News

Mesothelioma – The Future

What is the pathogenesis of mesothelioma? Nature vs nurture?

Nature
Genetics – in 2001 researchers found familial clustering of MM. In 2011 they identified BAP1 as a causative gene. This gene is related to a cancer syndrome – melanocytic intradermal lessons, clear cell renal carcinoma, cholangiocarcinoma. BAP1 is a tumour suppressor and a potential target for therapy. NF2 encodes merlin protein on Chromose 22. It is a tumour suppressor and inhibits of oncogenes in the mTOR pathway.

Clinical trials are ongoing with everolimus. This is a combined mTOR and AKT inhibitors. Mainly phase 1 trials. Other targets may include FAK inhibitors and CDKN2A (cyclin dependant kinase inhibitor on Ch9). It is deleted in 50-100% mesothelioma tumours. There is also epigenetic silencing. These factors have a role in regulating apoptosis and cell cycle arrest.

Nurture
The cancer cell exists within a permissive microenvironment. Arginine forms part of the urea cycle. Arginosuccinate synthetase ASS1 is an enzyme silenced in 63% mesothelioma. At Barts researchers have developed pegylated arginine deaminase ADI-PEG20. The ADAM study is a phase 1 and 2 trial, an RCT with 2:1 randomisation. There was improved progression free survivial (PFS) and overall survival. The effect was greater in tumours with greater loss of ASS1. The treatment was well tolerated. There was a greater effect seen in sarcomatoid patients. They are now conducting the ATOMIC trial – enrolling for non-epitheloid mesothelioma. cis/pem vs cis/pem+ADI-PEG. NCT02029690. Get your patients into clinical trials!

The cancer microenvironment is increasingly being recognised as a relevant treatment target. There are many immunotherapy targets – yay! Key targets:  PD1/PD-L1, VEGF, PDGF, FGF.
VEGF is critical in tumour growth and is highly expressed in mesothelioma.

Bevacizumab is a monoclonal antibody. The MAPS trial (480 patients) was triple therapy 1st line, in combination with cis/pem. There was improved PFS at 2 months and Overall Survival (OS) 2.7 months. Approved in USA and Europe. Not approved by NICE on cost effectiveness grounds.
Nintedanib is being investigated in the LUME-meso trial – actively recruiting in UK for patients with histologically confirmed epithelioid mesothelioma which is unresectable. 1st line therapy cis/pem + nintadenib. 4/12 longer PFS in initial phase. Now gone onto larger phase 3 trial for those with PS 0-1.

Pembroluzimab is a further target. 20-70% mesos are PD-L1 positive. Trials include:\

  • Checkmate-743 trial. Combined ipilimumab & nivolumab vs pemetrexed & platinum based drug.
  • CONFIRM trial – nivolumab vs placebo for pts who have progressed on chemo
  • PROMISE-meso – 2nd line treatment of mesothelioma for those who have progressed on chemo. 2nd line chemo (set by local guidelines) vs pembroluzimab. Cross-over trial.

What about surgery in mesothelioma?

  • MARS1 – showed that unselected surgery is bad
  • MARS2 – pleurectomy decortication vs no surgical intervention. Phase 3 trial
  • MesoVATS – did not address trapped lung
  • MesoTRAP – address issue of trapped lung. What is best way to manage? IPC vs VATS pleurectomy decortication.

Exciting times in mesothelioma research? Molecular stratification allows umbrella designs and personalised therapies.

From: https://jamanetwork.com/journals/jamaoncology/fullarticle/2591161There is a Mesothelioma stratification trial ongoing in Leicester. Umbrella trial design allows a common single entry point, then all tumours are pre-screened using nextgen sequencing (genetic/epigenetic). On basis of this the patient is enrolled into 1 of several trials – 4 at present. On postmortem or disease progression the tumour genetics are re-analysed. A major advantage of this trial design is that as new treatments come on line they can be added to another part of the umbrella design. Quicker throughput for new therapies.

By Dr Beth Sage (Training day at UCLH) RESPNet

Beyond Asthma

Image result for eilo versus asthma

 

3 must-know, never-miss conditions:

  • ILO (inducible laryngeal obstruction)
  • Large airway collapse with symptoms (LACS)
  • Subglottic stenosis
  • Christopher, Kent L., et al. “Vocal-cord dysfunction presenting as asthma.” New England Journal of Medicine 308.26 (1983): 1566-1570.

This paper from the archives shows that vocal cord dysfunction has been recognised for a long time. However, it uses problematic languages, and places a firm emphasis on psychiatric diagnoses and conversion disorder as the cause. On a positive note, patients had good outcomes following speech and language therapy.

The classic appearance is anterior closure, with a posterior chink. The is rarely seen but the same clinical problems occur with less dramatic examples, with abnormal movements and stridor. Is ‘brittle asthma’ largely VCD? Glottic closure can cause a sudden PEFR drop. PEFR is dependant on how much air you can get in before you perform a forced expiration. PEFR is unfortunately a waste of time diagnostically.

Thankfully, perjorative historical terminology is now decreasing.  ILO is now the favoured terminology – it is a physiological description of the problem and much more appropriate.

It is important to distinguish EILO (exercise-induced laryngeal obstruction) from EIB (exercise induced bronchoconstriction). 8-10% of all adolescents may have EILO as at peak exercise they get wheeze. It is also possible to have inducible laryngeal obstruction not linked to exercise. An odour e.g. when exposed to perfume  on the tube. Direct provocation can clinch the diagnosis.

The Pittsburgh VCD index is useful for screening patients for VCD. Remember, it is often a co-morbid condition – there is overlap between severe asthma and upper airway disorder. Therefore don’t cross off their asthma treatment straight away – de-escalate after therapy started.

Find out more at: http://www.laryngealobstruction.com/

Large Airway Collapse with symptoms (LACS) is the preferred current terminology for this group of conditions.
It includes excessive dynamic airway collapse (EDAC), which is often a benign phenomenon due to pressure changes and affects the posterior trachea. It may not be responsible for symptoms so don’t rush to operate/stent. Treatments are mainly physical therapy, cough assists, mucolytics +/- positive pressure support (CPAP). Portable CPAP may be an option – we expect a trial report soon. Early signals are it increases walking distance but it is not acceptable to patients to use in longterm. Relapsing polychondritis is a rare cause. ‘EDACS cough’ is a large airway centred problem, often associated with high BMI.

Tracheobronchomalacia can affect the anterior or lateral trachea and is a cartilaginous problem.

In subglottic stenosis inspiratory flow may be as low as 10% predicted. There is an audible wheeze. We often see attenuation of inspiratory flow and less attenuation of the expiratory phase of the flow volume loop. This is not VCD as wheeze is there all the time including at night. A Bronchoscopy/laryngoscopy is needed ASAP. This is potentially life threatening as a mucus plug could lead to obstruction.

Management: remove irritants (treat nasal/sinus disease/reflux – give promotility agent + gaviscon), remove caffeine, regular clear fluid every 20min. Then find therapists -SALT/physio who understand the upper airway. Encourage diaphragmatic breathing, and nasal predominant patterns. There are a few potentially useful drugs. Anecdotally – spiriva/atrovent seems to work better for upper airway than LABAs. Neuronal hypersensitivity is part of the pathophysiology, therefore amitryptilline may be effective. Botox to the larynx is better for laryngeal spasm than VCD (2/52 loss of voice, cough OK but reduced airway secretion protection).

There is a higher prevalence of psychopathology in people with BPD – this is likely compounded by trauma due to delays to diagnosis and recurrent trips to ED. SALT usually have training in psych assessments in voice problems so are well placed to assess.

 

By Dr James Hull (Training day at UCLH) RESPNet