Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression.

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

MesoTRAP: a feasibility study that includes a pilot clinical trial comparing video-assisted thoracoscopic partial pleurectomy decortication with indwelling pleural catheter in patients with trapped lung due to malignant pleural mesothelioma designed to address recruitment and randomisation uncertainties and sample size requirements for a phase III trial.

Introduction: One of the most debilitating symptoms of malignant pleural mesothelioma (MPM) is dyspnoea caused by pleural effusion. MPM can be complicated by the presence of tumour on the visceral pleura preventing the lung from re-expanding, known as trapped lung (TL). There is currently no consensus on the best way to manage TL. One approach is insertion of an indwelling pleural catheter (IPC) under local anaesthesia. Another is video-assisted thoracoscopic partial pleurectomy/decortication (VAT-PD). Performed under general anaesthesia, VAT-PD permits surgical removal of the rind of tumour from the visceral pleura thereby allowing the lung to fully re-expand. Methods and analysis: MesoTRAP is a feasibility study that includes a pilot multicentre, randomised controlled clinical trial comparing VAT-PD with IPC in patients with TL and pleural effusion due to MPM. The primary objective is to measure the SD of visual analogue scale scores for dyspnoea following randomisation and examine the patterns of change over time in each treatment group. Secondary objectives include documenting survival and adverse events, estimating the incidence and prevalence of TL in patients with MPM, examining completion of alternative forms of data capture for economic evaluation and determining the ability to randomise 38 patients in 18 months. Ethics and dissemination: This study was approved by the East of England-Cambridge Central Research Ethics Committee and the Health Research Authority (reference number 16/EE/0370). We aim to publish the outputs of this work in international peer-reviewed journals compliant with an Open Access policy. Trial registration: NCT03412357.

Extended pleurectomy decortication: the current role.

Extended pleurectomy/decortication (EPD) has been formally defined but there remain technical areas of debate between practitioners. This is partly attributable to the relative rarity of this operation which is largely confined to a small number of specialist centres. Nevertheless, there is a widespread acceptance that extended pleurectomy/decortication (P/D) is a realistic and favourable alternative to extrapleural pneumonectomy. There may, however, remain a small number of clinical cases where this more extensive operation may be indicated. Preservation of the lung has widened the selection criteria for this form of radical mesothelioma surgery but there remain important factors to consider when offering extended P/D. In many patients with poorer prognostic factors the less radical operation of video assisted partial pleurectomy may be preferable. However, a randomized trial showed no survival benefit for this operation over simple talc pleurodesis. The future for P/D may also lie in the outcome of the MARS2 randomized controlled trial which will report in the next few years. Meanwhile there is a clinical and ethical dilemma when asked to perform this operation outside of the context of a clinical trial in the face of the lack of high grade evidence. The role of P/D is in one respect expanding but this may be short lived pending the findings of its assessment against non-surgical treatment.

Surgical management of lung cancer with multiple lesions: implication of the new recommendations of the 8th edition of the TNM classification for lung cancer.

The 8th tumour, node and metastasis (TNM) revision of the staging classification for lung cancer has attempted to clarify the different properties of four distinct clinical presentations: synchronous multiple primary lung cancers; primary tumour with intrapulmonary metastases; pneumonic-type adenocarcinoma and multiple ground glass/lepidic lesions. The respective biological profiles determine different surgical strategies for each category. Accurate preoperative histological confirmation is required to identify synchronous primary tumours which should then be managed as two separate episodes within the confines of patient characteristics. Equally important is the confirmation of intrapulmonary metastasis which indicates a more conservative resection of the smaller lesion. In contrast, pneumonic-type adenocarcinoma may require larger parenchymal resection to achieve anatomical clearance but also symptom relief. Multiple subsolid lesions require a carefully planned strategy of parenchymal sparing and possible observation of less malignant abnormalities. In all the above situations careful clinical, radiological and pathological assessment is imperative to avoid one embarking on inappropriate invasive management. Either when the widespread nature of the disease renders extensive surgery futile or the relative benign or pre-malignant nature of the multiple lesions imply that the risks of surgery outweigh the prognostic benefits.

Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.

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.

Hybrid bilobectomy for treatment of an early-stage lung cancer in a patient with severe emphysema using the benefits of lung volume reduction.

Patients with resectable lung cancer and concomitant emphysema can fall outside the accepted guidelines for surgery. Lung volume reduction can improve their lung function but involves resecting an emphysematous lobe containing the tumour. Volume reduction can also be achieved by endobronchial one-way valve insertion, causing lobar collapse, but intact fissures are required. A 'hybrid bilobectomy' was performed on a 77-year-old ex-smoker with suspected T2aN0M0 bronchogenic carcinoma and severe pulmonary emphysema. The procedure consisted of endobronchial right lower lobe volume reduction and video-assisted middle lobectomy with stapled completion of the oblique fissure. Complete collapse of the right lower lobe was confirmed intraoperatively and on follow-up chest films. The recovery period was complicated by a prolonged air leak. We believe that concomitant endobronchial volume reduction of an ipsilateral lobe can facilitate video-assisted lobectomy in high-risk patients with severe emphysema. The success of endobronchial valves to achieve a hybrid bilobectomy is increased by stapled completion of fissure to prevent collateral ventilation.

Extended pleurectomy decortication for malignant pleural mesothelioma in the elderly: the need for an inclusive yet selective approach.

OBJECTIVES: The median age at diagnosis of patients with pleural mesothelioma in the UK is 73 years. Recent series have shown the feasibility of extended pleurectomy decortication in the elderly, but with continuing debate about the efficacy of this treatment, we reviewed our experience to identify more detailed selection criteria. METHODS: We reviewed prospectively collected data on all patients from 1999 to 2016 undergoing extended pleurectomy decortication. We compared clinical and pathological outcomes and survival data from patients 70 years and older (≥70 years) with those younger than 70 years (<70 years). RESULTS: Eighty-two of the 300 (27.3%) patients were ≥70 years of age at the time of surgery. More patients in the elderly group required intensive care postoperatively (6.2 vs 16.7%, P = 0.01) and developed atrial fibrillation (14.4 vs 24.4%, P = 0.05). There was no intergroup difference in length of hospital stay or in in-hospital, 30-day or 90-day mortality. Elderly patients were less likely to receive neoadjuvant (<70 years 21.2%, ≥70 years 11.0%; P = 0.045) or adjuvant chemotherapy (<70 years 45.4%, ≥70 years 29.3%; P = 0.04). Median overall survival was similar: <70 years 14.0 months, ≥70 years 10.3 months; P = 0.29. However, in node-positive patients, survival was poorer in the elderly (13.0 vs 9.1 months, P = 0.05), particularly in those with non-epithelioid tumours (3.8 vs 6.7 months, P = 0.04). On multivariable analysis, age was not a significant prognostic factor, although lack of adjuvant therapy (P = 0.001) and admission to the intensive care unit (P < 0.001) remained poor prognostic factors. CONCLUSIONS: Although age in isolation should not be an exclusion criterion for extended pleurectomy decortication for mesothelioma, in the elderly, a more rigorous preoperative evaluation of nodal disease and an additional assessment of fitness for adjuvant chemotherapy are recommended.

VATS and open chest surgery in diagnosis and treatment of benign pleural diseases.

A negative pressure normally exists between the visceral and parietal pleurae in the lungs, which can act as vacuum for fluid, air and small particles from different parts of the body, allowing them to move into the pleural space and be retained in it, thus resulting to different manifestations of pleural disorders. A pleural effusion is the result of fluid collection between the parietal and visceral pleural surfaces. The most common cause in developed countries is congestive heart failure, followed by pneumonia and malignancy. It is highly important that a systematic approach is undertaken during the investigation of pleural effusions. Treatment should be based on the nature of the effusion and underlying condition, while undiagnosed patients should remain under surveillance. Pleural infection is a serious clinical condition which affects approximately 65,000 patients every year in the UK and can result in mortality in rates as high as 20%. The selection of treatment as well as timing of intervention remains a debatable issue among pulmonologists and thoracic surgeons. Surgical intervention aims to control sepsis, by facilitating evacuation of necrotic material from the pleural space, and obliterate the empyema cavity, by allowing the trapped lung to re-expand via peeling of the organised cortex from its visceral pleura. Thoracoscopic surgery offers the advantages of visual assessment of the pleural space and direct tissue sampling and it can be useful for the diagnosis of unknown pleural effusions and in the management of complicated collections. Open thoracotomy remains the gold standard, however with the advancement of thoracoscopic instruments and techniques, minimally invasive approaches provide comparable outcomes and have been taking over the management of benign pleural diseases.

Video assisted thoracoscopic and open chest surgery in diagnosis and treatment of malignant pleural diseases.

Parenchymal cancers of lung, breast, gastrointestinal tract and ovaries as well as lymphomas and mesotheliomas are among the most common cancer types causing malignant effusions, though almost all tumour types have been reported to cause a malignant effusion. The prognosis heavily depends on patients' response to systemic therapy however, regardless of the causing pathology and histopathologic form, malignant pleural disease is normally associated with a poor prognosis. To date, there are not sufficient data to allow accurate predictions of survival that would facilitate decision making for managing patients with malignant pleural diseases. Interventions are directed towards drainage of the effusion and, when appropriate, concurrent or subsequent pleurodesis or establishing long-term drainage to prevent re-accumulation. The rate of re-accumulation of the pleural effusion, the patient's prognosis, and the severity of the patient's symptoms should guide the subsequent choice of therapy. In contemporary medicine, not many cancers have managed to generate as intense debates concerning treatment, as malignant pleural mesothelioma. The relative advantages of surgery, radiation, chemotherapy and any combination of the three are continuously reassessed and reconsidered, even though not always based on scientific evidence. The aim of surgery in mesothelioma may be prolongation of life, in addition to palliation of symptoms. Longer recovery periods from more extensive surgical procedures could be justified, in carefully selected patients. Surgical options include: Video assisted thoracoscopic (VATS) pleurodesis, VATS partial pleurectomy (VATS PP)-both parietal and visceral; open pleurectomy decortication (PD)-with an extended option (EPD) and extrapleural pneumonectomy (EPP). Current evidence implies that EPD can be performed reliably in specialised centres with good results, both in terms of mortality and survival; however, no operation has yet been shown to be beneficial in a prospective randomized controlled clinical trial.

Long-term survival and symptomatic relief in lower lobe lung volume reduction surgery.

OBJECTIVES: Lung volume reduction surgery (LVRS) has been demonstrated to provide symptomatic relief and improve lung function in patients with end-stage emphysema. The National Emphysema Treatment Trial specifically noted functional benefits in patients with predominantly upper lobe emphysema and demonstrated improvement in quality-of-life parameters, in patients with non-upper lobe emphysema and a low-baseline exercise capacity. We aimed to investigate whether physiological and health status benefits correlated with lower lobe LVRS. METHODS: A retrospective analysis was performed from our prospectively collected patient database. A total of 36 patients with severe, non-upper lobe predominant emphysema underwent lower lobe LVRS in our institution, over a 20-year period. The assessments consisted of measurements of body mass index, pulmonary function tests and health-related quality of life using the Short Form 36-item questionnaires. RESULTS: Forced expiratory volume in 1 s was seen to improve 3 months [coefficient of time = 1.55 (0.88, 2.21); P < 0.0001] after the procedure, maintained until the first 6 months [0.48 (0.12, 0.85); P = 0.010], decline over the second half of the first year and gradually return to preoperative levels after 2 years, while residual volume to total lung capacity (%) ratio was seen to follow a similar pattern with significant decrease from baseline after 3 months [coefficient of time = -1.76 (-2.75, -0.76); P = 0.001] and 6 months [-1.05 (-1.51, -0.59); P < 0.0001]. Quality-of-life improvements were mainly noted in physical components. CONCLUSIONS: Contrary to a widely held misconception following the National Emphysema Treatment Trial that lower lobe lung volume reduction does not offer significant benefits to patients with non-upper lobe predominant emphysema, we feel justified in offering lower lobe LVRS in these patients when they meet the same selection criteria as upper lobe LVRS.

Is a diagnostic video-assisted thoracoscopic thymectomy an acceptable first-line approach to the suspicious anterior mediastinal mass?

INTRODUCTION: The incidental early-stage thymic mass presents a diagnostic challenge. Video-assisted thoracoscopic (VAT) thymectomy is an attractive but potentially morbid solution. The aim was to show it can be safely applied as a first-line modality in those with undiagnosed thymic enlargement with acceptable long-term results. METHODS: A total of 45 patients were identified (24 male, median age 52 interquartile range [IQR]: 41-66 years) in a 14-year experience who had CT evidence of an enlarged, possibly malignant thymic mass, but no tissue diagnosis before undertaking VAT thymectomy. The clinical outcomes of both benign and malignant diagnoses were compared. RESULTS: Myasthenic symptoms were present in 20 patients (44%), whereas 15 (33%) were asymptomatic. Benign lesions were resected in 27 patients (60%): thymic hyperplasia (56%), thymic cyst (33%), lipoma (7%) and xanthogranulomatous inflammation (4%). Of the 18 malignant patients, 82% had thymoma (three had Masaoka Stage I, 11 Stage II and one Stage III), 6% thymic carcinoma, 6% teratoma and 6% seminoma. Seven patients required radiotherapy for R1 resection. There was no difference in median hospital stay in either group: Benign group: 4 versus 5 days (P = 0.07). One patient in both groups required conversion to open. Two patients in the malignant group had significant morbidity (one myocardial infarction and one pulmonary embolism). There were no cases of tumour recurrence or mortality at a median follow-up of 6.6 years (IQR: 4.4-9.5 years). CONCLUSION: Right-sided diagnostic VAT thymectomy is a safe and effective first-line approach to suspected malignant thymic enlargement. At 5-year follow-up, there were no cases of recurrence in the malignant group.

Randomized controlled trials in malignant pleural mesothelioma surgery-mistakes made and lessons learned.

Randomized surgical trials are of the most difficult to design and recruit, however, they are the only robust method available to establish a new surgical procedure. Mesothelioma is a disease with a perceived poor prognosis for which surgical intervention has relatively high complications and not insignificant mortality. This review will consider the mesothelioma and radical surgery (MARS) 1 and 2 trials, SAKK 17/04 trial and the EORTC 1205 trial all aimed at assessing the potential benefit of radical surgery for malignant pleural mesothelioma. In addition, MesoVATS and MesoTRAP will be explored assessing the value of debulking surgery for malignant pleural mesothelioma. We also endeavour to identify the mistakes made and the lessons learned which will inform future randomized controlled clinical trials in the field of malignant pleural mesothelioma. Despite the insurmountable problems with randomized controlled clinical trials, we show that they are possible and continuing with uncontrolled experiments will perpetuate unproven and potentially harmful operations.

Individualised risk in patients undergoing lung volume reduction surgery: the Glenfield BFG score.

Lung volume reduction surgery (LVRS) has been shown to be beneficial in patients with chronic obstructive pulmonary disease, but there is low uptake, partly due to perceived concerns of high operative mortality. We aimed to develop an individualised risk score following LVRS.This was a cohort study of patients undergoing LVRS. Factors independently predicting 90-day mortality and a risk prediction score were identified. Reliability of the score was tested using area under the receiver operating characteristic curve (AUROC).237 LVRS procedures were performed. The multivariate analysis factors associated independently with death were: body mass index (BMI)<18.5 kg·m-2 (OR 2.83, p=0.059), forced expiratory volume in 1 s (FEV1)<0.71 L (OR 5.47, p=0.011) and transfer factor of the lung for carbon monoxide (TLCO) <20% (OR 5.56, p=0.031). A risk score was calculated and total score assigned. AUROC for the risk score was 0.80 and a better predictor than individual components (p<0.01). The score was stratified into three risk groups. Of the total patients, 46% were classified as low risk. Similar improvements in lung function and health status were seen in all groups. The score was introduced and tested in a further 71 patients. AUROC for 90-day mortality in this cohort was 0.84.It is possible to provide an individualised predictive risk score for LVRS, which may aid decision making for both clinicians and patients.

Surgery as part of radical treatment for malignant pleural mesothelioma.

PURPOSE OF REVIEW: To review the latest developments in surgery for malignant pleural mesothelioma both in patient selection, surgical technique, and strategy. RECENT FINDINGS: The International Association for the Study of Lung Cancer mesothelioma staging project has produced data to inform the 8th tumour node metastasis revision. The difficulty in clinical N staging and clinical T staging are highlighted and the importance of tumour volume is recognized. New imaging techniques can be utilized to assess tumour volume. The transition from extrapleural pneumonectomy to lung-sparing pleurectomy/decortication has extended the role of cancer-directed surgery into a more elderly population. More aggressive multimodality regimes, including induction radiotherapy are available to a selected population and adjuvant radiotherapy and chemotherapy are feasible in the elderly majority. Additional chemotherapy should not be delayed in those with poorer prognosis node positive, nonepithelioid disease. SUMMARY: Radical surgery for malignant pleural mesothelioma can achieve significant survival when targeted in those with the best prognosis by careful staging. It can be made more accessible by lung preservation without compromising outcome. It should be part of multimodality therapy.