setting and Participants: Analysis of questionnaire data relating to puberty and fertility, genotyping of the GNRHR p.Q106R variant, and hormone profiling of a highly phenotyped Maltese adult cohort from the Maltese Acute Myocardial Infarction Study. Main Outcome and Results: Out of 978 adults, 43 GNRHR p.Q106R heterozygotes (26 men and 17 women) were identified. Hormone levels and fertility for all heterozygotes are within normal parameters except for TSH, which was lower in men 50 years or older. Conclusion: Hormone data and baseline fertility characteristics of GNRHR p.Q106R heterozygotes are comparable to those of homozygous wild-type individuals who have no reproductive problems. The heterozygous genotype alone does not impair the levels of investigated gonadotropins and sex steroid hormones or affect fertility. GNRHR p.Q106R heterozygotes who exhibit IHH characteristics must have at least another variant, probably in a different IHH gene, that drives pathogenicity. We also conclude that GNRHR p.Q106R is likely a founder variant due to its overrepresentation and prevalence in the island population of Malta.

Prevalence and incidence of pituitary adenomas: a population based study in Malta.

Epidemiological data is important to correctly quantify the extent of disease and needed health care resources. The aim of the study was to establish the prevalence and incidence of pituitary adenomas (PAs) in the same well defined population, with in-depth analysis of the various subtypes. The design involved a retrospective cross-sectional analysis of PA patients diagnosed prior to 31 July 2011 for prevalence estimates and those diagnosed between July 2000 and July 2011 for incidence estimation. A thorough search for patients with PAs was carried out in central hospital registries including outpatients departments, surgical registries, radiological department and specialty clinic databases. Prevalence rates/100,000 and Standardised incidence ratios (SIR)/100,000/year were worked out. The respective prevalence rates and SIR for PAs overall were 75.7/100,000, and 4.27/100,000/year, for Prolactinomas 35.0/100,000 and 2.05/100,000/year, for nonfunctioning PA 25.9/100,000 and 1.79/100,000/year and for GH-secreting PAs 12.5/100,000 and 0.31/100,000/year. The overall prevalence for macroadenomas was 32.8/100,000 and SIR was 1.49/100,000/year. The prevalence rate in males for PAs overall was 46.3/100,000 and SIR was 2.08/100,000/year and in females 104.8/100,000 and SIR was 6.58/100,000/year. Females had a lower proportion of macroadenomas than males (29.5 vs. 75.0%; P < 0.001) and macroadenomas tended to present at a later age compared to microadenomas (48 vs. 34.5; P < 0.001). The highest SIR was reached in the 30-39 age group at 7.42/100,000/year. Our data confirm the considerable disease burden that PAs bear on health care resources. Males and females have similar prevalence and SIR rates for macroadenomas but there is a significant increase in SIR in females of child bearing age compared to males. These observations may have important implications in terms of the economic burden and need for early intervention.

The environmental burden on endocrine neoplasia: a review on the documented impact of endocrine disrupting chemicals.

INTRODUCTION: Endocrine-disrupting chemicals (EDCs) have gained more importance in the past decade, mostly due to their role in the pathogenesis of disease, especially in carcinogenesis. However, there is limited literature on the environmental burden on some of the less common endocrine neoplasia. AREAS COVERED: This review focuses on both observational and experimental studies linking exposure to EDCs and endocrine neoplasia specifically pituitary, thyroid, adrenal and neuroendocrine tumors. Following PRISMA guidelines, a search of English peer-reviewed literature was performed using Medline and Google Scholar, giving preference to recent publications. EXPERT OPINION: Exposure to EDC occurs not only in the household but also at work, whether it is in the office, factory, or farm and during transport from one location to another. Many studies have evaluated the effect of single environmental agents; however, humans are rarely exposed to only one EDC. Different EDCs and different levels of exposure may interact together to provide either a synergistic and/or an antagonistic disruption on human health, and hence a complex mechanism to elucidate. The ultimate adverse effect is difficult to predict, as it is not only influenced by the degree of exposure, but also by genetics, lifestyle, comorbidities, and other stressors.

Metastatic paraganglioma presenting with spinal cord compression requiring urgent surgery.

We report a rare case of a functional bladder paraganglioma diagnosed in a young man who presented with acute compressive thoracic myelopathy secondary to vertebral metastasis. A histological diagnosis of a metastatic paraganglioma was made following biopsy of a rib lesion. CT revealed a lesion in the inferior wall of the bladder, which demonstrated avid uptake on 68Ga-DOTATATE PET/CT. Serum metanephrine levels were more than 40 times the upper limit of normal. The patient was hypertensive and treatment with doxazosin was initiated. In view of neurological deterioration, he required urgent spinal decompression to preserve neurological function and prevent permanent paraplegia. Despite inadequate alpha-blockade, surgery was successful, and the perioperative course was uneventful. Alpha-blockade was subsequently optimised. Treatment with cyclophosphamide, vincristine and dacarbazine was started but, in view of disease progression, treatment was subsequently changed to sunitinib.

Thiazide diuretics and primary hyperparathyroidism.

Thiazide diuretics exert a natriuretic and diuretic effect by inhibiting sodium reabsorption in the distal convoluted tubule. Furthermore, thiazide diuretics affect renal calcium handling by increasing calcium reabsorption, leading to hypocalciuria. The effect that thiazide diuretics exert on parathyroid hormone secretion is controversial. Some studies found parathyroid hormone levels were suppressed with the use of thiazide diuretics, while others found that thiazides were associated with initial parathyroid hormone suppression followed by raised parathyroid hormone levels. This makes the relationship between thiazide diuretics and primary hyperparathyroidism interesting. If a patient is taking thiazide diuretics, this may make it harder to establish the aetiology of hypercalcaemia and may unmask normocalcaemic or mild primary hyperparathyroidism. Thiazide diuretics may have a beneficial role in the diagnosis of patients with concomitant hyperparathyroidism and hypercalciuria by distinguishing secondary hyperparathyroidism caused by hypercalciuria from normocalcaemic primary hyperparathyroidism. In addition, thiazide diuretics may have a role in managing patients with primary hyperparathyroidism who have an indication for parathyroidectomy in view of significant hypercalciuria, but are unfit for surgery.

A current perspective of pituitary adenoma MRI characteristics: a review.

INTRODUCTION: MR imaging is an essential and fundamental tool in the diagnosis, management, and follow-up of patients with pituitary adenomas (PAs). Recent advances have continued to enhance the usefulness of this imaging modality. AREAS COVERED: This article focuses on signal intensity patterns of PAs and associated clinical characteristics, vertical extension patterns, and cavernous sinus invasion with a special focus on the clinical implications that arise. A search using Medline and Google Scholar was conducted using different combinations of relevant keywords, giving preference to recent publications. EXPERT OPINION: A higher proportion of GH-secreting PAs are hypointense on T2 weighted images compared to other tumor subtypes. Hypointense tumors are generally smaller compared to hyperintense ones, and among the GH-secreting subgroup, a better response to somatostatin analogue treatment was noted together with an association for a densely granulated pattern. Nonfunctional PAs show a predilection to extend upwards while GH-secreting PAs and prolactinomas show a predominantly inferior extension growth pattern. Further studies to better understand the mechanisms responsible for this behavior are anticipated. Further development, refining and validation of predictive scoring systems for tumor behavior might be useful adjuncts in the management of patients with PAs.

Epidemiology and blood parameter changes in Cushing's syndrome - a population-based study.

PURPOSE: To provide complete epidemiological data on Cushing's syndrome (CS) with analysis and differentiation of biochemical parameters, including blood count indices and serum inflammation-based scores. METHODS: Clinical records of 35 patients diagnosed with CS between 2008 and 2020 at Malta's only central National Health Service hospital were retrospectively analyzed. Detailed clinical and biochemical data were obtained for each patient. Correlation and receiver operator characteristics (ROC) curve analyses were used to establish a threshold value for different variables to predict malignant CS. RESULTS: Standardized incidence rate (SIR) (/million/year) of CS was 4.5, and SIR of Cushing's disease (CD) was 2.3, 0.5 for ectopic CS, 1.5 for cortisol secreting adrenal adenoma, and 0.3 cases for cortisol-producing ACC. Malignant cause of CS had statistically significantly higher cortisol levels and size of tumor and lower potassium at diagnosis (P < 0.001). Additionally, malignant causes had a higher neutrophil-to-lymphocyte ratio (NLR) (P = 0.001) and systemic immune inflammation index (P = 0.005) and a lower lymphocyte-to-monocyte ratio (P < 0.001). Using ROC curve analysis to predict malignant cause of CS, a potassium level of < 3.05 was 75% sensitive and 100% specific (ROC-AUC 0.907, P = 0.001), a post-ODST cortisol level of > 841 nmol/L was 100% sensitive and 91% specific (ROC-AUC 0.981, P < 0.001), while a NLR ratio > 3.9 was 100% sensitive and 57.7% specific (ROC-AUC 0.885, P = 0.001). CONCLUSION: Biochemical and blood count indices and serum inflammatory-based scores differ remarkably between benign and malignant causes of endogenous CS. Such indices can help predict the severity of disease and prognosis.

Inpatient hyperglycaemia, and impact on morbidity, mortality and re-hospitalisation rates.

INTRODUCTION: Hyperglycaemia is related to poorer outcomes among hospital inpatients. We investigated the impact of hyperglycaemia at admission on length of hospital stay, readmission rate and mortality rate. METHOD: We retrospectively analysed the records of 1,132 patients admitted to hospital in January 2019, April 2019, August 2019 and April 2020. RESULTS: Hyperglycaemia was present in 14.1% of patients. New-onset hyperglycaemia on admission (in 3.9% of patients) was related to a higher mortality rate than in patients known to have diabetes admitted with hyperglycaemia (43.3% vs 17.9%; p=0.006). Mortality at 90 days and 1 year increased with higher admission glucose levels (p=0.03 and p=0.005, respectively), severe hyperglycaemia (>20 mmol/L) having a 1-year mortality of 34.3%. After accounting for confounding variables, admission glucose and length of stay remained significant predictors of 1-year mortality (p=0.034 and p=0.003, respectively). CONCLUSION: Hyperglycaemia is an important prognostic marker and may indicate a more severe illness. These patients should be highlighted for a greater level of care.

Immobilisation hypercalcaemia.

Hypercalcaemia is a common metabolic abnormality and its differential diagnosis is vast. Immobility is an uncommon cause of hypercalcaemia. Immobilisation hypercalcaemia is independent of parathyroid hormone and is associated with low levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. In addition, it is characterised by elevated levels of markers of bone resorption and low levels of bone-specific alkaline phosphatase, highlighting an imbalance of bone remodelling favouring osteoclastic bone resorption. Although immobilisation hypercalcaemia is a diagnosis of exclusion, physicians need to be aware of this condition to avoid excessive and invasive investigations when all other causes of parathyroid hormone-independent hypercalcaemia have been excluded. Management of immobilisation hypercalcaemia revolves around early mobilisation and rehabilitation together with pharmacotherapeutic agents such as intravenous isotonic saline, calcitonin and bisphosphonates. Denosumab may be a potential alternative yet off-label treatment for immobility hypercalcaemia in patients with renal insufficiency.

Epidemiology of craniopharyngiomas: a population-based study in Malta.

Background: Despite being benign tumours, craniopharyngiomas are challenging to manage and can cause significant morbidity and mortality in both the paediatric and adult population. The aim of the study was to analyse the epidemiology of craniopharyngiomas, patient and tumour characteristics through a population-based study in Malta, enabling a better quantification of the disease burden. Methods: Thorough research was carried out to identify the number of patients who were diagnosed with craniopharyngiomas. Epidemiological data, including both standardised incidence rates (SIR) and prevalence rates, were established in a well-defined population. For incidence estimates, patients who were diagnosed between 2008 and 2019 were included. The background population formed 4.8 million patient-years at risk. Result: Twenty-nine subjects were identified and included in our study. The overall SIR was 0.3/100,000/year, with a higher SIR for males compared to females (0.4/100,000/year and 0.2/100,000/year, respectively). The highest SIR was recorded in the 10-19 year age group. The estimated prevalence rate amounted to 5.27/100,000 people, with a lower prevalence rate for childhood-onset when compared to the adult-onset category (2.03/100,000 vs 3.24/100,000 people). The median longest tumour diameter was 31.0 mm (IQR 21-41), with a statistically significant difference between childhood- and adult-onset disease; 43.0 mm (IQR 42.5-47.25) vs 27.0 mm (IQR 20.55-31.55) (P = 0.011). Conclusion: Through this population-based study, accurate and up-to-date prevalence and incidence rates for craniopharyngiomas are reported. These provide a clearer reflection of the true health burden of the disease.

Hypercalcaemia due to ovarian small cell carcinoma of the hypercalcaemic type.

A 37-year-old woman presented with a few days' history of lower abdominal pain and an incidental finding of hypercalcaemia. A thorough workup ensued, and the cause was found to be an exceptionally rare ovarian tumour-ovarian small cell carcinoma of the hypercalcaemic type. Acute treatment of hypercalcaemia consisted of aggressive intravenous fluids and bisphosphonates. She underwent surgery to remove the tumour and is currently receiving systemic platinum/etoposide chemotherapy combination to be followed by pelvic radiotherapy. This case highlights the wide range of differential diagnosis for hypercalcaemia and the importance of a stepwise and thorough approach during investigations. We discuss the pathophysiology of malignancy-related hypercalcaemia, focusing especially on parathyroid hormone-related peptide-associated hypercalcaemia.

Cotrimoxazole-induced hyperkalaemia in a patient with known hypoaldosteronism.

A70-year-old man, with established hypoadrenalism due to a previous bilateral adrenalectomy, was admitted with recurrent episodes of postural dizziness and presyncope. He had been discharged from hospital 3 weeks earlier on a 1-month course of cotrimoxazole following a diagnosis of prostatitis. His electrolytes on admission showed new onset hyponatraemia and hyperkalaemia.His usual glucocorticoid replacement dose was doubled in view of a presumed diagnosis of hypocortisolaemia. However, the hyperkalaemia persisted. On rereviewing his treatment, we suspected a possible diagnosis of cotrimoxazole-induced hyperkalaemia. Cotrimoxazole was stopped and ciprofloxacin started instead. His fludrocortisone replacement was doubled for 3 days after stopping treatment to decrease his postural symptoms. His postural symptoms improved, his serum potassium decreased to normal levels and he was safely discharged.It is essential to remember that cotrimoxazole, a commonly used antibiotic, can induce a potentially fatal hyperkalaemia especially in patients with known hypoadrenalism.

Ectopic ACTH secretion from a metastatic gastric carcinoma with neuroendocrine component.

An elderly gentleman was admitted to hospital with severe hypokalaemia of 1.75mmol/L. A background of a recently diagnosed metastatic gastric carcinoma with a neuroendocrine component pointed towards the diagnosis of ectopic ACTH secretion causing this dangerous electrolyte imbalance. He was treated with aggressive potassium supplementation and the adrenal steroid synthesis blocker metyrapone to acutely control his Cushing's syndrome. Chemotherapy consisting of carboplatin/etoposide combination was initiated but unfortunately the patients' health deteriorated, and he died three months after his initial diagnosis. This case highlights the accelerated presentation of hypercortisolism due to ectopic ACTH secretion. It discusses the classification of neuroendocrine tumours and their varied prognosis depending on the underlying tumour grade. It emphasises the importance of having a multidisciplinary team to be able to care for two underlying pathologies simultaneously: both the severe hypercortisolism and his metastatic gastric tumour.

Biochemically silent phaeochromocytoma presenting with non-specific loin pain.

A 55-year-old woman presented with a 4-month history of right-sided non-specific loin pain and 6 kg weight loss. A CT scan of the abdomen and pelvis showed an incidental 4.5 cm right-sided adrenal lesion which was not typical of an adrenal adenoma. This was further confirmed on MRI of the adrenals. Biochemical investigations to investigate for a functional adrenal lesion included serum catecholamines and metanephrines, an aldosterone to renin ratio and an overnight dexamethasone suppression test. These were all negative. A laparoscopic adrenalectomy was performed in view of the large size of the lesion. Histology was consistent with a phaeochromocytoma, which confirmed the diagnosis of a non-secreting phaeochromocytoma. Non-secreting phaeochromocytomas are rare and usually found in patients with known genetic mutations. Adrenal lesions not related to any mutations similar to our case are even rarer and reported even less in the literature.

Adrenal insufficiency in HIV/AIDS: a review.

INTRODUCTION: Adrenal insufficiency (AI) is one of the most common potentially life-threatening endocrine complications in people living with human immunodeficiency virus (PLHIV) infection and acquired immunodeficiency syndrome (AIDS). AREAS COVERED: In this review, the authors explore the definitions of relative AI, primary AI, secondary AI and peripheral glucocorticoid resistance in PLHIV. It also focuses on the pathophysiology, etiology, diagnosis and management of this endocrinopathy in PLHIV. A literature review was conducted through Medline and Google Scholar search on the subject. EXPERT OPINION: Physicians need to be aware of the endocrinological implications of HIV infection and its treatment, especially CYP3A4 enzyme inhibitors. A high index of clinical suspicion is needed in the detection of AI, especially in PLHIV, as it may present insidiously with nonspecific signs and symptoms and may be potentially life threatening if left untreated. Patients with overt primary and secondary AI require glucocorticoid replacement therapy. Overt primary AI also necessitates mineralocorticoid replacement. On the other hand, the management of relative AI remains controversial. In order to reduce the risk of adrenal crisis during periods of stress, the short-term use of glucocorticoids may be necessary in relative AI.

Plasma Total Ascorbic Acid and Serum 25-Hydroxy-Vitamin-D Status in Patients with Venous Leg Ulcers: A Case-Control Study.

Venous leg ulcers (VLUs) pose a significant burden on patients, health care systems, and national economies. Nutritional health is an important determinant of wound healing. Vitamin C and D levels and additional biochemical markers, C-reactive protein, and albumin in a group of patients with VLUs, were compared with a control group without VLUs. No significant difference in either nutrient marker was found with the presence, size, or duration of VLUs. Obesity was significantly more common in the VLU group, as noted in other studies. Additional controlled studies should be performed with measures of VLU size and duration to assess long-term outcomes with nutritional therapy.

Clinical reasoning: exploring its characteristics and enhancing its learning.

Clinical reasoning is an extensive and intricate field, dealing with the process of thinking and decision making in practice. Its study can be quite challenging because it is context and task dependent. Educational frameworks such as the conscious competence model and the dual process reasoning model have been developed to help its understanding. To enhance the learning of clinical reasoning, there are significant areas that can be targeted through learning processes. These include knowledge adequacy; ability to gather appropriate patient data; use of proper reasoning strategies to address specific clinical questions; and the ability to reflect and evaluate on decisions taken, together with the role of the wider practice community and the activity of professional socialisation. This article explores the characteristics of clinical reasoning and delves deeper into the various strategies that prove useful for learning.

A current perspective into young female sex hormone replacement: a review.

INTRODUCTION: Hormone replacement in females with hypogonadism is advocated to address the various clinical aspects of estrogen deficiency. AREAS COVERED: This article focuses on hormone replacement in young females with hypogonadism, including a rationale as to why hormone replacement in such patients differs from treatment in postmenopausal females, a summary of symptoms encountered by females with hypogonadism and a comprehensive discussion of the various treatment options available, specifically focusing on the latest advances in the subject. A Medline search was conducted using different combinations of relevant keywords, giving preference to recent publications. EXPERT OPINION: Whilst traditionally oral contraceptive pills (containing ethynyl estradiol) were commonly used as a form of hormone replacement, it is now increasingly recognized that this is not the optimal treatment option. Physiological hormone replacement with transdermal estradiol is found to be superior. Evidence suggests that micronized progesterone may be associated with fewer side effects, although its effect on endometrial protection is not yet proven. Synthetic progestins confer varying degrees of androgenic and thromboembolic properties which should be kept in mind when prescribing individualized treatment. Further studies in different sub-cohorts of female patients with hypogonadism might help address the specific needs of individual patients.