Separation of Craniopagus Twins.

Separation of craniopagus twins is fraught by ethical issues. The surgery is high risk and may involve the sacrifice of one twin. We review surgical successes in separation of craniopagus twins and consider ethical and legal concepts affecting the decision to undertake such procedures. Our discussion considers how Gillett's potentiality principle and the concept of moral permissibility may be used to arrive at fair and realistic decisions.

Insights on Epidemiology, Morbidity and Mortality of Cushing's Disease in Northern Ireland.

Cushing's disease is a rare condition occurring 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 from 2000-2019. 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 ≤50nmol/L (1.8µg/dL) and ≤138nmol/L (5µg/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 Northern Ireland general population (standardised mortality ratio 8.10, 95% confidence interval 3.3 - 16.7, p<0.001). Annual incidence of Cushing's disease in Northern Ireland 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.

CALR type 1 mutations are associated with an increased incidence of myelofibrosis in young male patients.

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.

Metabolic Alterations in Multiple Myeloma: From Oncogenesis to Proteasome Inhibitor Resistance.

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.

Succinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours.

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.

Systematic review of quality of life in the management of vestibular schwannoma.

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.