Journal Club October 2021

Role of thoracic ultrasonography in pleurodesis pathways for malignant pleural effusions (SIMPLE): an open-label, randomised controlled trial. 

Psallidas I, et al. Lancet Respir Med. PMID: 34634246

We had a sneak peek of these exciting results at the pleural research day so it is great to see the SIMPLE trial getting the recognition it deserves in a high impact journal.

Run by the Oxford group this is a trial of using bedside ultrasound findings to measure pleurodesis success. The focus was on the effect on hospital length of stay, an outcome that is important to patients (especially with a life limiting illness) and medical professionals.

313 patients with malignant effusions were randomised 1:1 to BTS standard care (basing chest drain removal on fluid output) versus a daily ultrasound assessment of lung sliding/adherence using a protocolised scoring system.

Headline….ultrasound based assessment reduced hospital length of stay by 1 day which seemed to be driven by earlier chest drain removal. This was achieved without a negative impact on pleurodesis success, quality of life or mortality.

This trial investigators should be applauded not just for a major study that will lead to a change in how we perform inpatient pleurodesis, but also for their timing. They finished recruitment just 3 weeks before SARS-CoV-2 was identified in Wuhan.

Risk Factors for Pneumothorax Development Following CT-Guided Core Lung Nodule Biopsy. 

Sargent T, et al. J Bronchology Interv Pulmonol. PMID: 34654044

Although a several studies exist documenting the risk factors for pneumothorax from CT-guided biopsy, this retrospective study has focused on an interesting protective factor- high BMI.

From 671 biopsies performed the risk of pneumothorax was 26% with 5% needing a chest drain. As well as the well-recognised risk factors (emphysema, traversing more than one pleural surface, patient needing supine positioning), increasing BMI was protective in a multivariable model). In fact, with every 1 unit increase of BMI the risk of pneumothorax fell by 5%.

The authors propose several potential explanations including the “stabilising nature of adipose tissue” around the introducer or reduced expansive capabilities of accessory muscles reducing movement of the needle during biopsy.

Predicting the nature of pleural effusion in patients with lung adenocarcinoma based on 18F-FDG PET/CT. 

Li Y, et al. EJNMMI Res. PMID: 34652524

How to stage a patient with lung adenocarcinoma and an ipsilateral pleural effusion is a difficult clinical quandary with sparse evidence to date. Many UK centres will be recruiting to Glasgow’s STRATIFY study using medical thoracoscopy. PET scans are another approach:

This well-designed study from Shanghai prospectively recruited 413 patients with known lung adenocarcinoma and an associated effusion. All patients had an 18F-FDG PET/CT prior to pleural cytology or histology. Effusions were either repeatedly sampled or were followed up to assess whether the effusion was benign or malignant.

Using a training cohort (n=289) they developed a predictive model for the clinical and PET features that accurately predicted a malignant effusion. This included a tumour with SUVmax ≥ 2.5 and attachment to the pleura, obstructive atelectasis or pneumonia, the SUVmax of pleura, the SUVmax of the effusion, and serum CEA levels. The model performed well in the training cohort but more impressively performed equally well in the validation cohort (n=124) with an AUC of 0.98, sensitivity of 92% and specificity of 90%.

Using a decision curve analysis they calculated that the model could be useful to decide which patients should have further investigations of their effusion and which should be radically treated regardless. However, without follow-up data the longer term consequences of this approach remain unknown.

The small (14 Fr) percutaneous catheter (P-CAT) versus large (28-32 Fr) open chest tube for traumatic hemothorax: A multicenter randomized clinical trial.

Kulvatunyou et al. J Trauma Acute Care Surg. PMID: 33843831.

Traumatic haemothorax is usually the domain of the surgeon which invariably means a massive drain in our centre to “reduce chance of blockage’. This approach has no evidence-base which is why it is great to see new randomised evidence on the topic. Retrospective analysis of the MIST 1&2 cohorts demonstrated that large drains are not needed in pleural infection, so why would they be needed in haemothorax?

In this multi-centre RCT, 119 patients presenting with a haemothorax were randomised to 14-Fr pigtail OR  28/32-Fr chest tube with a primary outcome of ‘failure’ (i.e. needing a second intervention) as a negative superiority study.

At follow-up there were no differences between the groups in terms of failure rate, hospital stay or chest tube duration. Patients also seemed to have a better experience with the smaller drains.

So 14Fr for all? Well, some reasons to be cautious. They excluded patients with urgent need for chest tube so only half of those screened were randomised. These might have been the patients to benefit the most from larger drains. Also, the patient reported outcome measure of “insertion perception experience (IPE) score” was simple but open to some bias given the open-label approach.

The pleural twitter community isn’t sold: “I would still currently use a large bore for most haemothorax but consider a smaller one of the patient was stable etc… now” (twitter quote). But it is good to see randomised data in a difficult to recruit population.

Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. 

Fennell DA, et al. Lancet Oncol. 2021

Although presented previously at the 2020 world conference on lung cancer the CONFIRM results have now been published in Lancet Oncology. This phase 3 placebo-controlled trial of nivolumab (a fully humanised, IgG4, PD-1-immune checkpoint inhibitor antibody) was opened in May 2017 after promising phase 2 trial results.

Patients who had progressed on platinum chemotherapy were enrolled provided they were ECOG 0-1 and had measurable disease on mRECIST.

Patients randomised to the intervention (2:1 fashion) received 240 mg of nivolumab IV every 2 weeks. Treatment was continued until disease progression, withdrawal or 12 months, whichever occurred first.

Results…the trial met both of its co-primary endpoints with median progression-free survival being higher in the nivolumab group (3 vs 1·8 months) (p=0·0012) AND higher overall survival (10·2 vs 6.9 months) (p=0·0090). The treatment also seemed well tolerated with similar adverse event data between intervention and placebo.

Importantly there was no evidence that PDL-1 status of the tumour was predictive of response to nivolumab, although the trial was not powered for this endpoint. Other subgroup analyses should also be viewed with caution but nivolumab seems to benefit epithelioid tumours to a greater extent which is contrary to previous immune-checkpoint trials.

There is a well written editorial by Prof Anna Nowak who discusses how these results might be reconciled with the positive results from other recent trials e.g. CheckMate-743 (1st line nivolumab and ipilimumab).

16S rRNA is a valuable tool in finding bacterial aetiology of community-acquired pleural empyema-a population-based observational study in South Sweden. 

Hjertman J et al. Infect Dis (Lond). PMID: 34606399

Northern Europe has been leading the way in adjunctive 16S PCR in pleural fluid in an attempt to improve on the poor growth from standard culture methods.

This is a retrospective study of all pleural fluid samples collected over a 7-year period in Skåne county. Those that were either culture negative or 16S negative were excluded. This whittled the cohort from 5725 to 291 patients so the actual utility of the approach is limited in most types of effusions.

The main additional benefit of 16S appears to be identifying a higher rate of anaerobic bacteria (23%), which are tricky to culture, and polymicrobial infections (21%).

Transposition of the great indwelling pleural catheter. 

Bedawi EO, et al. Thorax. PMID: 34716279

In keeping with tradition (of 2 months) we finish with an image, this one courtesy of the Oxford group. The post-procedure chest radiograph would have caused me some anxiety but with some detailed ultrasound the explanation became apparent.