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The Risk Of Malignant Pleural Mesothelioma
The UK currently endures the highest incidence of Mesothelioma worldwide: 45 annual fatalities/million population; 1/212 male lifetime risk (1), making asbestos the leading cause of occupation-related mortality in the UK. (2) Although the use of asbestos-containing building materials was banned in the UK in 1999, an estimated 1.5 million UK buildings are thought to contain up to six million tons of asbestos – including 94% of hospitals, 80% of schools and 74% of university buildings. (3)
This legacy of asbestos-containing buildings continues to drive new cases of MPM through passive environmental exposure of long-term building occupants, for instance, teachers and nurses, who develop Mesothelioma at five and three times the rate of the general public, respectively.(4) The projected decline in UK Mesothelioma by 2035 (5) appears to be based largely on the timing of legislation banning new use of asbestos but fails to adequately account for the continued threat of passive exposure arising from pre-1999 construction, as acknowledged by the UK Health & Safety Executive. (6)
Indeed, the projected decline in UK incidence looks increasingly unlikely to occur without government action to remove all forms of asbestos from UK buildings. Worldwide, mining and use of asbestos continue in many countries with inadequate labour protection, and Mesothelioma rates are rising rapidly. (7, 8)
Mesothelioma is difficult to diagnose, leading to delayed treatmentUnlike most cancers, Mesothelioma doesn't grow in a discrete focal mass – instead, it spreads insidiously over the lining of the chest cavity, presenting a diffuse multifocal field of cancer that, on the surface, appears very similar to benign pleural inflammation.
To date, there is no well-defined precursor lesion, and molecular diagnostics have failed to provide greater certainty than a microscopic examination of biopsied tissue by a trained pathologist. Diagnosis of Mesothelioma thus relies almost entirely on the manual detection of Mesothelioma cells invading into underlying tissue. (9)
A major difficulty is that even multiple biopsies taken with the assistance of an endoscope inserted into the chest can still fail to capture invading cells, leading to false negative diagnosis. Moreover, because only 12-15% of patients who present with symptoms of pleural inflammation develop Mesothelioma within two years of first presentation, international guidelines mandate observation, rather than therapeutic intervention, for patients whose biopsies show no signs of invasive disease. (9)
This "watch and wait" approach thus prevents immediate treatment of patients with early-stage disease that may be at high risk of developing Mesothelioma, or indeed those where Mesothelioma was missed at initial biopsy. Recent therapeutic advances such as immunotherapy (10) have shown significant survival benefits in patients with malignant disease and could be deployed earlier in the patients' journey if definitive diagnostic tools are developed to reliably differentiate low-risk inflammation from high-risk pre-malignancy.
How mouse models of Mesothelioma can helpThe onset of clinical symptoms of Asbestosis that sometimes precedes Mesothelioma can take up to 40 years following exposure. However, experiments in rodents have shown that the biopersistence of Asbestos fibres in the chest cavity drives chronic inflammation that persists from the time of exposure through to the onset of symptomatic disease and development of Mesothelioma. (11, 12)
The clinical picture of Mesothelioma is thus limited to the last mile of a long journey, and eventual Mesothelioma victims are typically symptom-free until their disease is very advanced. There is consequently a huge gap in the clinical understanding of what happens between exposure and onset of symptoms.
To address this gap, my lab has developed genetically engineered mouse models of Mesothelioma that combine controlled introduction of the same mutations that commonly arise in human Mesothelioma with a single injection of Asbestos to incorporate chronic inflammation in our models.
A single exposure to microgram levels of Asbestos (a microgram is one-millionth of a gram) dramatically accelerates the onset of malignancy in all of our models, demonstrating a vital role for Asbestos-driven inflammation in Mesothelioma development beyond mutagenesis.(13) Our mouse models resemble human mesothelioma in microscopic appearance, molecular characteristics, and crucially, in response to clinically relevant therapies, attesting to their relevance for human Mesothelioma.
However, because of their highly reproducible, genetically accelerated cancer development, we can investigate the entire course of disease progression, from initial exposure and the first appearance of cancer-causing mutations all the way through to terminal cancer. Our mouse models thus provide vitally needed insight into stages of cancer development that are simply impossible to follow in human subjects at risk of developing Mesothelioma.
IAMMED-Meso: Understanding the biological basis of riskWe have identified combinations of mutations that give rise to Mesothelioma in 100% of mice (this is called full penetrance) and other combinations that result in variable incidence of malignancy (this is called partial penetrance and is reflective of the risk of developing Mesothelioma).
Knowing that mice with fully penetrant mutation combinations are certain to develop Mesothelioma enables us to sample and examine tissue prior to the onset of symptoms and to compare those samples with fully developed Mesothelioma to determine what changes have taken place in between. Similarly, knowing how long it takes for Mesothelioma to emerge in fully penetrant mice allows us to compare samples from partially penetrant mice at the same time since tumour initiation (which is under experimental control).
This enables us to determine how high-risk pre-malignancy differs from lower-risk pre-cancerous lesions. The molecular and cellular characteristics of these comparisons give us clues of what to look for in samples from human patients with symptoms of Asbestosis that are at risk of developing Mesothelioma. In collaboration with the clinical teams of PREDICT-Meso (14), led by Prof. Kevin Blyth, we have access to tissue and pleural fluid samples from a projected cohort of up to 500 symptomatic patients at risk of developing Mesothelioma, along with follow-up samples from those whose disease does indeed progress to Mesothelioma, and from those with stable non-progressing benign disease.
Through cross-species comparisons, we hope to zero in on key molecular features than can be used to definitively distinguish high risk from low risk of Mesothelioma development, enabling earlier treatment of high-risk patients than is currently possible and provided solace and reassurance to patients at low risk of progression to Mesothelioma.
IAMMED-Meso and PREDICT-Meso are funded by Cancer Research UK. DEBiT-Meso is funded by Asthma + Lung UK ReferencesPlease Note: This is a Commercial Profile
Can A Breath Test Detect Mesothelioma? It's Too Soon To Tell.
Researchers are evaluating whether a breath test can detect malignant pleural mesothelioma in patients with asbestos exposure, and early results suggest it may be possible, but more research is needed.
The test, which detects volatile organic compounds in exhaled breath, is being evaluated in the MESOBREATH 5 study.
Early results showed that the test has high sensitivity and negative predictive value but low accuracy, specificity, and positive predictive value. These results were presented at the 2023 World Conference on Lung Cancer.
Patients included in this study were required to have a history of substantial occupational asbestos exposure, with a first exposure occurring at least 30 years ago and having at least 15 fiber years. The researchers also included a positive control group of patients with confirmed pleural mesothelioma.
The cohort included 121 patients with a history of asbestos exposure and 7 patients with confirmed mesothelioma. All patients in the asbestos-exposed group were men, as were 71% of patients in the mesothelioma group (P =.020). Patients in the asbestos-exposed group had a higher mean body mass index (27.42 kg/m2 vs 24.23 kg/m2; P =.042) and were younger (mean, 60.61 years vs 69.59 years; P =.002).
All patients underwent breath testing in 2022 and this year. The sensitivity and negative predictive value of the breath test were both 100%. However, the positive predictive value was 4.2%, the accuracy was 29.1%, and the specificity was 26.9%.
To reduce false positives, the researchers decided to test patients twice and look at patients with positive results from both tests. About 46% of patients had 2 positive test results, including all 7 patients with confirmed mesothelioma.
The next step in this study is for patients with 2 positive results to undergo low-dose CT scans to confirm whether they have mesothelioma or if other factors could have influenced their breath test results. The researchers plan to use this information to optimize the test further.
The researchers also plan to continue giving patients the breath test in 2024 and 2025, and this will be followed by CT scans to confirm the presence or absence of mesothelioma.
Disclosures: No disclosures were provided.
ReferenceLamote K, Zwijsen K, Schillebeeckx E, et al. Determining the clinical utility of a breath test to screen asbestos-exposed persons for pleural mesothelioma. Presented at WCLC 2023. September 9-12, 2023. Abstract MA17.03.
Exhaled Breath Offers Hope For The Early Detection Of Malignant Pleural Mesothelioma
Identifying and analyzing volatile organic compounds in exhaled breath of patients with malignant pleural mesothelioma showed promise as a screening method for MPM.This analysis is as per the research presented at the 2023 World Conference on Lung Cancer in Singapore by the International Association for the Study of Lung Cancer (IASLC).
Malignant pleural mesothelioma (MPM) is a difficult condition with few curative options and a dismal outlook. Researchers have been investigating predicting markers to enhance treatment outcomes and personalise medicines for specific patients. Volatile organic molecules (VOCs) in exhaled breath have recently gained attention as potential non-invasive disease indicators.
Kevin Lamote, PhD, from the University of Antwerp, Belgium, and colleagues conducted a study aimed to investigate whether exhaled breath analysis could differentiate treatment responders from non-responders (discriminative setup) and, if successful, predict treatment outcomes earlier (predictive setup) using VOCs as predictive biomarkers.
Dr Lamote and his team examined 13 patients with MPM and subjected them to a CT scan before and every three months after treatment, with treatment responses scored as stable (SD) or progressive (PD) based on mRECIST criteria.
Breath and background samples were collected from the patients at each time point using multi-capillary column-ion mobility spectrometry (MCC-IMS) to characterize VOCs. A lasso regression was performed to identify VOCs that could differentiate between responders and non-responders after treatment. Additionally, a predictive model was trained to forecast treatment outcomes based on associated breath samples from previous study visits.
The study demonstrated an 89 per cent accuracy (95 per cent CI: 67.9-98.1) in distinguishing between SD and PD patients during follow-up. Equally promising, the predictive model achieved the same level of accuracy at baseline in predicting treatment outcomes. Notably, there were no significant differences in treatment approaches between SD and PD patients, suggesting that the selected VOCs may be involved in general mechanisms or correlated with the tumor microenvironment rather than being treatment-specific.
The identification of VOCs in exhaled breath represents a promising opportunity for non-invasive detection and prediction of treatment outcomes in MPM patients, said Dr Lamote.
However, to further validate the utility of the VOC profile, larger population studies are required. Fine-tuning the VOC profile for each treatment could also help predict which patients are most likely to benefit from specific therapies, ultimately leading to improved overall treatment regimens for MPM. (ANI)
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