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Mesothelioma and asbestos-related pleural diseases

Thursday, July 31, 2008

Source: Respiration: International Review Of Thoracic Diseases

The journal Respiration: International Review of Thoracic Diseases has recently published an overview of mesothelioma and a number of other diseases caused by asbestos exposure. The article specifically covers the pleural conditions that exposure causes, so asbestos-related diseases that affect only the lungs, such as lung cancer and asbestosis, were excluded. After giving a brief introduction to the use of asbestos and the various types of fibers included in its definition, they cover four of the non-malignant conditions that have been linked to the fibers, as well as a review of the current knowledge regarding pleural mesothelioma.

This article is a summary of their article with a focus on the non-malignant diseases, as we have cover mesothelioma extensively throughout the site.

Introduction to Asbestos

The authors note that asbestos has been used for centuries, but it wasn’t until the 19th century that advances in the ability to process it enabled the large scale, general use that continued through much of the 20th century. The development of techniques that allowed the fibers to be spun and weaved into various forms led to their use in products as diverse as brake linings and cement.

Sadly, this large scale use is what led to the development of diseases specific to exposures to the fibers. Asbestos-related diseases now make-up an entire class of medical conditions. While lung cancer and mesothelioma are by the far the worst of these diseases, a number of other conditions can also lead to pain and trouble breathing. The following four pleural conditions are directly linked to asbestos exposure: benign asbestos pleural effusion (BAPE), pleural plaques, diffuse pleural thickening (DPT) and rounded atelectasis.

Benign Asbestos Pleural Effusion (BAPE)

Benign asbestos pleural effusions are non-malignant effusions that commonly occur within twenty years of asbestos exposure. The authors describe BAPE as “an effusion that occurs in the setting of asbestos exposure, in the absence of other conditions and is not followed by the development of malignancy within three years.” Thus, BAPE is a diagnosis given in the absence of more serious conditions. Whenever a patient presents with a pleural effusion a full round of tests should be conducted to rule out malignant conditions.

BAPEs commonly appear within 20 years of a person’s exposure to asbestos, but like many of the other asbestos-related diseases, a longer latency period is not out of the question. A BAPE is not a particularly dangerous condition and most people who develop one do not require treatment, but some individuals will present with large effusions that require draining.

The authors note that BAPEs are not themselves indicative of a future malignant development, but they do share a common causative ancestor to mesothelioma (and lung cancer).

Pleural Plaques

It is well known in medical circles that pleural plaques are a common development in asbestos-exposed individuals. Pleural plaques are a type of fibrosis that arises in the parietal pleura, typically 20-30 years after asbestos exposure. Epidemiological studies have demonstrated that pleural plaques are quite rare in non-asbestos-exposed populations and are found in a small number of people with environmental exposure to the fibers, but that their incidence greatly increases in individuals with occupational exposures to asbestos.

Many cases of pleural plaques are not symptomatic, but a subset of patients will experience restricted pulmonary function. Pleural plagues, like BAPEs, are a non-malignant condition and their development is not indicative of a future malignancy.

Diffuse Pleural Thickening (DPT)

Diffuse pleural thickening (DPT) is another condition that can be related to asbestos exposure, but is not solely caused by asbestos. It is a fibrosis of the visceral pleura that leads to its fusion with the parietal pleura. Among those exposed to asbestos, DPT is less common than pleural plaques, but—unlike pleural plagues—it is often associated with serious pulmonary symptoms, including chest pain and “significant restrictive ventilatory impairment.”

Rounded Atelectasis

Rounded atelectasis is another pleural disease that is strongly linked to asbestos exposure, even though it is less common than either pleural plaques or DPT. It affects the visceral pleura and can be confused with primary lung cancer during radiological analysis. The condition is also known as folded lung, asbestos pseduotumor, or Blesovsky syndrome.

Malignant Mesothelioma

As we have covered extensively on this site, malignant mesothelioma is the most serious asbestos-caused disease because there is no cure for it. Even as very isolated cases of significant survival have appeared in the literature, the disease is still associated with a median survival time of under 16 months.

To learn more about mesothelioma, we suggest you read the following articles: pleural mesothelioma, peritoneal mesothelioma, mesothelioma treatments.

Labels: asbestos, mesothelioma

posted by Belluck & Fox at 11:22 AM
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Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma

Friday, July 25, 2008

Source: Cancer

Even as improvements in the therapies available for mesothelioma patients have been made in recent years, the disease remains without cure. Most patients are ineligible for curative surgeries, so investigations into improving the efficacy of chemotherapy are among the most common research programs in contemporary mesothelioma treatment studies. Combination chemotherapy using pemetrexed and cisplatin (Alimta therapy) is considered first-line chemotherapy because it has demonstrated the most effective improvement in median time of survival when compared to every other chemotherapy regimen that has been tried. However, at some point during treatment, the disease always takes the upper hand and the chemo’s attempt to control the mesothelioma becomes more and more ineffective, until the drugs are no longer able to restrict the disease at all. When this happens in other cancers, one of the standard responses is for an oncologist to attempt another course of chemotherapy using different agents. This type of treatment regimen is known as second-line chemotherapy. Unfortunately, research has not yet identified an effective second-line chemotherapy regimen for pleural mesothelioma. Even as research into it continues, most results have been disappointing.

A group of renowned mesothelioma specialists has recently released the results of a study they conducted in hopes of identifying an effective second-line chemotherapy for pleural mesothelioma. Their study investigated the use of erlotinib plus bevacizumab for this purpose and their results have recently appeared in the journal Cancer.

This article is a summary of their findings.

Overview of the Study

A number of different agents and treatment regimens have been studied for the second-line use of chemotherapy in pleural mesothelioma patients. No standard has been identified though, so research into this question continues in hospitals around the world. Much of this research is being conducted based on our growing understanding of the biological foundations of the disease.

Some studies have demonstrated that vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are important co-factors in the growth and spread of mesothelioma, so the authors of the present study investigated whether agents that inhibit these growth factors would be effective for treatment of the disease. Erlotinib is an inhibitor of EGFR, while bevacizumab inhibits VEGF. Combination therapy using these agents has been shown to have clinical efficacy as second-line treatment for non-small cell lung cancer and the physicians were hopeful that it would demonstrate similar efficacy for pleural mesothelioma.

The treatment plan under study called for the daily administration of 150 mg of erlotinib and for the administration of 15 mg/kg of bevacizumab on Day 1 of a 21-day cycle. Patients would be assessed for individual reactions to the treatment at each administration, while tumor assessment would be conducted through CT every two cycles.

Results

A total of 24 patients were included in the final study. As in most mesothelioma-related studies, the majority of those studied were older Caucasian men. There were 15 men and 9 women, with an average age of 62.5 years. 23 of the patients were white and one was Hispanic. 8 of the patients began the study with a performance status of 0 and 16 began it with PS of 1. The authors report on a number of other breakdowns and classifications as well.

The overall results of the treatment were disappointing. This chemotherapy regimen was not nearly nearly as effective for mesothelioma patients as it was for patients with non-small cell lung cancer. There were no complete or partial responses, but temporary stable disease was achieved in 12 patients. The other 12 patients had had progressive disease throughout the study. Of the 12 patients who demonstrated stable disease, 7 (of were from the group with the best performance status (0) and 10 (of 16) presented with epithelial mesothelioma, the form of the disease with the best prognosis.

The patient cohort demonstrated a median time-to-progression of 2.2. months and a median survival time of 5.8 months. When studied at 6- month and 12- month intervals, the time-to-progression percentages were 29% and 6%, respectively, and the survival rate percentages were 46% and 24%, respectively.

Conclusion

Because of mesothelioma’s unique behavior pattern, chemotherapy remains the most commonly deployed treatment modality and this situation is unlikely to change in the near future. Advancements in the available therapies have already led to increased survival time, but more research is needed before medicine truly turns the corner on its ability to effectively treatment pleural mesothelioma. Even though this study did not demonstrate any clinical efficacy, other studies have identified alternative agents as possible treatment candidates and results from those investigations are eagerly awaited by doctors and patients alike.

Labels: chemotherapy, mesothelioma, pleuralmesothelioma, treatments

posted by Belluck & Fox at 10:14 AM
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Asbestos Fibre Concentrations in the Lungs of Brake Workers: Another Look

Wednesday, July 23, 2008

Source: Annals of Occupational Hygiene

The causative relationship between asbestos exposure and mesothelioma has been clearly established for almost a century. While scientists are still working out the precise biological mechanisms responsible for the development of the malignancy, there is no question that workers who’ve been exposed to asbestos are candidates for pleural mesothelioma, peritoneal mesothelioma or the rarer forms of the disease. Even as no safe exposure limit has been established, studies have shown that workers with a significant lung burden of asbestos fibers are more likely to be diagnosed with mesothelioma than are others workers. This means that workers from industries which featured greater uses of the mineral have an elevated risk for disease development as well.

One such industry that has been investigated for the risk that employment posed to its workers is the field of automotive brake mechanics. Vehicle brakes featured a significant amount of asbestos and workers in the field have definitely developed mesothelioma. However, the issue of general causation due to work exposure has become controversial due to the publication of some recent studies that have raised questions regarding the exposure that individual mechanics had to asbestos dust. These studies indicated that the sample of brake workers they investigated did not show higher lung burden counts than a control sample of workers who did not have occupational exposure to asbestos. Thus, these studies concluded that brake mechanics were no more likely to develop mesothelioma than were those other workers.

However, an article has recently been published in the Annals of Occupational Hygiene that calls these studies and their conclusions into question. The author, Murray M. Finkelstein of the Mount Sinai Hospital in Toronto, Canada, has identified a number of methodological problems in the previous studies that limit their conclusions. Mr. Finkelstein has deployed a statistical apparatus that overcomes these methodological problems and he has concluded that brake mechanics are more likely to develop an asbestos-related disease, such as mesothelioma, because of their occupational exposures to asbestos.

Overview of the Article

The author quotes two articles published in 2004 that individually concluded that brake mechanics were not of a higher risk for developing mesothelioma due to their occupational exposures to asbestos. He then identified the common sources of data between the two articles, which included a comparative analysis of asbestos fiber burden between 10 brake mechanics who developed mesothelioma and 19 control subjects who did not work in asbestos-exposed occupations. The analysis conducted by the original researchers indicated that the brake mechanics in their study did not have a significantly higher burden of asbestos fibers in their lungs when compared to workers from fields without occupational asbestos exposure, so it was concluded that brake mechanics are not more likely to develop asbestos-related illness because of their exposures.

It is at this interpretation of the original researchers’ data that the author’s article is directed at.

The author’s analysis and interpretation of the data is based on the same published dataset as the previous articles. In his analysis of their methods, he concluded that a different statistical apparatus was necessary for a proper investigation of the question, so his study is based on a combination of methods that each parsed the data in specific ways. It is through the analysis of these individual methods that he draws his conclusions from.

His study specifically compared the counts and distributions of two different asbestos fiber types, chrysotile and tremolite, in the lungs of the control and case groups. Along with the general carcinogenicity of asbestos, the incidence rate of mesothelioma, and other asbestos-related diseases, increases based on the type of asbestos fiber that a person has been exposed to. There are two main classes of asbestos fibers and the fibers identified in this study are representative of each class: tremolite is an amphibole fiber, while chrysotile is a serpentine fiber. The individual classes are distinguished by their shape and structure. Amphibole fibers have a needle-like shape and a rigid structure that make them quite durable. Once amphibole fibers lodge into a person’s tissue structures, they are very difficult for the body to remove. Serpentine fibers have a curved shape (hence their name) and are more pliable than the amphiboles, which means they are slightly easier for the body to breakdown. Even though both fiber classes have been shown to be carcinogenic, the amphibole fibers are known to be more dangerous than the serpentine fibers.

Conclusion

When the author compared the datasets using the modified statistical apparatus, he found that brake workers did, in fact, have a higher general concentration of these fibers than did the control group. More importantly though, he found that they had significantly higher count of tremolite fibers, which means they would be even more at risk for mesothelioma than if they “only” had a higher count of the chrysotile fibers.

Labels: asbestos

posted by Belluck & Fox at 4:56 PM
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Lung Cancer Trial Targets Asbestos-Related Disease

Tuesday, July 22, 2008

Source: U.S. News and World Report

U.S. News and World Report has recently written about a clinical trial for an experimental mesothelioma treatment that is being conducted at the Mesothelioma Center at New York-Presbyterian Hospital and Columbia University Medical Center. The trial is investigating the combined use of chemotherapy and radiation in the treatment of pleural mesothelioma, which is a departure from the standard therapies that normally specify some form of curative surgery. Patients who are enrolled in the trial will receive multiple cycles of a chemotherapy regimen consisting of either cisplatin and doxorubicin or cisplatin and pemetrexed (Alimta). The latter chemotherapy regimen is the current standard of care in chemotherapy for mesothelioma. All of these patients will receive radiation that is targeted directly at the pleural tissue on the lung.

Although the treatment regimen does not specify curative surgery, it will be available for patients who elect to undergo it. Patients can choose between extrapleural pneumonectomy and pleurectomy/decortication.

The trial is investigating whether this regimen will demonstrate any improvements in overall patient outcome than do the standard therapies.

The Mesothelioma Center at New York-Presbyterian Hospital and Columbia University Medical Center is the only cancer center in the country to offer this therapy.

Labels: chemotherapy, mesothelioma, radiation, treatments

posted by Belluck & Fox at 11:45 AM
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Image-guided pleural biopsy

Thursday, July 17, 2008

Source: Current Opinion in Pulmonary Medicine

Efficient diagnostic techniques are important in the diagnosis of all forms of cancer, but this is especially true for people who are presenting with symptoms that are indicative of mesothelioma. The disease ranks among the most aggressive malignancies and remains very difficult to treat effectively, especially when a diagnosis is received only in its later stages. A number of studies that have investigated prognostic factors in relation to effective treatments have concluded that an early diagnosis of pleural mesothelioma or peritoneal mesothelioma is among the most important variables in maximizing treatment potential. Thus, efforts to improve a physician’s ability to accurately diagnose the disease are among the most common research projects that are currently underway.

In an effort to add to the available literature on the subject, physicians from the United Kingdom conducted a study to determine the efficacy of using image-guided pleural biopsy techniques in the diagnosis of mesothelioma and other pleural diseases as well. They have recently published their findings in the journal Current Opinion in Pulmonary Medicine and have concluded that image-guided techniques are far superior to the traditional biopsy techniques.

Overview of the Study

When a patient presents with symptoms of mesothleioma, or another pleural disease, the physician will schedule a series of tests to determine the location and makeup of the (possible) disease as presented. Imaging tests will be used to identify the presence of specific physical signs of disease and a biopsy will be conducted for the removal and analysis of actual tissue samples. In cases where fluid from a pleural effusion can be extracted, this fluid can also be analyzed for the presence of malignant cells, but this kind of analysis does not provide the same diagnostic precision as does the analysis of a biopsy specimen. Thus, a definitive diagnosis requires efficient biopsy techniques for the extraction of tissue.

Traditional pleural biopsies have been conducted through either thoracotomy or through “blind” biopsies of the parietal pleura. The former technique provides a clear path to the pleural cavity and the removal of tissue from it, but is a highly invasive procedure that features significant patient burden. A blind biopsy is a much less invasive procedure and can be conducted as an outpatient procedure, but its accuracy is limited because the physician will make the insertion, and subsequent tissue extraction, from outside the patient’s body, without any tools guiding him or her to specific locations in the pleural cavity.

Recent innovations in diagnostic techniques have led to the development of new procedures for diagnosis. Image-guided biopsy refers to the use of imaging technologies to guide the physician in his or her biopsy procedure. Ultrasound and CT are two of the most common technologies used to do this. Ultrasound is beneficial because its feedback is delivered in real time, while CT offers higher resolution than ultrasound does and is able to image structures that ultrasound is not able to. Another recent innovation is video-assisted thoracoscopic surgery, or VATS for short. VATS is a minimally invasive procedure where small incisions are made in a patient’s side and a tiny video camera and specific surgical instruments are inserted. The camera allows the doctor to see the interior landscapes of the patient’s thorax, while the instruments allow whatever procedure is required to be completed. In our discussion here, the instruments would be whatever tools were selected for the biopsy, but VATS can be used for a number of other procedures as well.

In their study, the authors investigated the sensitivity and efficacy of blind biopsy vs. image-guided biopsy in the diagnosis of both pleural malignancies and benign pleural diseases, such as pleural tuberculosis.

Results

The authors found that image-guided biopsy was much more effective in the diagnosis of mesothelioma and other pleural diseases than was blind biopsy. Image-guided techniques allow the physician to choose a location from which to make the extraction, which enables the doctor to select areas that are already displaying signs of disease. This ability significantly cuts down on the chances of a false negative due to poor selection of a sample site. The authors state that their research indicates blind biopsy techniques achieve a diagnostic rate of, at best, 50%, while image-guided techniques demonstrate a success rate well over 80%.

The authors also compared the applicability of image-guided biopsy to that of VATS, or to other thorascopic techniques that doctors may currently use, and they concluded that both sets of techniques exhibited similar diagnostic accuracy, but that the choice of which procedure to deploy should be based on patient status. VATS allows both diagnostic and therapeutic procedures to be performed, but is limited by a need for a clear separation of the pleurae and the presence of pleural fluid to facilitate entry, while image-guided biopsy is a purely diagnostic procedure, but one that can performed in the presence of a fused parietal and visceral pleura. They state that patients who present with large pleural effusions and the need for drainage or pleurodesis should undergo VATS, while patients who present without therapeutic needs, small effusions, and/or with conditions that complicate VATS should undergo image-guided biopsy.

Another consideration that the authors discussed regarding choice of procedure had to do with the potential of mesothelioma to invade biopsy sites, which the disease has a tendency to do. They state that the diagnostic accuracy of a procedure increased with its invasiveness, but so did the chances of the malignancy spreading to the biopsy site. They quote a study that concluded thoracotomy was associated with the highest diagnostic accuracy (100%), but also the highest rate of “tumor-seeding,” (24%), while image-guided was associated with a slightly less accurate diagnostic sensitivity (86%), but a smaller seed potential (5%). However, they state that larger studies are needed before a firm conclusion can be drawn.

Conclusion

The authors conclude their article by recommending that image-guided pleural biopsy, or another innovative procedure such as VATS, should replace blind pleural biopsy whenever possible. They state that it has a much higher diagnostic accuracy than does traditional biopsy, and is safe and effective for the investigation of mesothelioma, and other pleural diseases.

Labels: diagnosis, mesothelioma

posted by Belluck & Fox at 4:51 PM
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Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma

Tuesday, July 15, 2008

Source: British Journal of Cancer

The chemotherapeutic treatment of mesothelioma is one of the major arms of contemporary mesothelioma research. A wide variety of investigations into new agents and treatment regimens are currently being conducted in hospitals and laboratories around the world. Even as the last few years have seen major advancements in the effectiveness of a number of mesothelioma treatments, the reality of the situation is that mesothelioma is still without cure. As impressive and welcome as the extension in median survival times are for patients and their families, physicians know that more work is required before the treatment of pleural mesothelioma and peritoneal mesothelioma will be seen within the same framework of successful therapies that other cancers are now seen within.

One of the newer chemotherapy agents that is increasingly being studied for the treatment of mesothelioma is vinorelbine, which is a member of the class of chemotherapy drugs known as vinca alkaloid agents. These drugs disrupt the mitosis phase in the cell cycle. Previous vinca agents were not active in the treatment of mesothelioma, but a number of recent studies have indicated that vinorelbine is not only active in the treatment of mesothelioma, but may be among the most active in terms of overall response rate.

To further investigate the efficacy of vinorelbine, researchers from Denmark conducted a study on its use with that of cisplatin as first-line chemotherapy in the treatment of pleural mesothelioma. They have recently published their results in the journal British Journal of Cancer.

Overview of the Study

The combination of vinorelbine and cisplatin has shown activity in the treatment of the non-small cell lung cancer, so the researchers were interested if the combination would be similarly active for pleural mesothelioma. Platinum agents, such as cisplatin, have already been shown to be active in the treatment of mesothelioma and are a part of the major chemotherapy standard of care for pleural mesothelioma, which is combination therapy using pemetrexed (Alimta) and cisplatin (or carboplatin).

To conduct their study, the researchers enrolled patients with histologically-proven pleural mesothelioma, who were not eligible for surgery and had not previously completed a chemotherapy regimen, among other requirements. The treatment dictated cisplatin every four weeks, with standard antiemetic therapy, and weekly vinorelbine administrations. The patients were monitored on a number of fronts for treatment response, as well as side effects and toxicity.

Results

A total of 54 patients were treated with the vinorelbine + cisplatin regimen. There were 46 males and 8 females. The breakdown of the histological subtypes of the disease were as follows: 40 patients presented with epithelial mesothelioma, 5 with sarcomatous mesothelioma and 9 presented with biphasic mesothelioma. Most of the patients were Stage III or Stage IV patients and the median age was 63 years old.

Of the full patient class, there were 14 partial responses and 2 complete responses, for an overall response rate of almost 30%. Of the 40 cases of epithelial mesothelioma, 13 patients demonstrated some response, while two patients with the sarcomatous subtype had a response and one with the biphasic response. Four of the eight women showed some response to treatment, while only 12 of the 46 men showed a response. The median survival time was 16.8 months, with a one-year survival figure of 61% and a two-year figure of 31%.

However, the authors note that a number of patients experienced significant side effects or some form of toxicity event. Even as the response rate of the procedure was more active as compared to some other treatments, the side effects experienced by the patients were also greater than those who’ve been studied with other regimens—including pemetrexed/cisplatin combination therapy.

Conclusion

The response rate figures show that the vinorelbine + cisplatin regimen is among the most active in the treatment of pleural mesothelioma. However, the authors state they are unable to recommend the treatment course for a number of important reasons. Even though their study demonstrated the efficacy of the regimen, they feel that precise comparisons between previous studies are not possible do to differences in the patients enrolled and the methodologies used to compare responses. Along with the high percentage of side effects associated with the therapy, they also feel that the weekly administration of vinorelbine makes it impractical to recommend this particular regimen of treatment.

However, the authors are hopeful regarding the future use of the treatment and state that improvements in the delivery mechanisms of vinorelbine, as well as other improvements in the overall treatment regimen, may be helpful in overcoming these issues. They also state that vinorelbine + cisplatin would be an excellent candidate in the use of induction chemotherapy before surgery.

Labels: chemotherapy, cisplatin, mesothelioma, treatments, vinorelbine

posted by Belluck & Fox at 12:18 PM
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Induction of Apoptosis by Intrapleural Perfusion Hyperthermo-Chemotherapy for Malignant Pleural Mesothelioma

Monday, July 14, 2008

Source: Annals of Thoracic and Cardiovascular Surgery

Chemotherapy is one of the most important treatment modalities for patients with mesothelioma. Due to the late stage at which the disease is normally diagnosed, many patients will not be eligible for surgery so chemotherapy is likely to be the only curative therapy that is available to them. For patients who are eligible for cytoreductive surgery, such as pleurectomy/decortication or extrapleural pneumonectomy, chemotherapy is likely to used as part of a multimodal treatment protocol. Recent advances in the effectiveness of the available chemotherapy agents have definitely led to improved survival times for some patients, but these successes are mitigated by the fact that the disease is still without cure. Because of this disappointing situation, a significant portion of contemporary mesothelioma research is directed at improving the efficacy of available mesothelioma treatments.

Some of these research programs involve the study of alternative chemotherapy regimens. Even as pemetrexed + cisplatin (Alimta Therapy) has been a real advancement in mesothelioma treatment, additional agents and delivery mechanisms are available from the treatment of other cancers and researchers from around the world are engaged with the application of these methods to mesothelioma. Researchers from Japan have recently published an article that describes their use of a custom-developed heated perfusion technique for the treatment of pleural mesothelioma.

This article is an overview of their method and a summary of their findings.

Overview of the Study

The article describes the authors’ use of intrapleural perfusion hyperthermo-chemotherapy (IPHC) for patients with pleural mesothelioma. Perfusion chemotherapy is an alternative to the standard intravenous delivery mechanism, where the chemotherapy drugs are administered to a particular area of the body instead of being injected into the blood stream. In the case of intrapleural perfusion, the chemotherapy is delivered directly to the pleural surfaces. The drugs are heated to enhance the absorption process, as research has shown that it is easier for tumors to absorb a drug when it is heated to a certain temperature.

The authors report that they had previously had good results when using this technique on patients with pleuritis carcinomatosa, so they decided to investigate its use for pleural mesothelioma. They enrolled six patients into their study, three men and three women. Of these 6 patients, five presented with epitheloid mesothelioma and one presented with the biphasic subtype. Five patients were staged as Stage III and one was declared Stage IV. Because of the small size of the study, the authors state that they were not investigating overall treatment efficacy, but were in fact studying the apoptotic effect the therapy had on the patients who were treated with it.

The procedure was accomplished with patients under general anesthesia. The authors used video-assisted thoracic surgery (VATS) to examine the patients and to perform a biopsy. Before the perfusion was begun, they removed tumor cells from a pleural effusion. When the perfusion was completed, tumor cells were immediately removed from the effusion, and then again at 24 hours and 48 hours post-perfusion. This was done so the authors could prepare an Apoptosis Index (A.I.), which would establish what effect, if any, the treatment had on the pleural mesothelioma.

Results

The authors found that the IPHC treatment demonstrated a significant apoptotic effect on each patient’s mesothelioma cells. The Apoptotic Index describes the percentage of cells within the sample that were undergoing apoptosis when analyzed. The AI of the untreated cells was 3.8% ± 2.0%, while the post-perfusion indices were as follows: immediately-following, 22.8% ± 5.1%, at 24 hours following, 63.8% ± 8.2%, and at 48 hours following, 47.8% ± 6.09%. These are clear indications of the treatment’s noteworthy effects.

Even though the authors were not directly studying treatment efficacy, when they looked at median survival time for these patients, they found figures much higher than normal: 30 months MST vs. the standard 8-12 months.

Conclusion

Recent research has shown that one of the factors that makes mesothelioma so difficult to treat is its natural resistance to apoptosis, so the results these authors are reporting are quite exciting indeed. Even if they were not specifically studying treatment efficacy, the extended survival times demonstrated in this study are also quite impressive. A sample size of six is definitely too small to draw any conclusions from, but the authors feel that the successful rests of their study of pleural mesothelioma are worthy of a larger study.

Labels: chemotherapy, mesothelioma

posted by Belluck & Fox at 3:58 PM
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Asbestos burden predicts survival in pleural mesothelioma

Friday, July 11, 2008

Source: Environmental Health Perspectives

Researchers have identified a number of factors in a patient’s presentation with mesothelioma that serve as important indicators of the disease’s treatability and overall prognosis. Two of the most significant indicators are the gender of the patient and the histological subtype of the disease. In terms of gender, studies have shown time and time again that men are more likely to be given a limited prognosis than are women. Regarding histology, other studies have shown that patients who are diagnosed with epitheloid mesothelioma have a better prognosis—in some cases, a much better prognosis—than do patients who are diagnosed with either biphasic mesothelioma or sarcomatoid mesothelioma, which are the other subtypes of the disease. This information is important to mesothelioma physicians as they develop individualized treatment plans because the particular forms these indicators take will dictate one particular therapy over another.

Even as researchers have confirmed the importance of these factors in numerous trials, they have also investigated if other presentational features can function in a similar manner. A feature of particular interest to physicians involves the relationship—if any—between overall asbestos burden and treatment outcomes. Researchers have known for almost one hundred years that asbestos is the only cause of mesothelioma and that longer exposures to its dust and particulate matter, especially in occupational settings, often correlate with a greater likelihood of developing the disease, but few quantitative studies have been completed that specifically addressed the relationship between asbestos burden and treatment outcome.

In response to this, a group of researchers from some of the finest hospitals and mesothelioma research programs in the United States conducted a study that addressed this question and have recently published their findings in the journal Environmental Health Perspectives.

This article is a summary of their findings.

Overview of the Study

To address the question of the relationship between asbestos burden and mesothelioma prognosis, the study looked at a population of 128 pleural mesothelioma patients that were treated in the International Mesothelioma Program at Brigham and Women’s hospital in Boston, MA. To analyze asbestos burden, the researchers used two sets of data: self-reported data from individual patients, or data given during interviews with a trained industrial hygienist, on their occupational histories and known asbestos exposures, as well as an analysis of actual lung and tumor tissue that was removed from the patients during surgery. Reported data was available for all 128 patients, while the tissue samples were available for 83 patients.

The researchers looked at a number of factors in relation to this data, including overall asbestos exposures, actual body burden of asbestos fibers, tumor characteristics and patient demographics. Each piece of information was analyzed singularly and in combination with the other factors.

Results

In the cohort of 128 patients, there were 98 males and 38 females, with a mean age of 62 years. There were 91 cases of epitheloid mesothelioma, 33 cases of biphasic mesothelioma and 4 sarcomatoid cases. When the researchers compared the relationships between histology and gender with survival time, they again confirmed the efficacy of these two factors as important indicators of survivability: epitheloid types were associated with significantly better survival times than the other histological types, and longer survival times were demonstrated, on average, by more women than men.

To compare asbestos burden levels between individuals, the researchers used the patient’s reported data as well as data from an analysis of actual tissues (when such tissues were available). They analyzed multiple samples from resected lung tissues to determine the number of asbestos bodies per gram of tissue (ABs/g lung). The median level for the entire cohort was 158 ABs/g lung. Three individuals demonstrated a radically higher ABs/g lung figure than all other patients, so their information was not included in any of the reported statistics. The researchers also created a three-tiered structure that identified different levels of exposure and categorized those levels using the following: low burden (0-99 ABs/g lung), moderate burden (100-1099 ABs/g lung) and high burden (> 1099 ABs/g lung).

The researchers did not find an overall relationship between self-reported asbestos exposures and survival times, but they did find a relationship between older age at diagnosis of mesothelioma and self-reported exposures. An analysis of asbestos body burden levels between genders showed that men had significantly-higher median fiber levels than did women (219 vs 20 ABs/g lung), which is not surprising given the greater number of men who worked in occupations with products containing asbestos.

When the researchers compared actual tissue burden levels to survival times, they were quite surprised to learn that burden level and survivability did not progress in a linear fashion. Instead, they found that those with moderate levels of exposure survived longer, on average, than those with low or high burdens. The researchers were not able to determine the reason why the low burden group demonstrated a greater risk of shorter survival than did the moderate burden group, but they suggest that if certain individuals have a natural susceptibility to the disease then they may be susceptible to a more aggressive form of it as well.

The researchers did find, however, a significant correlation between the high asbestos burden category and shorter survival times compared to the other two levels.

Conclusion

The researchers conclude that asbestos burden could be an important factor in mesothelioma prognosis, but they state that more research studies involving larger sample populations are necessary before a final determination can be established. Mesothelioma, especially its most common form of pleural mesothelioma,is a difficult disease to manage effectively and still remains an enigma in many ways. It is through the innovative research of dedicated physicians and scientists that we’ve learned all that we currently know about this terrible disease and it is through the continual renewal of this research that we’ll learn even more.

Labels: mesothelioma, pleuralmesothelioma

posted by Belluck & Fox at 3:45 PM
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Cancer Cured? Granulocytes Treatment Worked 100 Percent In Mice Work But Will It Work In Humans?

Wednesday, July 2, 2008

Source: Scientific Blogging

The scientificiblogging.com website has recently published an article on a very promising experimental cancer treatment that is set to begin clinical trials at the Wake Forest University Baptist Medical Center. The treatment involves transplanting specific kinds of white blood cells—known as granulocytes—from selected healthy individuals to cancer patients. Pre-clinical laboratory studies in mice have shown 100% effectiveness and the scientists who are running the trial hope to achieve a similar response in humans.

The treatment is based on the discovery of a mouse that was fully cancer-resistant and whose white blood cells contained cancer fighting properties that even cured cancer when they were injected into other mice. When the scientists looked for similar traits in human white blood cells they were amazed to find them among a subset of healthy adults. Because these cells are not produced by everyone, the scientists need to screen individuals for granulocytes with the specific properties they are looking for. When they find these donors, scientists are then able to draw blood and to separate the granulocytes from the rest of the plasma.

Subsequent research has revealed that people under 50 produce higher amounts of these granulocytes than older people do and that the cancer-fighting activity of the cells is greater in the summer than the winter. This information has been used to develop the research protocol of the clinical trial that is just beginning.

The trial will recruit 500 potential donors of healthy people under 50, all of whom will have their blood tested. From this sample, 100 people will be asked to donate their white blood cells. The granulocytes from these selected donors will then be transfused into the 22 cancer patients who have been enrolled in the study. The researchers are beginning the trial during the summer to maximize the cells’ cancer-fighting abilities. These patients will be closely monitored throughout the trial and their progress will be evaluated for efficacy three months in. Should the trial be considered a success, the researchers will then expand their investigations to see if particular types of cancers respond better to the treatment than do other types.

Labels: cancer

posted by Belluck & Fox at 12:15 PM
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Treatment News

Coming Soon

Labels: Treatment News

posted by Your Attorney at 9:10 AM
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Molecular targets and targeted therapies for malignant mesothelioma

Tuesday, July 1, 2008

Source: Current Medicinal Chemistry

Some of the most important work in contemporary mesothelioma research involves the attempt to create targeted therapeutic agents which work directly on the cellular aberrations that are ultimately responsible for the development of pleural mesothelioma and peritoneal mesothelioma. The great hope these therapies inspire is based on the idea that if medicine can develop agents that block the specific biophysical processes which lead to tumor growth, then physicians will be able to deploy mesothelioma treatments that are much more effective than the current treatment modalities that are being used to treat the disease. Traditional cancer treatments such as surgery and chemotherapy have seen improvements in their overall efficacy, but they are still not considered curative approaches to the disease because they are only able to extend patient life—they are not able to truly save it from mesothelioma. Not only would these targeted therapies be more effective, but researchers hope they would also be more tolerable and exhibit less serious side effects than surgery or chemotherapy do.

Researchers from Italy have recently published an article that describes some of the targets of these new therapies, as well as some of the therapies themselves. The remainder of this article will be a brief overview of the targets the researchers enumerated in their article and will include some discussion of the proposed therapies as well.

Inhibition of Growth Factor Receptor Signaling

The authors note that a number of studies have shown that mesothelioma development is definitively linked with malfunctions in growth factor signaling pathways. They note that the “aberrant activation” of the receptors for the following growth factors have all been implicated in some way in the genesis of the disease: epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF), transforming growth factor-beta (TGFB) and insulin-like growth factor (IGF). All of these growth factors are decidedly important for the proper function of the body, but they have also been shown to be essential in tumor genesis for a multitude of cancers.

Treatments for these aberrant activations are based on inhibiting the signaling pathways by deploying antibodies that block either the ability of a growth factor’s ligand to bind with its receptor or the ability of a receptor to receive a ligand. The authors note that research has shown that many of these agents are more effective when deployed during chemotherapy than if they are used as a single-agent therapy. They also note that agents specific to each of the individual growth factors are involved in clinical trials for mesothleioma treatment, as well as treatments for other cancers as well.

Inhibition of Intracellular Signaling Effectors: Targeting the AKT and Mammalian Target of Rapamycin Pathway

The PI3K/AKT pathway is another signaling pathway that has been implicated in mesothelioma tumorgenicity, as well as in the genesis of other cancers as well. The authors noted that “PI3K and AKT are frequently hyperactivated in cancer cells” and that this can lead to “increased tumor growth, metastatic efficiency, resistance to anticancer therapes and angiogenesis.” They also state that AKT plays a specific role in asbestos-induced disease and some previous studies have shown its inhibition can “induce growth arrest and apoptosis…” and can “sensitize MM [malignant mesothelioma] cells to different anticancer agents.”

Another class of therapeutic targets that research has identified are “downstream effectors” of the PI3K/AKT pathway, which simply means that scientists are looking for ways to not only block the signaling structures inherent in the PI3K/AKT pathway, but are looking to inhibit the activity of agents that start the signal cascade that can lead to PI3K/AKT activation. One such target that the authors describe is the mammalian target of rapamycin (mTor), whose inhibition by rapamycin has been shown to have anti-proliferative effects on cell growth.

Even as most of the therapies that have been developed to target AKT have not been fully studied on mesothelioma patients, the authors feel that the PI3K/AKT/mTor pathway is a very promising target for future mesothelioma treatments.

Inhibition of the Ubiquitin-Proteasome Degradation Pathway

Research has identified the ubiquitin-proteasome degradation pathway as another possible target for future mesothelioma treatments. The authors note that a number of preclinical studies have shown that the ubiquitin-proteasome pathway may be activated in mesothelioma genesis, as there is evidence to suggest that agents which target this pathway are cytotoxic to mesothelioma cells. There are at least two Phase II trials underway that are investigating the use of bortezomib, a compound in this class that has previously been approved for relapsed multiple myeloma, for the treatment of mesothelioma.

Inhibition of Histone Deacetylases

Agents that inhibit histone deacetylases (HDACs) are another area of contemporary mesothelioma treatment research. The authors note that these agents have been shown to “induce differentiation, growth arrest and/or apoptosis…” in research trials. Their use for the treatment of mesothelioma is being explored in multiple clinical human trials, due to the early successes these agents showed in the in vitro treatment of mesothelioma cells.

The authors note that one agent in particular—SAHA—has generated much excitement in pre-clinical studies. SAHA has already been approved for the use of T-cell lymphoma and its clinical trial for mesothelioma treatment is being watched with great interest.

Conclusion

As traditional mesothelioma treatments have not been effective for the long-term management of the disease, the creation of more effective therapeutic modalities is among the most important questions in the contemporary research of pleural mesothelioma and peritoneal mesothelioma. It will be a number of years before doctors and patients are able to look at the data from the treatments under current investigation to determine if they are truly more successful for the treatment of mesothelioma than are the current treatments, but even as these trials are ongoing, the greater knowledge that science has revealed about the disease’s underlying biology has given hope to many researchers in the field.

Labels: mesothelioma, treatments

posted by Belluck & Fox at 5:16 PM
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