Functional activity of Rh monoclonal antibodies in ADCC assay

A 58-year-old woman with malignant mesothelioma metastatic to the orbit is reported. Malignant pleural mesothelioma was diagnosed by pleural biopsy. Marked reduction of pleural effusion was obtained with intrapleural interleukin-2 therapy. Systemic chemotherapy failed to elicit a response after the first recurrence of the tumor. Multiple systemic metastasis, including metastasis to the orbit, developed and the patient died one year and 4 months after the initial diagnosis. Although malignant mesothelioma is known to spread hematogenously, sometimes producing brain metastasis, there have been few reports of orbital metastasis, and in fact the present report may be the first clinically documented account of its kind.     

Acute bacterial endocarditis following burns: case report and review

A 64-year-old man was admitted to our hospital because of abnormal shadows on chest X-ray films. Malignant mesothelioma was suspected. However a CT scan revealed a large mass in the right kidney and many nodules in the liver and pleura. This suggested that primary renal cell carcinoma had metastasized to the liver and pleura. The patient was treated with transarterial embolization (TAE), alpha and gamma interferon, and UFT, but died of respiratory failure caused by massive bleeding from the pleural metastases. At autopsy, renal cell carcinoma, clear cell subtype, was noted. The many pleural lesions were of the same histologic type, which suggested that they were metastases from the kidney. Renal cell carcinoma frequently metastasizes to the lungs or bones via the arteries. However, many pleural metastases without lung metastasis is rare. We report a case of renal cell carcinoma with many pleural metastases via Batson's venous plexus.     

Fluorotyping of HLA-A by sequence-specific priming and fluorogenic probing

AIMS: To determine the value of immunocytochemistry in differentiation of malignant pleural mesothelioma from carcinoma in a pleural biopsy using commercially available monoclonal antibodies. METHODS AND RESULTS: A panel of monoclonal antibodies against keratins, epithelial membrane antigen (EMA), epithelial antigen Ber-EP4, carcinoembryonic antigen (CEA), tumour-associated glycoprotein (B72.3), Leu-M1, CD30 (Ber-H2), vimentin and desmin, was applied to 40 cases of malignant pleural mesothelioma and 23 cases of carcinoma metastatic to the pleura (16 pulmonary and seven extrapulmonary). Positivities for Ber-EP4, CEA, B72.3 and Leu-M1 were found to have the highest nosologic sensitivities (87.0%, 65.2%, 52.5% and 43.5%, respectively) and specificities (97.5%, 97.5%, 100% and 95%, respectively) for carcinoma. Positive staining for vimentin had the highest sensitivity (87.5%) with 95.7% specificity for mesothelioma. Positive staining for desmin was found in 45% of mesotheliomas and 0% of carcinomas. Diagnostic sensitivity and diagnostic specificity (P-values) were calculated for these markers. In respect to the diagnostic power defined by the clinically relevant predictive values of positive and negative tests, we found that a two-marker panel of antibodies including vimentin and Ber-EP4 is most useful for the histopathological distinction between carcinoma (pulmonary or extrapulmonary) and malignant pleural mesothelioma. CONCLUSIONS: A combination of Ber-EP4 and vimentin provides the most sensitive and specific pair of markers for distinguishing between malignant pleural mesothelioma and carcinoma metastatic to the pleura. The prevalence of the tested tumours should be taken into account when evaluating the clinical value of ancillary techniques in pathology.     

Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor protein by region-specific antipeptide antisera

We hypothesized that manganese superoxide dismutase (MnSOD), known to be induced in rat mesothelial cells by asbestos fibers, cytokines, and hyperoxia, may also be induced in asbestos-related pleural diseases such as mesothelioma. MnSOD was assessed in healthy human pleural mesothelium (n = 6), in biopsy samples of human pleural mesothelioma (n = 7), in transformed nonmalignant human mesothelial cells (Met5A), and in two human mesothelioma cell lines (M14K and M38K) established from the tumor tissue of mesothelioma patients. There was no MnSOD immunoreactivity in five of the six samples of healthy pleural mesothelium, whereas MnSOD immunoreactivity was high in the tumor cells in all the mesothelioma samples. Northern blotting, immunohistochemistry, Western blotting, and specific activity measurements showed lower MnSOD in the nonmalignant Met5A mesothelial cells than in the M14K and M38K mesothelioma cells. In additional experiments the mesothelial and mesothelioma cells were exposed to menadione, which generates superoxide intracellularly, and to epirubicin, a cytotoxic drug commonly used to treat mesothelioma. The M38K mesothelioma cells were most resistant to menadione and epirubicin when assessed by LDH release or by adenine nucleotide (ATP, ADP, and AMP) depletion. These same cells showed not only the highest MnSOD levels, but also the highest mRNA levels and activities of catalase, whereas glutathione peroxidase and glutathione reductase levels did not differ significantly. We conclude that MnSOD expression is low in healthy human pleural mesothelium and high in human malignant mesothelioma. The most resistant mesothelioma cells contained coordinated induction of MnSOD and catalase.     

Malignant pleural mesothelioma in general practice; complex pain problems

In three patients, men aged 67, 57 and 69 years, malignant pleural mesothelioma was diagnosed. All three had worked as coal miners and were presented with thoracic pain. They were among seven cases of malignant pleural mesothelioma diagnosed in a period of five years in one suburban general practice (adherence: 5600 patients) in the former mining area in the province of Limburg. The terminal phase of the disease was characterized by intractable pain. High doses of opioids and adjuvants were necessary to achieve acceptable pain relief. It is suggested that step one of the 'analgesic ladder for cancer pain management' of the WHO (non-opioids) should be followed soon by step three (strong opioids). Because the incidence of pleural mesothelioma is not yet decreasing, it is important to know that pain management remains a serious problem.     

Pleural malignant mesothelioma with osseous cartilaginous and rhabdomyogenic differentiation

A 63-year-old man, who was formerly an asbestos factory worker who had been followed due to asbestosis, and was admitted to our hospital with left chest pain and dyspnea on exertion. A chest X-ray and chest computed tomogram (CT) on admission revealed a large tumor in the left lung field. Percutaneous needle biopsy determined that the tumor was a sarcoma. No clinical response was obtained by systemic chemotherapy. The autopsy revealed diffuse malignant mesothelioma of sarcomatous type with osseous, cartilaginous and rhabdomyogenic differentiation. Osseous and cartilaginous differentiation in a malignant mesothelioma is rare, and the presence of a malignant rhabdomyogenic component is the first to be described in the Japanese literature.     

CT and MR in pleural disease

A number of different imaging modalities can be used in the assessment of pleural disease. Although ultrasound has been the more traditional method, CT has found increasing utility for the assessment of the empyema and loculated pleural fluid collections prior to drainage and the evaluation of benign and malignant pleural tumors. MRI has a limited but important role particularly in the evaluation of focal pleural tumors such as lipomas and in determining the extent of malignant mesothelioma prior to therapy.     

Malignant pleural mesothelioma in 1997

Some recent data on malignant pleural mesothelioma are reviewed, viz. the French 1996 INSERM report, our mineralogic study of anthracotic parietal pleura, and the new TNM classification of the International Mesothelioma interest Group (I.M.I.G.). Among medical treatments, intrapleural immunotherapy achieves the best objective responses in early stage mesothelioma. Radiotherapy alone has little effect on advanced mesothelioma. By contrast, recent surgical series have shown better survival rates and underline the interest of the new TNM staging. Finally, malignant pleural mesothelioma behaves something like lung cancer, in that only in N- stages can prolonged survivals be expected.     

A case of malignant mesothelioma of the pleura and the peritoneum detected by sudden onset of back pain and pleural effusion and ascites

A case of malignant mesothelioma of the pleura and the peritoneum is reported. In April 1996, a 40-year-old men noticed sudden onset of back pain. Radiographic examinations and MRI revealed pleural effusions, ascites, ringed enhanced tumorous lesions in the right posterior diaphragm along the abdominal aorta, and marked thickening of the right diaphragm with moderate signal intensity. On thoracoscopic surgery, there were white small nodules on the intercostal parietal pleura. Tumor cells of a tubulopapillary pattern had large rounded nuclei and eosinophilic cytoplasms in a partially glandlike arrangement. Cytoplasms of tumor cells stained for alcian blue disappeared after hyaluronidase digestion. Immunohistochemical examinations showed positive staining for keratin but negative for CEA. Electron micrographs showed numerous long thin microvilli, desmosomes and intermediate tonofilaments. From these findings, malignant mesothelioma was diagnosed. The malignant mesothelioma cells of the pleura in this case were considered to disseminate the peritoneum directly through the diaphragm or its lymphatic canals. MRI and thoracoscopic surgery were useful for the demonstration of the pleural disseminations and abdominal invasions.     

Antimicrobial properties of human lysozyme transgenic mouse milk

To examine whether malignant mesothelioma due to asbestos has genetic alterations in the Ha- and Ki-ras oncogenes or in the p53 suppressor gene, we analyzed the point mutations of these genes in paraffin-embedded autopsy samples of the primary tumors of malignant mesothelioma in seven asbestos patients who died from malignant mesothelioma. The genetic analysis was conducted by the polymerase chain reaction-single strand comformation polymorphysms (PCR-SSCP) method in all patients, and through the sequencing of deoxyribonucleic acid (DNA) bases in one patient. No genetic alterations were found in exons 1 or 2 of Ha- and Ki-ras oncogenes, or in exons 5 to 9 of the p53 gene, in any of the patients. Further studies on a larger number of patients are required to reach a definite conclusion concerning the genetic effects of asbestos on malignant mesothelioma.     

The comparative study on occupational mortality, 1980 between Japan and Great Britain

Pleural and pulmonary malignancies are usually associated with well-known carcinogen exposure. Recently, the presence of simian virus 40 (SV40)-like DNA sequences has been detected in brain and bone-related human cancers and in pleural mesothelioma. In order to determine whether SV40-like DNA sequences are also present in bronchopulmonary carcinoma and non-malignant lung samples, 125 frozen pleural and pulmonary samples (including 21 mesotheliomas, 63 bronchopulmonary carcinomas, 8 other tumours, and 33 non-malignant samples) and 38 additional samples distant from tumours were studied for the occurrence of SV40-like DNA sequences by polymerase chain reaction (PCR) amplification followed by hybridization with specific probes. Sequences related to SV40 large T antigen (Tag) were present in 28.6 per cent of bronchopulmonary carcinomas, 47.6 per cent of mesotheliomas, and 16.0 per cent of cases with non-neoplastic pleural and pulmonary disease. No statistically significant difference in the occurrence of these DNA sequences was found between malignant mesothelioma and bronchopulmonary carcinoma, but a significantly higher number of mesothelioma cases exhibited SV40-like DNA sequences in comparison with cases of non-malignant pleural or pulmonary disease (P < 0.04). Among cases positive for SV40-like DNA sequences, a history of asbestos exposure was found in 3 out of 12 bronchopulmonary carcinomas and 8 out of 10 mesotheliomas. Immunohistochemistry using monoclonal antibodies directed against Tag did not demonstrate nuclear staining. The DNA sequences were not related to BK virus sequences, but three samples were positive with probes hybridizing with JC virus DNA sequences. In conclusion, this study demonstrates the presence of SV40-like DNA sequences in pulmonary neoplasms and in non-malignant lung tissues. It appears that the presence of SV40-like DNA is not unique to cancer.     

Malignant pleural mesothelioma. II. Modern therapeutic concepts

In the second part of our review of malignant pleural mesothelioma, we reviewed current concepts of the treatment of this highly malignant disease. Although there are still advocates for the use of best supportive care to the treatment of these patients, the accumulated evidence favorizes the combined modality approach. Surgery, followed by postoperative external beam radiotherapy (or intraoperative radiotherapy), offers increased response rates and median survival as well as a higher percentage of patients surviving a two-year period. Although widely tested, both single-agent and multiple-agent chemotherapy did not succeed in transmitting high response rates into an improved survival. New treatment approaches are needed to improve poor survival in patients with malignant pleural mesothelioma.     

Egg components and hatchling lipid reserves: parental investment in kinosternid turtles from the southeastern United States

PURPOSE: Identification of prognostic factors in patients with malignant pleural mesothelioma based on prospectively collected international data. PATIENTS AND METHODS: From October 1984 to October 1993, 204 eligible adult patients with malignant pleural mesothelioma were entered into five consecutive prospective European Organization for Research and Treatment of Cancer (EORTC) phase II clinical trials designed to assess the efficacy of various anticancer drugs (mitoxantrone, epidoxorubicin, etoposide, and paclitaxel). The Cox model was used to assess 13 factors related to biology and disease history with respect to survival. RESULTS: The median survival duration was 12.6 months from diagnosis and 8.4 months from trial entry. In the multivariate analysis, poor prognosis was associated with a poor performance status, a high WBC count, a probable/possible histologic diagnosis of mesothelioma, male gender, and having sarcomatous tissue as the histologic subtype. Taking these five factors into consideration, patients were classified into two groups: a good-prognosis group (1-year survival rate, 40%; 95% confidence interval [CI], 30% to 50%) and a poor-prognosis group (1-year survival, 12%; 95% CI, 4% to 20%). CONCLUSION: These results may help to design new clinical trials in pleural mesothelioma by selecting more homogenous groups of patients.     

The treatment of malignant mesothelioma with a gene modified cancer cell line: a phase I study

Malignant mesothelioma is a tumor of the pleura for which there is no satisfactory treatment. It is almost universally fatal, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with malignant mesothelioma, a new mode of treatment is desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-tk). By virtue of their expression of HSV-tk, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). and nearby tumor cells are killed by a phenomenon termed the bystander effect. In this protocol we propose a Phase I trial to study the safety and determine the maximal tolerated dose of an HSV-tk-transduced ovarian cancer cell line (PA1-STK cells) infused into the pleural cavities of patients with malignant pleural mesothelioma, followed by systemic administration of ganciclovir. The hope is that administration of ganciclovir will result in killing of the HSV-tk transduced ovarian cancer cells as well as the nearby malignant mesothelioma cells. This is a standard dose-escalation protocol.     

Biological verification of fluid-to-particle interfacial heat transfer coefficients in a pilot scale holding tube simulator

Mesothelioma is a malignant pleural or intraperitoneal tumor attributable to asbestos exposure in more than 80% of the cases. Manganese superoxide dismutase (MnSOD), a mitochondrial superoxide radical scavenging enzyme, is low in most tumors but is known to be induced by asbestos fibers and certain cytokines. Induction of MnSOD may be associated in asbestos-related pulmonary diseases in vivo. We investigated here MnSOD specific activity and MnSOD mRNA level using healthy human lung tissue, SV40-transformed human pleural mesothelial cells (Met5A), and six human malignant mesothelioma cell line cells. Total SOD (CuZnSOD + MnSOD) and MnSOD activities were 20.0 +/- 4.8 U/mg protein and 3.2 +/- 1.2 U/mg protein in healthy human lung tissue, and 25.6 +/- 10.7 U/mg and 3.8 +/- 1.0 U/mg in Met5A cells, respectively. In four mesothelioma cell lines MnSOD activity was significantly elevated, the highest activity (30.1 +/- 8.2 U/mg) was almost 10-fold compared to the activity in Met5A cells. The steady state mRNA level of MnSOD was low in Met5A cells and markedly higher in all mesothelioma cell lines roughly in proportion with enzyme activities. Cytotoxicity experiments, which were conducted in four cell lines, indicated that cells containing high MnSOD mRNA level and activity were resistant to the mitochondrial superoxide-producing agent menadione. In conclusion, our results suggest that human mesothelioma may express high levels of MnSOD, which is associated with high oxidant resistance of these cells.     

Environmental fibrous zeolite (erionite) exposure and malignant tumors other than mesothelioma

We studied the mortality in three villages in the Cappadocian region of Central Anatolia, Karain, Tuzk?y, and Sarihidir, which were exposed to fibrous zeolite (erionite), a known carcinogen more potent than the amphibole asbestos. Between 1970 and 1994, there were 305 deaths in Karain, and 177 (58%) were cancer related, including 150 (49.2%) malignant pleural mesothelioma, seven (2.3%) malignant peritoneal mesothelioma, and six (1%) gastroesophageal carcinoma. Four deaths (1.3%) from lung cancer included two nonsmoking females. There were three cases (1%) of leukemia and six of other malignancies (1.9%). Between 1980 and 1994, there were 519 deaths in Tuzk?y (T) and Sarihidir (S) (T = 432, S = 87). Of these, 257 were cancer related, and included 120 cases of malignant pleural mesothelioma and 64 cases of malignant peritoneal mesothelioma. Intraabdominal carcinoma was noted in 29 patients and 14 patients had lung cancer (four of whom were nonsmoking women). There were five cases of gastroesophageal cancer, five deaths due to leukemia, and 16 cases of various malignancies. These mortality figures support the hypothesis that erionite fibers cause cancer other than mesothelioma and lung cancer. Mineralogic analyses of the tissues should be performed to demonstrate this relationship.     

Malignant pleural effusions: recourse to early use of talc

INTRODUCTION: Our purpose was to assess the efficacy, permanence and safety of thoracoscopic talc poudrage (TTP) for pleurodesis in malignant effusions. We report the follow-up of 360 patients who received TTP in two centers in Marseille (France). CURRENT KNOWLEDGE AND KEY POINTS: Eighty-eight patients presented with mesothelioma and 272 had pleural metastasis. The mean follow-up time was 12 months (range: 2-120). Out of the 327 patients whose response could be evaluated, 90.2% had a successful pleurodesis at 1 month, and 82.1% had a life-long pleural symphysis. Adverse effects included one death 3 days after the procedure in an end-stage patient, fever (9.8%), infection of the parietal scar (2.5%) and pulmonary infection (0.8%). FUTURE PROSPECTS AND PROJECTS: TTP is an effective and safe method of life-long pleurodesis. It should be performed early on in the history of malignant effusions to avoid failures of the technic, mainly linked to trapped lung and to the general condition of patients.     

Clinical utility of liquid-chromatographic analysis of effusions for hyaluronate content

A previously described HPLC method for determining hyaluronate in effusions was used to analyze a consecutive series of effusions from 1039 patients with pleural fluids and from 571 patients with peritoneal fluids. A mesothelioma was verified histologically in 50 of the cases. The results were used to estimate the clinical utility of the analysis. With a cutoff of 75 mg/L for hyaluronate-derived uronic acid, assay specificity for a malignant mesothelioma was 100% and the sensitivity 56%. Only 20% of the effusions from the mesothelioma patients showed no evidence of increased production of hyaluronate. Cytological smears from the associated cell pellets were evaluated as malignant or suspicious for malignancy in only 28% or in a further 46% of the mesothelioma cases, respectively, leaving 30% of the pellets as cytologically false-negative. We also analyzed effusions from selected cases submitted from other hospitals, 154 of which had been diagnosed histologically as mesotheliomas. Concentrations of hyaluronate were increased in these cases too, but a considerable proportion of the samples showed evidence of losses of hyaluronate; consequently, the sensitivity of the assay in these samples was lower.     

Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography

BACKGROUND: The diagnosis of malignant mesothelioma is a challenging medical problem. CT often cannot differentiate between benign diffuse pleural thickening and malignant mesothelioma, while thoracentesis and CT-guided biopsies are insensitive. We have assessed the value of positron emission tomography (PET) with 2-fluoro-2-deoxy-D-glucose (FDG) in the evaluation of malignant mesothelioma. METHODS: Twenty-eight consecutive patients referred for the evaluation of suspected malignant mesothelioma were evaluated by FDG-PET imaging. Measured attenuation correction was performed in 26 of 28 cases for quantitation with the standardized uptake value (SUV) method. The results of PET imaging were compared with those of video-assisted thoracoscopy or surgical biopsies. RESULTS: Surgical biopsy specimens confirmed the presence of malignant disease in 24 patients and demonstrated benign processes in the remaining four. The uptake of FDG was significantly higher in malignant than in benign lesions (SUV=4.9+/-2.9 and SUV=1.4+/-0.6, respectively; p<0.0001). With a SUV cutoff of 2.0 to differentiate between malignant and benign disease, a sensitivity of 91% and a specificity of 100% could be achieved, although the activity in some epithelial mesotheliomas tended to be close to this threshold. FDG-PET images provided excellent delineation of the active tumor sites. Hypermetabolic lymph node involvement was noted on FDG-PET images in 12 patients, 9 of which appeared normal on CT scans. Histologic examination in six patients confirmed malignant nodal disease in five cases and indicated granulomatous lymphadenitis in one. CONCLUSION: In this highly selected population, FDG-PET imaging was a sensitive method to identify malignant mesothelioma and determine the extent of the disease process.     

Crossreactions to muscle relaxants in the operating room

A 62-year-old man was admitted to our hospital for evaluation of bilateral tumor-like shadows along the ribs. He had been a diamond-grinder for twenty years. Thoracoscopic examination with a flexible bronchoscope revealed many well-circumscribed tumors with shiny, smooth, convex surfaces on the parietal pleura. The biopsy specimen had hyaline collagen with no cellular components. Based on these findings the tumors were diagnosed as pleural plaques. Cases of pleural plaques are usually followed up with chest radiography only, but the clinical course may be complicated by malignant mesothelioma and other malignant disease. To differentiate these conditions we performed biopsy during intrathoracic observation. The flexible bronchoscope can be useful in such procedures because it is relatively easy to operate and the procedure is relatively non invasive.