New report discovers mesothelioma-causing mineral in US road gravel

As school buses drive down the gravel roads in Dunn County, North Dakota, they stir up more than dirt. The clouds of dust left in their wake contain such high levels of the mineral erionite that those who breathe in the air every day are at an increased risk of developing mesothelioma, a type of cancer of the membranes around the lungs, new research shows. Erionite is a natural mineral fiber that shares similar physical similarities with asbestos. When it's disturbed by human activity, fibers can become airborne and lodge themselves in people's lungs. Over time, the embedded fibers can make cells of the lung grow abnormally, leading to mesothelioma, a form of lung cancer most often associated with the related mineral asbestos.

Michele Carbone, M.D., Ph.D., director of the University of Hawaii Cancer Center in Honolulu, has previously linked erionite exposure in some Turkish villages to unusually high rates of mesothelioma. Recently, he and colleagues turned their attention to potential erionite exposure in the U.S., where at least 12 states have erionite-containing rock deposits. His research team -- which includes scientists from the National Institute of Environmental Health Sciences, Environmental Protection Agency, New York University, University of Chicago, University of Iowa, and University of Hacettepe -- focused their efforts on Dunn County, North Dakota, when they learned that rocks containing erionite have been used to produce gravel for the past 30 years. More than 300 miles of roads are now paved with the gravel.

The new study, reported in the July 25, 2011 issue of Proceedings of the National Academy of Sciences (PNAS) is the first to look at the potential hazards associated with erionite exposure in the U.S.

The scientists compared the erionite in North Dakota to erionite from the Turkish villages with high mesothelioma rates. They measured airborne concentrations of the mineral in various settings, studied its chemical composition, and analyzed its biological activity. When mice were injected with the erionite from Dunn County, their lungs showed signs of inflammation and abnormal cell growth, precursors to mesothelioma. Under the microscope, the fiber size of the erionite from North Dakota was similar to that of the Turkish erionite. Overall, the researchers found no chemical differences between the North Dakota erionite and samples of the cancer-causing mineral from Turkey. The airborne levels of erionite in North Dakota were comparable to levels found in Turkish villages with 6-8 percent mortality rates from mesothelioma, the researchers reported.

"Based on the similarity between the erionite from the two sources," says Carbone, "there is concern for increased risk of mesothelioma in North Dakota." The long latency period of the disease -- it can take 30 to 60 years of exposure to cause mesothelioma -- and the fact that many erionite deposits have only been mined in the past few decades suggests that the number of cases could soon be on the rise. In addition to North Dakota, California, Oregon, Arizona, Nevada and other states have erionite deposit, but the possibility of human exposure elsewhere in the U.S. has not yet been investigated.

In contrast to asbestos, which causes mesothelioma at lower rates, there are no established health benchmarks in the U.S. on safe levels of erionite exposure, because until recently, physicians thought that erionate was present only in Turkey. The new findings, however, indicate that precautionary measures should be put in place to reduce exposure to the mineral, says Carbone. In Turkey, his earlier findings led to moving villagers away from areas with high levels of erionite, into new housing built out of erionite-free materials. "Our findings provide an opportunity to implement novel preventive and detection programs in the U.S. similar to what we have been doing in Turkey," he says. Future studies could analyze erionite levels in other areas of the U.S. and develop strategies to prevent and screen for mesothelioma. The study was funded through grants from the National Cancer Institute and the 2008 AACR-Landon Innovator Award for International Collaboration in Cancer Research to Michele Carbone.

New Blood-Based Protein Signature Ascertained For Uncommon, Aggressive Lung Cancer

Researchers have discovered a panel of 13 blood proteins that may be effective biomarkers to detect malignant mesothelioma, according to a study published Oct. 3 in the open access journal PLOS ONE by Rachel Ostroff from the company SomaLogic, which developed the new test, and colleagues at other institutions.

Malignant mesothelioma is a rare, aggressive form of lung cancer that can develop after prolonged exposure to asbestos. Because early diagnosis is difficult, most patients face a poor prognosis and have few options for treatment. In the study, authors compared proteins in the blood of asbestos-exposed individuals without the disease to blood proteins in asbestos-exposed mesothelioma patients to identify 13 proteins that are linked to the disease, including in the early stages.

According to the researchers, the discovery of the new blood-based proteins linked to the disease could help to develop better, less invasive diagnostic tests to detect the disease at earlier stages.

"By measuring changes in blood concentration of a series of proteins we can potentially catch mesothelioma at an earlier stage," said Ostroff, Clinical Research Director at SomaLogic. "Our efforts are now focused on further development of this approach, and how best to get it rapidly into clinical use for the sake of individuals who can benefit from earlier detection of this devastating disease."

High Levels of Blood-Based Protein Particular to Mesothelioma

Researchers at NYU School of Medicine have discovered the protein product of a little-known gene may one day prove useful in identifying and monitoring the development of mesothelioma in early stages, when aggressive treatment can have an impact on the progression of disease and patient prognosis.

"This gene produces a protein, fibulin-3, that is present in levels four to five times higher in the plasma of patients with mesothelioma compared to levels in asbestos-exposed patients or patients with several other conditions that cause tumors in the chest," said lead investigator Harvey I. Pass, MD, the Stephen E. Banner Professor of Thoracic Oncology, vice chair of research for the Department of Cardiothoracic Surgery and division chief of General Thoracic Surgery at NYU Langone Medical Center. "We didn't know anything about this protein's role in mesothelioma before this study, but it may be an extremely useful tool for monitoring patients under treatment and possibly even diagnosing the development of mesothelioma at early stages. This marker is as exciting as any biomarker in mesothelioma today and warrants further research and validation by the scientific community."

The study appears in the October 11 issue of the New England Journal of Medicine.

Malignant mesothelioma is a rare but aggressive thoracic cancer that can develop several decades after exposure to asbestos. Diagnosis is often delayed until patients begin to show symptoms, including shortness of breath, cough, chest pain and, in advanced stages, weight loss and night sweats.

Often, patients with mesothelioma seek treatment when the shortness of breath becomes a noticeable problem. At that point, an x-ray typically reveals fluid in the chest, but many doctors fail to inquire about asbestos exposure upon receiving this report. Rather, doctors initially associate fluid in the chest with pneumonia or other inflammatory conditions, further delaying diagnosis, Dr. Pass explained.

Despite advances in chemotherapy, radiation therapy, and surgical management for malignant mesothelioma, the median survival for patients diagnosed with mesothelioma remains 12 months.

"There is a great need for something -- some marker or test -- that will heighten the alarm that a patient presenting with new onset chest fluid could have mesothelioma," Dr. Pass said. "Our findings indicate that a simple blood test may lead physicians to ask questions about asbestos exposure and consider whether the medical history and symptoms are compatible with mesothelioma."

Dr. Pass and his team are dedicated to finding diagnostic biomarkers -- genes, proteins or other molecules -- that are not only different in people with mesothelioma compared with cancer-free individuals who have been exposed to asbestos, but also different when compared to individuals with a variety of conditions that could cause fluid in the chest other than mesothelioma.

Fibulin-3 is a protein that floats around outside cells, coating the cells and free floating in blood plasma and extracellular fluid. For the current study, the research team compared levels of fibulin-3 in two separate cohorts of patients who were exposed to asbestos through their jobs: a group of iron workers and other asbestos-exposed individuals in Detroit, and a group of insulators in New York. Both cohorts included individuals who had been exposed to asbestos but did not develop mesothelioma, as well as individuals with a confirmed mesothelioma diagnosis. The researchers found that fibulin-3 expression was markedly elevated in the plasma of the patients with mesothelioma compared with the plasma of patients without mesothelioma. But the researchers wondered if maybe the elevated fibulin-3 levels were associated with other conditions, in addition to mesothelioma, that are associated with the development of chest tumors.

To test how specific the over-expression of fibulin-3 is to mesothelioma, they compared levels of the protein in the plasma of patients with mesothelioma to the plasma levels of the protein in patients afflicted by a variety of different types of cancer resulting in tumors in the chest -- individuals without mesothelioma, but with conditions that "look like mesothelioma," Dr. Pass said. They found that fibulin-3 also discriminated between non-mesothelioma patients with different kinds of chest-tumor cancers and patients with mesothelioma, confirming high specificity for mesothelioma and not for conditions that "look" like mesothelioma.

To validate their results, the researchers then performed a blinded study with another cohort of patients from Toronto, Canada for whom plasma fibulin-3 was measured, but the researchers had no knowledge of whether the individuals had mesothelioma or not. Based on the fibulin-3 levels, the researchers were able to differentiate the mesotheliomas from the non-mesotheliomas with high accuracy.

In addition, the researchers discovered that post-surgery levels of fibulin-3 were drastically decreased compared to pre-surgery levels in mesothelioma patients in whom the mesothelioma was removed. In selected cases of recurrence, the fibulin-3 level rose, hinting that the marker may be useful for monitoring treatment effects.

"This marker is as good, if not better, in terms of sensitivity and specificity than other known markers for mesothelioma, and its level in mesothelioma chest fluid appears to have prognostic implications," Dr. Pass said. "Moving forward, an international effort to validate these findings is needed, as well as an effort to understand whether this marker can diagnose mesothelioma prior to the development of symptoms in high-risk individuals. This needs to be performed prospectively in a well-defined high-risk for mesothelioma cohort."

Patients With An Inactive NF2 Gene, Mesothelioma Drug Decelerates Disease Advance

Preliminary findings from the first trial of a new drug for patients with mesothelioma show that it has some success in preventing the spread of the deadly disease in patients lacking an active tumour suppressor gene called NF2. The study is presented at the 24th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland [2].

Mesothelioma, which is usually caused by exposure to asbestos, has few treatment options and patients usually die within 9-17 months of diagnosis. Previous research has shown that the gene NF2, which produces a protein called merlin, is frequently inactivated in approximately 50% of mesotheliomas. Merlin negatively regulates another protein called focal adhesion kinase (FAK) in mesothelioma, and so when NF2 and merlin are inactivated, the activity of FAK is increased and mesothelioma cells become invasive and start to spread. When NF2 and merlin activity is restored, FAK activity and cell invasion are decreased.

Professor Jean-Charles Soria, Professor of Medicine and Medical Oncology at South Paris University and head of early drug development at the Institut Gustave Roussy in Paris (France), said: "This suggested that if we could inhibit FAK in mesothelioma patients, it might slow or stop the spread of the disease. Pre-clinical work has shown that an agent, currently known as GSK2256098, is a potent and specific inhibitor of FAK. Early in the clinical study presented today, a patient with mesothelioma, who had progressed quickly on prior therapies, had prolonged stable disease while on GSK2256098, which is suggestive of clinical activity."

Prof Soria and colleagues at nine centres in France, Australia and the United Kingdom recruited 29 mesothelioma patients to the phase I study of GSK2256098, starting in July 2010. The study is continuing.

The mesothelioma patients took the drug orally in capsule form twice a day at doses ranging from 300 - 1500 mg, with the majority (22) taking 1000 mg a day. There were no complete or partial responses; 14 patients had stable disease, nine had progressive disease, three had non-measurable disease, and three left the study before evaluation of response. Overall, patients had an average of 17 weeks before the disease progressed.

However, in patients in whom merlin was inactivated, the average time before the disease progressed was 24 weeks, compared to 11 weeks in patients with active merlin and nearly 11 weeks in patients in whom the activity of merlin was unknown.

Adverse side-effects were mainly low grade and tolerable.

"These findings are important but preliminary," said Prof Soria. "They show that merlin is a potential biomarker in mesothelioma that may enable us to identify a subset of patients who could benefit from GSK2256098 and have longer, progression-free survival. Mesothelioma is a deadly disease without many treatment options, and therefore identification of novel and effective therapies is needed."

The researchers will accumulate and analyse further data, and larger clinical trials will be needed to confirm these findings. In addition, other cancers such as melanoma and meningioma (tumours of the membranes around the central nervous system) show loss of NF2 and merlin function, and so researchers are also investigating whether the findings from this trial may be relevant to other cancers.

Professor Stefan Sleijfer, the scientific chair of the EORTC-NCI-AACR Symposium, from Erasmus University Medical Centre (The Netherlands), commented: "This study strongly suggests that inactivation of merlin may act as a marker to identify patients who may benefit from this compound. Furthermore, better insight into the role of merlin in mesothelioma may lead to novel targets of treatment. This is highly needed given the detrimental prognosis of patients suffering from mesothelioma."

Latest On Malignant Pleural Mesothelioma Induced By Contact With Asbestos

Patients with early stage malignant pleural mesothelioma (MPM), a cancer that develops in the lining of the lungs, may be eligible for aggressive multi-modality therapy involving surgery, radiotherapy and chemotherapy. There are two main approaches, and controversy has existed about which approach is superior. One is called extrapleural pnemonectomy (EPP), a very extensive surgery where surgeons remove the entire diseased lung, lung lining (pleura), part of the membrane covering the heart (pericardium) and part of the diaphragm. Another approach involves a less extensive surgery called pleurectomy/decortication (P/D), where surgeons remove part of the lining around the lungs, potentially part, but not all of the lung, and potentially part of the diaphragm and/or membrane around the heart. Research presented in the April 2012 issue of the International Association for the Study of Lung Cancer's (IASLC) Journal of Thoracic Oncology concludes that the P/D method had better results for patients in a recent analysis.

According to the study, "EPP resulted in higher mortality and morbidity than P/D, and P/D resulted in significantly better survival in our experience as in others." The authors, "propose that P/D becomes the standard surgical procedure offered as part of multi-modality therapy in malignant pleural mesothelioma."

Until recently, EPP was the considered the standard of treatment. But this latest study along with other recent research seems to point to P/D becoming the new standard of treatment. Dr. Michael Weyant, thoracic surgeon and assistant professor at the University of Colorado, wrote an editorial in the April JTO about this topic. He concludes that, "the results of the current study by Lang-Lazdunksi et al provide additional data that should lead us to consider P/D in all trials of treatment for MPM. It is too early based on this data to completely abandon EPP altogether as there may be patient subsets where the potential reward outweighs the risks of the procedure."

Mesothelioma: Hopeful Developments In Initial Analysis And Management

New results presented at 3rd European Lung Cancer Conference in Geneva, Switzerland show important steps being made to improve the diagnosis and treatment of malignant pleural mesothelioma, an aggressive cancer of the outer lining of the lungs caused by asbestos exposure.

Micro RNAs speed diagnosis Australian researchers have identified a small molecule that is more abundant in the blood of people with the deadly lung disease mesothelioma than in healthy people. Their findings bring scientists a step closer to being able to diagnose mesothelioma earlier than is currently possible.

At present diagnosing mesothelioma depends on the availability of a lung biopsy that contains enough tumour tissue. However suitable biopsies are not always available, which can leave doctors uncertain about the patient's diagnosis, sometimes resulting in a delay to the start of treatment. "If doctors could use a diagnostic marker based on a simple blood test to help with diagnosis, it could circumvent the problem of availability of tumor tissue and help to accelerate the diagnostic process," says Dr Michaela Kirschner from the Asbestos Diseases Research (Concord Hospital Campus) in Sydney, who reported the new findings.

So far a number of proteins have been proposed as blood-based markers for malignant pleural mesothelioma; however none of these has so far reached the accuracy required for routine clinical use.

In the new study, Dr Kirschner and colleagues explored whether molecules known as microRNAs in blood could serve as a diagnostic marker for the disease. Studying 5 patients with malignant pleural mesothelioma and 3 healthy controls, they identified 17 microRNAs with significantly differential abundance in the two groups. They then validated these miRNAs in a series of blood samples from 15 patients and 13 controls. These studies revealed that the level of a particular microRNA known as miR-625-3p was four-fold higher in the blood of mesothelioma patients.

Measuring levels of that molecule in blood samples allowed the researchers to discriminate between MPM patients and controls with an accuracy of 82.4%.

"Detailed analyses of our two independent sample series have shown that miR-625-3p performs as well as any previously proposed protein marker for detecting mesothelioma," Dr Kirschner said. "However, like most diagnostic markers, miR-625-3p is not 100% accurate, and therefore there is a chance the assay will produce both false positives as well as false negatives. Further studies on larger sample sizes are needed to see whether the accuracy of miR-625-3p can be confirmed or even turn out to be better than currently observed."

"Should further studies prove that microRNAs in plasma are accurate enough for the diagnosis of malignant pleural mesothelioma, this will lead to the development of a diagnostic test for routine clinical use," Dr Kirschner said. "This test would then represent a relatively simple way to circumvent the problems associated with obtaining a tissue biopsy. For a patient this would mean that appropriate treatment could be instituted at an earlier stage."

High-dose radiotherapy gives good response rates

Despite a widespread belief that mesothelioma does not respond to radiotherapy, Australian researchers have found that it may have the best response rates of any single treatment for patients with disease largely confined to one side of the chest.

Between 2003 and 2011, Dr Malcolm Feigen and colleagues from Austin Health Radiation Oncology Center in Melbourne gave radiotherapy to 45[1] patients aged 45 to 74 with doses of between 45 and 60 Gy to one side of the chest over six weeks. The radiation was administered using 3D-conformal or intensity-modulated radiotherapy. None had surgery to remove their affected lung. At the beginning of treatment more than 80% of patients had the more advanced stage III or IV disease, and all had prior chemotherapy and/or surgery, except for two.

The median survival for the patients was 12.4 months from starting radiotherapy, ranging from 2 to 87 months, the researchers say. There were no life-threatening or fatal toxicities from treatment.

"Many believe mesothelioma to be radioresistant and that toxicity is prohibitive if high doses are given with the affected lung in situ," Dr Feigen and colleagues say.

"Our experience provides clear evidence that radiation is arguably the most effective single agent for mesothelioma and new technologies including intensity-modulated radiotherapy allow high doses to be delivered safely."

Blood markers identified

Swiss, Italian and US researchers report that they have tested another group of potentially useful blood markers for mesothelioma.

Dr Ferdinando Cerciello from the Swiss Federal Institute of Technology and the University Hospital Zurich and colleagues studied 56 candidate biomarker peptides that they isolated from laboratory samples of mesothelioma and tested in the blood of patients with mesothelioma, healthy donors and non-small-cell lung cancer patients.

The study "revealed potential candidate biomarkers in serum, accessible simultaneously by mass spectrometry," the authors report. At the meeting, they will report the strategy for the selection and measurement of their 56 peptides in serum as well as the results of an evaluation in 75 blood samples.

Sorafenib well tolerated

The drug sorafenib is well tolerated in patients with mesothelioma after completion of platinum containing chemotherapy, British investigators report.

In a phase II trial of sorafenib following first-line chemotherapy in 53 patients with malignant mesothelioma, 34% of patients were progression-free after six months.

Dr Sophie Papa and Dr James Spicer from Kings College London and colleagues say that the drug was well tolerated and offered a length of progression-free survival that "compares favorably" to other targeted agents in this disease.

"Mesothelioma, one of the most important occupational diseases, is attracting more and more attention nowadays," noted Prof Paul Baas from the Department of Thoracic Oncology at The Netherlands Cancer Institute, member of the ESMO Chest Tumors Faculty Group. "New developments in the diagnostics and treatment of this disease are really important, including those presented during the ELCC 2012 meeting: improvements in the diagnosis by simply measuring biomarkers in peripheral blood samples will identify patients who may be candidates for new studies or financial reimbursement by their employers. The developments in molecular biology allow us now to detect circulating fragments of (micro)RNA and peptides that may play an important role. Furthermore the understanding that radiation therapy and targeted agents can be given to these patients will lead to new, promising, studies."