Objective Patients living with pituitary neuroendocrine tumours (PitNETs) present with a spectrum of clinical manifestations and often follow a circuitous route to diagnosis, resulting in diagnostic delays. The objective of this study is to identify and report the various sources of referrals for patients who underwent pituitary resection for PitNETs in a tertiary referral centre for pituitary disease. Design Retrospective population-based cohort study. Patients Patients undergoing a first surgery for management of PitNET in Northern Ireland between 01/01/2000-19/07/2019. Measurements Demographics, referral sources, incidentaloma rates, apoplexy rates, symptoms, age at diagnosis and diagnostic delay according to referral source. Results Data were retrospectively analysed for 520 patients in whom the referral source leading to diagnosis was known. Fifty-seven percent of patients were male. Median age at diagnosis was 54 years (range 18-85). Patients were referred from 29 different sources. The majority of referrals came from general practice (23%), ophthalmology (14%), emergency medicine (9%), optician/optometry (9%) and internists (8%). Twenty-nine patients were referred following radiological discovery of an incidentaloma. Twenty-seven patients were referred with an initial presentation of pituitary apoplexy, with emergency medicine accounting for 70% of these referrals. Visual disturbance and headache were the most frequently documented symptoms. Median diagnostic delay was 2 years (range 0-25 years). Conclusions Patients with PitNETs encounter a range of clinical services in their journey to pituitary surgery. Raising awareness of these tumours and educating healthcare professionals across all disciplines could reduce diagnostic delays, thereby minimising the adverse sequelae of delayed diagnosis.

Cushing’s disease is a rare condition that occurs due to an adrenocorticotrophin-producing corticotrophinoma arising from the pituitary gland. The consequent hypercortisolaemia results in multisystem morbidity and mortality. This study aims to report incidence, clinicopathological characteristics, remission outcomes and mortality in a regional pituitary neurosurgical cohort of patients diagnosed with Cushing’s disease in Northern Ireland (NI) from 2000 to 2019. Clinical, biochemical and radiological data from a cohort of patients operated for Cushing’s disease were retrospectively collected and analysed. Fifty-three patients were identified, resulting in an estimated annual incidence of Cushing’s disease of 1.39–1.57 per million population per year. Females accounted for 72% (38/53) of the cohort. The majority (74%, 39/53) of corticotrophinomas were microadenomas and in 44% (17/39) of these no tumour was identified on preoperative magnetic resonance imaging. Histopathological characterisation was similarly difficult, with no tumour being identified in the histopathological specimen in 40% (21/53) of cases. Immediate postoperative remission rates were 53% and 66% when considering serum morning cortisol cut-offs of ≤ 50 nmol/L (1.8 µg/dL) and ≤ 138 nmol/L (5 µg/dL), respectively, in the week following pituitary surgery. Approximately 70% (37/53) of patients achieved longer-term remission with a single pituitary surgery. Three patients had recurrent disease. Patients with Cushing’s disease had a significantly higher mortality rate compared to the NI general population (standardised mortality ratio 8.10, 95% CI 3.3–16.7, P < 0.001). Annual incidence of Cushing’s disease in NI is consistent with other Northern European cohorts. Functioning corticotrophinomas are a clinically, radiologically and histopathologically elusive disease with increased mortality compared to the general population.

Despite significant improvements in treatment strategies over the past couple of decades, multiple myeloma (MM) remains an incurable disease due to the development of drug resistance. Metabolic reprogramming is a key feature of cancer cells, including MM, and acts to fuel increased proliferation, create a permissive tumour microenvironment, and promote drug resistance. This review presents an overview of the key metabolic adaptations that occur in MM pathogenesis and in the development of resistance to proteasome inhibitors, the backbone of current MM therapy, and considers the potential for therapeutic targeting of key metabolic pathways to improve outcomes.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3–1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson’s two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx -related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.

Background Calreticulin ( CALR ) mutations are commonly identified in patients with essential thrombocythaemia or myelofibrosis. CALR type 1 mutations are known to have a higher overall incidence in males but little is known about the risks of mutation subtypes on myelofibrotic change across patient age and sex. Aims To identify differences in the incidence of myelofibrotic change within subgroups of patients with CALR type 1 mutations. Methods All patients with a positive CALR exon 9 mutation identified within our unit between February 2016 and September 2020 were reviewed with note taken of patient sex, age at diagnosis, initial MPN diagnosis, and subsequent disease transformation. Results In our cohort, young male patients with CALR type 1 mutations were shown to be at significantly increased risk of myelofibrosis compared to age matched female patients. Conclusions Male patients have a worse myeloproliferative neoplasm phenotype than female patients with it occurring at a younger age and being more myelofibrotic in nature. Further investigation is needed into the reasons for this variability.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.

INTRODUCTION:Primary bone lymphoma (PBL) is a rare bone malignancy which may present with atraumatic pain, swelling, or pathological fracture. Whilst the femur is the most commonly affected site, any bone may be involved. PBL should be distinguished from other bone lesions to determine clinical management.CASE REPORT:We report the case of an 89-year-old gentleman who presented to the local emergency department with atraumatic hip pain and inability to weight-bear. Multimodal imaging showed evidence of a tumor involving the proximal femur and adjacent acetabulum with an associated pathological intertrochanteric fracture. Biopsy specimens demonstrated this to be PBL of the diffuse large B-cell subtype. No other disease foci or nodal involvement was identified. The patient underwent proximal femoral replacement and acetabular reconstruction prior to commencing R-Mini-CHOP chemotherapy, during which time he has been permitted to fully weight-bear.CONCLUSION:To our knowledge, this is the first reported case of a patient having PBL with both femoral and acetabular involvements. Due to its infrequent occurrence, evidence remains limited to advise therapeutic guidelines. Our practice concurs with literature suggesting that surgery be reserved for cases of pathological fracture. However, the merits of undergoing surgical fixation prior to chemoradiation treatment have been considered.

Vestibular schwannoma (VS) is a benign tumour arising from the vestibular component of the vestibulocochlear nerve. Treatment protocols range from observation to microsurgical resection (MS) or radiation therapy using focused delivery techniques: either stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT). Most reported outcome measures explore medically orientated results such as extent of resection or facial nerve function and do not give any insight into how the initial disease, the treatment or operative complications impinge upon the patient's quality of life (QoL). The primary aim of this review was to appraise the quality of research concerning the measurement of QoL in patients with VS. A systematic review was performed including trials of patients with newly diagnosed VS undergoing MS, SRT/SRS, or observation with a measure of QoL. Only trials of prospective design were included. Excluded trials included participants with recurrent disease or comorbidities, and studies reporting patients with VS in association with neurofibromatosis type 2. Each trial for inclusion was assessed for bias and underwent formal data extraction. Between 1973 and 2010, 47 unique trials were identified with eight trials of prospective design. All included studies were prospective non-randomised, observational convenience sampled trials. No randomised control trials or systematic reviews were identified. The most common QoL measure used was the Short Form Questionnaire (SF-36), although it has not been validated in VS. The included trials suggest that the treatment protocols of MS and SRS/SRT are of equal efficacy with regard to impact on QoL; however, the trials were hetereogenous and suffered from a variety of methodological deficiencies. Given this heterogeneity, no meta-analysis was able to be performed. The available literature on QoL in the treatment of VS suffers from significant methodological weaknesses making it difficult to make any assessment as to the efficacy on QoL of available treatment options for VS. Further well-designed, randomised prospective research is necessary to understand this condition, its effect on QoL and how QoL outcomes may be used alongside clinical indicators in making treatment decisions.