Neelam Kumar

Malignant pleural mesothelioma (MPM) remains a devastating disease with a poor prognosis; median survival ranges from just 8 to 14 months from diagnosis.1 The incidence is the highest in the UK and Australia and while this is expected to peak by 2020, the global incidence is predicted to increase for several decades particularly in emerging economies. Treatment options remain limited. Chemotherapy using third-generation antifolate agents is the only treatment modality that has been shown to improve survival in MPM.2 Standard first-line treatment is combination pemetrexed and cisplatin (or carboplatin), however response rates to these regimens are low. An evaluation of over 1700 patients who received pemetrexed with either cisplatin or carboplatin demonstrated response rates of 26.3% and 21.7%, respectively.3 Surgical management is controversial with a lack of robust randomised trial data. Novel treatments are however on the horizon. The genomic era has led to the early development of precision therapies, and as with several other cancers, immunotherapy may hold promise.4 Alongside a paucity of current effective treatments, patients with MPM are also subject to a high symptom burden. In a study of 495 patients,5 92% reported three or more symptoms at diagnosis with fatigue (94%), dyspnoea (89%), chest pain (85%), appetite loss (87%) and cough (75%) being the most common. The psychological burden of a diagnosis of MPM can be equally distressing with patients reporting feelings of uncertainty and lack of control.6 Carers of patients with MPM similarly report an emotional and physical toll.7 Arguably, MPM is therefore the archetypal disease necessitating effective palliative care, defined by the WHO as ‘an approach that improves the quality of life of patients and their families facing life-threatening illness, through the prevention and relief of suffering by early identification and impeccable assessment and treatment of pain …

Introduction Malignant mesothelioma (MM) has no biomarker driven therapies in routine clinical use. We used a drug screen of molecularly characterised MM lines to identify novel genomic biomarker driven therapy. This led to the discovery of a subset of MMs, defined by loss of function (LOF) of the nuclear deubiquitinase BRCA associated protein 1 (BAP1), that demonstrate heightened sensitivity to tumour necrosis factor related apoptosis inducing ligand (TRAIL). We then validated this association across in vitro, in vivo and ex vivo models and delineated the underlying mechanism. Methods 15 MM lines were characterised for mutations in five MM tumour driver genes and screened for response to 95 compounds. The identified BAP1-TRAIL association was validated in an extended panel of MM lines with apoptosis and cell viability assays. 25 early passage MM cultures, mouse xenograft and human tumour explant models were used to further validate the association. Knock-in and knock-out models in BAP1 mutant and wild type lines confirmed the effect of loss of BAP1 expression on TRAIL sensitivity. 6 mutant BAP1 constructs were generated and identified which functional BAP1 sites modulate TRAIL sensitivity. The effect of BAP1 function on the downstream death receptor/apoptosis pathway components was determined using microarray and immunoblot analysis. Results BAP1 LOF significantly correlated with TRAIL sensitivity in established MM lines (p=0.015) and primary MM cultures (pBAP1 confirmed deubiquitinase activity and its ability to bind to ASXL proteins to form the polycomb repressor deubiquitinase complex (PR-DUB) as determinants of TRAIL sensitivity, implicating modulation of transcriptional programmes as an underlying mechanism. Consistent with this, knockdown of ASXL1 also increased TRAIL sensitivity in MM lines and loss of BAP1 deubiquitinase and ASXL binding activity altered gene, and protein expression of components of the apoptotic machinery favouring apoptosis upon activation of death receptors. Conclusions We identify loss of BAP1 as a novel biomarker for TRAIL sensitivity in MM. BAP1 LOF is observed in up to 67% of MM tumours and BAP1 immunohistochemistry is in use as a diagnostic tool; hence this approach is validated and ready for immediate and actionable clinical use for this disease.

Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.

COPD and radiographic bronchiectasis frequently coexist but the effect of this on the clinical course of COPD is not fully understood. We determined the impact of bronchiectasis on clinical outcomes in COPD patients, independent of coexisting emphysema and bronchial wall thickening (BWT). COPD patients admitted with first exacerbation 1998-2008 were identified retrospectively using ICD10 codes J44.0,1,8,9. Patients with suitable CT scans were graded for severity of bronchiectasis, emphysema and BWT on a 5 point scale (0-absent, 1-minor, 2-mild, 3-moderate, 4-severe). 406 patients (71 ± 11 years, 56% male, FEV1 52 ± 23% predicted) were included; 278 (69%) patients had bronchiectasis: minor, 112 (40%); mild, 81 (29%); moderate, 62 (22%); severe 23 (8%). Bronchiectasis severity correlated with severity of BWT (p < 0.001) but not emphysema (p = 0.090). Bronchiectasis independently determined sputum isolation of Pseudomonas aeruginosa (Odds ratio (OR) 1.39 (95% CI 1.07 to 1.80), p = 0.013) and atypical mycobacteria (OR 2.44 (95% CI 1.04 to 5.69), p = 0.040), annual respiratory admissions (p = 0.044) and inpatient days (p < 0.001), but did not predict survival (p = 0.256). Radiographic bronchiectasis in COPD patients is associated with increased respiratory infection and hospitalisation, independent of coexisting emphysema and BWT. COPD-related bronchiectasis is therefore an important diagnosis with potential implications for treatment.

A previously fit and well 26 year old male student of Chinese origin attended the emergency department with a five day history of a febrile illness. He had returned to the United Kingdom from a three week visit to Malaysia and Singapore the day before the illness began. His main symptoms were fever, headache, and nausea. He had also noted a faint widespread rash the day before admission. On examination his temperature was 39.7°C, his blood pressure was 134/77 mm Hg, and he had a regular heart rate of 75 beats/min. He had a respiratory rate of 14 breaths/min and oxygen saturations of 98% on room air. The only relevant clinical finding was a confluent erythematous macular rash across his chest, back, arms, and legs, with multiple small discrete areas of sparing. Full blood count showed haemoglobin 163 g/L (120-180), platelets 86×109/L (130-400×109), white cell count (WCC) 3.4×109/L (4.5-11.0×109), neutrophils 1.7×109/L (2.0-7.5×109; 40-75% WCC), lymphocytes 1.4×109/L (1.3-3.5×109; 20-45% WCC), and no eosinophilia (0.04-0.44×109/L; 1-6% WCC). A blood film was negative for malaria parasites and confirmed thrombocytopenia with atypical lymphocytes. Renal function, liver function, and clotting tests were unremarkable and C reactive protein was less than 4 mg/L. ### 1 What are the most likely clinical diagnosis and important differential diagnosis? #### Short answer On the basis of the history and clinical picture, the diagnosis is probably dengue infection. Malaria is an important differential diagnosis and should be excluded with serial blood film examination or direct antigen testing (or both). #### Long answer Dengue infection classically presents with an abrupt onset of fever, …