Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with Arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein VCP mice, which develop an inclusion body myopathy (IBM), treatment with Arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated the safety and tolerability of Arimoclomol in an investigator-lead, randomised, double-blind, placebo-controlled, proof-of-concept patient trial and gathered exploratory efficacy data which showed that Arimoclomol was safe and well tolerated. Although Arimoclomol improved some IBM-like pathology in vitro and in vivo in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in this proof of concept patient trial.

Total bilateral adrenalectomy remains the definitive procedure for cure in Cushing's disease. It is complicated by the development of Nelson's syndrome, the treatment of which remains troublesome. We report the long-term follow-up, median 17 yr (range, 8-22 yr), of 13 patients (3 males and 10 females) treated with pituitary surgery for Nelson's syndrome at a median age of 35 yr (range, 21-67 yr). The presence of a pituitary mass lesion necessitated neurosurgery in all. Preoperatively, the median plasma ACTH level was 664 pmol/liter (range, 92-3665 pmol/liter); this fell to 29 pmol/liter (range, <2 to 1124 pmol/liter) postoperatively (P < 0.0005). Cutaneous hyperpigmentation was reduced in all and resolved in 11 patients. The pituitary tumor bulk was clearly reduced in 12 patients. There was no perioperative mortality. No patient developed a visual field defect attributable to surgery. New anterior pituitary hormone deficiency occurred in seven patients, and permanent diabetes insipidus occurred in five patients. At latest follow-up, the median plasma ACTH is 73 pmol/liter (range, <2 to 7759 pmol/liter); six patients have levels of less than 44 pmol/liter and also have a resolution of their pigmentation and no evidence of a recurrence of a pituitary mass lesion. We conclude that pituitary surgery is an efficacious treatment for mass lesions associated with Nelson's syndrome, has long-term benefit with minimal side effects, and must be considered in the management of this distressing complication.

Primary cerebral phaeohyphomycosis due to Rhinocladiella mackenziei is an extremely rare infection carrying more than 80% mortality, with most cases reported from the Middle East region. This darkly pigmented black yeast is highly neurotropic, aggressive and refractory to most antifungal agents. Here we present an immunocompetent elderly male, presenting with multiple brain abscesses, with R. mackenziei confirmed by nuclear ribosomal repeat region sequencing, who was successfully treated by surgical debridement and intravenous voriconazole. To our knowledge this is the first case reported from the United Kingdom. We also present a review of all such cases so far reported in the English literature world-wide, which we believe is a step further to understanding the pathogenesis and establishing effective treatment of this rare, yet often fatal disease.

Background Despite an initially indolent course, all WHO grade II, LGGs inevitably transform to malignant, WHO grades III and IV, without current curative options. Malignant transformation (MT) remains unpredictable with limited prognostic markers to steer timing of interventions. The aim of this study was to review and assign predictive value to specific clinical, molecular and radiological markers impacting MT, thereby justifying timely therapeutic interventions. Methods Searches of MEDLINE, Embase and Cochrane databases were conducted from inception to April 28, 2021 and outputs were analysed in accordance with PRISMA protocol. Results From an initial 5,032 articles, 31 articles were included, totalling 5,193 patients. Forty-three prognostic factors were registered to significantly impact MT. These were categorised as 7 clinical; 14 neuroimaging; 8 biological/molecular; 3 volumetric; 5 topological; 3 histological; and 3 treatment-related. Following analysis, 10 factors were highlighted: the pre-operative prognosticators were 1. presentation with epileptic seizures; 2. VDE &gt;8mm/year; 3. VDE &gt;4mm/year; 4. rCBV &gt;1.75; 5. PTV ≥5 cm (65ml); 6. PTV ≥100 ml; and 7. cortical involvement. The post-operative prognosticators were 1.IDH-wt; 2. TP53 mutation; and 3. temozolomide monotherapy. Conclusions The management of LGGs remains controversial, as conservative and invasive treatment may be associated with MT and impaired quality of life, respectively. Our review indicates that MT can be predicted by specific metrics in VDE, PTV and rCBV, alongside cortical involvement. Additionally, patients with IDH-wt tumours TP53 mutations, or receiving TMZ monotherapy are more likely to undergo MT. Our data may form the basis of a predictive scoring system.