Showing papers in "Journal of the National Cancer Institute in 1988"
TL;DR: The predicted carboxy-terminal protein sequence encoded by the pNM23 cDNA clone is novel compared with Genebank animal, bacterial, and viral sequences and may be associated with intrinsic aggressiveness.
Abstract: We describe a gene, NM23, that is associated with the tumor metastatic process. NM23 RNA levels were highest in cells and tumors of relatively low metastatic potential in two experimental systems: (1) murine K-1735 melanoma cell lines, in which the gene was identified, and (2) N-nitroso-N-methylurea-induced rat mammary carcinomas. NM23 RNA levels did not correlate with cell sensitivity to host immunological responses and may, therefore, be associated with intrinsic aggressiveness. The predicted carboxy-terminal protein sequence encoded by the pNM23 cDNA clone is novel compared with Genebank animal, bacterial, and viral sequences.
1,283 citations
TL;DR: Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy.
Abstract: Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-01 between November 1977 and October 1986 Their average time on study was 641 months The patients were randomized to receive no further treatment (184 patients), postoperative adjuvant chemotherapy with 5-fluorouracil, semustine, and vincristine (MOF) (187 patients), or postoperative radiation therapy (184 patients) The chemotherapy group, when compared with the group treated by surgery alone, demonstrated an overall improvement in disease-free survival (P = 006) and in survival (P = 05) Employing the proportional hazards model, a global test was used to determine the presence of treatment interactions Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy When evaluated according to sex, the benefit for chemotherapy at 5 years, both in disease-free survival (29% vs 47%; P less than 001; relative odds, 200) and in survival (37% vs 60%; P = 001; relative odds, 193), was restricted to males When males were tested for age trend with the use of a logistic regression analysis, chemotherapy was found to be more advantageous in younger patients When the group receiving post-operative radiation (4,600-4,700 rad in 26-27 fractions; 5,100-5,300 rad maximum at the perineum) was compared to the group treated only by surgery, there was an overall reduction in local-regional recurrence from 25% to 16% (P = 06) No significant benefit in overall disease-free survival (P = 4) or survival (P = 7) from the use of radiation has been demonstrated The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant In conclusion, this investigation has demonstrated a benefit from adjuvant chemotherapy (MOF) for the management of rectal cancer The observed advantage was restricted to males Postoperative radiation therapy reduced the incidence of local-regional recurrence, but it failed to affect overall disease-free survival and survival
976 citations
TL;DR: This paper addresses the latter assumption of the distribution of the response variable by applying a direct and flexible approach, cubic spline functions, to two widely used models: the logistic regression model for binary responses and the Cox proportional hazards regression models for survival time data.
Abstract: Multiple regression models are increasingly being applied to clinical studies. Such models are powerful analytic tools that yield valid statistical inferences and make reliable predictions if various assumptions are satisfied. Two types of assumptions made by regression models concern the distribution of the response variable and the nature or shape of the relationship between the predictors and the response. This paper addresses the latter assumption by applying a direct and flexible approach, cubic spline functions, to two widely used models: the logistic regression model for binary responses and the Cox proportional hazards regression model for survival time data.
841 citations
TL;DR: The findings from this study are the first from a randomized prospective clinical trial to demonstrate that a significant disease-free survival and survival benefit can be achieved with postoperative adjuvant chemotherapy in patients with Dukes B and C carcinoma of the colon who have undergone curative resection.
Abstract: Data are presented from 1,166 patients with Dukes B and C carcinoma of the colon who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-01 between November 1977 and February 1983. Patients were randomized to one of three therapeutic categories: 1) no further treatment following curative resection (394 patients); 2) postoperative chemotherapy consisting of 5-fluorouracil, semustine, and vincristine (379 patients); or 3) postoperative BCG (393 patients). The average time on study was 77.3 months. A comparison between patients receiving postoperative adjuvant chemotherapy and those treated with surgery alone indicated that there was an overall improvement in disease-free survival (P = .02) and survival (P = .05) in favor of the chemotherapy-treated group. At 5 years of follow-up, patients treated with surgery alone were at 1.29 times the risk of developing a treatment failure and at 1.31 times the likelihood of dying as were similar patients treated with combination adjuvant chemotherapy. Comparison of the BCG-treated group with the group treated with surgery alone indicated that there was no statistically significant difference in disease-free survival (P = .09). There was, however, a survival advantage in favor of the BCG-treated group (P = .03). At 5 years of follow-up, patients randomized to the surgery-alone arm were at 1.28 times the risk of dying as were similar patients treated with BCG. Further investigation disclosed that this survival advantage in favor of BCG was a result of a diminution in deaths that were non-cancer related. When analyses were conducted on which events not related to cancer recurrence were eliminated, the survival difference between the BCG and control groups became nonsignificant (P = .40); the cumulative odds at 5 years decreased from 1.28 to 1.10. The findings from this study are the first from a randomized prospective clinical trial to demonstrate that a significant disease-free survival and survival benefit can be achieved with postoperative adjuvant chemotherapy in patients with Dukes B and C carcinoma of the colon who have undergone curative resection.
387 citations
TL;DR: There was an inverse relationship between fruit intake and risk of oral and pharyngeal cancer; individuals in the highest quartile of intake had about half the risk of those in the lowest quartile.
Abstract: A population-based case-control study of oral and pharyngeal cancer conducted in four areas of the United States provided information on a number of risk factors, including diet. Interviews were obtained from 871 oral cancer patients and 979 controls among whites, frequency matched for age and sex. Consumption frequency of 61 food items was assessed in the questionnaire; attention was given to foods that are sources of vitamins A and C and carotene. The major finding was an inverse relationship between fruit intake and risk of oral and pharyngeal cancer; individuals in the highest quartile of intake had about half the risk of those in the lowest quartile. Vitamin C, carotene, or fiber in fruit did not appear to account completely for this relationship, since these nutrients in vegetables did not provide similar protection. This finding suggests the influence of other constituents in fruits, although it is possible that cooking vegetables may have a nutrient-diminishing effect. Dietary intake of other nutrients, such as the B vitamins, vitamin E, folate, and iron, showed no consistent relationship to risk of oral and pharyngeal cancer. Coffee or other hot beverage consumption did not increase risk; intake of nitrite-containing meats or cooking practices, such as smoking, pickling, or charcoal grilling, also did not increase risk. All analyses were adjusted for the effects of tobacco and alcohol, strong risk factors for oral and pharyngeal cancer. Dietary findings among the few subjects who did not use tobacco or alcohol were similar to those for all subjects.
324 citations
TL;DR: The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels and Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rhTNF levels of 90-900 pg/mL, despite continuous infusion, no steady-state level was achieved.
Abstract: Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.
321 citations
TL;DR: The cytotoxicity of etoposide is caused by the induction of DNA damage, and the occurrence of the DNA lesions can be explained by the capacity of the drug to interfere with the scission-reunion reaction of mammalian topoisomerase II by stabilizing a cleavable complex.
Abstract: Metabolism studies of the antitumor drug etoposide show the formation of metabolites in the lactone ring, which are probably not important for the drug's mechanism of action, and oxidative transformations in the dimethoxyphenol ring (E ring), which lead to products that can cause DNA damage and may play a role in the drug's mechanism of action. The cytotoxicity of etoposide is caused by the induction of DNA damage. The occurrence of the DNA lesions can be explained by the capacity of the drug to interfere with the scission-reunion reaction of mammalian topoisomerase II by stabilizing a cleavable complex.
293 citations
TL;DR: The results suggest that the effectiveness of a given fatty acids in killing cancer cells correlated with the extent of lipid peroxidation of the added fatty acid in the cells.
Abstract: The contribution of lipid peroxidation to the killing of human breast cancer cells by gamma-linolenate (GLA) was examined. Other fatty acids of different cytotoxic potential containing 2, 4, 5, and 6 double bonds were also tested for comparison. It was found that the cytotoxic potential varied with the ability of the fatty acids to stimulate the production of superoxide radicals. Neither hydrogen peroxide nor hydroxy radicals are significantly involved in cell killing. As nonspecific indicators of lipid peroxidation, measurements of the loss of unsaturated fatty acid in the phospholipids together with the generation of hydroperoxide breakdown products were done with the use of the thiobarbituric acid test. The results of these experiments showed that the effectiveness of a given fatty acid in killing cancer cells correlated with the intracellular thiobarbituric acid-reactive material (TBARM) content: GLA and arachidonate with 3 and 4 double bonds generated the most TBARM and were the most cytotoxic fatty acids, whereas docosahexaenoate with 6 double bonds was the least effective either in raising TBARM or in killing the malignant cells. Iron and copper accelerated the rate of cell death, whereas antioxidants such as vitamin E and butylated hydroxyanisole inhibited the effect of GLA dose dependently. Indomethacin, an inhibitor of endoperoxide formation, did not reduce either cell kill or TBARM amounts. In contrast, the addition of vitamin E acetate to the cancer cell cultures challenged with eicosapentaenoate reduced both cell killing and TBARM content. These results suggest that the effectiveness of a given fatty acid in killing cancer cells correlated with the extent of lipid peroxidation of the added fatty acid in the cells.
285 citations
TL;DR: The reduced breast cancer mortality in the study group appears to result from lower mortality in stage I cases as well as from earlier case detection, and this may explain differences between the two age-at-entry cohorts in the length of follow-up time required to demonstrate a mortality reduction due to screening.
Abstract: The Health Insurance Plan (HIP) of Greater New York conducted a clinical trial to determine if screening for breast cancer with mammography and clinical examination would decrease breast cancer mortality. The extent of disease at diagnosis among breast cancers detected by screening and the effect of screening on breast cancer mortality have been evaluated in the cohort of all HIP women diagnosed with breast cancer within 6 years of entry into the trial and followed at least 18 years after trial entry. Six years was the earliest time at which the number of cases diagnosed in the control group was equal to the number of cases diagnosed in the study group. In the cohorts of women 40-49 and 50-64 years of age at entry, shifts were significant to lower stages for screen-detected cases. As a result, the study group women in each age cohort had significantly lower breast cancer mortality than control group women when statistical analyses were restricted to data from cases only. In the 40-49 age-at-entry cohort, the reduced breast cancer mortality in the study group appears to result from lower mortality in stage I cases as well as from earlier case detection, and this may explain differences between the two age-at-entry cohorts in the length of follow-up time required to demonstrate a mortality reduction due to screening.
277 citations
TL;DR: It is postulated that cancer risk is proportional to the number of proliferating cells, which in turn depends on both theNumber of cells and the rate of cell division within the tissue.
Abstract: Relatively little is known about the mechanisms underlying carcinogenesis in humans. Caloric restriction strongly inhibits the development of neoplasia in rodents, and there is evidence of a positive relationship between cancer and body weight in humans. Caloric restriction early in life is also known to permanently diminish organ cellularity. A recent link between adult stature and cancer incidence similarly implicates a lasting effect for growth and possibly for early nutrition in carcinogenesis. It is postulated that cancer risk is proportional to the number of proliferating cells, which in turn depends on both the number of cells and the rate of cell division within the tissue. This hypothesis is consistent with several aspects of human carcinogenesis, including multistage models and the epithelial origin of most cancers.
264 citations
TL;DR: While the inherent radiosensitivity of tumor cells is likely to affect treatment outcome, the biochemical and physiologic state of the cell may have a major impact.
Abstract: While the inherent radiosensitivity of tumor cells is likely to affect treatment outcome, the biochemical and physiologic state of the cell may have a major impact. Tumors are likely to be highly heterogeneous for these dynamic properties. Hypoxic cells are radioresistant, requiring two to three times the radiation dose to kill them compared to the same cells in a eu-oxic state. Hypoxia can be of two types: 1) chronic hypoxia, which is diffusion limited, and 2) acute hypoxia, which is perfusion limited. The mechanism of and approaches toward these are different and can serve as a model for other biochemical and physiologic processes that may affect treatment outcome.
TL;DR: When the anti-EGF receptor antibodies were added together with cisplatin, the antitumor effect was greatly enhanced, suggesting that the toxic activity of these agents is synergistic.
Abstract: Iodine-125-labeled monoclonal antibody 108.4 (108.4 mAb), raised against the extracellular domain of the epidermal growth factor (EGF) receptor, was shown to visualize sc xenografts of human oral epidermoid carcinoma (KB) cells in nude mice. In vitro, although EGF caused an increase in the number of KB cell colonies (150% at a concentration of 160 mM), the anti-EGF receptor antibodies reduced clone formation. At a concentration at which EGF caused a 50% increase in colony number, the addition of a 100-fold molar excess of 108.4 mAb resulted in a decrease in the number of cell colonies to 20% of the original value. Therefore, the effect of antibody on the KB tumor was studied in vivo in three different modes of tumor transplantation. Antitumor activity was demonstrated first by retardation (versus controls) of the growth of tumor cells as sc xenografts (P greater than .017), then by prolongation of the life span of animals with the ip form of the tumor (P less than .001), and finally on an experimental lung metastasis by a reduction in the number and size of tumors (P less than .05). When the anti-EGF receptor antibodies were added together with cisplatin, the antitumor effect was greatly enhanced, suggesting that the toxic activity of these agents is synergistic (P less than .007). The antitumor effect persisted when animals were treated with the F(ab)'2 fragment of the antibody, although it was less efficient. The Fab fragment of the antibody, whose ability to bind to the cell-associated receptor was completely conserved, did not affect the growth of the tumor. The activity manifested by the F(ab)'2 fragment of the anti-EGF receptor antibodies suggested that the antitumor effect was not due to immune mechanisms requiring the Fc portion of the antibody.
TL;DR: Postirradiation sarcoma (PIS), while still uncommon, is a complication which is appearing more frequently as the number of long-term survivors increases, and it should be weighed in the decision to use this modality of therapy.
Abstract: The number of cancer patients who live longer and are cured of their disease is increasing. Many of them have received radiotherapy as part of their treatment. Postirradiation sarcoma (PIS), while still uncommon, is a complication which is appearing more frequently as the number of long-term survivors increases. Studies of the clinical characteristics of PIS, such as stage of disease, grade, survival, and prognosis, are therefore of increasing importance, and may lead to different strategies for early detection and prevention. In a literature review of PIS, we identified 344 cases with sufficient data for analysis of these clinical characteristics. In these selected cases, we found that: (a) PIS was most often diagnosed at an advanced stage and high grade; (b) most of the tumors were located in areas where radical surgery could not be performed; (c) the response rate to chemotherapy was almost always poor; and (d) most patients with PIS died from locally advanced and/or metastatic disease within a few months after diagnosis. PIS is a serious, usually fatal, late complication of radiotherapy and it should be weighed in the decision to use this modality of therapy. In the follow-up of cancer patients, a low threshold of suspicion for PIS is recommended in order to detect it early for possible resection. Because of the poor prognosis, more aggressive and investigative chemotherapeutic regimens are warranted.
TL;DR: Data from international, migrant-population, and analytic epidemiologic investigations are used to motivate the basic relative risk assumption of study designs thus far proposed for the Women's Health Trial, and some continuing motivations for a dietary intervention (low-fat diet) trial are discussed.
Abstract: A 5.5-fold range in breast cancer incidence rates in 21 countries shows strong correlation with national estimates of per capita intake of dietary fat, but not with other caloric sources (proteins and carbohydrates). It is argued that certain breast cancer and hormone factors may contribute little to the explanation of such international variations in incidence of this neoplasm. It is further argued that experimental studies in animals support a specific role for dietary fat in the promotion of mammary tumors, but the effects of calories alone seem to be largely restricted to tumor initiation. Finally, data from international, migrant-population, and analytic epidemiologic investigations are used to motivate the basic relative risk assumption of study designs thus far proposed for the Women's Health Trial, and some continuing motivations for a dietary intervention (low-fat diet) trial are discussed.
TL;DR: The results indicate that for all three sensitizers the effects of photodynamic therapy leading to rapid necrosis of tumor tissue are not the result of direct tumor cell kill but are secondary to destruction of the tumor microvasculature.
Abstract: The effect of photodynamic therapy on the tumor microvasculature in the first few hours after treatment was studied at the light and electron microscopy levels. BALB/c mice with EMT-6 tumor received ip injections of hematoporphyrin derivative, chlorin, or phthalocyanine, and 24 hours later, the tumors were treated with light at 100 J/cm2 at the appropriate therapeutic wavelength for each photosensitizer. Animals were killed and their tumors removed at time 0, 30 minutes, 1 hour, and 2, 4, 6, 8, 12, 16, and 24 hours after treatment. The results indicate that for all three sensitizers the effects of photodynamic therapy leading to rapid necrosis of tumor tissue are not the result of direct tumor cell kill but are secondary to destruction of the tumor microvasculature. The first observable signs of destruction occur in the subendothelial zone of the tumor capillary wall. This zone, composed of dense collagen fibers and other connective tissue elements, is destroyed in the first few hours after phototherapy. However, the ultrastructural changes seen in this zone are different for the hematoporphyrin derivative, compared with chlorin and phthalocyanine. Binding of photosensitizers to the elements in this zone as well as altered permeability and transport through the endothelial cell layer because of the increased intraluminal pressure may be key features of tumor destruction.
TL;DR: It is suggested that deletion of a gene or genes on 9p, possibly interferon genes, is an initial step in the malignant transformation of melanocytes.
Abstract: We karyotypically analyzed cultured melanocytes from a variety of lesions, including congenital and dysplastic nevi, primary melanoma, and metastatic melanoma. The cells derived from congenital nevi had normal karyotypes, as did 22 of the 26 cultures derived from dysplastic nevi. The karyotypes of melanocytes from primary and metastatic melanomas were all abnormal. The only chromosome change in common between the nevi with abnormal karyotypes and the melanomas was the loss of one copy of chromosome 9 (two of four nevi and four of 11 melanomas, including three from the same patient) or the loss of the short arm of chromosome 9, especially of region 9pter-p22 (three of 11 melanomas). We suggest that deletion of a gene or genes on 9p, possibly interferon genes, is an initial step in the malignant transformation of melanocytes.
TL;DR: Simultaneous implantation of intact Noble (Nb) rats with testosterone and 17 beta-estradiol (E2)-filled silastic capsules for 16 weeks caused atypical hyperplasia (dysplasia) and striking enlargement exclusively in the dorsolateral prostates (DLPs) of all animals, implicating estrogen as a key factor in the genesis of the proliferative lesion.
Abstract: Simultaneous implantation of intact Noble (Nb) rats with testosterone and 17 beta-estradiol (E2)-filled silastic capsules for 16 weeks caused atypical hyperplasia (dysplasia) and striking enlargement exclusively in the dorsolateral prostates (DLPs) of all animals. The dysplastic lesion may be preneoplastic since long-term administration of these steroids to Nb rats is known to induce a high incidence of adenocarcinoma in the DLP. Treatment of rats with nonaromatizable 5 alpha-dihydrotestosterone (DHT) for 16 weeks caused enlargement but not dysplasia, implicating estrogen as a key factor in the genesis of the proliferative lesion. Compared with controls, the testosterone plus E2 treatment caused a 2.5-fold increase in nuclear type II estrogen binding sites which were confined to the DLP. Neither treatment significantly altered androgen content or levels of androgen receptor in the ventral prostate or DLP. Organ cultures of enlarged DLP containing foci of dysplasia metabolized more [3H]DHT than control tissue, which resulted in increased formation of the 5 alpha-androstane-3 beta, 17 beta-diol (3 beta-androstanediol) metabolite by these explants. Because 3 beta-androstanediol has previously been shown to displace [3H]E2 from cytosolic type I estrogen binding sites, the dysplasia may be caused by hyperstimulation of the DLP by the hormones and their normal metabolites produced in abnormal amounts.
TL;DR: Observations suggest that both MDR and cytochrome P-450 gene families are evolutionarily selected by the capacity of various xenobiotics to induce their own detoxification either through metabolism to hydrophilic derivatives by the cyto Chrome P- 450 system or direct excretion from the cell by the MDR gene family.
Abstract: The levels of mRNA for multidrug-resistance (MDR-1) and selective cytochrome P-450 genes were determined in adult rat liver following administration of various natural and synthetic xenobiotics. MDR-1 (also known as PGY1) was induced following administration of aflatoxin B1, 2-(acetylamino)fluorene (AAF), N-hydroxy-2-(acetylamino)fluorene, isosafrole, phenothiazine, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but not after phenobarbital or 7-hydroxy-2-(acetylamino)fluorene treatment. Cytochrome P-450 isoform d was induced by TCDD, isosafrole, phenothiazine, and AAF, while cytochrome P-450 isoform b was induced by phenobarbital, and to a lesser extent by isosafrole. These observations suggest that both MDR and cytochrome P-450 gene families are evolutionarily selected by the capacity of various xenobiotics to induce their own detoxification either through metabolism to hydrophilic derivatives by the cytochrome P-450 system or direct excretion from the cell by the MDR gene family. Furthermore, the data indicate that induction of selective members of the MDR and the cytochrome P-450 gene families may depend on overlapping regulatory elements.
TL;DR: Two important mechanisms for the antineoplastic activity of NDV are suggested: induction of TNF-alpha secretion by human PBMCs and enhancement of the sensitivity of neoplastic cells to the cytolytic effects of T NF-alpha.
Abstract: The oncolytic strain 73-T of Newcastle disease virus (NDV) has been reported to be beneficial in the treatment of cancer patients, but little is known about its mechanism of action. In this study, NDV strain 73-T and a wild-type isolate of NDV were found to be potent inducers of tumor necrosis factor (TNF) production by both human peripheral blood mononuclear cells (PBMCs) and rat splenocytes. Antibody inhibition experiments identified TNF-alpha as the major species of TNF induced by NDV in PBMCs. The effect of recombinant human TNF-alpha (rHuTNF-alpha) on human cancer cells was then examined. Neither rHuTNF-alpha nor supernatants from NDV-stimulated PBMCs were cytotoxic toward the TNF-resistant human malignant melanoma cell line MEL-14. However, when MEL-14 cells were treated with NDV strain 73-T, both rHuTNF-alpha and supernatants from NDV-stimulated PBMCs killed 48% and 55%, respectively, of these tumor cells. Treatment with NDV also conferred TNF susceptibility to the TNF-resistant human malignant melanoma cell line MEL-21 and the human myelogenous leukemia cell line K562. In contrast to its enhanced cytotoxicity toward NDV-treated cancer cells, rHuTNF-alpha had no effect on NDV-treated normal human PBMCs proliferating in response to concanavalin A. These results suggest two important mechanisms for the antineoplastic activity of NDV: (a) induction of TNF-alpha secretion by human PBMCs and (b) enhancement of the sensitivity of neoplastic cells to the cytolytic effects of TNF-alpha.
TL;DR: The findings suggest that efforts aimed at reducing tobacco and alcohol use will help to lower the elevated rates of esophageal cancer in coastal South Carolina.
Abstract: A case-control study involving interviews of 207 men with esophageal cancer and 422 control subjects or their next of kin was conducted to identify reasons for the unusually high rates of esophageal cancer among men in coastal South Carolina. Tobacco and alcohol, including moonshine, were identified as the major determinants of esophageal cancer risk. Increased risk was also associated with low intake of fresh fruits but not with drinking of local herbal teas. The findings suggest that efforts aimed at reducing tobacco and alcohol use will help to lower the elevated rates of esophageal cancer in coastal South Carolina.
TL;DR: Most patients with metastatic gastrointestinal adenocarcinoma had an antibody response to 17-1A, with peak levels occurring 15-22 days after infusion, and the administration of four doses of 400 mg over 1 week provided continuously circulating 17- 1A for 10 days.
Abstract: Twenty-five patients with metastatic gastrointestinal adenocarcinoma received one to four infusions of large doses (400 mg) of murine monoclonal antibody CO17-1A (17-1A). The pharmacokinetics of 17-1A at the time of first, second, third, or fourth infusion were not statistically different; plasma half-lives were 15.0 +/- 1.7 hours (n = 5), 15.1 +/- 1.8 (n = 10), 25.3 +/- 6.2 (n = 3), and 14.4 +/- 1.8 (n = 5), respectively. Most patients had an antibody response to 17-1A, with peak levels occurring 15-22 days after infusion. The presence of serum antibody to 17-1A at the time of the second or third infusion did not significantly alter the pharmacokinetics of this large dose of antibody. Four of 25 patients failed to develop an antibody response, but this did not correlate with the amount of 17-1A administered. The administration of four doses of 400 mg over 1 week provided continuously circulating 17-1A for 10 days.
TL;DR: A total of 277 patients with untreated Hodgkin's disease, clinical stages I-II, were randomized to cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) alone for 6 monthly cycles or to CVPP plus radiation therapy (RT), 3,000 rad, to involved areas (C VPP plus RT).
Abstract: A total of 277 patients with untreated Hodgkin's disease, clinical stages I-II, were randomized to cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) alone for 6 monthly cycles or to CVPP plus radiation therapy (RT), 3,000 rad, to involved areas (CVPP plus RT). One or more of the following factors were considered as unfavorable prognosis: age greater than 45 years, more than two lymph node areas involved, or bulky disease. In the favorable group, disease-free survival (77% vs. 70%) or overall survival (92% vs. 91%) at 84 months for CVPP versus RT plus CVPP was similar. Patients with unfavorable prognosis treated with RT plus CVPP had longer disease-free survival (75% vs. 34%) (P = .001) and overall survival (84% vs. 66%) than patients treated with CVPP alone.
TL;DR: The evidence suggests that cancer risk is associated with some aspect of diet that is reflected in the effect of plasma beta-carotene, and vitamin C and beta- carotene are likely candidates.
Abstract: Both plasma and dietary measures of vitamin A status were investigated along with previously established risk factors (number of sexual partners, age at first intercourse, smoking, and oral contraceptive use) in a study of 117 in situ cervical cancer patients and 196 matched community controls in Sydney, Australia. Neither total calories nor retinol from foods was related to cancer risk, nor was plasma retinol. When plasma and dietary indexes were considered together, vitamin C, fruit juices, and plasma beta-carotene showed protective effects. Plasma beta-carotene reduced risk from top to bottom quartile by 80%, vitamin C by 60%, and fruit juices by 50%. Thus the evidence suggests that cancer risk is associated with some aspect of diet that is reflected in the effect of plasma beta-carotene. There is no clear effect of any one nutrient but fruit juices appear protective. Thus vitamin C and beta-carotene are likely candidates.
TL;DR: It is demonstrated that IL-2 given alone without lymphokine-activated killer cells in this manner can induce antitumor effects with acceptable toxicity.
Abstract: A phase I trial of repetitive weekly cycles of human recombinant interleukin-2 (IL-2) was performed in 23 patients with metastatic carcinoma. Patients received 4 days of IL-2 each week, followed by 3 days of observation, for 4 consecutive weeks. IL-2 was administered iv at 1.0 or 3.0 X 10(6) U/m2/day by one of three schedules involving continuous or bolus infusions. All treatment was carried out in a general hospital ward without intensive care unit monitoring or support. Seventeen patients had metastatic renal cell carcinoma; three of these demonstrated measurable (greater than 50% shrinkage) partial responses. This study demonstrates that IL-2 given alone without lymphokine-activated killer cells in this manner can induce antitumor effects with acceptable toxicity.
TL;DR: This study confirmed the association of malignant tumors with prior radiation treatment to the head or neck; 28% of these tumors are attributable to exposure of the parotid gland from diagnostic and therapeutic radiation.
Abstract: Findings from this population-based study in Los Angeles County suggest, for the first time, that tumors of the parotid gland are related to prior exposure to diagnostic medical and dental radiography. Responses to interviews with 408 patients with a parotid tumor (269 benign tumors and 139 malignant tumors) were compared to responses of 408 neighborhood controls. Cumulative exposure of the parotid gland from diagnostic radiography was associated with a dose-related increase in risk of malignant tumors (P for trend less than .05; relative risk for exposure to greater than or equal to 50 rad = 3.4; 95% confidence interval = 1.02-11.46). Benign tumors showed a weaker positive association, and exposure before age 20 to a major diagnostic examination (full-mouth or panoramic dental radiography or medical radiography to the head) increased risk (relative risk = 1.8; confidence interval = 1.13-2.91). This study also confirmed the association of malignant tumors with prior radiation treatment to the head or neck; 28% of these tumors are attributable to exposure of the parotid gland from diagnostic and therapeutic radiation.
TL;DR: The ability to produce all four human IgG subclass chimeric molecules which retain biologic activity is demonstrated and the subclass preferences of human lymphocyte and monocyte Fc receptors forhuman IgG subclasses previously determined by studies with monomeric or aggregated IgG are confirmed.
Abstract: Variable region genes from mouse monoclonal antibody 17-1A (gamma 2a kappa) with specificity for human gastrointestinal malignancies have been paired with human immunoglobulin constant region genes (for heavy and light chains) to produce mouse/human chimeric immunoglobulin molecules (chIgG) for each of the four human IgG subclasses. Mouse 17-1A and the four chIgG bound similarly to two human colon cancer cell lines and had comparable binding affinities. The chIgG1 and chIgG3 molecules mediated lymphocyte and monocyte antibody-dependent cell-mediated cytotoxicity (ADCC) to colon cancer tumor cell lines comparable to that of the parent murine 17-1A. The chIgG2 and chIgG4 molecules were able to mediate ADCC to colon cancer cell lines but were clearly inferior to the chIgG1 and chIgG3 reagents. None of the chIgG antibodies or the murine 17-1A was able to mediate complement lysis of colon cancer cell lines. These studies demonstrate the ability to produce all four human IgG subclass chimeric molecules which retain biologic activity. We have confirmed the subclass preferences of human lymphocyte and monocyte Fc receptors for human IgG subclasses previously determined by studies with monomeric or aggregated IgG. These data may aid in the selection of chimeric antibodies for in vivo trials.
TL;DR: It is demonstrated that combination immunotherapy can result in substantial reduction of established metastatic deposits and provide a rationale for the application of this treatment to patients with advanced cancer.
Abstract: Attempts have been made to design optimal strategies for the immunotherapy of established tumors. In mice bearing pulmonary metastases from sarcomas, a substantial therapeutic synergy was seen when both interleukin-2 (IL-2) and alfa interferon (alpha-IFN) were administered compared with the effect of either agent given alone. This synergy was dependent on Lyt-2+ T cells, since therapeutic effects were abrogated in Lyt-2-depleted mice. The alpha-IFN and IL-2 combination was also synergistic with tumor-infiltrating lymphocytes in mediating the reduction of established lung metastases. These experiments demonstrate that combination immunotherapy can result in substantial reduction of established metastatic deposits and provide a rationale for the application of this treatment to patients with advanced cancer.
TL;DR: To assess the relationship between TNF and weight loss among cancer patients, serum levels in serum were assayed from 19 patients who had lost 8%-40% of premorbid weight and no TNF was detected.
Abstract: Tumor necrosis factor (TNF) has been implicated in the pathogenesis of cachexia in neoplastic and infectious diseases. To assess the relationship between TNF and weight loss among cancer patients, we assayed TNF levels in serum from 19 patients who had lost 8%-40% of premorbid weight. The weight loss experienced by these patients was not attributable to anticancer therapy, gastrointestinal disorders, or other medical problems. TNF was measured using a quantitative sandwich enzyme-linked immunosorbent assay that is sensitive to human TNF in serum at concentrations greater than or equal to 40 pg/mL. No TNF was detected in serum samples from the 19 patients studied.
TL;DR: Although the frequency of latent prostate carcinoma and the LIT:LNT in the samples obtained most recently were comparable to those of U.S. whites, cancer incidence and mortality rates remain lower in Japan and may presage a time when these differences may be greatly reduced or nonexistent.
Abstract: By analyzing serial step-sections of whole prostate obtained at autopsy, we determined the chronologic change of the frequency of latent prostate tumor in Japan in two periods: 1965-1979 and 1982-1986. Methods of specimen preparation and examination were identical for both periods. The frequency with which latent prostate carcinoma was found in the 660 samples for 1982-1986 was 34.6% and was significantly higher than the 22.5% seen in the 576 observed for 1965-1979 (P less than .0001). This significant finding can be attributed to an increase in the frequency of latent infiltrative tumor (LIT). However, the increase in the frequency of noninfiltrative tumor (LNT) was less significant (P = .045). Both sets of specimens were subsequently combined and reanalyzed according to the year of birth of the decedents. The LIT has progressively increased in frequency in each age-specific category. By morphometry, we determined that the mean tumor volume decreased due to an increase in the number of smaller tumors during the study periods. Although the frequency of latent prostate carcinoma and the LIT:LNT in the samples obtained most recently were comparable to those of U.S. whites, cancer incidence and mortality rates remain lower in Japan. Apparently, the initial step in the induction of prostate carcinoma in indigenous Japanese is now similar to that in U.S. whites. The rates of clinical carcinoma in Japan are still low when compared with those in the United States and countries in Western Europe, but our findings may presage a time when these differences may be greatly reduced or nonexistent.
TL;DR: The results demonstrate that MACE and DACE are effective photosensitizing agents in vitro and compare favorably to DHE.
Abstract: The characteristics of two new chlorin photosensitizers were studied in cell culture by determining phototoxicity, subcellular localization, and photophysical properties. Monoaspartyl chlorin e6 (MACE) and diaspartyl chlorin e6 (DACE) are new photosensitizers that show promise for use in photodynamic therapy. These chlorins are pure, monomeric compounds as determined by high-pressure liquid chromatography. Both compounds absorb substantially at a longer wavelength (664 nm) than does dihematoporphyrin ether-ester (DHE). Tumor diagnosis with the use of fluorescence should be facilitated due to the purity of the compounds and the single fluorescence emission peak. Phototoxicity dose-response curves of the sensitizers were completed using a standard clonogenic assay to determine cell viability. The chlorins showed good sensitizing capabilities with light. In addition, subcellular localization of MACE, DACE, and DHE was studied using fluorescence microscopy. Whereas DHE was located throughout the cytoplasm, the primary site of localization of the chlorins appeared to be in the lysosome. The results demonstrate that MACE and DACE are effective photosensitizing agents in vitro and compare favorably to DHE.