[Pancreatic Acinar Cell Carcinoma with Peritoneal Recurrence Treated with Peritonectomy and Intraoperative Hyperthermic Intraperitoneal Chemotherapy-A Case Report].

A 31-year-old man with a big epigastric mass from pancreas body was completely removed by distal pancreatectomy and segmental gastrectomy. Two years after oral administration of S-1 for 4 courses, peritoneal dissemination on the right subdiaphragmatic space was detected. Laparotomy revealed white colored round nodules were found scattered on the peritoneal surface, and the peritoneal cancer index(PCI)was 18. To achieve complete resection of peritoneal nodules, peritonectomy was performed. After complete removal of macroscopic peritoneal metastasis(PM), intraoperative hyperthermic intraoperative peritoneal chemotherapy using 1 gr of gemcitabine and 60 mg of docetaxel was performed for 40 min with thermal dose of 41.5 min. Postoperative course was uneventful. Drug sensitivity test(HDRA method)showed that gemcitabine that gemcitabine showed the highest inhibition rate. The patient was treated with systemic gemcitabine chemotherapy. He is still alive without recurrence 18 months after peritonectomy plus intraoperative HIPEC. Pathological examination showed pancreatic acinar cell carcinoma(PACC)demonstrating positive for chymotrypsin. In conclusion, we present a PACC-case with PM successfully treated by a comprehensive treatment. Intraoperative HIPEC using gemcitabine may be effective for PACC patients with PM in treating residual micrometastasis after peritonectomy.

Targeted therapy of spinal cord glioma with a genetically modified Salmonella typhimurium.

OBJECTIVE: Spinal cord tumours are highly malignant and often lead to paralysis and death due to their infiltrative nature, high recurrence rate and limited treatment options. In this study, we measured antitumour efficacy of the Salmonella typhimurium A1-R tumour-targeting bacterium strain, administered systemically or intrathecally, to spinal cord cancer in orthotopic mouse models. MATERIALS AND METHODS: Tumour fragments of U87-RFP were implanted by surgical orthotopic implantation into the dorsal site of the spinal cord. Five and 10 days after transplantation, eight mice in each group were treated with A1-R (2 x 10(7) CFU/200 microL i.v. injection or 2 x 10(6) CFU/10 microL intrathecal injection). RESULTS: Untreated mice showed progressive paralysis beginning at day 6 after tumour transplantation and developed complete paralysis between 18 and 25 days. Mice treated i.v. with A1-R had onset of paralysis at approximately 11 days and at 30 days; five mice developed complete paralysis, while the other three mice had partial paralysis. Mice treated by intrathecal injection of A1-R had onset of paralysis at approximately 18 days and one mouse was still not paralysed at day 30. Only one mouse developed complete paralysis at day 30 in this group. Intrathecally treated animals had a significantly better survival than the i.v. treated group as well as over the control group. CONCLUSIONS: These results suggest that S. typhimurium A1-R monotherapy can effectively treat spinal cord glioma.

Microwave thermotherapy for benign prostatic hyperplasia.

BACKGROUND: Transurethral resection of the prostate (TURP) has been the gold-standard treatment for alleviating urinary symptoms and improving urinary flow in men with symptomatic benign prostatic hyperplasia (BPH). However, the morbidity of TURP approaches 20%, and less invasive techniques have been developed for treating BPH. Preliminary data suggest that microwave thermotherapy, which delivers microwave energy to produce coagulation necrosis in prostatic tissue, is a safe, effective treatment for BPH. OBJECTIVES: To assess the therapeutic efficacy and safety of microwave thermotherapy techniques for treating men with symptomatic benign prostatic obstruction. SEARCH STRATEGY: Randomized controlled trials were identified from the Cochrane Collaboration Library, MEDLINE, EMBASE, bibliographies of retrieved articles and reviews, and by contacting expert relevant trialists and microwave manufacturers. SELECTION CRITERIA: All randomized controlled trials evaluating transurethral microwave thermotherapy (TUMT) for men with symptomatic BPH were eligible for this review. Comparison groups could include transurethral resection of the prostate, minimally invasive prostatectomy techniques, sham thermotherapy procedures, and medications. Outcome measures included urinary symptoms, urinary function, prostate volume, mortality, morbidity, and retreatment. Two reviewers independently identified potentially relevant abstracts and then assessed the full papers for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted study design, baseline characteristics and outcomes data and assessed methodological quality using a standard form. We attempted to obtain missing data from authors and/or sponsors. MAIN RESULTS: Fourteen studies involving 1493 patients met inclusion criteria, including six comparisons of microwave thermotherapy with TURP, seven comparisons with sham thermotherapy procedures, and one comparison with an alpha blocker. Study durations ranged from 3 to 60 months. The mean age of subjects was 66.8 years, and the baseline symptom scores and urinary flow rates, which did not differ across treatment groups, demonstrated moderately severe lower urinary tract symptoms. The pooled mean urinary symptom scores decreased by 65% with TUMT and by 77% with TURP. The weighted mean difference (WMD) (95% confidence interval) for the symptom score was -1.36 (-2.25 to -0.46), favoring TURP. The pooled mean peak urinary flow increased by 70% with TUMT and by 119% with TURP. The WMD for peak urinary flow was 5.08 (3.88 to 6.28) mL/s, favoring TURP. Compared to TURP, TUMT was associated with decreased risks for retrograde ejaculation, treatment for strictures, hematuria, blood transfusions, and the transurethral resection syndrome, but increased risks for dysuria, urinary retention, and retreatment for BPH symptoms. Microwave thermotherapy improved symptom scores (IPSS WMD -4.75, 95% CI -3.89 to -5.60) and peak urinary flow (WMD 1.67 mL/s, 95% CI 0.99 to 2.34) compared with sham procedures. Microwave thermotherapy also improved symptom scores (IPSS WMD -4.20, 95% CI -3.15 to -5.25) and peak urinary flow (WMD 2.30 mL/s, 95% CI 1.47 to 3.13) in the one comparison with alpha blockers. No studies evaluated the effects of symptom duration, patient characteristics, prostate-specific antigen levels, or prostate volume on treatment response. AUTHORS' CONCLUSIONS: Microwave thermotherapy techniques are effective alternatives to TURP and alpha-blockers for treating symptomatic BPH for men with no history of urinary retention or previous prostate procedures and prostate volumes between 30 to 100 mL. However, TURP provided greater symptom score and urinary flow improvements and reduced the need for subsequent BPH treatments compared to TUMT. Small sample sizes and differences in study design limit comparison between devices with different designs and energy levels. The effects of symptom duration, patient characteristics, or prostate volume on treatment response are unknown.

Laser prostatectomy for benign prostatic obstruction.

BACKGROUND: Symptomatic benign prostatic obstruction is a common problem for older men. The gold standard treatment, transurethral resection of the prostate (TURP), significantly improves urinary symptoms and urinary flow. However, TURP has up to a 20% morbidity. Currently, there are a number of minimally invasive procedures that may be safe, effective alternatives to TURP. One promising surgical technique is laser prostatectomy. OBJECTIVES: To assess the therapeutic efficacy and safety of laser prostatectomy techniques for treating men with symptomatic benign prostatic obstruction. SEARCH STRATEGY: Randomized controlled trials were identified from the Cochrane Collaboration Library, MEDLINE, EMBASE, bibliographies of retrieved articles and reviews, and contacting expert relevant trialists and laser manufacturers. SELECTION CRITERIA: All randomized controlled trials evaluating laser prostatectomy treatment for men with symptomatic BPH. Trials were eligible if they (1) were randomized comparisons of a laser technique with TURP, (2) included at least 10 men with BPO in each treatment arm, (3) provided at least 6-months follow-up, and (4) included clinical outcomes such as urologic symptom scales or urodynamic measurements. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of methodologic quality was performed independently by two reviewers. Information on study design, subject and treatment characteristics, adverse events, urinary symptoms, and urinary flow were extracted using a standard form. MAIN RESULTS: 20 studies involving 1898 subjects were evaluated, including studies 4 with multiple comparisons. We found 8 comparisons of TURP with contact lasers, 8 with non-contact lasers, 4 with hybrid techniques, and one with interstitial laser coagulation (ILC). Two studies compared transurethral electrovaporization (TUVP) with contact lasers, one study compared interstitial laser coagulation with transurethral microwave thermotherapy (TUMT), and one study compared holmium contact lasers (HoLRP) with open prostatectomy. Among the studies comparing laser prostatectomy with TURP, follow-up duration ranged from 6 to 36 months. Mean age (67.2 yrs), mean baseline symptom score (20.2), and mean baseline peak urinary flow (9.2 ml/s) did not differ by treatment group. The pooled percentage improvements for mean urinary symptoms ranged from 59% to 68% with lasers and 63% to 77% with TURP. The improvements for mean peak urinary flow ranged from 56% to 119% with lasers and 96% to 127% with TURP. Overall, laser subjects were less likely to receive transfusions or develop strictures and their hospitalizations were shorter. Non-contact laser subjects were more likely to have dysuria, urinary tract infection, and retention. Re-operation occurred more often following laser procedures. REVIEWER'S CONCLUSIONS: Laser techniques are a useful alternative to TURP for treating BPO. Small sample sizes and differences in study design limit any definitive conclusions regarding the preferred type of laser technique. Data were insufficient to compare laser techniques with other minimally invasive procedures.

Antioxidant supplementation and subsequent oxidative stress of horses during an 80-km endurance race.

This study tested the development of oxidative stress and the effects of antioxidant supplementation in an 80-km ride. A precompetition survey revealed that no competitor would participate without vitamin E supplementation; therefore, 46 horses were paired for past performances and randomly assigned to two groups of 23 each for 3 wk of supplementation before the ride. One group (E) was orally supplemented with 5,000 IU of vitamin E per day; the other group (E+C) received that dose of vitamin E plus 7 g/d of vitamin C. Blood samples, temperature, and heart rate were taken the day before the race, at 21 and 56 km during the ride, at completion, and after 20 min of recovery. Plasma was assayed for lipid hydroperoxides, alpha-tocopherol, total ascorbate, albumin, creatine kinase (CK), and aspartate aminotransferase (AST). Total glutathione and glutathione peroxidase activity were determined in red blood cells and white blood cells. Thirty-four horses completed the race, 12 horses (six in E and six in E+C) did not finish for reasons including lameness, metabolic problems, and rider option. Plasma ascorbate was higher (P = 0.045) in the E+C group than in the E group. Other than ascorbate, neither antioxidant status nor CK and AST activities were affected by supplementation with E+C vs. E. Red blood cell glutathione peroxidase, white blood cell total glutathione, lipid hydroperoxides, CK, and AST increased, and red blood cell total glutathione and white blood cell glutathione peroxidase activity decreased with distance (P < 0.001). Positive correlations were found for plasma lipid hydroperoxides on CK (r = 0.25; P = 0.001) and AST (r = 0.33; P < 0.001). These results establish an association between muscle leakage and a cumulative index of oxidative stress.

Speed associated with plasma pH, oxygen content, total protein and urea in an 80 km race.

To test the hypothesis that endurance performance may be related quantitatively to changes in blood, we measured selected blood variables then determined their reference ranges and associations with speed during an 80 km race. The plan had 46 horses in a 2 x 2 factorial design testing a potassium-free electrolyte mix and a vitamin supplement. Blood samples were collected before the race, at 21, 37, 56 and 80 km, and 20 min after finishing, for assay of haematocrit, plasma pH, pO2, pCO2, [Na+], [K+], [Ca++], [Mg++], [Cl-], lactate, glucose, urea, cortisol, alpha-tocopherol, ascorbate, creatine kinase, aspartate amino transferase, lipid hydroperoxides, total protein, albumin and creatinine, and erythrocyte glutathione and glutathione peroxidase. Data from 34 finishers were analysed statistically. Reference ranges for resting and running horses were wide and overlapping and, therefore, limiting with respect to evaluation of individual horses. Speed correlations were most repeatable, with variables reflecting blood oxygen transport (enabling exercise), acidity and electrolytes (limiting exercise) and total protein (enabling then, perhaps, limiting). Stepwise regressions also included plasma urea concentration (limiting). The association of speed with less plasma acidity and urea suggests the potential for fat adaptation and protein restriction in endurance horses, as found previously in Arabians performing repeated sprints. Conditioning horses fed fat-fortified and protein-restricted diets may not only improve performance but also avoid grain-associated disorders.

Hydrolyzable carbohydrates in pasture, hay, and horse feeds: direct assay and seasonal variation.

Carbohydrates may be hydrolyzed or fermented in the digestive tract, and this distinction is important for the evaluation of the diet of herbivores. Both hydrolyzable and fermentable carbohydrates are included in the nonstructural carbohydrate (NSC) fraction as estimated by difference using proximate analysis. Our objectives were to measure hydrolyzable carbohydrates in forages and concentrates, to compare these values with nonstructural carbohydrate, to test for prediction of hydrolyzable carbohydrate concentration in forages from its near-infrared spectrum, and to examine seasonal variation of carbohydrates in pasture. Samples of forages (107) and concentrates (25) were collected, dried, ground, and analyzed for NSC (calculated as 100 - water - CP - fat - ash - NDF), hydrolyzable carbohydrate (CHO-H, direct analysis), and rapidly fermentable carbohydrate (NSC minus CHO-H). Hydrolyzable carbohydrate accounted for 97% or more of the NSC in the concentrates but only 33% in pasture and hay. A two-term polynomial equation fit all the data: CHO-H = 0.154 x NSC + 0.00136 x NSC2, R2 = 0.98, P < 0.0001, n = 132. In 83 pasture samples, CHO-H concentrations were predicted by near-infrared spectra with a calibration R2 of 0.97, a mean of 48 g/kg, and a SE of calibration of 3.5 g/kg DM. In pasture samples collected between September 1995 and November 1996, the coefficient of variation was 31% for both CHO-H and rapidly fermentable carbohydrate (CHO-FR); the largest increments were 31 g/kg of CHO-H from September to October and 41 g/kg of CHO-FR from February to March. The increased risk of certain diseases, such as laminitis and colic, that have been previously associated with an abrupt overload of NSC may be more precisely attributed to CHO-H in grain concentrates, and to CHO-H as well as CHO-FR in pastures.

Efficacy of intra-hepatectomy 5-FU on recurrence and metastasis of human hepatocellular carcinoma in nude mice.

A novel intra-operative chemotherapy nude mouse model for human hepatocellular carcinoma (HCC) has been developed. Intra-peritoneal (i.p.) administration of 5-fluorouracil (5-FU) was begun 2 hr before hepatic resection of HCC and then continued post-operatively for 4 consecutive days. This regime, termed intra-hepatectomy chemotherapy (IHC), significantly prolonged animal survival compared with pre-operative 5-FU, neoadjuvant therapy, 5-FU post-operative adjuvant therapy, surgery alone, 5-FU without surgery, and the untreated control. The median survival of the intra-operative 5-FU-treated group was 127 days compared with 78 days for the neoadjuvantly-treated animals and 53 days for the control group (p<0.006). When all animals with neoadjuvant 5-FU treatment had died, 60% of the animals in the IHC group were still alive (p<0.011). Survival of all other treatment groups, including 5-FU without surgery, surgery alone, and adjuvant post-operative chemotherapy, was not significantly different from the untreated control group. Five animals in the IHC group were free of tumor when sacrificed at day 150 post-surgically. While 100% of animals in the control group had lymph nodes draining the liver involved with metastases, only 20% of animals in the IHC group had lymph node metastases. These data suggested that IHC therapy increased survival by preventing metastases of cancer cells not removed in the liver resection procedure. The results of this study indicate that IHC therapy for resection of HCC should be investigated clinically.

Antimetastatic intraoperative chemotherapy of human colon tumors in the livers of nude mice.

We have developed a new antimetastatic chemotherapeutic strategy for combination with hepatic resection of human colon cancers in a high-metastasis nude mouse model. The new procedure involves i.p. administration of 5-fluorouracil (5-FU) 2 h before hepatic resection of the human colon tumors, with therapy continued postoperatively for 4 consecutive days. We termed this strategy neo-neoadjuvant chemotherapy. The regime significantly prolonged animal survival compared with preoperative 5-FU neoadjuvant therapy, 5-FU postoperative adjuvant therapy, surgery alone, 5-FU without surgery, or the untreated control. The median survival of neo-neoadjuvant i.p. 5-FU-treated group was 81 days, compared with 27 days for the control group (P < 0.009). The median survival of animals in the neoadjuvant group was 37 days (P < 0.021 compared with the control group). There was also a significant difference between the median survival of neo-neoadjuvant, and the neoadjuvant group (P < 0.031). When all animals in the control group had died, 70% of animals with neo-neoadjuvant and 60% of animals with neoadjuvant 5-FU were still alive (P < 0.003 and P < 0.011, respectively). When all animals with neoadjuvant 5-FU treatment had died, 70% of animals with neo-neoadjuvant treatment were still alive (P < 0.003). Survival of all other treatment groups, including 5-FU without surgery, surgery alone, and adjuvant postoperative chemotherapy, was not significantly different from the untreated control group. Two animals in the neo-neoadjuvant group were free of tumors when sacrificed at days 154 and 165 post surgery. Whereas 100% of animals in the control, 90% in the 5-FU alone, 70% in the surgery alone, 60% in the 5-FU adjuvant, and 40% in the neoadjuvant groups had metastases in the lymph nodes draining the liver, only 10% of animals in the neo-neoadjuvant group had metastases. These data suggest that the neo-neoadjuvant therapy increased survival by preventing metastasis of cancer cells not removed in the liver resection procedure. The results of this study indicate that the neo-neoadjuvant treatment strategy for resection of colon cancer liver metastasis should be explored clinically.

Alpha-tocopherol supplementation for men with existing coronary artery disease: a feasibility study.

BACKGROUND: Recent studies have suggested that alpha-tocopherol supplementation can help reduce the incidence of coronary disease. Our objectives were to determine the feasibility of providing alpha-tocopherol supplements to male veterans with existing coronary artery disease and determine its effects on alpha-tocopherol levels and the susceptibility of low-density lipoprotein (LDL) to oxidation. METHODS: Fifty-seven percent of 138 coronary disease patients were willing to participate in a placebo-controlled trial -25% were already taking antioxidants. Thirty-nine men were randomly assigned to either 400 mg/day of alpha-tocopherol (n = 27) or placebo (n = 12). alpha-Tocopherol levels and LDL oxidation (measured by formation of thiobarbituric acid-reactive substance) were measured at baseline and at 6 months. RESULTS: Thirty-three subjects (22 alpha-tocopherol, 11 placebo) completed the study; 3 subjects withdrew after suffering coronary disease events. Supplement compliance exceeded 90% and alpha-tocopherol was well tolerated. The alpha-tocopherol group had a significantly greater mean increase in lipid-adjusted alpha-tocopherol levels (73% vs. -4.6%, P < 0.0001), but oxidized LDL did not change significantly. CONCLUSIONS: A secondary prevention trial among veterans would be feasible because the rates of enrollment, completion, compliance, and clinical events were high. alpha-Tocopherol supplements did not decrease the susceptibility of LDL to oxidation, suggesting that higher dosages or longer duration of supplementation may be required for secondary prevention.

Dietary carbohydrates and fat influence radiographic bone mineral content of growing foals.

Hydrolyzable carbohydrate intake in horse diets may become excessive when rapidly growing pastures are supplemented with grain-based concentrates. The substitution of fat and fiber for hydrolyzable carbohydrate in concentrates has been explored in exercising horses but not in young, growing horses. Our objective was to compare bone development in foals that were fed pasture and concentrates rich in sugar and starch (corn, molasses) or fat and fiber (corn oil, beet pulp, soybean hulls, oat straw). Forty foals were examined, 20 each in 1994 and 1995. In each year, 10 mares and their foals were fed a corn and molasses supplement (SS) and 10 others were fed a corn oil and fiber supplement (FF). The concentrates were formulated to be isocaloric and isonitrogenous, and mineral content was balanced to complement the pastures and meet or exceed NRC requirements. Dorsopalmar radiographs were taken of the left third metacarpal monthly from birth to weaning and then every other month until 1 yr of age. Bone density was estimated using imaging software and an aluminum stepwedge. Radiographic examination indicated differences in medial, lateral, and central bone mineral content of the metacarpal III. Bone mineral content increased with age, and a plateau was observed during winter. Bone mineral content was lower in weanlings and yearlings fed the FF supplement than in those fed SS. Subjective clinical leg evaluations indicated differences in physitis, joint effusion, and angular and flexural limb deformities in response to age, and possibly to season. Regression analysis indicated positive relationships between bone mineral content and body weight, age, and body measurements. Nutrient and chemical interactions, such as the binding of calcium by fat and fiber, may alter the availability of elements necessary for bone development.

Preweaning diet and stall weaning method influences on stress response in foals.

The stress response of foals during weaning was examined in terms of a behavioral protocol and the responses of plasma ascorbate, serum cortisol, and the serum cortisol response to an ACTH challenge. The experimental plan was a 2 x 2 factorial of two preweaning diets and two stall weaning methods. Dietary groups included foals raised on pasture supplemented with hay and a pelleted concentrate (PHC) and foals raised on pasture supplemented with hay only (PH). Stall weaning methods included foals placed in stalls singly or in pairs. Sex influences were also examined. The foals exhibited characteristic behavioral and physiological responses to weaning stress. Behavior scores indicated fewer outward signs of stress in single than in paired foals (P = .008) and tended to indicate fewer signs of stress in PHC than in PH foals (P = .15). No differences in plasma ascorbate concentrations were found among treatments. Responses of serum cortisol to an ACTH challenge were lower (representing adrenal depletion arising from stress) in PH than in PHC foals (P = .001) and in paired than in single foals (P = .058). Behavior scores were positively correlated with the response of serum cortisol to ACTH. Both behavioral data and the ACTH response indicated that foals may cope better with weaning when supplemented with concentrate before weaning or when placed singly in stalls rather than in pairs.

Clinical applications of the histoculture drug response assay.

There is a need for a clinically useful drug-response assay for cancer patients to individualize their chemotherapy. Collagen sponge-gel-supported histoculture has been shown to maintain tissue architecture and function in vitro and has been utilized to develop the histoculture drug-response assay (HDRA) for individualizing chemotherapy. In order to evaluate the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point for clinical use, chemosensitivity to mitomycin C, doxorubicin, 5-fluorouracil, and cisplatin of 107 advanced gastric and 109 advanced colorectal cancers was determined in vitro in a correlative clinical trial. Two hundred eight (96.3%) of 216 of the patient specimens were evaluable in the HDRA. Thirty-eight patients with remaining measurable lesions after surgery were evaluable for comparison of the effects of chemotherapy in the HDRA with clinical outcome. Their overall response in the HDRA to all four drugs correlated to published historical data. Twenty-nine patients were treated with drugs shown to be ineffective in the HDRA, and all 29 cases showed clinical chemoresistance. In nine patients treated with drugs shown to be effective in the HDRA, six showed clinical chemoresponse and three showed arrest of disease progression. The correlation rate of the assay to clinical drug-sensitivity response was thus calculated to be 92.1% (35/38), with 100% (29/29) true-negative and 66.7% (6/9) true-positive rates, 100% (6/6) sensitivity, and 90.6% (29/32) specificity. Thirty-two patients with stage III and IV gastric cancer without remaining measurable tumor lesions after surgery were treated with mitomycin C and a fluoropyrimidine adjuvantly. The survival rate of 10 patients whose tumors were sensitive to either mitomycin C and/or 5-fluorouracil in the assay was significantly (P < 0.005) better than that of 22 patients whose tumors were shown to be insensitive to both drugs. Twenty-nine patients with stage III and IV colorectal cancer without remaining measurable tumor lesions after surgery were treated with fluoropyrimidines adjuvantly. The recurrence-free survival rate of 7 patients whose tumors were sensitive to 5-fluorouracil in the assay was significantly (P < 0.05) better than that of 22 patients whose tumors were insensitive. Thus the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point should be of clinical value to choose optimal chemotherapy for response as well as for survival.

Antioxidants and the prevention of coronary heart disease.

Oxygen-free radical reactions have been implicated in many chronic disease processes, including atherosclerotic cardiovascular disease. Recent studies of lipid metabolism have suggested that oxidative modification of low-density lipoprotein accelerates atherogenesis. Micronutrient antioxidants, including alpha-tocopherol and beta-carotene, however, can neutralize oxygen-free radicals and inhibit low-density lipoprotein oxidation. This review examines (1) the role of oxidized low-density lipoprotein in atherogenesis, (2) the association between nutritional antioxidant intake and atherosclerosis, and (3) observational and clinical trial data on the effect of antioxidants in reducing the risk of coronary heart disease. While evidence suggests that antioxidant supplements protect against coronary heart disease, definitive recommendations await results from ongoing randomized trials of primary and secondary prevention.

In vivo-like drug responses of human tumors growing in three-dimensional gel-supported primary culture.

An in vitro test of cell sensitivity to drugs that indicates in vivo response is an important need in cancer therapy and cancer drug development. Toward this end, we previously developed a collagen gel-supported culture system for growth of human tumors. This three-dimensional culture system is general and grows tumors at high frequency directly from surgery or biopsy that maintain important in vivo properties in vitro, including tissue architecture. We report here that with autoradiographic techniques measuring cellular DNA synthesis the drug responses of individual cells within the tissue structure of in vitro-grown tumors can be determined. Twenty tumor classes, including all the major ones, have been measured in toto at greater than 50% frequency. Quantitative and qualitative results show increasing cell kill with rising cytotoxic drug concentration, differential drug sensitivities of multiple cell types within individual cultured tumors, differential sensitivities of a series of tumors of the same histopathological classification to a single drug, differential sensitivities of individual tumors to a series of drugs, and sensitivity patterns of various tumor types similar to the sensitivities found in vivo. Therefore, the results indicate that potentially important therapeutic data can be obtained from tumor specimens growing in vitro for the individual cancer patient as well as for rational and relevant screening for new agents active against human solid tumors.

High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine.

Unlike normal cells, malignant rat and two simian virus 40-transformed human cell lines can neither grow nor survive in B12-and folate-supplemented media in which methionine is replaced by homocysteine. Yet three lines of evidence indicate that the malignant and transformed cells synthesize large amounts of methionine endogenously through the reaction catalyzed by 5-methyltetrahydropteroyl-L-glutamate; L-homocysteine S-methyltransferase (EC 2.1.1.13). (1) The activities of this methyltransferase were comparable in extracts of malignant and normal cells. (2) The uptake of radioactive label from [5-14C]methyltetrahydropteroyl-L-glutamic acid (5-Me-H4PteGlu) was at least as great in the malignant cells as in the normals and was nearly totally dependent on the addition of homocysteine, the methyl acceptor; furthermore, 59-84% of the label incorporated by cells was recovered as methionine.