Journal Club September 2021

Objective Thoracoscopic Criteria in Differentiation between Benign and Malignant Pleural Effusions.

Ellayeh M, et al. Respiration. 2021 Aug 30:1-11. doi: 10.1159/000517910. Online ahead of print. PMID: 34515216

An observational study from the Oxford group looking the correlation between macroscopic appearances at medical thoracoscopy and the final diagnosis. Although such analyses have been done before this was performed in a very structured way using independent assessors blinded to the patient details watching recorded video footage.

They assessed footage from 96 thoracoscopies with objective assessment of nodules, lymphangitis and inflammation on each of the visceral, diaphragmatic costoparietal surfaces. As you might expect, widespread nodules were indicative of malignant disease and were mostly distributed in the middle and inferior surfaces of the lateral costoparietal pleura. However, be warned, nodules were seen in nearly a quarter of the benign cases…

Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy.

Harber J et al. J Immunother Cancer. 2021 Sep;9(9):e003032. doi: 10.1136/jitc-2021-003032. PMID: 34518291 Review.

After decades of disappointing results from randomised trials of systemic treatment in mesothelioma there has been a relative flurry of promising new therapies. Harber and colleagues from Leicester summarise the advances in this review published in the Journal of Immunotherapy for Cancer. The article is geared towards translational advances around the tumour micro-environment. But even if understanding the interplay between FOXP3 activity and helper T cells isn’t your thing the article offers some lovely explanatory diagrams of T-lymphocyte biology. Figure 1A and B is a timeline of the major chemo/immunotherapy trial of the last 6 years which is worth a look.

Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial.

Pinto C, et al Lancet Oncol. 2021 Sep 6:S1470-2045(21)00404-6. doi: 10.1016/S1470-2045(21)00404-6. Online ahead of print. PMID: 34499874

Continuing on the theme of promising advances in mesothelioma treatment is impressive randomised controlled trial of second -line therapy from Pinto and colleagues published in Lancet Oncology, the RAMES (RAmucirumab MESothelioma treatment) trial.

Background: Few agents have shown good activity against mesothelioma that has progressed following 1st-line therapy (including vinorelbine, gemcitabine, repeated pemetrexed +/- pembrolizumab). Ramucirumab is a fully humanised monoclonal antibody selectively directed against the extracellular domain of VEGFR­2 (high VEGF being repeatedly associated with poor prognosis in mesothelioma)

Methods: Patients with pleural mesothelioma (any histology) who had progressed on conventional Pemetrexed plus platinum 1st line therapy.

Exclusions: patients had to have mRECIST measurable tumour, could not be on an anticoagulant or anything else that might increase bleeding risk. ECOG performance status of 0-2 only.

Patients were double blind randomised (1:1) to IV gemcitabine in combination with or without IV Ramucirumab.

Primary outcome was overall survival.

Results: The trial over-recruited to 165 pts. The demographic of patients was fairly typical with a median age of 69 and 85% epithelioid.

For the primary outcome, median OS was 7.5months in the Gemcitabine & placebo group versus 13.8 months in the Gemcitabine & Ramucirumab group (p=0.03). Secondary outcomes were also positive with improved progression free survival in the Ramucirumab arm. Serious adverse events were balanced between the groups (6% vs 5%).

Author’s Conclusion: Ramucirumab in addition to standard care (gemcitabine) was associated with improved overall survival in patients who had already received first line chemotherapy.

Strengths: Used overall survival as an endpoint as opposed to mRECIST. It does mean it took 5 yrs from trial opening to reporting. A small price to pay for a firm outcome! Not overly selective of patients in term of demographics, comorbidity or histology

Limitations: Although a sub-group analysis the same benefit was not seen in patients over 70 years old, worrying as this is an increasing demographic of the UK mesothelioma population.

In an ever-changing landscape of mesothelioma treatments it is not clear where Ramucirumab might sit alongside other monoclonal antibodies especially given patients previously given anti-VEGF agents (e.g. Bevacizumab) were excluded from RAMES.

Intrapleural use of urokinase and DNase in pleural infections managed with repeated thoracentesis: A comparative cohort study.

Luque Paz D, et al. PLoS One. 2021 Sep 21;16(9):e0257339. doi: 10.1371/journal.pone.0257339. eCollection 2021. PMID: 34547022

In the UK, the “standard care” of complex parapneumonic effusions or pleural empyema is early chest drain and antibiotics. The MIST3 trial is generating important data about the role of early surgery or firbrinolytics alongside. However, this case series from France demonstrates positive results from repeated therapeutic thoracentesis (TT) to manage pleural infection.

This group has published a case series on the topic before in 2014 with this latest PlosOne publication assessing the addition of fibrinolytics to TT. With the exception of patients on intensive care they manage all cases of pleural infection with TT, 133 cases over the 17 years analysed. Their protocol involves the use of a 8-French laparoscopic trocar (‘Boutin Trocart’), which only more recently was guided by ultrasound (in 72% overall), to aspirate the pleural space to dryness. Fibrinolytics are instilled at the end of the procedure: Urokinase pre-2010, Urokinase plus DNase post-2010.

As non-comparative data their outcomes are difficult to compare to chest drain management but seem similar with a hospital length of stay of 16 days, 11% surgical referral rate and 9% mortality. Although only 4% went on to need a chest drain the median number of TT procedures performed per patient performed was 4. There is no comment on patient tolerability of the approach and complications are similar to those reported in chest drain literature.

A feasibility trial comparing chest tube drainage to repeated therapeutic aspiration is currently recruiting in Bristol. Whilst this study would suggest the approach is safe it does not have remarkably different outcomes to what we would consider ‘standard-care’ and is unlikely to change practice in its own right.

Images of the month 1: ‘Soy sauce’ pleural effusion: what causes black pleural fluid?

Newman J, et al. Clin Med (Lond). 2021 Sep;21(5):e531-e532. doi: 10.7861/clinmed.2021-0403. PMID: 34507940

Finally, a short article some interestingly coloured pleural fluid drained from a patient who presented to a Hertfordshire hospital. I won’t give away the author’s hypothesised explanation as to the cause of the “soy sauce” effusion but it is compelling.