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The role of chlorambucil in end stage platinum resistant epithelial ovarian cancer was evaluated in women with end stage ovarian cancer. They had received platinum based chemotherapy and all other intravenous chemotherapeutic options had been exhausted. Over a 15 year period, 30 patients were identified. The median age was 64.5 years (range 45-81). The median number of chlorambucil pulses was 4 (range 1-16). The median survival following the introduction of chlorambucil was 5.5 months (range 0.72-38.8). The 22 patients who survived for longer than three months were significantly younger than those who did not (p = 0.03). Apart from two patients who developed transient myelosupression there were no toxic side effects. Chlorambucil should be considered as a therapeutic option in end stage ovarian cancer. It is has minimal toxicity, and can be prescribed safely for long term use. In younger women, an increase in benefit may be anticipated.

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A 66-yr-old white male with a long-standing history of gastroesophageal reflux and Barrett's esophagus developed squamous cell dysplasia proximal to the site of the metaplastic epithelium. Two months later, he presented with progressive dysphagia. Upper endoscopy revealed near obliteration of the lumen from a large friable mass in the distal esophagus. Repeat endoscopic biopsies revealed areas of focal dysplasia but were inconclusive for the presence of malignancy. At surgery, a large inflammatory fibrotic mass was resected that was confirmed histologically to be a verrucous squamous cell carcinoma. Twenty-two months after the resection, there is no evidence of tumor recurrence. The case and relevant literature is discussed.

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Vitamin B6 is effective in the treatment of carpal tunnel syndrome and related disorders in patients with vitamin B6 deficiency. Hyperhomocysteinemia, a risk factor for atherosclerosis, is associated with deficiencies of vitamin B6, folate, and cobalamin. Patients who were given vitamin B6 for carpal tunnel syndrome and other degenerative diseases were found to have 27% of the risk of developing acute cardiac chest pain or myocardial infarction, compared with patients who had not taken vitamin B6. Among elderly patients of the author (JE) expiring at home, the average age at death from myocardial infarction was 8 years later in those who had taken vitamin B6, compared with those who had not taken vitamin B6. The preventive effect of vitamin B6 on progression of coronary heart disease may be related to increased formation of pyridoxal phosphate, the coenzyme that is required for catabolism of the atherogenic amino acid, homocysteine.

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The homocysteine thiolactonyl derivative, thioretinaco ozonide, is believed to function as an electron acceptor in oxygen metabolism and as the binding site for adenosine triphosphate (ATP) synthesis by mitochondria, preventing damage by free radical oxidants in resting cells. During cell division, methionine is converted to homocysteine thiolactone, converting thioretinaco to thioco, increasing free radical oxidants, and oxidizing cellular glutathione and ascorbate. Homocysteic acid has growth hormone activity and releases insulin-like growth factor in hypophysectomized rats, promoting oxidation of homocysteine thiolactone to sulfated glycosaminoglycans of cartilage. The free base of homocysteine thiolactone produces keratinization, squamous metaplasia, dysplasia, and carcinogenesis in normal mouse tissues. The efficiency of homocysteine thiolactone metabolism declines with aging, explaining decreased formation of adenosyl methionine in aging and suggesting loss of thioretinaco ozonide from membranes of aging cells. The effects of aging on enzyme activity, connective tissues, lipid synthesis, auto-immune diseases, atherogenesis and carcinogenesis are related to these changes in homocysteine metabolism.

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Abnormalities of methionine metabolism in malignancy include carcinogenicity of methionine deficiency, methionine auxotrophy of cultured malignant cells, deficient methylation of DNA, and aerobic glycolysis that is reversed by methionine. Cells from children with homocystinuria form an aggregated sulfated extracellular matrix and grow in a pattern similar to cultured malignant cells. Normal cells metabolize homocysteine thiolactone to sulfate, but malignant cells accumulate homocysteine thiolactone, which thiolates proteins and other cellular macromolecules. Thioretinamide, the amide of retinoic acid homocysteine thiolactone, and its cobalamin complex, thioretinaco, are antineoplastic and chemopreventive against carcinogenesis. Deficiency of these compounds in malignant cells is believed to increase conversion of methionine to homocysteine thiolactone and thioco, its cobalamin complex. These compounds are believed to participate in oxidative phosphorylation by formation of thioretinaco ozonide disulfonium complexes that are the active sites of adenosine triphosphate (ATP) binding in mitochondrial membranes. Hypothetical deficiency of thioretinaco may explain important metabolic abnormalities of malignant cells.

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The atherogenic properties of homocysteine were discovered by observation of arteriosclerosis in children with homocystinuria caused by inherited deficiency of three different enzymes. Hyperhomocysteinemia is generally recognized as an independent risk factor for coronary, cerebral, and peripheral atherosclerosis. Hyperhomocysteinemia is caused by heterozygosity for homocystinuria, micronutrient deficiency from dietary imbalance, toxins, drugs, hormones, and other factors, explaining many key observations concerning the epidemiology of atherosclerosis. The etiological factors for atherosclerosis are believed to increase conversion of methionine to homocysteine thiolactone, the reactive cyclic internal lactone of homocysteine. The free amino groups of low density lipoprotein (LDL) are thiolated by homocysteine thiolactone, causing aggregation and increased uptake of LDL by macrophages, explaining lipid deposition in atheromas. Homocysteine thiolactone, released from homocysteinylated LDL within vascular wall, promotes intimal injury, oxidation of cholesterol and unsaturated lipids, platelet aggregation, thrombogenic factors, myointimal hyperplasia, deposition of sulfated glycosaminoglycans, fibrosis and calcification of atherosclerotic plaques.

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Altered homocysteine metabolism is implicated as a pathogenic factor in atherogenesis, neoplasia, and aging. Hereditary enzymatic deficiencies and nutritional deficiencies of folate, pyridoxine, or cobalamin are associated with elevated blood homocysteine, accelerated atherosclerosis, and manifestations of aging. The failure of malignant cells to metabolize homocysteine thiolactone to sulfate is attributed to deficiency of thioretinaco, a complex containing cobalamin, homocysteine thiolactone, and retinoic acid. The sulfhydryl group of homocysteine is believed to act catalytically with ferric or cupric ions in a mixed function oxidation system to generate hydrogen peroxide, oxygen radicals, and homocysteinyl radicals. These reactive species may interact with the active site of enzyme protein to cause inactivation of catalytic activity. Homocysteine thiolactone is oxidized to sulfate by a process involving ascorbate, thioretinamide, and superoxide, under the control of thyroxine and growth hormone. Thioretinaco is believed to be the active site of adenosine triphosphate (ATP) binding in oxidative phosphorylation with the participation of oxygen, ascorbate, proton gradient, and electron transport. Depletion of thioretinaco from mitochondrial and microsomal membranes may be associated with increased formation and release of radical oxygen species within neoplastic and senescent cells. Specific proposals are made for investigating the importance of homocysteine metabolism in the oxidative modification of proteins and lipids.

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BACKGROUND: Because of the inverse relation between dietary fish consumption and coronary heart disease and because of the importance of serum homocysteine as an independent risk factor for atherosclerosis, the effect of fish oil on serum homocysteine was studied in hyperlipemic men. METHODS: Fifteen men with either type IIa or IIb lipoproteinemia or hypertriglyceridemia were maintained on a controlled, balanced diet and given either fish oil or olive oil supplements, 12 g/d for 3 weeks, followed by a cross-over period of 3 weeks during which the olive oil or fish oil supplements were given in reverse order. Serum homocysteine was determined by liquid chromatography of acid hydrolyzates of whole serum. RESULTS: Fish oil was found to diminish serum homocysteine levels in 14 of 17 subjects (P < 0.01). Serum homocysteine was 48% +/- 33% less than control values in seven of nine patients and 36% +/- 22% less than values in seven of eight subjects who had first received olive oil. There was no effect of olive oil supplements on serum homocysteine, compared with control values, but olive oil produced an increase in serum homocysteine in those who had first received fish oil. Serum triglycerides and very low-density lipoprotein were decreased by fish oil in patients who were first given olive oil, in agreement with previous studies. There was no effect of either fish oil or olive oil on total cholesterol, apolipoprotein B, low-density lipoprotein, or high-density lipoprotein. CONCLUSIONS: The protection against coronary heart disease afforded by a diet rich in fish may be attributed to the lowering of serum homocysteine levels by the n-3 polyunsaturated fatty acids of fish oils.

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The original case of Cb1 C disease with homocystinuria, cystathioninuria, methylmalonic aciduria, and hypomethioninemia was reexamined because of its importance in the discovery of the homocysteine theory of arteriosclerosis. The vascular lesions in the case consist of proliferative fibrous intimal plaques and focal necrosis of the artery wall, which are attributed to effects of excess homocysteine thiolactone on aggregation of low-density lipoproteins (LDL) and on respiration of endothelial cells. Atrophic, metaplastic, and dysplastic changes within the gastric mucosa are attributed to effects of excess homocysteine thiolactone on synthesis of keratin, sulfomucins, and nucleoproteins within affected cells. The case illustrates how investigation of an inborn error of metabolism illuminates pathophysiological disease processes, normal metabolic pathways, and important aspects of cellular function.

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In order to study the connection between homocysteine and lipid metabolism in atherosclerosis, homocysteine was determined in lipoprotein fractions from men with hypercholesterolemia. All lipoprotein fractions contain a considerably higher level of homocysteine in hypercholesterolemia, compared to normolipemic men, varying from 2.2 to 7.2 times higher estimated per unit volume of serum used for lipoprotein isolation, and from 2.4 to 4.1 times higher, estimated per gram protein. The largest difference in homocysteine content, estimated per gram protein, is present in the LDL fraction, amounting to 4.1 times higher in the hypercholesterolemic than the normolipemic group. In contrast, cholesterol is not higher in hypercholesterolemic than normolipemic men in any lipoprotein fraction, estimated per gram protein, and cholesterol is higher in hypercholesterolemic men only in the LDL fraction, estimated per unit volume. In both LDL and VLDL fractions homocysteine is correlated with cholesterol (r = 0.78, P less than 0.001; r = 0.59, P less than 0.01, respectively) and with protein (r = 0.72, P less than 0.01; r = 0.78, P less than 0.001, respectively). The atherogenic index for homocysteine, LDLHCy/HDLHCy, is 3.5 times higher in the hypercholesterolemic than the normolipemic group. The atherogenic index for cholesterol, LDLChol/HDLChol, is 2.2 times higher in the hypercholesterolemic than the normolipidemic group. The results suggest that analysis of the homocysteine content of the serum and lipoprotein fractions may prove to be useful for assessing risk, prognosis and response to therapy in persons with atherosclerosis.

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A case of extranodal non-Hodgkin's diffuse, mixed small and large cell lymphoma of the extrahepatic biliary tract with jaundice as the initial manifestation is reported in this paper. Obstructive jaundice is very rarely an early symptom in lymphoma. The pathogenesis of jaundice in this case was infiltration of the extrahepatic bile duct by lymphoma cells and fibrosis.

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In order to study the relation of homocysteine and lipid metabolism to atherogenesis, rabbits were fed a synthetic atherogenic diet and treated with parenteral thioretinaco (N-homocysteine thiolactonyl retinamido cobalamin), thioretinamide (N-homocysteine thiolactonyl retinamide) or homocysteine thiolactone hydrochloride. All three substances were found to increase dietary atherogenesis. Thioretinaco and thioretinamide increase total homocysteine of serum, but there is no effect of parenteral homocysteine thiolactone hydrochloride on serum homocysteine. The synthetic diet with corn oil significantly lowers serum homocysteine, compared either to baseline chow diet or to the synthetic diet with butter. Atherogenesis is correlated with total homocysteine, total cholesterol and LDL + VLDL cholesterol, and serum homocysteine is correlated with total cholesterol, LDL + VLDL, and HDL cholesterol in the total sample. Both synthetic diets elevate serum cholesterol, triglycerides and LDL + VLDL, but not HDL, compared to baseline values. Thioretinamide causes significant elevation of cholesterol and LDL + VLDL, compared to controls. The results show that increased dietary saturated fat and cholesterol cause deposition of lipids within the arteriosclerotic plaques produced by homocysteine, converting fibrous to fibrolipid plaques. Facilitation of atherogenesis is attributed to the effect of homocysteine on artery wall, either from parenteral homocysteine or from the increased synthesis of homocysteine from methionine, produced by thioretinaco and thioretinamide.

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Because of the importance of glycosaminoglycans and glycoproteins in the pathogenesis of atherosclerosis, the hexosamine concentrations of plasma were determined in 28 male survivors of acute myocardial infarction and in 50 healthy males aged 30-60 years. Glucosamine and galactosamine were determined by ion-exchange chromatography of hydrolyzed whole plasma and hydrolyzed deproteinized plasma. Considerably higher plasma levels of non-protein-bound hexosamine (500 nmol/ml) and lower levels of protein-bound hexosamines (3770 nmol/ml) were observed in the ischemic heart disease group, compared with the plasma levels of non-protein-bound hexosamine (320 nmol/ml) and protein-bound hexosamine (4260 nmol/ml) of the control group. This difference is due to changes in glucosamine concentration. The galactosamine concentration is similar in the two groups. The ratio of non-protein-bound to protein-bound hexosamines in patients is about twice as high as the ratio found in controls. The glucosamine/galactosamine ratio of protein-free plasma is significantly higher in patients (12.1) than in controls (8.3). These changes in plasma hexosamines correlate with increased plasma homocysteine, cholesterol, and triglycerides observed in the patient group. The findings show that characteristic quantitative and qualitative changes in plasma hexosamine levels accompany atherosclerosis. Determination of these substances may be helpful in diagnosis and management of patients with atherosclerosis.

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A retrospective study examined 194 consecutive autopsies to determine the proportion of cases of atherosclerosis without elevated serum cholesterol, diabetes mellitus, or hypertension. The study cases were classified into four groups, according to the cause of death and the degree of atherosclerosis. Cases in Group 1, in which death resulted from complications of severe atherosclerosis, have a mean serum cholesterol of 186.7 +/- 41.8 mg/dL, and the cholesterol is less than 200 in 65% and less than 250 in 92% of cases. Cases in Group 2, with severe atherosclerosis dying of other diseases, have a mean serum cholesterol of 174.6 +/- 60.4 mg/dL, and the cholesterol is less than 200 in 79% of cases and less than 250 in 89% of cases. Cases in Groups 3 and 4, with moderate and minimal atherosclerosis, respectively, have mean serum cholesterol values of 172.3 +/- 54.8 and 143.5 +/- 47.8 mg/dL, and the cholesterol is less than 200 in 71% and 92% and less than 250 in 92% and 96% of cases, respectively. Serum cholesterol is significantly associated with severity of atherosclerosis in the total sample (P = 0.01). Three fourths of all cases (147/194) have neither diabetes nor hypertension, and in 74% of these cases (109/147) the cholesterol is less than 200 and in 92% (135/147) the cholesterol is less than 250. In 66% (80/122) of the cases with severe atherosclerosis, the disease developed without evidence of elevated serum cholesterol, diabetes, or hypertension. Blood homocysteine, which has been shown by other studies to be an independent risk factor for atherosclerosis, is recommended for assessing prognosis in these cases.

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