MALIGNANT MESOTHELIOMA
A. PHILIPPE CHAHINIAN, MD
HARVEY I. PASS, MD
CLINICAL FEATURES
The onset of mesothelioma is usually insidious; a common pre-senting symptom is persistent localized pain.PLEURAL MESOTHELIOMA Chest pain or dyspnea is almost constant, although of varying degree.63,214 Pleural effusion is present initially inup to 95% of cases. 63 Later, tumor growth usually results in complete obliteration of the pleural space and encasement of the lung. 93,214,264Cough, weight loss, and fever are not uncommon. In contrast to benign mesothelioma, clubbing is rare and was seen only in 6% of cases. 51 Mediastinal invasion with dysphagia, phrenic nerve paralysis, pericar-dial effusion, and superior vena cava syndrome can occur. 225 Sponta- neous pneumothorax or hydropneumothorax and Horner’s syndrome have been described. 127,206 Progressive invasion of the chest wall often leads to intractable pain. Chest radiographs reveal a variable amount of fluid, with pleural thickening or pleural nodules, often several centimeters in diameter, imposing a scalloped appearance (Fig. 89.2). Predominance at the base is almost constant. In advanced cases, psilateral shift of the mediastinum and retraction of the involved hemithorax are characteristic, unless the tumor volume becomes very large.
63,93 The electro cardiogram (ECG) is abnormal in almost 90% of patients, showing various arrythmias (sinus tachycardia is the single most common change [42% of cases] but also premature atrial or ventricular contractions, atrial fibrillation, or flutter), conduction abnormalities (right-side bundle branch block, left hemiblocks), nonspecific ST-T changes, or left or right hypertrophy. 289 Computed tomography (CT) is most valuable in showing the extent of disease (including chest wall, mediastinum, pericardium, and diaphragm), relative amount of fluid and tumor, involvement of interlobar fissures, and retraction of the involved hemithorax (Fig. 89.3). In addition, signs of asbestos exposure, such as contralateral pulmonary fibrosis and/or pleural plaques, are seen in 50% of cases and pleural calcifications in 15%.202 Furtherstudies are needed to evaluate the role of magnetic resonance imaging (MRI). MRI has been better than CT in showing tumor spread into the fissures, diaphragm, and bony structures, whereas both procedures are equally effective to detect invasion into the chest wall, lung, and mediastinum.
145a Echocardiography is useful to reveal pericardial involve ment, especially if cardiac tamponade is suspected. 289 Uptake of gal lium 67GA citrate by mesothelioma tumors has been experimentally demonstrated, 273 and gallium scan was positive in 43 of 49 patients (88%) with pleural mesothelioma.265 Recently, the role of fluo rodeoxyglucose (FDG) positron emission tomography (PET) imaging has been examined in a cohort of 28 patients with suspected mesothelioma (confirmed in 22). 26b Standardized uptake values (SUVs) were determined from the most active tumor site in each patient. The mean SUV of the deceased patients was 6.6 +/- 2.9, compared with 3.2 +/- 1.6 among the combined survivors. The deceased patients had tumor SUVs that were highly correlated with duration of survival after the PET study. The survival distribution of the high-SUV group showed significantly shorter survivals, compared with the low-SUV group.
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HARVEY I. PASS, MD
CLINICAL FEATURES
The onset of mesothelioma is usually insidious; a common pre-senting symptom is persistent localized pain.PLEURAL MESOTHELIOMA Chest pain or dyspnea is almost constant, although of varying degree.63,214 Pleural effusion is present initially inup to 95% of cases. 63 Later, tumor growth usually results in complete obliteration of the pleural space and encasement of the lung. 93,214,264Cough, weight loss, and fever are not uncommon. In contrast to benign mesothelioma, clubbing is rare and was seen only in 6% of cases. 51 Mediastinal invasion with dysphagia, phrenic nerve paralysis, pericar-dial effusion, and superior vena cava syndrome can occur. 225 Sponta- neous pneumothorax or hydropneumothorax and Horner’s syndrome have been described. 127,206 Progressive invasion of the chest wall often leads to intractable pain. Chest radiographs reveal a variable amount of fluid, with pleural thickening or pleural nodules, often several centimeters in diameter, imposing a scalloped appearance (Fig. 89.2). Predominance at the base is almost constant. In advanced cases, psilateral shift of the mediastinum and retraction of the involved hemithorax are characteristic, unless the tumor volume becomes very large.
63,93 The electro cardiogram (ECG) is abnormal in almost 90% of patients, showing various arrythmias (sinus tachycardia is the single most common change [42% of cases] but also premature atrial or ventricular contractions, atrial fibrillation, or flutter), conduction abnormalities (right-side bundle branch block, left hemiblocks), nonspecific ST-T changes, or left or right hypertrophy. 289 Computed tomography (CT) is most valuable in showing the extent of disease (including chest wall, mediastinum, pericardium, and diaphragm), relative amount of fluid and tumor, involvement of interlobar fissures, and retraction of the involved hemithorax (Fig. 89.3). In addition, signs of asbestos exposure, such as contralateral pulmonary fibrosis and/or pleural plaques, are seen in 50% of cases and pleural calcifications in 15%.202 Furtherstudies are needed to evaluate the role of magnetic resonance imaging (MRI). MRI has been better than CT in showing tumor spread into the fissures, diaphragm, and bony structures, whereas both procedures are equally effective to detect invasion into the chest wall, lung, and mediastinum.
145a Echocardiography is useful to reveal pericardial involve ment, especially if cardiac tamponade is suspected. 289 Uptake of gal lium 67GA citrate by mesothelioma tumors has been experimentally demonstrated, 273 and gallium scan was positive in 43 of 49 patients (88%) with pleural mesothelioma.265 Recently, the role of fluo rodeoxyglucose (FDG) positron emission tomography (PET) imaging has been examined in a cohort of 28 patients with suspected mesothelioma (confirmed in 22). 26b Standardized uptake values (SUVs) were determined from the most active tumor site in each patient. The mean SUV of the deceased patients was 6.6 +/- 2.9, compared with 3.2 +/- 1.6 among the combined survivors. The deceased patients had tumor SUVs that were highly correlated with duration of survival after the PET study. The survival distribution of the high-SUV group showed significantly shorter survivals, compared with the low-SUV group.
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Label:
mesothelioma data
MESOTHELIOMA IN AUSTRALIA INCIDENCE 1982 TO 2005 DEATHS 1997 TO 2006
Report summary
Data on the number of new cases of mesothelioma are collected nationally by the Australian Institute of Health and Welfare (AIHW) in the National Cancer Statistics Clearing House, via the State Cancer Registries. Information on deaths from mesothelioma is also collected by the AIHW as part of the National Mortality Database. Data are available from 1982 to 2005 for the number of new cases, and from 1997 to 2006 for the number of deaths.
New cases diagnosed
> In 2005 there were 597 new cases of mesothelioma diagnosed in Australia. Although this fgure is considerably higher than the 156 reported in 1982, the earliest data available, it is a reduction from the fgure of 645 new cases reported in 2003. Over the period since 1982 the large majority of new cases involved men: typically accounting for between 80% and 90% of new cases. > In 2005, the age-standardised rate of new cases of mesothelioma was 2.8 per 100 000 population. This rate has increased over time, from 1.2 cases in 1982. In 2005, the highest age-specifc incidence rate of new cases, 47 cases per 100 000 population, occurred among men aged 80–84 years.
Deaths due to mesothelioma
> In 2006 there were 486 deaths attributed to mesothelioma. Data on the number of deaths due to mesothelioma are available for the years 1997 to 2006. Refecting the incidence of new cases diagnosed, the overall number of deaths resulting from mesothelioma generally increased over the period between 1997 and 2006: reaching a maximum of 545 in 2004. > In 2006, the age-standardised rate of death due to mesothelioma was 2.3 deaths per 100 000 population.
The overall age-standardised rate has remained relatively stable over the 10 years for which data are available. Over the period the standardised rate has ranged between a minimum of 2.1 deaths per 100 000 population in 1999 and a maximum of 2.7 in 2001.
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Data on the number of new cases of mesothelioma are collected nationally by the Australian Institute of Health and Welfare (AIHW) in the National Cancer Statistics Clearing House, via the State Cancer Registries. Information on deaths from mesothelioma is also collected by the AIHW as part of the National Mortality Database. Data are available from 1982 to 2005 for the number of new cases, and from 1997 to 2006 for the number of deaths.
New cases diagnosed
> In 2005 there were 597 new cases of mesothelioma diagnosed in Australia. Although this fgure is considerably higher than the 156 reported in 1982, the earliest data available, it is a reduction from the fgure of 645 new cases reported in 2003. Over the period since 1982 the large majority of new cases involved men: typically accounting for between 80% and 90% of new cases. > In 2005, the age-standardised rate of new cases of mesothelioma was 2.8 per 100 000 population. This rate has increased over time, from 1.2 cases in 1982. In 2005, the highest age-specifc incidence rate of new cases, 47 cases per 100 000 population, occurred among men aged 80–84 years.
Deaths due to mesothelioma
> In 2006 there were 486 deaths attributed to mesothelioma. Data on the number of deaths due to mesothelioma are available for the years 1997 to 2006. Refecting the incidence of new cases diagnosed, the overall number of deaths resulting from mesothelioma generally increased over the period between 1997 and 2006: reaching a maximum of 545 in 2004. > In 2006, the age-standardised rate of death due to mesothelioma was 2.3 deaths per 100 000 population.
The overall age-standardised rate has remained relatively stable over the 10 years for which data are available. Over the period the standardised rate has ranged between a minimum of 2.1 deaths per 100 000 population in 1999 and a maximum of 2.7 in 2001.
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Label:
mesothelioma data
Alternative Medicine? A History
Whether acupuncture from China, Ayurvedic therapies from India, or home opathy in Europe, in her scholarly book, Roberta Bivins presents the belief systems that gave rise to such ancient practices and then follows their subsequent problematic global voyages to other cultures. Neither an allopathic doctor nor an alternat ive pract it ioner, Bivins provides readers with a social examination of these “exotic” techniques, from moxabustion to mesmerism, and explains how each was int roduced (and then studied, simulated, ridiculed, or rejected) by Western physicians in Europe and the United States. The nearly four-century transcontinental propagation was
not always easy — especially when corresponding bel ief systems could not be t ranspor ted along
with the therapeutic techniques.
The basis of many premodern medical practices rested on the belief that the human body was
a microcosm of the universe. For instance, with out the benefit of anatomical dissection (which
was then amoral and illegal) or microscopic analysis (which was then unavailable), the cupunc
turists in ancient China believed there were 12 waterways in the body that mirrored the coun
try’s 12 great rivers and canals. Ayurvedic medical pract it ioners believed in a deep philosophical and cosmological spiritual world of reincarnation and karma. A person’s balanced and healthy interactions with the environment were necessary not only for the body but also for the soul. The translat ion of these principles and techniques f rom East to West paralleled the interaction of the cultures themselves, with all the inherent stereotyping, superstitions, and feelings of racial and cultural superiority. Ultimately, despite British imperialism or the medical profession’s turf wars, it was often the realities of — and the lack of therapies forepidemics of cholera and the plague, or ailments such as gout, that encouraged quick investigation and resulted in rejection or eventual co-optation of the unfamiliar treatments.
Of note, the authorities investigating and discounting alterative therapies were also often “borrowing” the practices for reintroduction as their own. One example was moxabustion, a therapy that uses heat and was apparently effective in the treatment of gout.
Label:
traditional
Therapy of Mesothelioma
Immune and Antitumor Effects of Transfected Interleukin-12Irina Caminschi, Eleni Venetsanakos, Clement C. Leong, Michael J. Garlepp, Bruce W. S. Robinson, and Bernadette Scott Department of Medicine, University of Western Australia; Australian Neuromuscular Research Institute,Queen Elizabeth II Medical Centre, Nedlands, Australia; and DNAX Research Institute, Palo Alto, California Malignant mesothelioma (MM) is a solid tumor of the mesothelium for which there is no curative treat- ment. MM appears to be sensitive to immunotherapeutic approaches, and one of the most powerful immu- nomodulatory cytokines with antitumor effects is interleukin (IL)-12.
We have previously shown in a mu- rine model of MM that systemic administration of recombinant IL-12 induces a potent anti-MM immune response.
The nature and accessibility of MM tumors means that they are suitable candidates for direct cy-
tokine and gene-transfer therapeutic approaches. Therefore, we undertook a study to assess the antitumor effects induced by the local production of IL-12 within MM tumors by transfecting a murine MM line with the genes for IL-12. The IL-12 transfectant (AB1–IL-12) did not produce tumors in normal mice, but did so in athymic nude mice, implicating T cells in the prevention of MM tumor growth. In mixing experi- ments, paracrine IL-12 production inhibited growth of untransfected MM cells provided that cells produc- ing IL-12 represented more than 50–80% of the inoculum. Furthermore, BALB/c mice previously chal- lenged with AB1–IL-12 were protected against rechallenge with parental AB1 tumor, indicating that the
transfectant induced long-term immunity. AB1–IL-12 induced systemic immunity that was effective at re-ducing the incidence of parental AB1 tumor at a distal site, but its effects were dose-dependent. Though both CD41 and CD81 cells infiltrated the rejecting tumor, CD81 effector cells were essential for protec-tion against development of parental AB1 tumor. This study shows that paracrine secretion of IL-12, gen-erated by gene transfer, can induce immunity against MM that can act locally and also at a distant site. In addition, there was no evidence of toxicity, which has been associated with the systemic administration of IL-12, indicating that this cytokine is a good candidate for experimental gene therapy in MM. Caminschi,
I., E. Venetsanakos, C. C. Leong, M. J. Garlepp, B. W. S. Robinson, and B. Scott. 1999. Cytokine
gene therapy of mesothelioma: immune and antitumor effects of transfected interleukin-12. Am. J. Respir. Cell Mol. Biol. 21:347–356.
Materials and Methods
Mice
BALB/c and BALB/c-nu/nu mice were obtained from the Animal Resource Center (Perth, Western Australia) and maintained under standard conditions at the animal facil- ity of the Department of Medicine, University of Western Australia.
Cell Lines
The establishment of the BALB/c mouse-derived MM tumor cell line AB1 has been described previously (23). Cell lines were maintained in RPMI 1640 medium (GIBCO, Grand Island, NY) supplemented with 5% fetal bovine serum (GIBCO), 20 mM 4-(2-hydroxyethyl)-1-piperazine-
N-2-ethanesulfonic acid, 200 mM L-glutamine (GIBCO), 0.05 mM mercaptoethanol, 100 mg/ml gentamicin, and 120 mg/ml of penicillin. Additionally, cell lines transfected with the bacterial neomycin phosphotransferase gene were maintained in medium containing G418 (Geneticin; GIBCO; 400 mg/ml). All cell cultures were grown at 378C in a 5% CO2 humidified atmosphere.
We have previously shown in a mu- rine model of MM that systemic administration of recombinant IL-12 induces a potent anti-MM immune response.
The nature and accessibility of MM tumors means that they are suitable candidates for direct cy-
tokine and gene-transfer therapeutic approaches. Therefore, we undertook a study to assess the antitumor effects induced by the local production of IL-12 within MM tumors by transfecting a murine MM line with the genes for IL-12. The IL-12 transfectant (AB1–IL-12) did not produce tumors in normal mice, but did so in athymic nude mice, implicating T cells in the prevention of MM tumor growth. In mixing experi- ments, paracrine IL-12 production inhibited growth of untransfected MM cells provided that cells produc- ing IL-12 represented more than 50–80% of the inoculum. Furthermore, BALB/c mice previously chal- lenged with AB1–IL-12 were protected against rechallenge with parental AB1 tumor, indicating that the
transfectant induced long-term immunity. AB1–IL-12 induced systemic immunity that was effective at re-ducing the incidence of parental AB1 tumor at a distal site, but its effects were dose-dependent. Though both CD41 and CD81 cells infiltrated the rejecting tumor, CD81 effector cells were essential for protec-tion against development of parental AB1 tumor. This study shows that paracrine secretion of IL-12, gen-erated by gene transfer, can induce immunity against MM that can act locally and also at a distant site. In addition, there was no evidence of toxicity, which has been associated with the systemic administration of IL-12, indicating that this cytokine is a good candidate for experimental gene therapy in MM. Caminschi,
I., E. Venetsanakos, C. C. Leong, M. J. Garlepp, B. W. S. Robinson, and B. Scott. 1999. Cytokine
gene therapy of mesothelioma: immune and antitumor effects of transfected interleukin-12. Am. J. Respir. Cell Mol. Biol. 21:347–356.
Materials and Methods
Mice
BALB/c and BALB/c-nu/nu mice were obtained from the Animal Resource Center (Perth, Western Australia) and maintained under standard conditions at the animal facil- ity of the Department of Medicine, University of Western Australia.
Cell Lines
The establishment of the BALB/c mouse-derived MM tumor cell line AB1 has been described previously (23). Cell lines were maintained in RPMI 1640 medium (GIBCO, Grand Island, NY) supplemented with 5% fetal bovine serum (GIBCO), 20 mM 4-(2-hydroxyethyl)-1-piperazine-
N-2-ethanesulfonic acid, 200 mM L-glutamine (GIBCO), 0.05 mM mercaptoethanol, 100 mg/ml gentamicin, and 120 mg/ml of penicillin. Additionally, cell lines transfected with the bacterial neomycin phosphotransferase gene were maintained in medium containing G418 (Geneticin; GIBCO; 400 mg/ml). All cell cultures were grown at 378C in a 5% CO2 humidified atmosphere.
Label:
teraphy
MESOTHELIOMA
Mesothelioma
The U.S. government reports that 70% to 80% of all cases of mesothelioma occur in people with a traceable history of exposure to asbestos. These numbers are from epidemiological surveys. There is a good chance that many of the remaining mesothelioma cases are also due to asbestos, but that the patient could not identify exactly where or when the asbestos fiber exposure occurred.
Mesothelioma is a very tough cancer. Most patients undergo surgery and chemotherapy. Sometimes radiation therapy is employed, including innovative techniques such as tomotherapy and intensity modulated radiation therapy. Oncologists use Brachytherapy for targeted radiation treatment of the tumor.
The antifolate drug pemetrexed (Alimta) in combination with cisplatin has been embraced by many mesothelioma specialists. Median survival time, even with good medical care, is fairly low.
Effusions into the bodily cavities is a common symptom. The chest, or pleural cavity, gets effusions, as well as the peritoneal (abdominal) cavity, depending on the site and shape of the tumor. Mesothelioma is classified as either pleural (the most common type) or peritoneal, depending on the location of the disease. (There are other types, but pleural and peritoneal are the most common.) To diagnose mesothelioma, the doctor takes a sample, usually of the pleural fluid, and conducts a biopsy in a lab. Immunohistochemical markers are employed in biopsy to distinguish mesothelioma from adenocarcinoma. These markers are usually glycoproteins.
Other markers can be detected in the blood to help identify mesothelioma. Soluble mesothelin-related (SMR) proteins released by mesothelioma cells are distinctive enough to show up in the blood, if the appropriate test is conducted. However, definitive diagnosis still requires a laboratory biopsy.
Tests and trials with gene therapy and immunotherapy are sometimes done on mesothelioma cases, but the standard cancer treatment modalities of surgery, radiation, and chemotherapy remain the most used techniques in mesothelioma treatment.
Label:
mesothelioma
