AboutMesothelioma.Net

Incidence of Atrial Fibrillation after Extrapleural Pneumonectomy versus Pleurectomy in patients with Malignant Pleural Mesothelioma

Friday, August 29, 2008

Source: Interactive Cardiovascular and Thoracic Surgery

The two most common surgeries for the treatment of pleural mesothelioma are extrapleural pneumonectomy (EPP) and pleurectomy-decortication (PD). Both are considered radical surgery and both have been associated with significant postoperative complications, with EPP being the more radical procedure and the one more likely to have serious side effects. One of the side effects seen in both procedures is atrial fibrillation (AF), a type of irregular heartbeat where the upper chambers of the heart (the atria) quiver and beat in a chaotic fashion instead of properly contracting in a controlled and efficient manner. AF can increase a person’s chance of developing a blood clot that can travel to the brain and cause a stroke, or even death, so it’s clearly a serious condition to watch out for. Even as contemporary surgical techniques have reduced the gross number of surgical complications, side effects are always possible, so research is being conducted to investigate the conditions under which they can occur.

An article was recently published in the journal Interactive Interactive Cardiovascular and Thoracic Surgery that compared the incidence of atrial fibrillation in mesothelioma patients after EPP and P/D. The study was designed to discover which procedure was more likely to cause AF and what co-factors were most likely to affect this causation.

Overview of the Study

To investigate the incidence of atrial fibrillation following extrapleural pneumonectomy and pleurectomy, the authors of the article conducted a retrospective analysis of patients who were treated for pleural mesothelioma between November 2001 and October 2003. 130 patients were initially identified, but the study only looked at 127 of them because three patients had experienced atrial fibrillation at some point prior to the surgeries under consideration. The study specifically looked at the number of patients that experienced atrial fibrillation within three days of surgery and it used the patients who did not experience AF as the control group. The authors conducted a statistical analysis that utilized and reported on single variable causation factors, as well as a multivariate analysis that reported on the likelihood of AF when a number of interacting variables were considered as co-factors.

Results

127 patients were specifically included in the study results. 70 patients underwent an EPP and 57 underwent pleurectomy-decortication. Within the total patient population, the study sample included 45 patients who experienced atrial fibrillation within three days of surgery, leaving a control sample of 82 patients. 36 patients in the study sample underwent EPP, while only 9 underwent P/D.

The authors compared the two groups along a number of standard classification variables, but the only statistically significant, single variable differences between the two groups were incidence of AF and cell histology. Along with the higher incidence of postop AF, the EPP group also had a larger number of epithelial mesothelioma cases as compared to the P/D group. There is no indication that cell histology has any relationship to likelihood of atrial fibrillation, but EPP was found to be a definite risk factor for AF.

Other factors that appeared to contribute to the likelihood of AF were EPP + patient age and pre-existing structural abnormalities in the heart. The authors found that patients older than 65 had a significantly higher risk of AF after undergoing EPP than did patients who were younger than 65 that also underwent EPP. When studying echocardiogram results from a subgroup of the patient population, they found that those patients whose results suggested structural abnormalities were also at increased risk of atrial fibrillation. However, EPP was still the primary risk factor.

Deploying both univariate and multivariate analyses of the following variables and patient characteristics did not reveal any significant increase in risk: gender, affected side, preoperative heart rate, heart disease or preoperative use of beta-blockers.

Conclusion

Extrapleural pneumonectomy is the one of the most important techniques in the treatment of pleural mesothelioma because it allows the most extensive resection of malignant tissue, so limiting post-op complications is clearly an important factor for patient health. Contemporary surgical methods have definitely reduced the incidences of associated side effects, but this study has clearly shown that the nature of the procedure itself be a risk factor for atrial fibrillation. The authors suggest that the “increased pulmonary pressure and right atrial stress after complete removal of one lung causes right heart distention in the early postoperative phase” and that this could “increase the risk of arrhythmias” in patients who undergo the procedure. Because of this, they recommend that steps be taken to prepare for AF or that measures be enacted to limit the heart stress associated with EPP.

Labels: epp, mesothelioma, pd, treatments

posted by Belluck & Fox at 3:51 PM
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Pemetrexed plus Gemcitabine as First-Line Chemotherapy for Patients with Peritoneal Mesothelioma: Final Report of a Phase II Trial

Wednesday, August 27, 2008

Source: Journal of Clinical Oncology

Mesothelioma is an asbestos-caused cancer of the lining that surrounds many of the body’s vital organs. Pleural mesothelioma is the most common form of the disease and is diagnosed in 2000-3000 people every year. Peritoneal mesothelioma is the next most common form of the disease, but it is relatively rare and is diagnosed in only a few hundred cases per year. Because of this situation, detailed clinical trials and other treatment-related studies are difficult to perform and no standard of care yet exists for peritoneal mesothelioma.

Chemotherapy with pemetrexed is the standard of care for the treatment of pleural mesothelioma and many of the studies investigating effective therapies for peritoneal mesothelioma have incorporated pemetrexed into their treatment plans as well. An article was recently published in the Journal of Clinical Oncology that describes an open-label, multicenter study of the use pemetrexed in combination with gemcitabine for the treatment of peritoneal mesothelioma. This was the first study to investigate combination chemotherapy using these two chemo agents and the initial results, while limited, do show some efficacy for the treatment of peritoneal mesothelioma.

Overview of the Study

In order to evaluate the therapeutic efficacy of pemetrexed in combination with gemcitabine, the researchers enrolled 20 patients with histologically-proven peritoneal mesothelioma into their study. As is the case with most diagnoses of mesothelioma, the majority of patients were Caucasian men and epithelial mesothelioma was the most common histological sub-type of the disease. Enrollment criteria included good performance status (0-2), adequate organ function, and a malignancy not currently eligible for curative surgery. While some patients had previously undergone some form of cytoreductive surgery, patients were excluded from the study if they received prior systemic chemotherapy or radiotherapy to the target area, or they presented with evidence or suspicion of metastatic spread to the brain.

The study design indicated at least six chemotherapy cycles, with each cycle defined in 21-day increments. On Day 1 of the cycle, 1250mg/m² of gemcitabine would be delivered intravenously for 30 minutes. On Day 8, 500mg/m² of pemetrexed would be delivered over IV for 10 minutes, immediately followed by another IV administration of gemcitabine at the same dose as before. Because of previously reported toxicities related to pemetrexed delivery, a number of supplements were also given to patients. Folic acid was orally administered a week or two prior to beginning pemetrexed and was then given daily for the remainder of the patient’s enrollment in the study. Vitamin B12 was delivered by injection 1 or 2 weeks prior to beginning the first cycle and then subsequently delivered every 9 weeks the patient stayed enrolled. Dexamethasone was given one day before pemetrexed and was continued for three days per cycle.

Adjustments to the study design in terms of dose reductions and/or cycle delays could be made in response to individual patient treatment effects, but patients who received dose reductions would not be eligible for subsequent dose escalations and any patients whose cycle delay exceeded the cycle-length of 21 days were removed from the study. Physicians were able to add additional cycles if patients could tolerate them, or were able to remove patients from the study for other treatment effects as well. Any patient who demonstrated progressive disease during intracycle assessment was also removed from the study.

The principal endpoint of the study was determining tumor response rate, with secondary end points identified as disease control rate, overall survival, time to progression and response duration.

Results

10 patients completed the treatment course, while 10 others did not complete the study. 1 patient died in response to the chemotherapy, 5 were removed due to severe toxicity-related treatment effects, 3 patients experienced progressive disease during treatment and 1 patient dropped out of the study for “personal reasons.” 15 patients (75%) completed four chemotherapy cycles, while 12 patients (60%) completed at least six cycles.

The primary endpoint of the study was the determination of overall tumor response and even though not every patient completed the treatment plan, all were included in the determination of overall response rate. No patient experienced a complete response to the treatment, while 3 experienced a partial response and 7 others achieved stable disease (for a time). This leaves a tumor response rate of 15%. Disease control rate, a summation of all patients who achieved a partial response or stable disease, was a much higher 50%. 5 patients could not be fully evaluated for tumor response, either because of early removal from the study or because response data could not be independently-validated, so when these patients were excluded from the results, tumor response rate rose to 20% and disease control rate rose to 67%.

Median survival for the patient cohort was 26.8 months, with a one-year survival rate of 67.5% and a median time to progression of 10.4 months. The two-year survival figure was reported at 50%.

Treatment-related side effects were experienced by a number of patients, with neutropenia and fatigue the most commonly experienced effects. Neutropenia is a serious condition where the body has an abnormally low level of neutrophils, which are a type of blood white cell responsible for fighting infections in the body. 12 patients experienced grade 3 neutropenia and eight experienced grade 4 neutropenia. These figures are significantly higher than some of the earlier studies featuring pemetrexed and cisplatin, which reported neutropenia rates at under 5%.

Conclusion

The authors conclude their article by stating that the combination of pemetrexed and gemcitabine shows clear activity in the treatment of peritoneal mesothelioma and they call for more research into the use of this therapy for patients with peritoneal disease. While objective response rate was low, their statistics demonstrated an overall survival time of 26.8 months, which is longer than some of the figures reported in studies of pemetrexed and cisplatin combination therapy. However, they also state that treatment-related side effects were higher in this patient cohort than in previously-reported on cohorts, and they suggest that future studies should look to a reduction in gemcitabine dosage levels to counter these toxic events.

Studies of peritoneal mesothelioma are few and far between, so this article represents an important addition our knowledge of this rare form of mesothelioma. For patients who are diagnosed with peritoneal mesothelioma and who are not eligible for multimodal treatment plans involving significant cytoreductive surgery, combination chemotherapy using pemetrexed and gemcitabine may be an important new avenue of treatment.

Labels: mesothelioma, peritonealmesothelioma, treatments

posted by Belluck & Fox at 4:58 PM
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Prevalence and Pattern of Lymph Node Metastasis in Malignant Pleural Mesothelioma

Monday, August 25, 2008

Source: Annals of Thoracic Surgery

Lymph node status is an important indication of disease spread and treatment prognosis for patients with pleural mesothelioma and peritoneal mesothelioma, just as it is for patients with other forms of cancer. Patients who present with lymph nodes that are negative for cancerous invasion are considered early stage patients and they typically respond to treatment in a more robust manner than do patients with “positive nodal status,” that is, patients whose disease has metastasized to their lymph nodes. Mesothelioma staging sees any indication of positive nodal status as increasing the staging diagnosis, but little is presently understood about the meaning of the nodal groups that do exhibit infiltration. The mediastinal lymph nodes are the nodes most likely to experience metastasis, but the hilar lymph nodes are also a common location of cancerous invasion and the question remains open if positive nodal status of both the mediastinal and the hilar nodes is indicative of a more advanced stage of the disease than is mediastinal metastases alone.

To answer this question, researchers from Egypt conducted a study in which they investigated the “prevalence and pattern” of lymph node metastases in a selected group of patients. Their research has recently been published in the Annals of Thoracic Surgery.

Overview of the Study

The researchers conducted a retrospective study of 53 patients with biopsy-proven malignant pleural mesothelioma. During treatment, each patient received a contract-enhanced CT scan of the chest and upper abdomen, as well as chest roentgenogram and ultrasound of the abdomen and pelvis. All patients underwent spirometry, while some patients received MRI and others underwent bone or brain CT if clinical analysis suggested it.

The study group was divided into two cohorts for analytical purposes. The first cohort, made up of 37 patients, did not receive pre-operative mediastinoscopy and each patient underwent a multimodality treatment protocol. The second cohort, made up of the remaining 16 patients, received preoperative staging assessments via mediastinoscopy. In this cohort, patients whose lymph nodes were negative for metastases underwent trimodal therapy using surgery, radiation and chemotherapy, while patients who demonstrated positive nodal status were excluded from the trimodal therapy.

All of the patients eligible for extrapleural pneumonectomy underwent EPP and during surgery, the physicians conducted lymph node dissection and sampling which revealed a patient’s true disease stage.

Results

There were 33 men in the study and 20 women. 34 patients presented with epithelial mesothelioma, while 16 presented with biphasic mesothelioma and 3 with sarcomatoid mesothelioma. Among the patients who did not receive preoperative staging assessments, 12 patients were subsequently identified as having mediastinal or hilar lymph node involvement. 11 patients were identified as having mediastinal metastases and 5 were identified with hilar metastases. However, of the latter group, four patients had both hilar and mediastinal involvement, while one patient was positive for hilar node involvement without concurrent mediastinal involvement, so the group figure for nodal involvement was set at 12. In the second group, 6 patients demonstrated nodal metastases. Mediastinoscopy revealed the nodal involvement in four of these cases, while two were discovered after surgery. All in all, 18 (34%) cases of lymph node metastases were uncovered in this study.

When analyzing the relationship between histological subtype, overall aggression and nodal infiltration, the researchers confirmed that the sarcomatoid and biphasic subtypes of the disease were more aggressive than the epitheloid subtype. They found that all patients whose disease had infiltrated their lungs presented with either sarcomatoid or biphasic mesothelioma. The researchers also found that this group of patients was more likely to demonstrate lymph node metastases than were patients with epitheloid mesothelioma. Of the 18 total cases with nodal metastases, 42% (8 cases) had sarcomatoid or mixed mesothelioma, while only 29.4% (10 cases) had epitheloid mesothelioma.

While nodal metastases are always indicative of a more advanced stage of the cancer, the authors conclude that differences in the nodes that were invaded must also be considered when staging. They state that the mediastinal lymph nodes should be considered the primary mesothelioma nodal station and indications of positive mediastinal lymph node status should be staged as N1 disease, while hilar metastases represent a more advanced cancer and should be recognized as N2 disease.

The authors also state that while mediastinoscopy is not a prefect diagnostic tool, it can be important for the preoperative staging of mesothelioma patients because it can reveal the presence of nodal metastases that PET or CT cannot. EBUS-TBNA represents the latest diagnostic advancement for the staging of pleural mesothelioma, but is not yet widely used, so until it becomes more commonly utilized, the authors state that PET, CT and mediastinoscopy should be the basic staging tools deployed in the diagnosis of mesothelioma.

Conclusion

The authors conclude their article with a call for revisions to the mesothelioma staging guidelines, as well as for more research into this topic. A number of previous studies have shown that early diagnosis of mesothelioma is an important indication for disease treatability, so improvements in the accurate diagnosis and staging of the disease will be helpful to many people whose lives have been touched by this difficult disease.

Labels: diagnosis, mesothelioma

posted by Belluck & Fox at 5:02 PM
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A Phase II Trial of Tetrathiomolybdate After Surgery for Malignant Mesothelioma: Final Results

Friday, August 15, 2008

Source: The Annals of Thoracic Surgery

The development of novel therapeutic techniques is a major focus of contemporary mesothelioma research. Due to the disease’s uncanny resistance to conventional treatments, mesothelioma specialists and other research scientists are actively exploring new treatment strategies for this asbestos-caused disease. Their goal is to reverse the historic difficulties in fighting the disease by developing therapies that bring the same life-saving efficacy to patients with pleural mesothelioma and peritoneal mesothelioma (as well as patients with the rarer forms of the disease) that modern medicine has brought to patients with other forms of cancer.

Overview of the Study

One of the new therapeutic strategies under investigation for mesothelioma patients is the disruption of angiogenesis, the process by which new blood vessels are formed from pre-existing vessels. Angiogenesis is an important process for many of the body’s essential functions. For example, angiogenesis is necessary for any healing involving tissue damage because the development of replacement tissues require the generation of new blood vessels to continue their growth. However, angiogenesis is also a significant factor in the development of cancer. Tumors also need a fresh supply of blood to fuel their growth, so the malignancy co-opts the angiogenic process for its own stimulation. Contemporary research into the biochemical foundations of mesothelioma suggests that angiogenesis is especially important for the development of this malignancy, so a number of researchers are now investigating the use of anti-angiogenic treatments for mesothelioma patients.

Therapies targeting angiogenesis represent a growing frontier of cancer treatment. One such therapy that is currently being investigated for the treatment of multiple cancers is the administration of a copper-depleting agent to disrupt angiogenesis. Research has shown that angiogenesis requires the consumption of copper for its complete expression, so the theory behind the use of copper-depleting agents is that angiogenesis will falter if there isn’t enough copper to consume.

In light of this knowledge, researchers from some of the most well-known mesothelioma clinics conducted a feasibility study on the use of a copper-depleting agent for the treatment of mesothelioma and have recently published very exciting results.

Results

The researchers investigated the use of the copper-depleting agent tetrathiomolybdate in mesothelioma patients following surgery. 30 patients were enrolled in the study and their results were compared to a cohort of 164 patients the researchers had previously studied after surgery.

The study reports that median survival for all patients was 23 months and the median time to progression was 12 months. When the numbers were broken down by stage, Stage I and Stage II patients demonstrated a median survival of 41 months and time to progression of 20 months. Stage III patients had a median survival of 15 months and time to progression of 7 months.

Conclusion

These are truly excellent results as compared to the historical efficacy of most mesotheloima treatments, where median survival is less than 16 months for most patient groups.The authors found that the procedure was generally well-tolerated and quite effective. Though they were quick to qualify their results as limited by the small sample size and nature of the study itself, they also felt that more extensive studies should be conducted because their results compared very favorably to previous studies. Much more needs to be learned about copper-depleting treatments before they could become standard, but if the results of this study hold up, it represents a significant advance in our ability to treat patients with mesothelioma.

Labels: mesothelioma, treatments

posted by Belluck & Fox at 4:23 PM
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Report: Expect cancer epidemic

Tuesday, August 12, 2008

Source: DailyInterLake.Com

With one of the highest rates of mesothelioma in the United States and thousands of people with other asbestos-related diseases, Libby, Montana is already the location of a serious public health disaster and—according to a report in the American Journal of Industrial Medicine—the situation is due to get worse in the next two decades. The article, written by pulmonologist and asbestos-disease expert Dr. Alan Whitehouse, concludes that the current situation is merely “the tip of the iceberg” and that a true epidemic of mesothelioma is likely gestating among the citizens of Libby and the surrounding towns.

The cause of this health tragedy was an asbestos-contaminated vermiculite mine that was once the region’s economic lifeblood. The mine was in operation for decades and it employed thousands of people during this time. Even citizens who didn’t work in the mine were likely to be affected by its dust and airborne debris, either by living near it or living with someone who worked there.

The relationship between the mine and the town’s health effects was initially reported in 1999 and the scope of the tragedy has only increased since then. Much of this extra knowledge has come from the clinic that Libby started to track asbestos-related illnesses and provide care for affected residents. The Center for Asbestos Related Disease (CARD) has already documented over 200 deaths related to asbestos exposure and is tracking 2,000 other additional cases of asbestos-related disease.

Dr. Whitehouse’s report, written in close consultation with a number of other doctors—including Dr. Brad Black, the Medical Director for the Center for Asbestos Related Disease—includes studies of people of who worked in the mine, as well as people who had no exposure to asbestos outside of simply being in Libby. Because mesothelioma has a latency period of 30 to 50 years from initial exposure, the report concludes that “The extent of the epidemic of environmental mesothelioma due to exposures based at Libby will probably not peak for another 10 to 20 years…”

Labels: mesothelioma

posted by Belluck & Fox at 11:46 AM
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Assessment of Biomarkers in asbestos-exposed workers as indicators of cancer risk

Monday, August 11, 2008

Source: Mutation Research

That exposure to asbestos is the cause of all forms of mesothelioma has been definitively known for many years. Evidence for this relationship was uncovered as early as the 1920s, but the asbestos companies hid this information for as long as they could, so it wasn’t until the 1960s that the carcinogenic aspects of asbestos became true public knowledge. In the wake of the incontrovertible evidence of the mineral’s disastrous health effects, the United States—and nearly all other developed nations—enacted stringent regulations regarding the use of asbestos or outright bans on it. However, these regulations came too little and too late for workers with previous exposures to the fibers. To this day, the United States sees approximately 2500 yearly deaths from mesothelioma and international health organizations estimate that, worldwide, asbestos-related diseases claim 15,000–20,000 lives each year.

Pleural mesothelioma is the most common form of mesothelioma and is commonly associated with a poor prognosis. Mesothelioma treatments are not effective for the long-term management of the disease and most people who are diagnosed will die within 16 months. One of the major reasons for this poor prognosis is that the disease is often misdiagnosed or not diagnosed at all until it hits the later stages, when pleural tissue structures feature significant infiltration and tumor spread that make effective treatment impossible. Studies have shown that earlier diagnoses often correlate with better prognosis and treatability, so there is a great attempt to develop tests that can return a mesothelioma diagnosis earlier than current methodologies allow.

One such research project is actively investigating what, if any, biomarkers are indicative of mesothelioma. A biomarker is a biochemically-expressed substance, such as a protein, that can be used to identify a cancer before its regular symptoms assert themselves. The hope among mesothelioma specialists is that the development of effective biomarker tests will lead to much earlier diagnoses of the disease. Researchers from Italy have recently released the results of a study they commissioned on the use of biomarkers in the diagnosis of mesothelioma and lung cancer. Their data suggests that a combination of elements can be used together to identify the malignancy in high-risk populations.

Overview of the Study

Previous research into the biochemical and genetic foundations of mesothelioma has revealed that a number of specific proteins, growth factors and other substances are significantly over-expressed in mesothelioma patients. These studies have indicated that some of these substances, either singularly or in combination, could be effective for the early diagnosis of asbestos-related diseases (ARDs). The identified substances include 8-hydroxy-2 -deoxyguanosine (8OHdG), interleukine-6 (IL-6), platelet-derived growth factor (PDGF-BB), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and soluble mesothelin-related peptides (SMRPs).

To investigate the efficacy of these substances for marker purposes, the authors enrolled 119 subjects with a history of asbestos exposure into their study. This group was analyzed according to occupational exposures to the fibers, including total exposure burden and duration of exposure. This information was used to develop a risk factor analysis for asbestos-disease and mesothelioma development. They also enrolled a control sample of 54 age-matched individuals who did not have a history of asbestos exposure.

The asbestos workers underwent clinical examination, chest radiography and high-resolution CT, while the control group received chest x-rays that all returned normal results. Both groups had blood drawn that was analyzed for the presence of the identified markers using the standard tests for each substance.

Results

The authors analyzed the presence and distribution of the various markers by sex, smoking history, age, gender and asbestos-group vs. control-group membership. Within the asbestos group they created a job risk assessment that showed that some occupations, such as hands-on work related to pipe fitting, maintenance work and other shipbuilding functions, carried the highest levels of exposures, while office work in environments surrounding areas that featured direct exposures was associated with a significantly less fiber burden.

They found that risk of malignant mesothelioma increased according to cumulative asbestos exposure. 80HdG and IL-6 levels correlated with high levels of SMRPs, which were associated with workers demonstrating the highest asbestos burden. They also found that these groups were most likely to have other asbestos-related diseases (ARDs), such as pleural plaques and fibrosis. The maintenance worker subgroup presented with a 71% of ARDs, pipe fitters with a 57% ARD rate and 50% of electricians were found with ARDs. This is a strong indication of the risks associated with direct exposure, especially when compared to the office worker subgroup which only demonstrated a 10% ARD rate.

Workers demonstrating the highest risk for mesothelioma due to occupational exposure to asbestos also demonstrated higher levels of angiogenic growth factors, such as platelet-derived growth factor (PDGF-BB), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Angiogenesis is the process by which new blood vessels are formed within tissue structures and it is directed through growth factor signaling pathways. While angiogenesis and growth factor expression are necessary processes for many aspects of tissue growth and are not directly representative of malignant developments, they are absolutely essential for tumor growth, as tumors need blood to fuel their growth and spread.

The authors indicate that prevoiusly-identified “preclinical and clinical evidence suggests that angiogenesis may be a critical step in the pathogenesis of mesothelioma.” Several studies have previously reported on the high levels of VEGF, bFGF, HGF and PDGF found in mesothelioma cells. There is even evidence to suggest that these growth factors form autocrine growth loops in mesothelioma, which means that aside from their facilitation of blood vessel development to mesothelioma tumors, these growth factors may also stimulate the proliferation of mesothelioma cells themselves.

Conclusion

The authors conclude that combination analytics using both growth factor levels and SMRP levels in high-risk populations could be used for mesothelioma diagnoses. Growth factor expression can be indicative of underlying tumor genesis, but these proteins are not specific to mesothelioma, while SMRP levels can be used to separate healthy individuals from mesothelioma patients, but haven’t had the same success in screening out potential mesothelioma patients from other high-risk, asbestos-exposed populations. Thus, screening methodologies that take both elements into account could possibly function as an early diagnostic marker for pleural mesothelioma.

Labels: diagnosis, mesothelioma

posted by Belluck & Fox at 4:24 PM
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Malignant Mesothelioma of the Tunica Vaginalis Testis: A Case Illustrating Doppler Color Flow Imaging and Its Potential for Preoperative Diagnosis

Thursday, August 7, 2008

Source: Journal of Ultrasound in Medicine

There are four basic forms of malignant mesothelioma: pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and mesothelioma of the tunica vaginalis. Pleural mesothelioma is the most common form of the disease, followed by peritoneal mesothelioma. The other two forms are actually quite rare. Pericardial mesothelioma is only diagnosed in a small percentage of cases, while diagnoses of mesothelioma of the tunica vaginalis are exceptionally rare.

The available literature on reproductive mesothelioma, as it’s sometimes called, is made up of less than 100 individual cases, so little is known about its etiology and overall behavior. New case reports are generally the only way in which physicians can share their experiences with this disease, so the findings are widely reported on when they do appear. A recent issue of the Journal of Ultrasound in Medicine has published the latest report on this rare malignancy. The article describes the authors’ experience treating a 60 year-old man diagnosed with mesothelioma of the tunica vaginalis, as well as their use of a new imaging technology in the preoperative diagnosis of the disease.

Overview of Mesothelioma of the Tunica Vaginalis

Mesothelioma of the tunica vaginalis is the rarest form of malignant mesothelioma. The authors of this article state their awareness of only 98 other cases. Different articles have reported slightly different numbers, but the basic truth of these statements refers to the extreme rarity of the disease. Asbestos exposure is the most commonly reported causative factor, but specific conclusions are very difficult with such a small population set to learn from. Histologically speaking, most cases of the disease are of the epitheloid subtype (60-75%), with the biphasic subtype making up the remainder of diagnoses. The authors state that “pure sarcomatous mesothelioma is exceedingly rare.” The average age of diagnosis is 60 years-old and because the disease specifically grows from the tunica vaginalis—the lining that surrounds the testes—it only affects men.

In most cases, the disease remains undiagnosed until the area is operated on or an autopsy reveals the presence of the malignancy after a patient has died. If a patient does present with a testicular issue, the disease is likely to be misdiagnosed for a number of more common conditions. This situation—as is the case with most forms of mesothelioma—means that the malignancy is likely to be in a less treatable state when a diagnosis is finally returned.

Overview of the Case

The authors describe the patient as a 60 year-old man with swelling on the left side of his scrotum. The man smoked for twenty years, but was not occupationally exposed to asbestos. Like all forms of mesothelioma, asbestos exposure is the main indication for this varient, so it is likely that the patient was simply not aware of his exposure to the mineral. Many diagnostic tests returned normal results, but sonographic testing revealed a number of troubling findings, including an enlarged left testicle and a large hydrocele in the left scrotum. A 1.5 x 1 x1.5-cm polypoid mass (polyp) demonstrating “increased vascularity” was discovered in the scrotal wall, and two similar masses were discovered in the tunica vaginalis.

The patient then received a left hydrocelectomy and scrotal exploration and had tissue removed for biopsy. The biopsy revealed mesothelioma of the tunica vaginalis, biphasic subtype. After a left radical orchitectomy and hemiscrotectomy, a 4-cm tumor attached to the tunica vaginalis was discovered. Immunohistochemical analysis conducted on the tumor confirmed the mesothelioma diagnosis.

Further testing revealed that the cancer had metastasized to the retroperitoneal lymph nodes. The patient then began chemotherapy. 21 months after initial diagnosis, PET indicated distant tissue infiltration and CT demonstrated significant metastases in the lungs and mediastinum. After this discovery, the patient was started on another course of chemotherapy.

Color Doppler Sonography

As we stated above, most cases of mesothelioma of the tunica vaginalis are not diagnosed until surgery or autopsy. Due to its rarity, most physicians will not have any experience with the disease and will certainly not be on the lookout for it. Regarding the case under discussion, the authors were able to identify the disease fairly early and were able to start treatment for it soon after discovery—which was almost certainly a factor in the patient’s survival 21 months after initial diagnosis. The authors state that imaging methodologies have traditionally been of limited use, but research into the sonographic representation of the tumor has begun to identify characteristics particular to it. Along with that research, the use of newer technologies in the analysis of tissue structures has also been important. For this particular case presentation, the authors used color Doppler sonography to identify areas of increased blood flow (hypervascularity) in the identified scrotal masses, which indicated the presence of a possible malignancy. Color Doppler sonogrography is an ultrasonic imaging technology that identifies blood flow and represents these varying rates using colors. Many scrotal masses are relatively benign conditions and do not demonstrate increased vascularity, so the use of an imaging technology that is sensitive to increased blood flow can help to differentiate the mesothelioma from other conditions. If a malignancy is suspected, fine needle aspiration or the removal of tissue—in addition or, or instead of, the excision of the affected testicle—can be attempted to definitively determine a diagnosis.

Conclusion

The authors conclude that color Doppler sonography may be an important new tool for the diagnosis of mesothelioma of the tunica vaginalis. Mesothelioma is a very aggressive tumor in all its forms, so early diagnosis and treatment is a key element in maximizing patient survival time. Because the disease is so rare, it is unlikely that studies will be attempted to precisely quantify this technology’s diagnostic value, so case reports such as these remain the best way to learn more about mesothelioma of the tunica vaginalis.

Labels: diagnosis, mesothelioma

posted by Belluck & Fox at 4:04 PM
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Long-term indwelling pleural catheter (PleurX) for malignant pleural effusion unsuitable for talc pleurodesis

Wednesday, August 6, 2008

Source: European Journal of Surgical Oncology

A pleural effusion is a build-up of fluid in the pleural cavity that restricts proper lung expansion, causing chest pain and breathing troubles in affected patients. Effusions are the most common symptom of pleural mesothelioma and are often indicative of late-stage disease in patients suffering from other cancers. Effective palliation for pleural effusions is possible by undergoing a procedure, known as a pleurodesis, that removes the space where fluid builds-up by fusing together the parietal and the visceral pleura. However, not all patients are eligible for pleurodesis, so alternative treatments are required to ease the burden of disease for these patients. One such procedure involves the implantation of a long-term, indwelling pleural catheter, a thin, hollow tube that draws the fluid out of the pleural cavity and drains it from the body.

Pleural catheters have been used for the palliative treatment of pleural effusions due to mesothelioma, lung cancer and other malignancies for many years, but few studies have examined their overall efficacy for this purpose. Researchers from Finland have recently released the results of a study they conducted which did look at this topic and they found long-term use of pleural catheters to be an effective remedy for many of the symptoms commonly associated with pleural effusions.

Overview of the Study

As we said above, pleurodesis is the preferred procedure for most patients with pleural effusions, but not everyone is eligible for it. The two most common indications against pleurodesis are the following: restricted lung expansion that does not allow contact between the pleurae and the secretion of greater than 250 ml/day of fluid. Patients who present with either or both of these symptoms are likely to fail a pleurodesis, so alternative procedures will be substituted.

To analyze the efficacy of pleural catheters for symptom palliation of pleural effusions, the authors of the article under discussion analyzed the treatment courses of 51 patients treated for a malignant effusion at their institution between March 2004 and July 2005. All patients presented with a disease status that made pleurodesis a difficult or unworkable procedure and each received a PleurX® brand, indwelling pleural catheter for the palliative management of the effusion. The patients underwent monthly follow-ups and their progress was tracked until their deaths.

Results

Of the 51 patients who received the catheter implantation, 24 were male and 27 were female, while the average age for the study population was 63 years-old. At 19 diagnoses, non-small cell lung cancer was the most common malignancy of this patient cohort, closely followed by ovarian cancer (8 diagnoses), mesothelioma (7 diagnoses) and breast cancer (also 7 diagnoses).

39 patients received a right-sided catheter, 10 received a left side catheter and 2 patients had bilateral implantations. 36 patients were discharged back home within a day of the operation, while 10 were transferred to another hospital or to full-time nursing care. Five patients died during the hospital stay in which they received the catheter. These deaths were not directly related to the implant procedure, but were likely the cause of advanced disease.

11 patients experienced some type of complication, but the majority of the cohort were relatively side effect-free. Mean survival was only three months for the entire group, but there were great variations in this figure when individual cancers were accounted for. Mean survival for patients with non-small cell lung cancer—the most common of the diagnoses in the patient cohort—was 2.5 months, while mean survival in mesothelioma patients was 11 months. The breast cancer patients and the ovarian cancer patients demonstrated mean survival times of 6 months and 5.5 months, respectively.

Conclusion

The authors conclude that pleurodesis should still remain the treatment of choice for those who are eligible for it, but they definitively state that indwelling pleural catheters are an effective means of symptom palliation for patients with malignant pleural effusions who are not eligible for pleurodesis. In their study, the overall complications were low and there were no treatment-related deaths. The patients who died within two weeks of the procedure were already quite ill and cause of death was considered more likely from concomitant morbidities than catheter implantation. The authors state that the successful results of this study have led them to change their institutional policy regarding catheter use and they now consider the standard of care for patients who are not eligible for pleurodesis.

Labels: cancer, mesothelioma, treatments

posted by Belluck & Fox at 4:34 PM
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The comparative accuracy of different pleural biopsy techniques in the diagnosis of malignant mesothelioma

Tuesday, August 5, 2008

Source: Histopathology

An early diagnosis of mesothelioma is one of the most important aspects of maximizing a patient’s prognosis. A number of studies have correlated early diagnosis with enhanced survival time, so the identification of the most efficient diagnostic technologies is an important aspect of contemporary mesothelioma research.

Physicians have developed a number of biopsy procedures for cancer diagnosis and some of these procedures are used to diagnosis pleural mesothelioma or peritoneal mesothelioma. There are two basic biopsy strategies for most forms of cancer diagnosis: closed biopsy and open biopsy. A closed biopsy refers to the removal of tissue samples from outside the body, using small incisions and the insertion of specific surgical tools for the removal of tissue. A “blind” biopsy refers to a closed biopsy where the physician has no visual indication where his or her instruments are actually taking tissue samples from. Image-guided biopsy refers to the use of CT, or another imaging modality, to guide the physician’s needle during a closed biopsy. An open biopsy traditionally refers to a biopsy completed during invasive surgery, where the physician has a wide view of the affected areas.

When a biopsy is taken for pleural mesothelioma, it is called a pleural biopsy and the same basic strategies apply: closed pleural biopsy refers to a biopsy where tissue samples are removed from the pleural cavity, while open pleural biopsy refers to a biopsy completed during a thoracotomy, a highly invasive surgical procedure that provides wide access to the pleural cavity through a large incision made on the patient’s side and the spreading of the patient’s ribs to facilitate access to the thorax. In contemporary times, an open pleural biopsy may refer to a biopsy conducted through video-assisted thorascopic surgery (VATS), which is a much less invasive procedure than is a thoracotomy.

From these descriptions here, it is easy to assume that open pleural biopsy would give a physician the greatest diagnostic accuracy, while a blind, closed pleural biopsy would provide the least. Even though this is true, the invasiveness of the thoracotomy is generally avoided where possible, so mesothelioma specialists have had to settle for other less accurate techniques when the symptoms displayed during patient presentation are not necessarily indicative of a more serious illness. Image-guided pleural biopsy and VATS have very much increased the accuracy of the less invasive techniques, but they are not yet universally deployed.

Researches from the United Kingdom have recently entered this discussion with their publication of an article that analyzed the accuracy of the aforementioned biopsy techniques.

Overview of the Study

The researchers analyzed the postmortem records of 45 patients who died from pleural mesothelioma at Llandough Hospital in Penarth, Wales in the UK. These records identified the various diagnostic tests completed for each patient, from biopsy procedure to immunohistochemical analysis, and they served as the researcher’s primary data set for their analysis. Among these 45 cases, there were 21 cases of epithelioid mesothelioma, 11 cases of biphasic mesothelioma and 13 cases of sarcomatoid mesothelioma. 41 of the 45 cases were diagnosed when the patient was still alive, while 4 were suspected of mesothelioma, but a diagnosis was never returned.

Of the diagnosed cases, 36 underwent a closed needle biopsy. 31 of these were “blind” biopsies and 5 were CT-guided. Within the same population of diagnosed cases, 21 patients underwent an open pleural biopsy through thoracotomy.

Results

The researchers found results similar to other researchers who have also looked at this question: open pleural biopsy was the most accurate and sensitive procedure, while a blind, closed biopsy was the least accurate. Of the 21 cases of open biopsy performed through thoracotomy, all 21 cases were correctly identified as pleural mesothelioma and the histological subtype was correctly identified in 20 of the 21 cases. The blind biopsies were considerably less accurate and often required multiple procedures to return a diagnosis. When the procedures were quantified, the authors reported a diagnostic accuracy of only 16% of the 31 cases.

However, the accuracy of CT-guided closed biopsy was again confirmed. All five of the CT-guided cases returned an accurate diagnosis on the first attempt at biopsy, for a diagnostic accuracy of 100%—a figure that is directly comparable to thoractomy. Five is a rather small number though, and the other studies that have looked at image-guided biopsy have returned accuracy results in the high 80s or low 90s. That said, CT-guided biopsy is clearly a highly accurate diagnostic method.

Conclusion

This article is the latest among a number of recent publications that confirms the poor diagnostic accuracy of blind biopsy techniques. While open biopsy remains the surest way to determine a diagnosis, the use of CT-guided, or other image-based, closed biopsy has also shown a remarkable accuracy in the diagnosis of mesothelioma. These techniques are much less invasive and can be conducted under less extreme situations. Along with immunohistochemical analysis, as well as other pathology and marker tests, these diagnostic advances have enabled physicians to diagnose the disease much earlier than they ever have been able to. Because of this, patients can begin treatment at an earlier point in time, which may extend their survival time. Even as mesothelioma remains without a cure, recent improvements in diagnostics and patient survival are cause for some hope.

Labels: diagnosis, mesothelioma

posted by Belluck & Fox at 4:08 PM
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Malignant mesothelioma 2008

Friday, August 1, 2008

Source: Current Opinion in Pulmonary Medicine

An article has recently been appeared in the journal Current Opinion in Pulmonary Medicine that reviews the latest knowledge that medical science has developed regarding malignant mesothelioma. “Malignant Mesothelioma 2008” was written by a number of mesothelioma specialists at the New York University of School of Medicine, one of whom was Harvey I. Pass, an internationally-recognized expert on mesothelioma. The following piece is a summary of the literature review provided in that article. While we normally cover the latest individual studies and clinical trials, we want to take the opportunity to review the latest information regarding the diagnosis and treatment of pleural mesothelioma.

Introduction to Mesothelioma

Mesothelioma is diagnosed in 2500–3000 people per year in the United States and is directly responsible for 15,000–20,000 yearly deaths worldwide. It has been known for almost a century that asbestos is the major cause of the disease, but there is some data to suggest that a DNA virus known as SV40 may also play a co-causative role in some cases. SV40 is a controversial topic in mesothelioma research because it has been shown to cause the disease in hamsters, and a subset of human cases also shows evidence of SV40 infiltration, but its etiological significance in humans has not been confirmed. The authors conclude that the virus can be considered a cofactor at best.

Mesothelioma Histology

As is well known in mesothelioma studies, there are three histological subtypes of the disease, meaning there are differences among the cell types in which the malignancy arises. The most common form of the disease is epithelial mesothelioma, which arises in epithelial cells and is diagnosed in more than 50% of all cases. The other categorical subtype of the disease is known as sarcomatoid mesothelioma, which arises in mainly in sarcoma cells. The third major mesothelioma subtype is known as mixed mesothelioma or biphasic mesothelioma and this form of the disease has a mixed distribution of the other two cell types.

The diagnostic identification of the histological subtype is important because each of the various forms affects a patient’s prognosis differently. While mesothelioma is known for its resistance to treatment and is presently without cure, different forms of the disease do respond better than others to treatment. All other factors being equal, epithelial mesothelioma is associated with the best prognosis, while sarcomatoid mesothelioma is associated with the worst. The mixed type’s prognostic indications depend on the overall distribution of the individual cell types.

Mesothelioma Diagnosis

Improving the diagnostic abilities of physicians is one of the most important advances that can be made in mesothelioma research. A number of studies have shown that early diagnosis is associated with longer survival, so it is clearly in the patient’s best interest to receive the diagnosis as early as possible.

The authors describe a number of techniques that can be used for diagnostic purposes. Immunohistochemical staining is a technique where tissue samples are treated for the presence of particular antibodies and positive values are seen through a dye-based reaction to the treatment. Mesothelioma is often misdiagnosed in its earlier stages, so the development of IHC-based testing has been helpful to differentiate it from other forms of cancer. Mesothelioma “stains” for a number of specific markers, so their presence in a tissue sample is indicative of a positive mesothelioma diagnosis.

Another diagnostic front that is being investigated refers to tumor markers, which are antibodies secreted into the blood stream or proteins found within tissue samples that can conclusively determine a mesothelioma diagnosis. Two of the most promising markers are osteopontin (OPN) and mesothelin (SMRP).

Imaging techniques are very important in the diagnosis of mesothelioma and in tracking one’s progress during treatment. Chest x-ray is the standard first technique for the presentation of any pulmonary or thoracic issue, but it does not have high enough resolution for the purposes of mesothelioma diagnosis. CT is the current standard for mesothelioma diagnosis, with MRI being used to answer questions CT is unable to. PET is being increasingly utilized to diagnose distant metastases, while integrated CT/PET is being explored to enhance the accuracy of staging the disease. The authors also write that FDG-PET is being used to monitor tumor response to treatment.

Other important diagnostic tools includes thoracentesis, thoracoscopy and video-assisted thorascopic surgery (VATS) and open pleural biopsy.

Mesothelioma Prognosis

The authors state that most people with mesothelioma will die of local complications to the disease and not because of metastatic spread. The tumor mass grows and continues to encapsulate the lung until it can no longer function. However, as some of the multimodal treatment techniques become more effective at local control of the disease, the occurrence of death due to distant metastases is growing in proportion.

The most important prognostic factor for the disease is performance status at time of diagnosis. Patients with PS of 0 have been shown to have the best prognosis. Other important factors include histology, gender and a number of other lab findings. For example, epithelial histology functions as an indicator of good prognosis and non-epithelial histology as an indicator of worse prognosis, while male gender is an indicator of worse prognosis over female gender.

Treatment Options

Mesothelioma is notoriously-resistant to curative treatments and median survival for most patients is under 16 months from diagnosis. There have been some recent improvements in the efficacy of the available treatments and innovative physicians are actively exploring new techniques and trying to advance on the current ones. In many cases, a patient will only be treated with supportive, or otherwise palliative, options because their diagnosis was only given after the disease had advanced to a later stage where curative surgery was not an option. For these patients, minimally-invasive surgeries may be offered to palliate symptoms, and chemotherapy may be given to extend life.

Patients who are eligible for radical surgery have the best chances to extend survival. There are two major surgical techniques used for radical surgery: pleurectomy-decortication (P/D) and extrapleural pneumonectomy (EPP). During a P/D, both the parietal and the visceral pleura will be removed, and possibly the diaphragm and pericardium, while EPP will feature the removal of the entire affected lung, along with the parietal pleura and possibly the diaphragm and pericardium. Both procedures are highly invasive operations, but EPP is clearly the more radical of the two.

Studies have revealed that the trimodal treatment of the disease, i.e., using surgery, chemotherapy and radiation in combination, is the most effective option to extend life for patients who are candidates for it. However, there are serious questions regarding the order in which the procedures should be deployed and if this order affects overall survival time. Until the studies that are looking into these questions are completed, we will not the answer, but the dedication these physicians bring to mesothelioma treatment is clear.

The authors also describe a number of other treatment options that have been proposed for mesothelioma treatments. Some of them included intrapleural photodynamic therapy, hyperthermic perfusion of the pleura, and immunotherapy.

The chemotherapy combination of pemetrexed and cisplatin is the chemo standard of care for the treatment of the disease.

Conclusion

As this article makes clear, there is much that still needs to be learned about malignant mesothelioma. Even as treatments have improved in recent years, the disease remains without a cure and because of that, innovative physicians and scientists continue to investigate the disease and inquire into its secrets. Mesothelioma treatments have not replicated the same advancements that treatments for other cancers have experienced during the last ten years, but there is hope that the improving efficacy of the current therapies will continue.

Labels: mesothelioma

posted by Belluck & Fox at 4:30 PM
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