RNASeq of pituitary adenomas reveals dysfunctional metabolic, secretory and differentiation molecular pathways

Pituitary adenomas consist of a group of highly heterogeneous intracranial tumours with variable presentation, clinical prognosis and management. High throughput sequencing was used in order to try and identify common de-regulated pathways and characterize tumours according to specific molecular behaviour. RNA sequencing (RNAseq) was chosen since it provides not only information regarding the expression profile but also the mutational load of each specific tumour analysed. 58 locally resected tumours (36 non-functional tumours; 17 growth hormone-secreting; 3 prolactin-secreting; 2 Cushing’s) were stored in RNAlater (Qiagen, US) and RNA was extracted to purified. RNAseq was performed on all samples plus a control on the BGI-Seq500 platform (Beijing Genomics Ind., China). Bioinformatic analyses was also performed by BGI with additional analyses still being carried out. Preliminary data reveals a number of known and novel de-regulated pathways which characteristically differentiate between different tumour types such as hormone signalling and production pathways. However, novel metabolic pathways also appear to differ significantly, not only between controls and tumours but also between different tumour types with changes in lipid transport and glucose metabolism being observed. Additionally various hormone receptor signalling pathways were also found to be altered. Verification and additional bioinformatic analyses will be required to further delve into the vast data that is generated by this technique which has provided a wealth of information.peer-reviewe

Ipilumumab induced hypophysitis

INTRODUCTION: Immunotherapy has advanced significantly over the past years. Immune-related adverse events (IRAEs) are various and include endocrinological complications such as Ipilimumab-induced hypophysitis (IIH). The incidence of this cytotoxic T-lymphocyte antigen 4 antibody ranges from 0 to 17%. Patients usually present with symptoms secondary to hormonal insufficiencies.CASE REPORT: A 73 year-old lady, known case of metastatic melanoma on immunotherapy presented with a 1 week history of pre-syncopal episodes and nausea. She gave a few week history of non-vertiginous dizziness, lethargy and headache. The patient had received her third course of ipilimumab few days prior to presentation. Cortisol level during admission was 23 nmol/l, from a previously normal level of 993 nmol/l few weeks prior. The patient had low T4 and TSH levels (0.080 mIU/ml and 6.7 pmol/l respectively) together with low FSH (2.4 U/l), LH (0.6 U/l) and prolactin levels (59 mIU/l) in keeping with panhypopituitarism. The patient was started on glucocorticoids and thyroxine with rapid improvement of her symptoms.IMAGING: MRI brain at presentation showed a 1.5×1.4×1.2 cm sellar lesion involving the pituitary gland with mild suprasellar extension. The lesion demonstrated low T1 and mildly hyperintense T2 signal intensity and enhanced avidly following contrast administration, with a central non-enhancing component. The infundibulum was thickened. Repeat MRI after 3 months revealed complete resolution of the sellar and infundibular changes with normalization of the gland confirming the initial hypothesis of hypophysitis.DISCUSSION: Literature suggests that a high index of suspicion for hypophysitis needs to be kept in mind in patients receiving immunotherapy. It is advised that patients undergo 6 monthly assessment of pituitary function and MR scans should be compared to previous imaging if available to assess for a change in pituitary size. In hypophysitis, the degree of pituitary enlargement should reduce after treatment as was in our case. If this is not observed, alternative diagnoses such as pituitary metastasis should be considered. It is debatable whether patients with IIH should be administered higher dosages of glucocorticoids in contrast to physiological replacement, since there are concerns that treatment with high dosages of glucocorticoids may affect the antitumor efficacy of Ipilimumab. In our patient, a physiological replacement dose was sufficient for her to improve clinically and have complete resolution of symptoms after 3 months.CONCLUSION: Development of IIH can precipitate acute adrenal failure or crisis. Early diagnosis and management are vital to prevent complications including increased morbidity and mortality rates.peer-reviewe

When a rare syndrome keeps behaving in rarer manners over and over again!

Pituitary apoplexy arises when haemorrhage and/or infarction occurs within a pituitary tumour. In Malta, the estimated standardised incidence rate (SIR) of apoplexy is 0.15/100,000/yr. ACTH secreting pituitary adenomas have a SIR of 0.17/100,000/year.CASE REPORT: A 46 year-old gentleman with a history of poorly controlled diabetes mellitus was referred following the diagnosis of a pituitary adenoma. He had presented with a 1.5 year history of left third cranial neuropathy with complete ptosis. Magnetic resonance imaging (MRI) showed a 3.2×1.5 cm lesion extending into the suprasellar cistern, abutting the optic chiasm and extending into the cavernous sinuses, more pronounced on the left side. Biochemical assessment revealed cortisol of 483 nmol/l, prolactin 31 mIU/l, Testosterone 3.5 nmol/l, LH 1.9 U/l, FSH 4.5 U/l, TSH 2.34 micIU/l and T4 12.27 pmol/l. The patient had an inadequately suppressed cortisol level (149 mmol/l) on a 48-hour low dose dexamethasone suppression test and a high ACTH (102 pg/ml) in keeping with ACTH-dependent Cushing’s syndrome. The patient was referred for infra-petrosal sinus sampling, which confirmed an ACTH secreting pituitary macroadenoma. The patient could not undergo surgery at the time in view of an infected diabetic foot ulcer. He was initiated on Metyrapone in an effort to control his hypercortisolaemia. The patient presented two months later with severe headache and new onset visual disturbances. He developed a right III and VI cranial nerve (CN) palsies. Ophthalmological assessment revealed a reduction in visual acuity. Areas of hyperintensity in the pituitary adenoma were noted on unenhanced T1 MRI scan and there was lack of enhancement on a contrast scan, in keeping with apoplexy. Urgent debulking was carried out through a trans-sphenoidal approach. Clinical symptoms and visual disturbances showed improvement post-operatively; the right 3rd and 6th CN palsies improved but he had a persistent right temporal visual field defect. Histology confirmed pituitary apoplexy due to tumour infarction of a functional (ACTH secreting) pituitary macroadenoma.CONCLUSION: Presentation of Cushing’s Disease can be very varied and the work up is extensive and elaborate with a number of different steps. Cushing’s syndrome is associated with multiple comorbidities including increased risk of cardiovascular events, neurological consequences osteoporosis and poor quality of life. Hence, it is imperative that an early diagnosis is made as early as possible so that the condition is appropriately treated. Although apoplexy is rare, this complication needs to be kept in mind as an inherent risk when managing patients with pituitary adenomas.peer-reviewe

Causes and outcomes of hyponatraemia at Mater Dei Hospital, Malta

CONTEXT: Hyponatraemia is the most common electrolyte balance disorder in clinical practice, amounting to 15–20% of casualty visits. While there is general agreement that associated mortality rates are high, most studies are uncontrolled.OBJECTIVE: To determine the characteristics, causes and outcome of severe hyponatraemia (<125 mmol/l) in hospitalised patients and to indentify mortality predictors.DESIGN: This is a retrospective case-controlled study of all medical admissions in the months of February, June and November, who at any point during the index admission developed a serum sodium <125 mmol/l. For each case, an age- and gender-matched control was identified.RESULTS: A total of 5195 medical admissions were reviewed. Of these, 193 patients had a sodium level <125 mmol/. 26 patients were excluded from the case group leaving a total of 167 cases and 193 controls. Length of hospital stay was more prolonged in the case group (12 vs 8 days, P<0.001). There was a highly significant excess mortality, both during the index admission (25% in cases vs 7% in controls (P < 0.001)) as well as till the end of the follow-up period (52% in cases vs 22% in controls (P<0.001)). Mortality was unrelated to severity of hyponatraemia. Patients who developed the lowest serum sodium later on during their admission (ie sodium levels continued falling during the admission or fell de novo), had a higher rate of mortality than patients whose lowest serum sodium was on the day of admission (64.3% vs 45%, P 0.019). A cox regression analysis showed that hyponatraemia (P<0.001), male gender (P 0.033), age (P 0.021), and serum creatinine level (P 0.008) were independent risk factors for mortality. There was no statistically significant difference between the rates of ITU admission at different levels of hyponatraemia <125 mmol/l (P=0.497). Thus, serum sodium levels of <125 mmol/l should be used to identify patients who need more intensive monitoring and therapy irrespective of the degree of hyponatraemia. Only 41% of cases developed neurological symptoms, of these, confusion and altered level of consciousness were the more prevalent at 12% each, followed by falls (9%), unsteady gait (4%) and seizures (4%). The cause for hyponatraemia was frequently poorly evaluated and in 23% of cases no definite diagnosis was made.CONCLUSION: Data on assessment, investigation and management of hyponatraemia illustrates variability and shortcomings in clinical practice. The question remains whether the relationship between hyponatraemia and increased mortality is causal or associative.peer-reviewe