Surgically debulked malignant pleural mesothelioma: Results and prognostic factors

Background: We analyzed morbidity and mortality, sites of recurrence, and possible prognostic factors in 95 (78 male, 17 female) patients with MPM on phase I–III trials since 1990. A debulking resection to a requisite, residual tumor thickness of ≤ 5 mm was required for inclusion. Methods: Preoperative tumor volumes were determined by three-dimensional reconstruction of chest computerized tomograms. Pleurectomy (n=39) or extrapleural pneumonectomy (EPP; n=39) was performed. Seventeen patients could not be debulked. Preoperative EPP platelet counts (404,000) and mean tumor volume (491 cm³) were greater than that seen for pleurectomy (344,000, 114 cm³). Results: Median survival for all patients was 11.2 months, with that for pleurectomy 14.5 months, that for EPP 9.4 months, and that for unresectable patients 5.0 months. Arrhythmia (n=14; 15%) was the most common complication, and there were two deaths related to surgery (2.0%). Tumor volume of >100 ml, biphasic histology, male sex, and elevated platelet count were associated with decreased survival (p<0.05). Both EPP and pleurectomy had equivalent recurrence rates (27 of 39 [69%] and 31 of 39 [79%], respectively); however, 17 of 27 EPP recurrences as opposed to 28 of 31 pleurectomy recurrences were locoregional (p₂=0.013). Conclusions: Debulking resections for MPM can be performed with low operative mortality. Size and platelet count are important preoperative prognostic parameters for MPM. Patients with poor prognostic indicators should probably enter nonsurgical, innovative trials where toxicity or response to therapy can be evaluated. Presented at the 49th Annual Cancer Symposium of The Society of Surgical Oncology, Atlanta, Georgia, March 21–24, 1996.     

Empirical assessment of the factorial structure of clinical symptoms in schizophrenic patients: formal thought disorder.

Male schizophrenic patients (n = 142) were examined with a clinical assessment of their language dysfunctions with the Scale for the Assessment of Thought, Language, and Communication (TLC). Confirmatory factor analyses were conducted to test the relative fit of several differential theoretical models of the factorial structure of thought disorders. The models examined were positive-negative thought disorder, a three-factor model based on the results of an earlier exploratory factor analysis, and a simpler verbal productivity-disconnection model that can be extracted from other exploratory analyses and empirical studies. The positive-negative thought disorder model failed to fit the data, while the three-factor model fit the data, but no better than the simpler verbal productivity-disconnection model.     

Hemolytic and sphingomyelinase activities of Clostridium perfringens alpha-toxin are dependent on a domain homologous to that of an enzyme from the human arachidonic acid pathway.

The N-terminal domain of Clostridium perfringens alpha-toxin, homologous with the nontoxic phospholipase C of Bacillus cereus, was expressed in Escherichia coli and shown to retain all of the phosphatidylcholine hydrolyzing activity of the alpha-toxin, but not the sphingomyelinase, hemolytic, or lethal activities. The C-terminal domain of alpha-toxin showed sequence and predicted structural homologies with the N-terminal region of arachidonate 5-lipoxygenase, an enzyme from the human arachidonic acid pathway which plays a role in inflammatory and cardiovascular diseases in humans.     

Lymphocyte subpopulation monitoring in cyclosporine-treated patients following heart transplantation

Circulating lymphocyte subpopulations were studied in 18 consecutive patients treated with cyclosporine-prednisone immunosuppression during the first month following heart transplantation. Eleven patients showed no evidence of graft rejection. There were eight episodes of acute rejection demonstrated at endomyocardial biopsy in 7 patients. Three patients were treated with corticosteroids, 3 were treated with rabbit antithymocyte globulin (RATG), and 1 died before treatment (early mortality: 5.6%). Using the monoclonal antibody technique, 150 determinations of lymphocyte subpopulations were performed and were correlated with 72 endomyocardial biopsy specimens. Cyclosporine immunosuppression caused a significant (p less than 0.05) decrease in total lymphocyte count (38%) and in the number of OKT3 (52%) and OKT4 cells (55%). During acute rejection, total lymphocytes and OKT3, OKT4, and OKT8 cells all increased significantly, but the T4 to T8 ratio did not change significantly. Treatment of rejection with corticosteroids resulted in a moderate but not significant decrease in all T-cell types, whereas RATG caused a marked but not selective decrease in all T-cell groups. In conclusion, T cells decrease with cyclosporine immunosuppression and with treatment of rejection and increase at onset of rejection, but the T4 to T8 ratio has no predictive value for the diagnosis and severity of rejection, and the sensitivity of the method does not permit its use to assess the degree of immunosuppression with cyclosporine following heart transplantation.     

Standardization and quantification of radionuclide solid gastric-emptying studies.

The purposes of this investigation were to standardize and validate a simple quantitative method for performing radionuclide solid gastric emptying that can be used for any dual-head gamma-camera and to establish reference values. METHODS: After eating a solid meal (egg sandwich) labeled with a radionuclide, 20 healthy volunteers (9 male, 11 female) underwent a 90-min gastric-emptying study performed with a triple-head gamma-camera. Two sets of 3 simultaneous projections were acquired sequentially for 30 s each: anterior, right posterior oblique (RPO), left posterior oblique (LPO), posterior, left anterior oblique (LAO), and right anterior oblique (RAO), and this sequence was repeated continuously for 90 min. Time-activity curves were generated using a gastric region of interest for each of the views as well as the conjugate-view geometric mean (GM) data for the anterior/posterior, LAO/RPO, and RAO/LPO combinations. Quantitative parameters were determined: percentage gastric emptying (%GE) at 90 min, half-time (min) based on an exponential fit, and clearance rate (%/min) based on a linear fit. Reference values were determined on the basis of a 95% confidence interval of the t distribution. The results were statistically analyzed and compared. RESULTS: The %GE reference values were greater for the anterior/posterior GM (>or=33%) than for the LAO (>or=31%) and anterior (>or=30%) GMs. The 3 %GE GM methods, the 3 exponential-fit GM methods, and the 3 linear-fit GM methods had high correlation coefficients (r >or= 0.874), and with only a single exception, there was no statistical difference among them. The LAO method and LAO/RPO GM mean method correlated strongly (r = 0.900) and had similar mean values (52% vs. 51%) and reference values (29% vs. 30%). All 3 methods of GM quantification also correlated strongly, and there was no significant difference among them. CONCLUSION: We have described and validated a simple method for radionuclide solid gastric emptying that can be used with a dual-head gamma-camera. We recommend the anterior/posterior GM method and have established reference values (>or=33%).     

Chicken mucin-cross-reactive antigen

We have previously described a chicken heterophile antigenic determinant (CHAD-1) shared by Mycobacterium smegmatis and chicken tissues. We then demonstrated that CHAD-1 is present on several chicken glycoproteins and that its immunoreactive domains are highly branched asparagine-linked oligosaccharides terminating in N-acetylglucosamine residues. In the present study, we have shown that CHAD-1 is also expressed by mucin purified to homogeneity from a soluble mucus of chicken intestine. Another antigen found on chicken mucin is a chicken mucin-cross-reactive antigen (CMCRA). Antisera to this antigen were produced by immunization of rabbits with an enriched preparation of CHAD-1 isolated from the bursa of Fabricius. These antisera were absorbed with Mycobacterium smegmatis (to block the anti-CHAD-1 antibody) and with chicken serum, and then used for immunoperoxidase staining of chicken tissue sections for CMCRA. The latter antigen was detected in most medullary cells of the bursa, in epithelial cells and Hassal's corpuscles of the thymus, and in mucus-producing cells of the intestine, esophagus, trachea, and bronchi. Using Western immunoblot analysis, we demonstrated that CMCRA is expressed by a number of polypeptides extracted from bursal lymphoid cells. These polypeptides could not be detected in extracts of thymus, spleen, peripheral blood or bone marrow mononuclear cells.     

Acute hypercalcemia, pancreatic duct permeability, and pancreatitis in cats

We investigated the effects of hypercalcemia on pancreatic duct permeability and pancreatitis in cats. Acute hypercalcemia was maintained by an infusion of calcium gluconate; controls received saline solution. Chronic hypercalcemia was maintained by diet and by vitamin D and dihydrotachysterol injections. Portal venous blood was analyzed for large dextran molecules that had been perfused through the pancreatic duct. In a separate group of hypercalcemic animals, we perfused the duct with activated pancreatic enzymes to induce acute pancreatitis. After 24 hours of hypercalcemia, dextrans were detected in the portal venous blood of 6 of 11 hypercalcemic and none of the 6 control animals (p less than 0.05). After 12 hours of hypercalcemia, dextrans were detected in all 7 hypercalcemic and 1 of 7 control animals (p less than 0.001). The degree of pancreatic inflammation was greater in the 12-hour animals than in the controls (p less than 0.001). After 14 days of hypercalcemia, however, there were no differences in dextran permeability or pancreatitis in experimental or control animals. Our results indicate that acute hypercalcemia increases the permeability of the pancreatic duct to molecules the size of pancreatic enzymes. This could be important in the pathogenesis of acute pancreatitis associated with hypercalcemic states.     

Sinusoidal lining cell damage: the critical injury in cold preservation of liver allografts in the rat

We have previously defined viability limits in a rat transplantation model. All liver allografts stored in a simple preservation solution (NaCl 0.9%, CaCl2 2 mM) at 4 degrees C for 4 hr or at 37 degrees C for 1 hr were viable upon transplantation, but all those stored at 4 degrees C for 8 hr or at 37 degrees C for 2 hr were nonviable. Only cold-preserved, nonviable livers showed increased vascular resistance, platelet trapping and an initially low, but then high, rise in aspartate transaminase (AST) upon reperfusion, all suggesting injury to the microcirculation, with secondary injury to the hepatocyte. In the present study, we investigated the morphological changes that occur in livers stored for the defined critical times, using light and electron microscopy after perfusion-fixation. Accurate and reproducible identification of specimens as belonging to viable or nonviable and warm- or cold-preserved could be made in this way. Preservation in the cold first resulted in reversible changes consisting of cellular swelling, alterations of intracellular organelles, and partial denudation of the sinusoidal lining (cold-preserved viable group). Later, under conditions of nonviable cold preservation, detachment of cell bodies of sinusoidal lining cells with nuclear changes and almost complete denudation of the sinusoidal lining was observed. Endothelial cells of larger vessels were only injured mildly. In contrast, under conditions of warm preservation, changes involving mitochondria and later nuclei were found in hepatocytes, and blebbing was more extensive. Endothelial cells were spared relatively. We also examined livers stored in isotonic citrate solution at 4 degrees C for 8 hr and 16 hr, the critical times determined for this solution in another model of rat liver transplantation. The findings were very similar to storage in saline with respect to the changes in the sinusoidal lining cells after cold preservation for the two critical times. The results provide convincing evidence of a qualitative difference between warm and cold preservation injury, with relatively selective damage to hepatocytes or sinusoidal lining cells, respectively. Endothelial damage represents the primary event, resulting in the loss of organ viability following hypothermic storage. Thus morphology may serve as a useful viability marker after preservation.     

The tumor promoters 12-O-tetradecanoylphorbol-13-acetate and okadaic acid differ in toxicity, mitogenic activity and induction of gene expression

Okadaic acid (OA) and 12-O-tetradecanoylphorbol-13-acetate (TPA)are both potent tumor promoters in a mouse skin carcinogenesisexperiment. OA was much more toxic than TPA for murine embryocell lines such as Swiss 3T3 cells or C3H10T? cells. TPA isa potent mitogen for 3T3 cells; in contrast OA was unable tostimulate DNA synthesis in these cells. TPA induces a familyof primary response genes, the TPA induced sequence (TIS) genes,in a wide variety of cells. Although OA induced modest levelsof TIS mRNA expression, the time course of the induction ofTIS1 and TIS8 mRNA was delayed when compared to induction byTPA or peptide mitogeas such as fibroblast growth factor (FGF).In addition TPA-mediated down-regulation of protein kinase Cattenuated TIS gene induction by OA, but not by FGF.     

Corticosterone does not cause testicular toxicopathology in the rat: relevance to methylxanthines, ACTH and stress.

1. Methylxanthines, ACTH and stress are well known to produce testicular pathology (e.g. seminiferous tubule atrophy). Methylxanthines, ACTH and stress alter hormone secretion, particularly from the pituitary-adrenocortical system. Consequently, it has recently been suggested that there may be a causal relationship between changes in endogenous physiological adrenocortical secretions, particularly corticosterone, and testicular pathology. 2. This study tested the hypothesis that corticosterone mediates the testicular effects of both methylxanthine treatment and stress. Corticosterone was administered daily by subcutaneous injection to groups of 10 male rats at dose levels of 2 or 20 mg kg-1 in propylene glycol (1 ml kg-1) for 1 month (the shortest duration of methylxanthine or ACTH exposure known to produce testicular pathology). The highest dose of corticosterone resulted in plasma concentrations that closely matched values resulting from stress (200-700 ng ml-1) compared with controls (< 25 ng ml-1). 3. The highest dose of corticosterone caused reduced body weight gain, lower thymus, adrenal, seminal vesicle and prostate weights, but did not induce any testicular pathology. 4. That a high, but physiologically relevant, dose of corticosterone did not cause testicular pathology in this experiment excludes this steroid in the direct aetiology of methylxanthine, ACTH and stress-induced testicular pathology. Other steroids secreted from the adrenal, in combination with corticosterone, may be involved.