William S. Rosenthal

Photodynamic therapy for obstructing esophageal cancer: Light dosimetry and randomized comparison with Nd: YAG laser therapy

BACKGROUND & AIMS Light dosimetry analysis to achieve predictable tumor necrosis has not been performed for photodynamic therapy (PDT) in the gastrointestinal tract. We evaluated dihematoporphyrin ethers for sensitizing esophageal carcinomas to 630 nm light and compared PDT with neodymium:yttrium-aluminum-garnet (Nd:YAG) laser therapy in a randomized trial. METHODS Of 52 patients with dysphagia, 32 received palliative PDT. Ten patients treated with PDT participated in a preliminary trial using various doses of 630-nm light, and 22 patients treated with PDT participated in a randomized trial using a derived standardized light dose for comparison with 20 patients treated with the Nd:YAG laser. RESULTS Light dosimetry correlated with depth of tumor necrosis (r = 0.664; P < 0.001). PDT activity was similar for squamous cell and adenocarcinoma. Among randomized patients, both PDT and Nd:YAG therapy relieved dysphagia, but PDT resulted in improved Karnofsky performance status at 1 month (+7 vs. -7; P < 0.001) and longer duration of response (84 vs. 57 days; P = 0.008). Skin photoreactions were unique to PDT. CONCLUSIONS The extent of PDT tumor ablation correlates with light dosimetry, enabling selection of a standardized light dose. PDT can relieve esophageal obstruction from squamous cell and adenocarcinoma and is an alternative to Nd:YAG thermal necrosis with a longer duration of response. However, PDT requires patient precautions to minimize skin photoreactions.

Selenium Deficiency in the Acquired Immunodeficiency Syndrome

Severe protein-calorie malnutrition is common in patients with AIDS (acquired immunodeficiency syndrome). These nutritional deficits are likely to further impair immune responses and other organ functions vital for recovery from serious infectious diseases. Since selenium deficiency is known to be associated with oral candidiasis and abnormal phagocytic function in animals and depressed helper T-cell numbers in man, we evaluated both selenium status and other nutritional parameters in 12 patients with AIDS compared to 27 healthy controls. Selenium was measured by a spectrofluorometric method. The mean (+/- SD) plasma selenium level in AIDS was 0.043 +/- 0.01 microgram/ml vs 0.095 +/- 0.016 microgram/ml in controls (p less than 0.001). Whole blood selenium and red blood cell selenium levels were also significantly reduced in AIDS (p less than 0.005). The mean weight loss in AIDS patients was 35.5 +/- 21.2 pounds. Serum albumin was significantly (p less than 0.01) lower in AIDS patients compared to controls. A good correlation between serum albumin and plasma selenium was noted (r = 0.77; p less than 0.001). We conclude that selenium deficiency is a common component of the malnutrition seen in AIDS patients. Therefore, aggressive nutritional support, including attention to selenium status, should be considered an integral part of the therapy of AIDS patients.

Androgen metabolism in cirrhosis of the liver

Abstract Androgen metabolism was studied in male patients with cirrhosis of the liver. The plasma level, metabolic clearance, and production rates of testosterone were decreased while the conversion ratio and rate transport constant of testosterone to androstenedione was increased. Administration of testosterone produced a marked increase in the metabolic clearance rate of testosterone indicating that parenchymal hepatic dysfunction per se was not the cause for the reduced clearance rate. Moreover, the patients were found to have normal testicular reserve for the biosynthesis of testosterone as indicated by an almost fourfold increase in the plasma concentration of testosterone following the administration of human chorionic gonadotropin. These data demonstrate that the reduced production rate of testosterone in male cirrhotics is not due primarily to testicular disease but possibly reflects hypothalamic-pituitary suppression secondary to increased circulating estrogens. The increase in the rate of conversion of testosterone to androstenedione, found in the present study, is consistent with this hypothesis. The present investigation thus provides quantitative data on the hypogonadal state in cirrhosis and suggests possible mechanisms for the alteration in androgen metabolism.

Abnormalities of blood selenium and glutathione peroxidase activity in patients with acquired immunodeficiency syndrome and aids-related complex

Severe protein-calorie malnutrition is common in patients with AIDS and could contribute to the progressive deterioration characteristic of that disease. Selenium deficiency could also have a negative impact on immune function and other organ functions vital for recovery from infectious diseases. Therefore, to assess any role for selenium in AIDS, we determined plasma and erythrocyte selenium levels and glutathione peroxidase activity in 13 patients with AIDS compared to 8 patients with AIDS-related complex (ARC) and 14 healthy controls. Plasma selenium levels were significantly reduced in AIDS patients compared to controls (p<.0001) and to ARC (p<.02). Erythrocyte selenium levels in both AIDS and ARC were also reduced compared to controls (p<.02), but not to each other. Glutathione peroxidase activity in AIDS was 28.9±1.4 U/g Hb vs 38.4±6.9 in ARC (p=NS) and 52.3±1.7 in controls (p<.0001 vs AIDS;p<.02 vs ARC). When all groups were combined, there were significant correlations between total lymphocyte count and both plasma selenium (r=.53;p<.002) and erythrocyte glutathione peroxidase activity (r=.65;p<.0001). In addition, strong correlations were noted between plasma selenium and serum albumin (r=.68;p<.0001), plasma selenium and glutathione peroxidase (r=.77;p<.0001), and glutathione peroxidase and hematocrit (r=.66;p<.0001). In AIDS or ARC, no correlations between selenium with disease duration or weight loss were present. We conclude that, in comparison to normals, patients manifesting infection with human immunodeficiency virus have evidence of selenium deficiency as determined by diminished plasma and erythrocyte levels and glutathione peroxidase activity. These abnormalities are most marked in patients with AIDS, but are also present in patients with AIDS-related complex. Selenium deficiency has important implications for the progression and pathogenesis of clinical disease in AIDS.

Diminished Blood Selenium Levels in Renal Failure Patients on Dialysis: Correlations with Nutritional Status

Selenium deficiency has been implicated as contributing to the development of cardiovascular disease, skeletal muscle myopathy, anemia, increased cancer risk, and deranged immune function. Since these problems may also be associated with renal failure, and the kidney plays an important role in selenium homeostasis, we measured selenium and compared it with nutritional status in 24 stable hemodialysis patients, 12 chronic intermittent peritoneal dialysis patients, and 29 healthy controls. Whole blood and plasma selenium was determined by a spectrofluorometric method. For whole blood the mean (±SD) selenium levels were 0.11 ± 0.02 ug/ml in controls vs. 0.071 ± 0.01 ug/ml in hemodialysis cases and 0.052 ± 0.006 ug/ml in peritoneal dialysis (p < 0.005). Significant decreases were seen also for plasma and red blood cell selenium in all groups respectively. Pre- and postdialysis plasma and whole blood selenium levels showed no significant changes in both dialysis groups. However, predialysis residual peritoneal fluid did contain selenium (0.029 ± 0.005 ug/ml).Some evidence of protein-energy undernutrition was noted in both dialysis groups compared with controls. However, no significant differences in nutritional parameters were noted between hemodialysis and peritoneal dialysis patients. When all groups were combined, significant correlations were found between whole blood selenium and serum albumin (r = 0.61; p < 0.001), triceps skin fold in females (r = 0.62; p < 0.001), and midarm muscle circumference in males (r = 0.71; p < 0.001).We conclude that low blood selenium is present in renal failure patients undergoing hemodialysis. This abnormality is even greater in peritoneal dialysis cases. Although pre- and postdialysis selenium levels do not change appreciably, peritoneal fluid contained selenium and represents a source of loss. Poor proteincalorie nutritional status was also evident in both dialysis groups and probably contributed to this abnormality.

Reduced Cardiac Selenium Content in the Acquired Immunodeficiency Syndrome

Selenium deficiency has been implicated in the pathogenesis of a dilated congestive cardiomyopathy in areas of China (Keshan disease) and in several patients on long-term total parenteral nutrition. Recently a clinically and pathologically similar cardiomyopathy has been described in AIDS. Since blood selenium levels are low in AIDS, we assayed cardiac selenium status by a spectrofluorometric method in eight AIDS patients at autopsy compared to nine age-matched, non-AIDS autopsy controls with histologically normal hearts. We found (mean +/- SD) a cardiac selenium level of 0.327 +/- 0.082 microgram/g dry weight in AIDS vs 0.534 +/- 0.184 microgram/g dry weight in controls (p less than 0.01; Students t test). There were no significant differences between the groups for heart weight, serum CPK, or other laboratory parameters. No specific chest x-ray or electrocardiographic abnormalities were present. Histologically, all AIDS hearts were abnormal; mostly with mild degrees of muscle hypertrophy or fibrosis. Foci of myocytolysis and myocyte necrosis and fibrous replacement of myocytes and monocytic infiltration were present in two AIDS cases. We conclude that heart tissue in AIDS demonstrates a significant selenium deficit. These data provide a potential link between selenium deficiency and cardiomyopathy in AIDS.

Pruritus in chronic hepatitis C: association with high serum bile acids, advanced pathology, and bile duct abnormalities.

Pruritus is a common symptom of chroniccholestatic liver diseases but is considered rare inchronic hepatitis. We observed pruritus to be anunusually common complaint in patients with advancedchronic hepatitis C. We reviewed the records of 175chronic hepatitis C patients to identify patients withsevere, diffuse, unexplained pruritus; 12 consecutiveprospective patients undergoing liver biopsy for chronic hepatitis C served as controls.Assessment included laboratory biochemical tests andassessment of liver pathology by stage, grade, hepaticactivity index, and a bile duct score. Pruritus waspresent in nine (5.1%) patients. Serum AST, ALT,alkaline phosphatase, GGTP, total bilirubin, andferritin were similar in pruritics and controls.Pruritics had higher serum bile acids (2028.4 ±223.1 mmol/liter vs 423.1 ± 194.3, P < 0.001), highertransferrin saturation (57.5 ± 6.8% vs 33.2± 3.3, P < 0.01), and lower HCV RNA by bDNA(24.5 ± 12.7 ± 10 vs 172.7 ± 54.1× 105, P < 0.05). Pathology revealedcirrhosis in 6/9 (66.6%) pruritics vs 1/12 (8.3%) controls (P < 0.01).Pruritics had higher pathologic stage (3.7 ± 0.2vs 2.2 ± 0.4, P < 0.01), grade (4.4 ±0.2 vs 2.1 ± 0.2, P < 0.001), activity index(14.3 ± 1.9 vs 8.6 ± 1.9, P < 0.025),and bile duct score (7.6 ± 0.6 vs 4.7 ± 0.4, P <0.01). Of eight pruritics treated withIFN-α2b, two had complete ALT responseand one relapsed. Pruritus followed a relapsing courseand only three patients partially responded despite a variety of interventions. Inconclusion, pruritus is a common complication ofadvanced CHC. Its presence is associated with high serumbile acids, advanced pathology and bile ductabnormalities. The clinical course of pruritus is relapsingand response to therapy is inconsistent. These featuressuggest that pruritus in CHC has a pathogenesis that mayvary from that of chronic cholestaticdiseases.

Chronic, liver disease in asymptomatic narcotic addicts.

Abstract Liver sections from 44 consecutive autopsies of addicts (none died of liver disease) were compared with 28 age-matched nonaddict controls and 28 controls with gross liver abnormalities. Fo...

Decreased hepatic selenium content in alcoholic cirrhosis

Selenium deficiency has been implicated as contributing to hepatic injury in alcoholics. The mechanism by which this occurs is most likely lipoperoxidation secondary to decreased activity of the selenoenzyme glutathione peroxidase. To further assess this relationship, we measured selenium content in autopsy livers in 12 patients with alcoholic cirrhosis compared to 13 patients matched for age and sex dying from other causes, mostly with cardiopulmonary diseases. The mean (±sem) hepatic selenium content in cirrhosis was 0.731±0.077 Μg/g dry weight versus 1.309±0.166 Μg/g in controls (P< 0.005; Students t test). Clinical and biochemical indices of significant hepatic dysfunction, including encephalopathy, ascites, and elevations of serum bilirubin or prothrombin time, were only present in the cirrhotic group. A significant inverse correlation between hepatic selenium content and the prothrombin time was noted (r=−0.50; Ps<0.02). No significant relationships between hepatic selenium and the abnormalities of bilirubin, albumin, or aspartate aminotransferase were found. We conclude that significantly decreased hepatic selenium stores are present in patients with severe alcoholic cirrhosis compared to controls. The magnitude of that selenium deficit does correlate with some indices of hepatic function, specifically the prothrombin time. These data lend further support to a true selenium deficiency state in alcoholic cirrhosis. It is highly possible that selenium deficiency represents an important link, synergistically joining the nutritional and hepatotoxic backgrounds of alcoholic liver injury and cirrhosis.

Effect of Chronic Alcohol Use on Hepatic Testosterone 5α-A-Ring Reductase in the Baboon and in the Human Being

Hepatic testosterone 5-alpha-A-ring reductase (HTAR) activity was measured in open liver biopsies in eight alcohol-fed baboons and eight pair-fed controls. The animals were studied after at least 1 yr of alcohol feeding. In the alcholol-fed animals, a significant fall in enzyme activity was noted. This occurred whether the enzyme levels were related to soluble protein, to DNA, or to wet tissue weight, showing that the change was due to a decrease in the specific activity of the enzyme. In addition, aspiration liver biopsy specimens were obtained from 14 men and women with alcoholic liver disease. Again, there was a significant decrease in HTAH activity in these patients compared with a normal population. No relationship was found between hepatic histology and HTAR levels in either the baboon or human population with alcoholic liver disease, suggesting that the changes in enzyme activity were related to an alcohol effect rather than to liver disease per se. This study demonstrates that chronic alcohol use decreases the function of the enzyme which controls an important rate-limiting step in the metabolism of testosterone in the liver and that this effect may be due primarily to alcohol.