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The chronic alcoholic patient is usually immunosuppressed, but the significance of this phenomenon in terms of bile duct injury is unclear. The immunoreactivity of the bile duct cells was examined in a series of 69 frozen liver biopsy specimens obtained from patients with alcoholic liver disease, comprising 29 cases of cirrhosis, 26 of alcoholic hepatitis, 10 cases of alcoholic fatty liver, and 4 specimens from normal livers. Liver diseases such as primary biliary cirrhosis and human hepatic allograft rejection, known to have an autoimmune basis, share the characteristic feature of damage to the bile duct epithelial cells. In both instances the damage seems to be immune mediated, but the nature of the antigens involved is not established. We used the avidin-biotin-peroxidase complex method to test in alcoholic liver disease for the expression of a battery of surface antigen markers that have been incriminated in tissue injury and are usually present in lymphoid cells but also expressed by epithelium. In this study we investigated the expression of the following molecules: HLA class I (ABC) and class II (HLA-DR, HLA-DP, HLA-DQ), CD29, CD45RA, CD45RO, CD56, interleukin 1 (IL-I), IL-2, IL-4, interferon (IFN-gamma), tumor necrosis factor beta, and transforming growth factor beta1 (TGF-beta1). The bile duct epithelial cells strongly expressed HLA-ABC in all cases, CD56 in 47 of 55, IL-4 in 15 of 41, TGF-beta1 in 14 of 25, and CD29 in 4 of 25 cases. The other markers including IFN-gamma, HLA-DR, HLA-DP, and HLA-DQ were not expressed by bile duct cells. The expression of HLA class I agrees with previous observations while the absence of class II expression does not. The expression by the bile duct epithelium of CD56 confirms our own previous report. A new observation is the finding of molecules such as IL-4, TGF-beta1, and CD29 strongly expressed in the bile ducts cells. The presence of these molecules, taken together with the lack of IFN-gamma expression, contradicts previous speculations that attributed to IFN-gamma a role in the induction of major histocompatibility antigens and adhesion molecules in immune-mediated alcoholic liver disease.

Health-related quality of life has not been evaluated as a predictor of mortality following coronary artery bypass graft (CABG) surgery. Evaluation of health status as a mortality predictor may be useful for preoperative risk stratification.To determine whether the Physical and Mental Component Summary scores from the preoperative Short-Form 36 (SF-36) health status survey predict mortality following CABG surgery after adjustment for known clinical risk variables.Prospective cohort study conducted between September 1992 and December 1996.Fourteen Veterans Affairs hospitals.Of the 3956 patients undergoing CABG surgery only and who were enrolled in the Processes, Structures, and Outcomes of Care in Cardiac Surgery study, the 2480 who completed a preoperative SF-36.All-cause mortality within 180 days after surgery.A total of 117 deaths (4.7%) occurred within 180 days of CABG surgery. The Physical Component Summary of the preoperative SF-36 was a statistically significant risk factor for 6-month mortality after adjustment for known clinical risk factors for mortality following CABG surgery. In multivariate analysis, a 10-point lower SF-36 Physical Component Summary score had an odds ratio (OR) of 1.39 (95% confidence interval [CI], 1.11-1.77; P=.006) for predicting mortality. The SF-36 Mental Component Summary score was not associated with 6-month mortality in multivariate analyses (OR, 1.09; 95% CI, 0.92-1.29; P=.31).The Physical Component Summary score from the preoperative SF-36 is an independent risk factor for mortality following CABG surgery. The baseline Mental Component Summary score does not appear to be predictive of mortality. Preoperative patient self-report of the physical component of health status may be helpful for risk stratification and clinical decision making for patients undergoing CABG surgery.

More than 600,000 coronary artery bypass graft (CABG) procedures are done annually in the United States. Some data indicate that 10 to 20% of patients who are undergoing a CABG procedure have a serum creatinine of more than 1.5 mg/dl. There are few data on the impact of a mild increase in serum creatinine concentration on CABG outcome.We analyzed a Veterans Affairs database obtained prospectively from 1992 through 1996 at 14 of 43 centers performing heart surgery. We compared the outcome after CABG in patients with a baseline serum creatinine of less than 1.5 mg/dl (median 1.1 mg/dl, N = 3271) to patients with a baseline serum creatinine of 1.5 to 3.0 mg/dl (median 1.7, N = 631).Univariate analysis revealed that patients with a serum creatinine of 1.5 to 3.0 mg/dl had a higher 30-day mortality (7% vs. 3%, P0.001) requirement for prolonged mechanical ventilation (15% vs. 8%, P = 0.001), stroke (7% vs. 2%, P0.001), renal failure requiring dialysis at discharge (3% vs. 1%, P0.001), and bleeding complications (8% vs. 3%, P0.001) than patients with a baseline serum creatinine of less than 1.5 mg/dl. Multiple logistic regression analyses found that patients with a baseline serum creatinine of less than 1.5 mg/dl had significantly lower (P0.02) 30-day mortality and postoperative bleeding and ventilatory complications than patients with a serum creatinine of 1.5 to 3.0 mg/dl when controlling for all other variables.These results demonstrate that mild renal failure is an independent risk factor for adverse outcome after CABG.

To evaluate the hepatic regenerative response in patients with alcoholic liver disease, sera from 263 patients with severe alcoholic hepatitis and/or cirrhosis were analyzed for hepatocyte growth factor (HGF) and alpha-fetoprotein (AFP). HGF concentration was elevated above healthy controls in 95% of the patients (median level = 2.4 ng/ml), whereas AFP tended to be depressed below controls (median level = 4.1 ng/ml). Correlations with parameters of liver injury (i.e., ascites, encephalopathy, AST bilirubin, and protime) all showed a more significant correlation with HGF concentrations than those of AFP. Patients with HGF levels below the mean (4 ng/ml) exhibited significantly better survival (median survival = 35 months vs. 8.5 months for those with HGFor = 4 ng/ml; p = 0.007). Serum HGF levels were associated with various specific histologic features of alcoholic hepatitis that included, but were not exclusively related to, necrosis.

Active nutrition therapy and the anabolic steroid oxandrolone (OX), in selected patients with severe alcoholic hepatitis, significantly improved liver status and survival. We report here on the changes in their nutritional parameters.Protein energy malnutrition (PEM) was evaluated and expressed as percent of low normal in 271 patients initially, at 1 month and at 3 months. Active therapy consisted of OX plus a high caloric food supplement vs a matching placebo and a low calorie supplement.PEM was present in every patient; mean PEM score 60% of low normal. Most of the parameters improved significantly from baseline on standard care; the largest improvement seen in visceral proteins, the smallest in fat stores (skinfold thickness). Total PEM score significantly correlated with 6 month mortality (p = .0012). Using logistic regression analysis, creatinine height index, hand grip strength and total peripheral blood lymphocytes were the best risk factors for survival. When CD lymphocyte subsets replaced total lymphocyte counts in the equation, CD8 levels became a significant risk factor (p = .004). Active treatment produced significant risk factor (p = .004). Active treatment produced significant improvements in those parameters related to total body and muscle mass (ie, mid arm muscle area, p = .02; creatinine height index, p = .03; percent ideal body weight, p = .04).Deterioration in nutritional parameters is a significant risk factor for survival in severe patients with alcoholic hepatitis. This deterioration is reversible with standard hospital care. Active therapy further improves creatinine height index, mid arm muscle area and total lymphocyte counts. Hence, these later parameters appear to be the best indicators for follow-up assessments.

In both animal and human studies, ethanol seems to modulate host immune function. In a variety of animal studies, ethanol has been shown to decrease lymphocyte function and number. In human studies of patients with alcoholic hepatitis, these abnormalities were also seen with specific correlation with protein malnutrition. Hepatic pathological lesions were also correlated with lymphocyte subset infiltration. However, peripheral blood lymphocytes did not correlate consistently with hepatic histopathology.

To determine whether infection with Helicobacter pylori is a risk factor for portosystemic encephalopathy in patients with acute, moderate or severe alcoholic hepatitis.Prospective, multicenter cohort study.Eight Veterans Affairs Hospitals.A cohort of 273 male patients enrolled in a Department of Veterans Affairs Cooperative Study performed to evaluate the efficacy of oxandrolone in combination with nutritional supplementation in moderate or severe alcoholic hepatitis.Admission serum IgG antibody titers against H. pylori by a specific and sensitive ELISA, demographic characteristics of patients, degree of protein calorie malnutrition, presence of ascites, bilirubin level, and known risk factors for hepatic encephalopathy (gastrointestinal bleeding, azotemia, hepatorenal syndrome, infection, and severity of disease); outcome was the presence of portosystemic encephalopathy.Of 188 patients with decompensated alcoholic hepatitis available for analysis, 117 (62.2%) had encephalopathy. Ninety-two (78.6%) of these were infected with H. pylori, compared with 62% of patients without encephalopathy (p = 0.013). In a step-wise regression model, H. pylori was an independent risk factor (relative risk: 2.4, 95% CI: 1.2-4.8) adjusting for ascites and protein-calorie malnutrition.Patients with acute, moderate or severe alcoholic hepatitis have a high H. pylori infection rate (as determined by serology), and those infected are at higher risk for portosystemic encephalopathy.

In the active stages of alcoholic liver disease (ALD), we have shown previously an enhanced expression of either CD4 or CD8 molecules on CD3+T cells. Class I and II MHC molecules expression were enhanced on lymphocytes, and on the cell membrane of hepatocytes, thus suggesting that an intrahepatic antigen-dependent lymphocyte-hepatocyte interaction occurs. Here we report the pattern of expression of several additional molecules known to participate in nonspecific cell-cell adhesion preceding alloantigen recognition i.e., the beta 1 chain of integrins (CD29) and the isoforms of the leukocyte common antigen CD45RA and CD45RO.Frozen liver samples from 38 patients with advanced ALD were examined immunohistochemically by the avidin-biotin-peroxidase complex method using monoclonal antibodies. Nine patients with alcoholic fatty liver and six patients with only hepatitis C infection were included as controls and studied in a similar manner.CD29 was strongly expressed on the cell membrane of hepatocytes in 18/20 patients with cirrhosis, in 17/18 with alcoholic hepatitis without cirrhosis, in 5/9 of fatty liver and in all six with hepatitis C. CD45RA was present in 5/18 cases of alcoholic hepatitis and in 3/20 cases of cirrhosis on the hepatocytes plasma membrane, in none of the controls, and rarely on lymphocytes. CD45RO was expressed on the surface of lymphocytes in 14/18 cases of alcoholic hepatitis, 13/20 patients with cirrhosis, in 5/9 of fatty liver and in one with hepatitis C. The CD45RO lymphocytes were predominantly CD8 positive.Our results indicate that in ALD the hepatocytes exhibit on their plasma membrane an enhanced expression of the beta 1 chain of the integrins and less commonly CD45RA. Furthermore, the expression of only CD45RO on the surface of lymphocytes favors the postulate that the intrahepatic lymphocytes in ALD are most likely of the "memory" type. The results of this study lend further support to the contention that a cell-cell contact precedes a cell-mediated mechanism in the pathogenesis of ALD.

A study was performed to distinguish between genetic vs socioeconomic factors or artifacts inherent in retrospective studies to discover explanations for the apparent shorter survival of blacks than whites with lung and colon cancer.Detailed biological and socioeconomic data were collected prospectively from a large cohort of patients with advanced lung and colon cancer who had not previously received chemotherapy and who consented to be entered in the clinical trial. Twelve medical centers within the Department of Veterans Affairs hospital system (Veterans Affairs Cooperative Study 188) entered patients between May 1981 and May 1986. These patients were evaluated and treated in a uniform manner within this hospital system and followed up to death. Outcome measures included time to tumor progression, tumor response, and survival.A total of 719 patients were entered in the study, 704 of whom were either black or white men. Blacks were found to have a significantly lower socioeconomic status than whites as measured by marital and educational status, occupation, income, housing, and number of individuals residing in household. Blacks had a significantly lower frequency of prior tumor resection and a significantly increased frequency of mediastinal lymph node involvement and of metastasis than whites. Trends existed toward a shorter time interval from original diagnosis to entry and a lower frequency of prior radiation therapy among blacks in comparison with whites at the time of entry to the study. However, no differences in intensity of treatment or follow-up, time to progression, response to treatment, or overall survival (measured from entry to the study to death) were observed for blacks vs whites.Lung and colon cancer are not necessarily more aggressive diseases in blacks than in whites. Based on a comparison of these data with those reported from other practice settings, we postulate that lung and colon cancer outcomes may be similar among black and white patients who receive equal access to comparable medical care in spite of socioeconomic differences. Findings suggest that future studies might focus profitably on racial factors that may exist at the time of patient entry to the health care system.

The mechanism responsible for the initiation and perpetuation of alcoholic liver disease (ALD) remains poorly understood. This investigation attempted to elucidate the role of cell-mediated immune phenomena in the pathogenesis of ethanol-induced liver injury.Frozen liver biopsy specimens from 144 patients with moderate to severe ALD were examined by the avidin-biotin immunoperoxidase technique for the expression of antigenic markers of T and B lymphocytes, natural killer cells, and class I and II MHC molecules in the tissue.Expression of CD3 by lymphocytes correlated significantly with regenerating nodules, intralobular inflammation, central sclerosis, and abnormalities of Kupffer cells. B cells were rarely present, and natural killer cells were absent. CD3+ lymphocytes expressed either CD4 or CD8 surface molecules. Enhanced class I MHC expression correlated significantly with portal inflammation, limiting plate erosion, vascular abnormalities, and hemosiderosis. Expression of class II MHC molecules correlated significantly with necrosis, bile stasis, and Mallory bodies.The distribution and persistence of CD4+ and CD8+ cells in actively advancing ALD, the enhanced MHC expression on hepatocytes, and their relationship to alcoholic hyalin and necrosis lend support to the hypothesis that a cytotoxic T lymphocyte-hepatocyte interaction plays a role, perhaps via lymphokine production, in the genesis or perpetuation of ALD.

Plasma warfarin and its R,S enantiomer concentrations, one-stage prothrombin times, and mean daily warfarin doses were analyzed in 196 patients given warfarin. These individuals were part of a controlled clinical trial that examined the effect of warfarin as an adjuvant to "standard" treatment in a variety of malignancies. Neither the plasma warfarin concentration nor the daily warfarin dose required to produce a given degree of prothrombin-time prolongation was influenced by age or body weight in these subjects. When the data were analyzed by performance status, we noted several variations of interest. Individuals with different tumor types demonstrated disparities in warfarin disposition. Patients with colorectal cancer, for example, required lower mean daily warfarin doses to achieve a given degree of one-stage prothrombin time prolongation. Analysis of warfarin enantiomers (R,S) in a selected group of patients demonstrated a lower-than-normal ratio (2:1) for the colorectal cancer group (1.42:1) because of an apparent decrease in the plasma R component. In contrast, patients with head and neck cancer demonstrated a ratio of 2.85:1, and the R component was elevated. Warfarin disposition and the effect of warfarin on vitamin K-dependent clotting factor production were altered in the patients with cancer reported in this study. The mechanisms for these alterations are complex and not completely understood.

The purpose of this study was to delineate the etiological factors for iatrogenic pneumothorax in the era of increased use of invasive procedures and to determine its impact on morbidity. Between 1983 and 1987 the Department of Veterans Affairs conducted a cooperative study at 13 medical centers to assess the utility of the intrapleural instillation of tetracycline for the prevention of recurrent pneumothorax. Since all patients with any type of pneumothorax were screened at each medical center, it was decided to collect data on all the iatrogenic pneumothoraces during that period. During the study period, the number of reported iatrogenic pneumothoraces were 538. Because of incomplete data, 3 iatrogenic pneumothoraces reported from one center were excluded. The leading causes of iatrogenic pneumothorax were transthoracic needle aspiration (128), subclavicular needle stick (119), thoracentesis (106), transbronchial biopsy (54), pleural biopsy (45) and positive pressure ventilation (38). Most patients required treatment for 4-7 days; however, hospitalization was prolonged due to this treatment in only 8% of patients, presumably because of their underlying disease which required long hospitalization. Patients with underlying chronic obstructive pulmonary disease required significantly longer duration of treatment than those without. We conclude that in our patient population, the three leading causes of iatrogenic pneumothorax are transthoracic needle aspiration, subclavicular needle stick and thoracentesis. Hospitalization is prolonged in only a small percentage of the patients who required treatment for the iatrogenic pneumothorax.

To explore mechanisms of coagulation activation in adenocarcinoma of the prostate, the occurrence and distribution of components of coagulation and fibrinolysis pathways in situ were studied by means of immunohistochemical techniques applied to frozen sections of fresh malignant and benign hyperplastic prostatic tissue obtained at transurethral resection. Fibrinogen was distributed throughout the perivascular and tumor connective tissue in both malignant and benign disease but was not present in adjacent areas of normal prostate. Antibodies specific for fibrin and D-dimer crosslink sites stained vascular endothelium focally in both malignant and benign tissues. Both neoplastic cells and benign hyperplastic glandular epithelial cells stained weakly and in a patchy distribution for tissue factor and focally for low-molecular-weight urokinase-type plasminogen activator. Focal staining of vascular endothelium was also observed for tissue plasminogen activator and plasmin-antiplasmin complex neoantigen. By contrast, no tissue staining was observed for factor VII, factor X, factor XIII "a" subunit, high-molecular-weight urokinase-type plasminogen activator, plasminogen activator inhibitors 1 to 3, protein C, and protein S. Thus, the similarity in findings between benign hyperplastic and neoplastic prostate tissue, the lack of either an intact tumor cell-associated coagulation pathway or fibrin formation, and the presence of fibrin on vascular endothelium are consistent with the concept that coagulation activation in prostatic cancer may not be due to a direct effect of the tumor cells on the clotting mechanism. Rather, such activation may be induced by a soluble tumor product that activates procoagulant activity on certain host (for example, vascular endothelial) cells. These findings, together with the lack of effect of warfarin anticoagulation on the clinical course of patients with prostatic cancer, contrast with findings in certain other tumor types and suggest that coagulation activation may not contribute to progression of adenocarcinoma of the prostate.

Studies in experimental tumor systems attest to the importance of abnormal prostaglandin metabolism in the pathogenesis of malignancy. The extensive literature on this subject has been reviewed (1–4) which has shown that inhibition of prostaglandin synthesis by nonsteroidal antiinflammatory drugs (NSAIDs) is capable of inhibiting carcinogenesis, tumor cell proliferation, and metastatic dissemination; and also restoration of depressed cellular immune function that is a feature of the tumor-bearing host. Relationships, presented schematically in simplified form in Figure 1, have been relatively well worked out in experimental models of colon carcinogenesis (3,5,7). Evidence indicates that deoxycholate (DOC) serves as a tumor promoter. DOC induces synthesis of the enzyme, ornithine decarboxylase (ODC). This enzyme induction requires the presence of prostaglandin E2 (PGE2). ODC is a rate-limiting enzyme in polyamine synthesis and polyamines stimulate tumor cell proliferation. NSAIDs inhibit PGE2 production and thereby inhibit induction of ODC. ODC may be a marker for human, as well as animal, colon carcinogenesis (2,8).

Platelet counts were evaluated in 714 patients with advanced non-small cell lung cancer (N-SCLC), small cell carcinoma of the lung (SCCL), and colon cancer entered to a clinical trial. Patients had not received prior chemotherapy. Platelet counts were not different in patients who had received radiation therapy prior to entry to the study. In comparison to the other tumor types, patients with N-SCLC demonstrated an increased prevalence of thrombocytosis (counts greater than 400,000/mm3), higher platelet counts at the time of entry to the study, higher over all mean platelet counts, relative preservation of high platelet levels during disease progression, and no relationship between platelet numbers and the amount of chemotherapy given. By contrast, platelet counts in patients with SCCL were negatively correlated with the absolute amount of cyclophosphamide and adriamycin given, and declined most dramatically with disease progression and death. Platelet numbers did not correlate with fibrinopeptide A or fibrin split product levels suggesting that disseminated intravascular coagulation or fibrinolysis may have had less influence on platelet numbers than certain other factors. By contrast, significant correlations were found for all three tumor types between platelet numbers and other indicators of bone marrow function including anemia, total leukocyte count, and absolute neutrophil count; and the fibrinogen level. Based upon these findings, we postulate that the host response to malignancy, possibly in the form of production of bone marrow-stimulating cytokines, may play a prominent role in regulation of platelet counts in these (and perhaps other) neoplasms, and that a particularly prominent and persistent degree of marrow stimulation exists in patients with N-SCLC.

This prospective, multicenter, randomized, "unblinded," controlled clinical trial was designed to determine if the intrapleural instillation of 1500 mg of tetracycline hydrochloride would be effective in diminishing the ipsilateral rate of recurrence for spontaneous pneumothorax. During the 4-year enrollment period, 113 patients were assigned to the tetracycline group; 116 patients were assigned to the control group. During the 5-year study period, the recurrence rate in the tetracycline group (25%) was significantly less than that in the control group (41%). Use of tetracycline seemed to reduce the recurrence rates for patients with either primary or secondary spontaneous pneumothorax and for patients with either an initial or a recurrent pneumothorax. We conclude that the intrapleural administration of tetracycline in patients with spontaneous pneumothorax significantly reduces the rate of ipsilateral recurrence but is associated with intense chest pain. Intrapleural tetracycline therapy is indicated for patients with a spontaneous pneumothorax who are hospitalized and are treated with tube thoracostomy.

RA-233 (mopidamole) is a phosphodiesterase inhibitor that has been shown previously to limit progression of malignancy in certain experimental animal models and in a pilot study in humans. RA-233 plus chemotherapy was compared with chemotherapy alone in a five-year double-blind trial involving 719 patients with advanced carcinoma of the lung and of the colon. No difference existed between treatment groups for a variety of demographic, clinical, and laboratory parameters evaluated at entry to the study. There were no instances of unblinding and no patients were lost to followup. Minimum followup was 1 year. Patients ingested RA-233 or placebo for over 85% of their total survival interval and took 66% of the number of pills originally prescribed. RA-233 treatment was associated with a statistically significant prolongation of survival in patients with non-small cell lung cancer limited to one hemithorax, and also with reduction in mean plasma fibrinogen concentration, and with reduction in the incidence of bleeding episodes. RA-233 was not toxic.The favorable effects on survival could not be explained by any factor other than the RA-233 treatment. In other tumor categories tested no differences in survival were observed. These results suggest that RA-233 may be useful in the treatment of non-small cell lung cancer of limited extent (and possibly other tumor types). They also suggest that therapeutic intervention aimed at modified pathways within tumor cells might constitute an innovative investigational approach to the treatment of cancer.