Showing papers in "International Journal of Cancer in 1984"
TL;DR: A second multivariate analysis introducing clinical prognostic features showed that the histological grade was the most important prognostic factor for soft‐tissue sarcomas and appears to be highly interesting because of its prognostic value and the facility of its elaboration.
Abstract: The pathological features of 155 adult patients with soft-tissue sarcomas were studied retrospectively, in an attempt to set up a grading system for these tumors. As the first step, seven histological criteria (tumor differentiation, cellularity, importance of nuclear atypia, presence of malignant giant cells, mitosis count, pattern of tumor necrosis and presence of vascular emboli) were evaluated in a monofactorial analysis. Five of these (tumor differentiation, cellularity, mitosis count, tumor necrosis, and vascular emboli) were correlated with the advent of metastases and with survival. A multivariate analysis, using a Cox model, selected a minimal set of three factors (tumor differentiation, mitosis count, and tumor necrosis) the combination of which was necessary and sufficient to retain all the prognostic information. A grading system was elaborated, which turned out to be correlated with the advent of metastasis and with patients' survival. A second multivariate analysis introducing clinical prognostic features showed that the histological grade was the most important prognostic factor for soft-tissue sarcomas. Thus, this grading system appears to be highly interesting because of its prognostic value and the facility of its elaboration. However, its reproducibility should be tested.
1,100 citations
TL;DR: The specificity of the antibodies, tested individually, was not sufficient for further differential diagnosis of the carcinomas, but when some of these antibodies were used in a panel they contribute to an important improvement of the diagnosis.
Abstract: Mouse monoclonal antibodies have been raised against human milk-fat globule membranes (HMFGM) to obtain reagents for mammary tumor diagnosis. A panel of 17 anti-HMFGM antibodies was selected for further investigation. Antibody-blocking studies indicated that with these antibodies at least nine different non-overlapping epitopes could be distinguished on six different molecules, MAM-1 to MAM-6. Electron microscopic studies of the cellular localization of the antigens detected by some of these antibodies revealed that they were present on the cell membrane mainly, on the microvilli, lining intercellular and intracytoplasmic lumina. The reactivity of the antibodies was studied on normal and tumor tissues and on in vitro cell lines. All antibodies reacted with the resting mammary gland while eight antibodies also bound to breast tumors. None of the antibodies was specific for the mammary gland or its tumors only, but most antibodies also reacted with other epithelial cells, especially of secretory tissues. When tested on a variety of cell lines a distribution reflecting the tissue distribution could be demonstrated. One of the antibodies reacted with nearly all carcinomas and their metastases and did not react with lymphomas, sarcomas, neuroblastomas, melanomas or nervous system tumors. The specificity of the antibodies, tested individually, was not sufficient for further differential diagnosis of the carcinomas, but when some of these antibodies were used in a panel they contribute to an important improvement of the diagnosis.
503 citations
TL;DR: TNF from mice had an antitumor activity against not only murine tumors but also human tumors, and in addition to direct cytotoxicity against tumor cells, TNF induced a host‐mediated factor which contributed to the antitumors effects.
Abstract: The antitumor activity of highly purified tumor necrosis factor (TNF) was tested against eight kinds of murine tumor and five kinds of human tumor heterotransplanted into nude mice. Mice were treated by intravenous or intratumoral injection of TNF, commencing when the tumors were well established. TNF showed an excellent curative effect against all kinds of murine and human tumors tested. Meth A sarcoma, Colon 26, Ehrlich, sarcoma 180, MM 46, MH 134, B16 melanoma, and Lewis lung tumors transplanted into mice underwent tumor necrosis and regression following a single injection of TNF. Sometimes a complete cure was observed in Meth A sarcoma, sarcoma 180, Ehrlich, and MM 46 tumors. Human cancers, SEKI, HMV-I, KATO-III, MKN 45, or KB, heterotransplanted into nude mice, also exhibited tumor necrosis and regression in size following several intratumoral injections of TNF. A great difference in curative effects of TNF was observed in Meth A sarcomas between those transplanted into BALB/c nu/+ and into BALB/c nu/nu mice: following a single intravenous administration the effect was stronger in BALB/c nu/+ than in nu/nu mice. In contrast, tumor necrosis was almost the same in nu/+ and nu/nu mice following intratumoral administration. The present results thus indicate that TNF from mice had an antitumor activity against not only murine tumors but also human tumors. In addition to direct cytotoxicity against tumor cells, TNF induced a host-mediated factor which contributed to the antitumor effects.
320 citations
TL;DR: Increased risks were seen with alcohol consumption and, less strongly, with smoking, which for all sites could be adequately fitted by either a multiplicative or an additive model, however, the site‐specific relationships were different.
Abstract: A case-control study of 374 patients with primary epithelial cancers of the oral cavity, oro- and hypopharynx, and larynx is reported, the controls being patients with selected other cancers, matched for age and sex. Of all eligible patients, 93% were interviewed. Increased risks were seen with alcohol consumption and, less strongly, with smoking, which for all sites could be adequately fitted by either a multiplicative or an additive model. However, the site-specific relationships were different, alcohol consumption being significantly associated only with oral cavity, pharyngeal and extrinsic laryngeal tumours, and smoking only with intrinsic laryngeal tumours. Increased risks were associated with low socio-economic status, the unmarried state, and poor dental care. No significant associations were seen with specific occupational exposures.
299 citations
TL;DR: Anti‐human immunoglobulin (Ig) antibodies with single‐chain specificities induced Epstein‐Barr virus (EBV) in various Burkitt lymphoma lines when the corresponding Ig chain was expressed on the cell surface, indicating that cross‐linking of surface Ig was required for the induction.
Abstract: Anti-human immunoglobulin (Ig) antibodies with single-chain specificities induced Epstein-Barr virus (EBV) in various Burkitt lymphoma lines when the corresponding Ig chain was expressed on the cell surface. The F(ab')2 fragments of IgG antibody were as potent as intact Ig, while the Fab and Fc fragments gave no induction, indicating that cross-linking of surface Ig was required for the induction. Simultaneously with EBV induction, anti-Ig inhibited the uptake of 3H-thymidine. This inhibition was also seen in EBV-genome-negative Burkitt lymphoma lines. In contrast, no effect on virus induction and cell growth was noted in lymphoblastoid lines of non-neoplastic origin. The possible relationship between cell differentiation and latency of EBV-carrier state is discussed.
259 citations
TL;DR: Results strongly suggest that proliferative activity as assessed by LI is directly related to metastatic dissemination probability, independent of other prognostic factors.
Abstract: A prospective study of the prognostic significance of the labelling index (LI) was undertaken in 1972. The LI of the primary tumor was measured consecutively on 128 patients with mammary carcinoma at the time of initial treatment, following in vitro incubation of specimens with tritiated thymidine. The follow-up for all patients has now extended over 10 years. Relapse-free survival and total survival are significantly higher in patients with a low LI. A multivariate analysis of the prognostic factors, carried out with Cox's model, showed that LI is the most predictive indicator with respect to survival. The size of the tumor is the second most predictive indicator, while histological grading and the number of involved lymph nodes are less predictive. These results strongly suggest that proliferative activity as assessed by LI is directly related to metastatic dissemination probability, independent of other prognostic factors.
223 citations
TL;DR: The improved CA 19‐9 immunoradiometric assay may have clinical utility as a diagnostic adjunct for adenocarcinoma of the upper GI tract and that the assay also may have some value in monitoring patients with advancing colorectal carcinoma, particularly in combination with CEA determinations.
Abstract: More than 1,600 coded sera obtained from blood donors and the NCI/Mayo Clinic Serum Bank were analyzed with an improved immunoradiometric assay for the carbohydrate antigenic determinant, CA 19-9. Results indicated that CA 19-9 is elevated in a large fraction of sera (67%) from patients with advanced adenocarcinomas of the upper gastrointestinal (GI) tract, including those with pancreatic, hepatobiliary and gastric carcinomas. Several of these sera had CA 19-9 exceeding 300,000 U/ml. A smaller fraction (18%) of patients with carcinomas of the large bowel had elevated serum CA 19-9 levels, the majority among patients with metastatic disease. In contrast, none of the healthy donors from the serum bank and only 4 of 1,023 of the blood donor specimens (0.4%) had CA 19-9 levels greater than or equal to 40 U/ml. Three of 235 sera (1.3%) from benign disease patients had levels of CA 19-9 in excess of 40 U/ml. These data suggest that the improved CA 19-9 immunoradiometric assay may have clinical utility as a diagnostic adjunct for adenocarcinoma of the upper GI tract and that the assay also may have some value in monitoring patients with advancing colorectal carcinoma, particularly in combination with CEA determinations. Rigorous prospective clinical trials will be necessary to verify these hypotheses.
219 citations
TL;DR: A correlation has been found between the incidence of F. moniliforme in home‐grown maize and the human oesophageal cancer rate in Transkei, southern Africa and the chemical nature of the hepatotoxic and hepatocarcinogenic mycotoxin(s) produced by F. MONILiforme is unknown.
Abstract: Fusarium moniliforme Sheldon is one of the most prevalent fungi associated with maize throughout the world. A correlation has been found between the incidence of F. moniliforme in home-grown maize and the human oesophageal cancer rate in Transkei, southern Africa. Culture material on maize of F. moniliforme strain MRC 826, isolated from maize in a high-risk area for oesophageal cancer in Transkei, was either freeze-dried or oven-dried and fed to groups of 20 inbred male BD IX rats on a life-long basis. At a dietary level of 8%, both types of culture material were hepatotoxic and caused 100% mortality. Hepatic lesions in rats that died were characterized by cirrhosis, nodular hyperplasia and bile-duct proliferation. At a dietary level of 4% for 286 days followed by 2% for the remainder of the experiment, both types of culture material were hepatocarcinogenic and caused hepatocellular carcinoma in 80% and ductular carcinoma of the liver in 63% of the rats surviving more than 450 days. Only one of 30 such rats did not have a primary hepatic carcinoma. No hepatocellular or ductular carcinomas occurred in the controls. Hepatocellular carcinomas in the experimental rats invariably developed in severely cirrhotic livers showing nodular hyperplasia. Adenofibrosis also developed concurrently with hepatocellular carcinoma. A higher incidence of basal cell hyperplasia occurred in the oesophageal epithelia of rats fed freeze-dried than in those fed oven-dried material. The chemical nature of the hepatotoxic and hepatocarcinogenic mycotoxin(s) produced by F. moniliforme is unknown.
194 citations
TL;DR: The effect of partially purified rat interferon (RIFN) was evaluated in CC531 colon tumor‐bearing rats and the same cyclic RIFN treatment which was effective in the lung metastases model had no influence on the growth of liver metastases evoked by the intraportal injection of 5 × 105 tumor cells.
Abstract: The effect of partially purified rat interferon ( RIFN ) was evaluated in CC531 colon tumor-bearing rats. Tumor CC531 is a DMH-induced, transplantable adenocarcinoma exhibiting weak immunogenicity. When small tumor fragments were implanted under the renal capsule, daily treatment with RIFN for 5 days led to a highly significant (p less than 0.001) inhibition of tumor growth, measured 7 days after implantation. Cyclic treatment with RIFN (10(5) units/kg/day, for 7 days in weeks 2, 4, 6 and 8) significantly retarded the development of artificial lung metastases, induced by intravenous (i.v.) injection of 5 X 10(5) colon tumor cells. The median survival time was 177 days in the RIFN group as compared to 116 days in the control group. Three of eight animals treated with RIFN showed no sign of lung metastases when they were killed 250 days after tumor cell injection. The same cyclic RIFN treatment which was effective in the lung metastases model had no influence on the growth of liver metastases evoked by the intraportal injection of 5 X 10(5) tumor cells. Laparotomy performed at days 30 and 50 after inoculation revealed equal numbers of liver metastases in the RIFN -treated group and the control group. The mean survival times obtained in the two groups were 96 +/- 20 days and 108 +/- 14 days, respectively (0.05 less than p less than 0.10). The results indicate that (1) there is no inherent resistance of this solid tumor to RIFN therapy and (2) the effect of RIFN treatment is determined by the site of tumor development. The finding that the liver can provide a protective environment against tumor immunity may have important clinical implications.
193 citations
TL;DR: Human T‐cell leukemia/lymphoma virus (HTLV)‐carrying cells from various origins were characterized by cell surface markers and expression of HTLV antigens, which were not always identical among the cell lines.
Abstract: Human T-cell leukemia/lymphoma virus (HTLV)-carrying cells from various origins were characterized by cell surface markers and expression of HTLV antigens. Eight cell lines named TCL were obtained by transformation of peripheral blood leukocytes (PBL) of healthy donors or HTLV carriers in cocultures with HTLV-producer MT-2 cells. Nine cell lines named ILT were interleukin 2 (IL2)-dependent cell lines cloned from PBL of ATL patients and healthy HTLV-carriers. Tc-Kan9 cell line was also an IL2-dependent cell line clonally established from PBL culture stimulated with autologous TCL cells. Five cell lines named TL were established in vitro directly from PBL of an adult T-cell leukemia (ATL) patient and from ILT cells of an ATL patient and three HTLV-carriers, respectively, to grow autonomously without IL2. All the TCLs, ILTs, TLs and Tc-Kan9 possessed Leu-I antigen, a pan-T-cell marker. Leu3a antigen, a helper/inducer T-cell marker, was expressed on five of eight TCLs and all of the ILTs and TLs. Leu-2a, a cytotoxic/suppressor T-cell marker, was detected only on Tc-Kan9 but not others. Fresh ATL leukemic cells of patients had a helper/inducer T-cell marker. Ia, OKT9 and Tac antigens, markers for activated and differentiated T cells, were strongly expressed on all of the cell lines tested and fresh ATL leukemic cells were weakly positive for these antigens. Expression of HTLV antigens detected by mouse monoclonal antibodies and an ATL-patient serum varied among these cell lines. One TL, two ILTs and most of the fresh ATL leukemic cells did not express HTLV antigens on the cell surface. The other cell lines were all positive for the surface viral antigens. However, molecular species of antigens defined by radioimmunoprecipitation with an ATL-patient serum were not always identical among the cell lines. Molecular weights of polypeptides detectable in most of the cell lines were 62K, 46K, 40K, 24K, 21K and 19K which could never be detected in several control T-cell lines. 68K and 28K polypeptides were frequently detected in MT-2 and TGLs. GIN14, a mouse monoclonal antibody against HTLV core protein (p19) detected not only p19 in various cell lines but also p28, p29, p31 or p40 in certain cell lines tested. B-cell lines named LCL were established and cloned from PBL of two HTLV-carriers by EB-virus-induced transformation and they also expressed HTLV antigens, Ia, OKT9 and Tac antigens.(ABSTRACT TRUNCATED AT 400 WORDS)
183 citations
TL;DR: The reported observations are in favour of a dose‐dependent anti‐tumour action mediated by IL‐2 instead of foreign proteins, which is likely to be ascribed to the foreign protein of bovine origin contained in the authors' IL‐1 preparation.
Abstract: Six bladder cancer patients received intralesional injections by needle, under cystoscopic control, of 1969-4046 units (U) of xenogeneic IL-2 of high biological activity (324 U/ml; 397 micrograms/ml protein; 1.22 protein/U ratio). The treatment was spread over 7-54 days and 0.5 ml was injected each time. In 3/6 patients complete tumour regression was seen 43, 60 and 105 respectively days after the first IL-2 injection. In 2 a 70% regression was observed at days 45 and 75. In the last patient massive necrosis throughout the tumour mass was recorded on day 25 at radical cystectomy. In order to evaluate the minimum IL-2 U required to obtain positive clinical results and/or to assess whether the anti-tumour effect observed could be ascribed to the foreign protein of bovine origin contained in our IL-2 preparation, 4 additional bladder cancer patients were treated in 7-14 days with 156-1404 U of a second IL-2 lot with a much lower biological activity and similar protein content (52 U/ml; 289 micrograms/ml of protein; 5.55 protein/U ratio). No clinical or histological improvement was noted over a 42- to 54-day observation period. When we evaluated the 2 groups of patients by Student's t-test for both total U injected and U/kg of body weight (bw) we found a statistically significant differences (0.0025 less than p less than 0.0005 and p less than 0.0005, respectively). In contrast, no difference was seen for the injected protein amounts. The reported observations are in favour of a dose-dependent anti-tumour action mediated by IL-2 instead of foreign proteins. In none of the patients treated were any early or late adverse clinical side effects observed. Immunological monitoring (E, EAC, E-active rosettes, mitogen lymphocyte stimulations and leukocyte migration inhibition in the presence of allogeneic bladder cancer cells) performed on the peripheral blood (PB) showed significant but contrasting modifications after IL-2 injection. There was no clear correlation with the clinical course. The patients in whom we observed complete regression are still tumour free after 2, 4 and 7 months. In addition, in all the patients of the first group we observed an increase in tumour lymphoid infiltrate after IL-2 injection and in 2 patients lymphoid pseudo-follicles were also noted. In 2 of these patients we also observed scar-like areas in the place of the tumours previously seen.
TL;DR: The findings indicate that prevention activities should continue to emphasize smoking cessation, although switching to low‐tar cigarettes may also yield some reductions in lung cancer risk.
Abstract: A case-control study of lung cancer involving interviews with 7,804 cases and 15,207 hospital-based controls was carried out in seven locations in Western Europe. The large study size permitted the calculation of precise estimates of the relative risk of lung cancer associated with smoking different types of cigarettes. Lifelong nonfilter smokers were at nearly twice the risk of lung cancer compared to lifelong filter smokers after controlling for duration of cigarette use and number smoked per day (RR = 1.7 for males and 2.0 for females). Lung cancer risks for filter, nonfilter and mixed smokers increased in proportion to intensity and duration of smoking and decreased with years since stopping smoking. The findings indicate that prevention activities should continue to emphasize smoking cessation, although switching to low-tar cigarettes may also yield some reductions in lung cancer risk.
TL;DR: The newly identified N CA‐95 appears to differ from NCA‐55 not only in terms of molecular size and antigenicity but also by the fact that in normal lung and pancreas it is found in granulocytes but not in epithelial cells.
Abstract: During the selection of monoclonal antibodies (MAb) raised against purified carcinoembryonic antigen (CEA), two MAbs were identified which immunoprecipitated a glycoprotein of 95 kD present both in perchloric acid extracts of normal lung and on the surface of normal granulocytes. This antigen was distinct from the previously reported normal glycoprotein crossreacting with CEA (NCA) which had a molecular weight of 55 kD. The difference between the smaller and the larger crossreacting antigens termed NCA-55 and NCA-95, respectively, was demonstrated by SDS-polyacrylamide gel electrophoresis, by elution from Sephadex-G200 and by selective binding to a series of anti-CEA MAb. Out of six MAb which all bound CEA purified from colon carcinoma, three did not react with these two crossreacting antigens, one bound only NCA-95, one reacted only with NCA-55 and one reacted with both NCA-55 and NCA-95. Immunoadsorbent purified preparations of 125I labelled NCA-95 and NCA-55 were found useful for the screening of new anti-CEA MAb. In addition, when tested on frozen sections of colon carcinoma, normal spleen, normal lung and pancreas, each type of MAb gave a clearly different pattern of reactivity. The three anti-CEA MAb which did not bind any of the crossreacting antigens stained only the colon carcinoma cells; the MAb binding to either one of the two types of NCA gave a similar pattern of reactivity both on colon carcinoma cells and on granulocytes. However, on normal lung and pancreas, the MAb binding NCA-55 stained granulocytes as well as bronchiolar and alveolar epithelial cells in lung and inter- and intra-lobular duct epithelial cells in pancreas, whereas the MAb binding only NCA-95 stained only the granulocytes. Thus, the newly identified NCA-95 appears to differ from NCA-55 not only in terms of molecular size and antigenicity but also by the fact that in normal lung and pancreas it is found in granulocytes but not in epithelial cells.
TL;DR: The clinical records and histological material from 294 adult Chinese patients with malignant lymphoma were examined and the low incidence of Hodgkin's disease and of follicular lymphomas is comparable to figures from other “oriental” countries such as Japan.
Abstract: The clinical records and histological material from 294 adult Chinese patients with malignant lymphoma were examined. These patients were first seen at the Queen Mary Hospital, Hong Kong, during the 8-year period 1975-82. There were 27 patients (9.2%) with Hodgkin's disease (HD) and 267 with non-Hodgkin's lymphoma (NHL). The median age at presentation was younger for HD (45 years) and the male: female ratio was higher (2:1) than the corresponding figures for NHL of 51 years and 1.4:1. In 76 patients (28.5% of NHL), the disease was thought to have originated in an extra-nodal site, 48 of these cases being gastrointestinal lymphomas. It was possible to reclassify 234 NHL according to the Rappaport and Kiel classifications, and the Working Formulation (WF) proposed by the US National Cancer Institute Study; for HD, the Rye classification was used in 26 cases where suitable material was available. Nodular/follicular lymphomas made up 17.1% of nodal NHL and 5.3% of extra-nodal NHL. The "histiocytic" (Rappaport) or large-cell (WF) subtype was the commonest amongst diffuse NHL. There were only four cases of Burkitt's lymphoma. For HD, the nodular sclerosing subtype was commonest in females (5 out of 8 cases) and for males, the commonest was mixed cellularity (10 out of 18 cases). Of patients with nodal NHL 64.7%, presented with Stage IV disease. For HD, there were about equal numbers of patients presenting with Stage II and Stage IV disease (10 and 9 respectively). The low incidence of Hodgkin's disease and of follicular lymphomas is comparable to figures from other "oriental" countries such as Japan.
TL;DR: The isolation and characterization of differentiating human epithelial cell lines at different stages in malignant transformation provide an opportunity to examine the cellular and molecular mechanisms controlling tumour progression in the large intestine, and to obtain an insight into the multistep process of human epithel carcinogenesis.
Abstract: The genetic disease familial polyposis coli (hereditary adenomatosis of the colon and rectum) provides an excellent model for the study of tumour progression in the large bowel. We have isolated and characterized four epithelial cell lines from colorectal tumours from polyposis coli patients. These cell lines are grown on collagen-coated Petri dishes in the presence of mouse 3T3 feeder cells in medium containing 20% foetal bovine serum. Of these cell lines three were isolated from premalignant adenomas and one from an adenocarcinoma. All four lines have a characteristic cuboidal epithelial morphology, and their epithelial origin was confirmed by positive staining with a monoclonal antibody which reacts specifically with the keratin filaments of simple epithelia. The adenoma-derived lines display ultrastructural features characteristic of colonic epithelium including desmosomes, microvilli and mucin droplets. One of the adenoma-derived cell lines, designated PC/AA, has retained differentiated functions in culture, namely mucin production, after 21 in vitro passages. PC/AA has a karyotype of 46, XY with no detectable chromosome rearrangements. The adenoma-derived lines could be passaged from clumps of cells but not from single cells even in the presence of 3T3 feeder cells. The carcinoma-derived line, designated PC/JW, could however grow from single cells in the presence of a feeder layer. The one premalignant adenoma-derived line tested so far, PC/AA, did not produce tumours in athymic nude mice. In contrast, the carcinoma-derived line, PC/JW was tumorigenic in athymic nude mice. PC/JW produced moderately well-differentiated tumours which were histologically similar to the adenocarcinoma from which the cell line was isolated. PC/JW has a near-diploid chromosome number with an isochromosome (1q), an isochromosome (14q) and an (Xp; 17q) translocation. Unidentified marker chromosomes were present in a few cells. The features at present which distinguish the carcinoma-derived line from the adenoma-derived lines are tumorigenicity, growth from single cells and chromosomal abnormalities. The isolation and characterization of differentiating human epithelial cell lines at different stages in malignant transformation provide an opportunity to examine the cellular and molecular mechanisms controlling tumour progression in the large intestine, and to obtain an insight into the multistep process of human epithelial carcinogenesis.
TL;DR: The availability of the purified TATA from a rat tumor provides, for the first time, a handle for the identification and further characterization of such molecular species.
Abstract: A unique cell surface antigen of a chemically induced rat hepatoma (Zajdela Ascitic Hepatoma, ZAH) has been identified serologically and purified to apparent homogeneity. ZAH cells, when injected subcutaneously or intradermally into syngeneic hosts, elicit a weak humoral antibody response directed against a single cell surface antigen. In spite of prolonged and extensive immunization, the syngeneic anti-tumor antibodies are solely of the IgM class. Antisera from such immunized animals lyse tumor cells in the presence of complement. These observations were utilized in developing methods for the identification and purification of the antigen. It was observed that administration of purified preparations of this antigen confers ZAH-specific tumor immunity in syngeneic animals. Hence the serologically unique antigen is also the tumor-associated transplantation antigen (TATA) of this tumor. This is the first reported purification of a TATA from a rat tumor. There is considerable earlier evidence for the existence of tumor-associated factors which elicit a strong suppressor-cell response in tumor-bearing rats. The availability of the purified TATA from a rat tumor provides, for the first time, a handle for the identification and further characterization of such molecular species.
TL;DR: The lack of protective activity of canthaxanthin, which is a good trapper of oxygen singlets but cannot be converted into vitamin A, suggests that vitamin A and beta‐carotene exert their inhibitory effect on the formation of micronuclei by a mechanism not involving the scavenging of free radicals.
Abstract: The frequency of exfoliated cells with micronuclei in buccal swabs was used to estimate the protective effect of vitamin A, beta-carotene and canthaxanthin (4,4'-diketo-beta-carotene) on the buccal mucosa of betel (areca) nut/tobacco chewers. Micronuclei were scored on exfoliated cells taken by swabbing and stained with the Feulgen reaction and fast green. The betel (areca) nut/tobacco chewers served as their own controls. Prior to the administration of vitamin A and beta-carotene, the examined betel quid chewers had elevated frequencies of micronucleated buccal mucosa cells, averaging 4.03% +/- 1.24 SD (n = 26) and 3.43% +/- 1.22 SD (n = 25), respectively. The frequency of micronucleated buccal mucosa cells in non-chewers and non-smokers was 0.51% (n = 52). Following a 9-week ingestion of vitamin A (150,000 IU/week) and beta-carotene (180 mg/week in 6 capsules), the frequency of micronucleated cells decreased significantly (p less than 0.001) to 1.70% and 1.16%, respectively. No significant shift in the frequencies of micronucleated cells was observed following the intake of canthaxanthin (180 mg/week in 6 capsules) for 9 weeks or that of a placebo. The lack of protective activity of canthaxanthin, which is a good trapper of oxygen singlets but cannot be converted into vitamin A, suggests that vitamin A and beta-carotene exert their inhibitory effect on the formation of micronuclei by a mechanism not involving the scavenging of free radicals. The efficacy of beta-carotene as an inhibitor of micronucleated cell formation, the lack of toxicity, and its availability from a multitude of dietary sources should focus attention on this carotenoid as a promising chemopreventive agent.
TL;DR: Cancer patients who were pregnant at the time of cancer diagnosis were identified by the National Cancer Registry of the German Democratic Republic for the years 1970 through 1979, with a significantly reduced observed to expected ratio of 0.64.
Abstract: Cancer patients who were pregnant at the time of cancer diagnosis were identified by the National Cancer Registry of the German Democratic Republic for the years 1970 through 1979. A total of 355 such cases occurred in women aged 15-44, and during the same period 2, 103, 112 live births were registered. Rank by site in order of decreasing frequency was cervix, breast, ovary, lymphoma, melanoma, brain and leukemia. On the basis of general female population rates, 555.8 cases were expected, giving a significantly reduced observed to expected ratio (O/E) of 0.64. O/E ratios rose with age. The O/E for invasive carcinoma of the cervix was significantly elevated at 1.15; carcinoma in situ of the cervix occurred significantly less frequently than expected (O/E = 0.57). For breast, brain, melanoma and leukemia, significantly fewer cases were observed than expected. Explanations considered for the low number of pregnancy-associated incident cancer cases include underreporting of pregnancy-associated cancer, altered tumor progression in pregnancy or decreased fertility in women with early neoplastic disease.
TL;DR: The TK activity in sera from patients with both mononucleosis and tumor disease was characterized by electrophoresis and by its ability to utilize cytidine triphosphate as the phosphate donor, and showed that the serum TK has the same properties as the human cytosolar TK1, except in connection with varicella.
Abstract: An improved method for the detection of deoxythymidine kinase (TK) in human sera is reported. The method which utilizes 125I-iododeoxyuridine (IdUrd) as a substrate was used to measure TK in sera from patients with different diseases. Sera collected during the acute stage of infectious mononucleosis were found to contain elevated levels of TK, in most cases 10–40 times the normal value. The serum TK activity disappeared gradually and reached a normal level within 4 weeks. Sera from patients with other viral infections contained in most cases normal serum TK levels except in connection with measles, rubella, varicella, herpes simplex virus and cytomegalovirus infections. Additional studies revealed that sera from patients with different types of advanced lymphomas, acute leukemias, chronic granulocytic leukemia and lung cancer of the small-cell type with metastases, contained high TK level which fluctuated in parallel with alterations in activity of the disease. The TK activity in sera from patients with both mononucleosis and tumor disease was characterized by electrophoresis and by its ability to utilize cytidine triphosphate as the phosphate donor. The results showed that the serum TK has the same properties as the human cytosolar TK1, except in connection with varicella.
TL;DR: Monoclonal antibodies were used to define the cells involved in the various phases of MDV infection and it was learned that infected T cells also comprise part of the early cytolytic phase ofMDV infection but constitute a minority population compared to B cells at 3 or 4 days post infection.
Abstract: Previous reports from this laboratory identified bursa-derived lymphocytes (B cells) and non-B cells as the predominant cell types respectively involved in the early cytolytic and subsequent latent infection of chickens with Marek's disease virus (MDV). It was not known whether these differences were qualitative or quantitative or if the method for detection of latent infection (viral antigen production after 48 h of in vitro cultivation) was sensitive enough. To further define the cells involved in the various phases of MDV infection, we used monoclonal antibodies which specifically react with B cells, or T cells, or la-antigen-bearing cells. Dual fluorescence tests to detect surface markers and viral internal antigen (VIA) were conducted with infected spleen cells freshly collected from MDV-infected chickens or after in vitro cultivation of those cells. The same antibodies were also used for a rosetting procedure to yield fractions enriched or depleted of T cells, B cells or la-bearing cells. These were examined directly for viral DNA by in situ hybridization or dot blot DNA hybridization and for VIA cultivation. We learned that infected T cells also comprise part of the early cytolytic phase of MDV infection but constitute a minority population (approximately 2-3%) compared to B cells (83-92%) at 3 or 4 days post infection. Latently infected cells were definitively identified as mostly la-bearing T cells, although a few (2-4%) were B cells. Prior to in vitro cultivation, latently infected cells apparently had insufficient viral DNA for detection by in situ hybridization, but the more sensitive dot blot procedure revealed viral DNA in fractions later found positive by VIA expression after in vitro cultivation. Viral DNA replication in latently infected cells apparently had occurred after 48 h cultivation because in situ hybridization detected infected cells at that time. Treatment of cell cultures with iodo-deoxyuridine, 12-O-tetradecanoyl phorbol-13-acetate or n-butyrate failed to increase the number of spleen cells which expressed VIA.
TL;DR: Data indicate that some colon tumors exhibit a typical pattern of enterocytic differentiation which is of foetal type and which involves at least 3 brush border membrane hydrolases.
Abstract: The expression of small intestinal hydrolases associated with the enterocyte brush border membrane was studied in human colon cancers and foetal colons, by means of monoclonal antibodies against human small intestinal sucrase-isomaltase (SI), maltase-glucoamylase (MGA), lactase (L), aminopeptidase N (APN), and dipeptidylpeptidase IV (DPP-IV). The enzymes were visualized by indirect immunofluorescence on cryostat sections of tumors developed in nude mice with 6 human colon carcinoma cell lines (HT-29, Caco-2, SW-480, HRT-18, HCT-8R, and Co-115), of 27 primary colorectal carcinomas from patients, and of human foetal (16 to 20 weeks of gestation) and normal adult small intestines and colons. All 5 monoclonals bound to the brush border of the adult small intestine, but not to that of the adult colon mucosa. Antibodies against SI, APN and DPP-IV also bound to the brush border of the foetal colons, to apical borders in HT-29 and Caco-2 tumors in nude mice, and to brush border-like structures in 7/27 tumors from patients. No binding was observed for MGA and L in either tumors or foetal colons. Binding of anti-SI antibodies to the brush border of the juxta-tumoral mucosal epithelium was observed in 9/11 samples tested. These data indicate that some colon tumors exhibit a typical pattern of enterocytic differentiation which is of foetal type and which involves at least 3 brush border membrane hydrolases. Monoclonal antibodies to small intestinal hydrolases may, therefore, be important tools for identification and characterization of some differentiated colonic tumors.
TL;DR: The antimetastatic effects of heparin and PGI2 are dependent on levels of NK activity in the host, and platelet aggregation and fibrin coating of the surface of tumor cells may be among the mechanisms by which hematogenously spread tumor cells are protected from destruction by NK cells.
Abstract: The antimetastatic effects of heparin (40 units) and prostacyclin (PGI2, 100 microgram)1 were investigated in normal mice and in mice with depressed or activated natural killer (NK) cell activity. Both anticoagulants inhibited the formation of lung metastases after inoculation of the FI or F10 sublines of B16 melanoma. Inhibition of NK activity by treatment of mice with anti-asialo GM1 serum abrogated the antimetastatic effects of PGI2 or heparin. Conversely, augmentation of NK-cell activity by poly I:C plus treatment with anticoagulants produced synergistic antimetastatic effects. A similar pattern of results was obtained with heparin treatment of mice challenged with the Madison lung carcinoma (M109), but PGI2 alone or in combination with theophylline had little or no detectable antimetastatic effect on M109 or on the parental B16 melanoma. Studies of the mechanism of the interaction between heparin nd NK cells revealed that the anticoagulant treatment did not affect splenic NK activity in vitro. However, heparin treatment caused a significant increase in the clearance of radiolabelled tumor cells from the lungs of normal mice. Combined treatment of mice with poly I:C and heparin synergistically accelerated the elimination of radiolabelled tumor cells. In contrast, heparin did not affect the clearance of tumor cells from the lungs of mice with depressed NK activity. Thus the antimetastatic effects of heparin and PGI2 are dependent on levels of NK activity in the host. Platelet aggregation and fibrin coating of the surface of tumor cells may be among the mechanisms by which hematogenously spread tumor cells are protected from destruction by NK cells. Anticoagulant drugs may exert antimetastatic effects by making tumor cells more vulnerable to the cytotoxic effects of NK cells, rather than by blocking adherence of tumor cells to vascular endothelium.
TL;DR: It is demonstrated that the frequency of seropositive donors increased with age, and that four centers in this district showed distinctly high incidences of seropsitive donors, while the other four centers showed low incidences.
Abstract: A nation-wide survey of carriers of adult T-cell leukemia virus (ATLV) detected as anti-ATLA (ATLV-associated antigens) in volunteer blood donors was made in Japan. A total of 200 sera from donors between 40 and 64 years of age, collected in each of 64 blood centers located in eight districts, were tested for anti-ATLA by an indirect immunofluorescence test. The highest rate (8%) of seropositive donors was found in Kyushu and lower rates of 0.3 to 1.2% in other districts. However, the positive rate varied considerably in different localities even within districts with a high or low seropositive incidence. Further studies of all the donors (16 to 64 years old) in eight centers in Kyushu demonstrated two facts: (1) that the frequency of seropositive donors increased with age, and (2) that four centers in this district showed distinctly high incidences of seropositive donors, while the other four centers showed low incidences. The seropositive rate among all donors was estimated to be about 3% in Kyushu and 0.08 to 0.3% in all other districts.
TL;DR: The clear‐cut difference between the geographical distribution of seropositive simians and that of humans indicates the improbability of direct transmission of ATLV from simians to humans.
Abstract: The prevalence of adult T-cell-leukemia virus (ATLV) infection was examined in Japanese monkeys living naturally in various parts of Japan and in other species of non-human primates imported into and kept in Japan. Sera of 2,650 Japanese monkeys from 41 troops throughout Japan were tested. High incidences of anti-ATLV-associated antigen (ATLA)-positive monkeys were found in most troops, not only in the endemic area of human ATL(Southwestern Japan), but also in non-endemic areas. The incidence of sero-positive individuals increased gradually with age, reaching a maximum when the animals became adult, indicating age dependency, like that found by epidemiological studies on humans. Anti-ATLA antibodies were also detected in 90 of 815 sera of imported non-human primates of 33 species other than Japanese monkeys. All the anti-ATLA sero-positive monkeys were Catarrhines (Old World monkeys), mainly macaques of Asian origin. Some sero-positive monkeys were also found among animals of African origin, but no antibody was detected in Prosimians and Platyrrhines (New World monkeys). The clear-cut difference between the geographical distribution of sero-positive simians and that of humans indicates the improbability of direct transmission of ATLV from simians to humans.
TL;DR: The levels of the human milk fat globule 1 and 2 antigens have been measured in the sera of patients with advanced breast cancer, using a “sandwich” type radioimmune assay which exploits the carbohydrate nature of the antigenic determinants.
Abstract: The levels of the human milk fat globule 1 and 2 antigens have been measured in the sera of patients with advanced breast cancer, using a "sandwich" type radioimmune assay which exploits the carbohydrate nature of the antigenic determinants. In the series studied, 30% of sera from advanced breast cancer patients contained elevated levels of the HMFG-I antigen as compared with 6% of sera from healthy control women, whereas 53% of the advanced breast cancer patients showed elevated levels of HMFG-2 antigen compared with 16,6% of the controls. By means of the immune blotting technique, the components carrying the antigenic determinants in sera have been identified and compared for size with those molecules expressing the determinants in primary and secondary breast tumours. Both antibodies react with similar molecular weight components of 320kd and 280kd which are present in serum and tumour samples, although lower molecular weight bands of 230kd and 190kd can be seen in some tumours. These components are much smaller than the glycoprotein (greater than 400kd) present in the human milk fat globule, which carries the antigenic determinants recognized by HMFG-I and 2.
TL;DR: Sera obtained at enrolment in the study from patients suffering from moderate to severe dysplasia, carcinoma in situ, or developing any of these conditions in the course of the prospective study, and from control subjects were examined for herpes simplex type‐2 (HSV‐2) antibody presence.
Abstract: Sera obtained at enrollment in the study from patients suffering from moderate to sever dysplasia (cervical intraepithelial neoplasia grade II), carcinoma in situ (cervical intraepithelial neoplasia grade III) and invasive carcinoma, or developing any of these conditions in the course of the prospective study, and from control subjects, were examined for herpes simplex type-2 (HSV-2) antibody presence. The controls were matched with the patients by age, age at first intercourse, number of sexual partners, smoking habits and history of diathermoelectrocoagulation of the ectopic epithelium and transformation zone of cervix. Only those subjects were selected as controls who remained free of pathological colposcopical and cytological findings throughout the observation period, i.e. for at least 4 years after their serum sample was obtained. The microneutralization test (MNT) and type-2-specific solid-phase radioimmunoassay (SPRIA) were used as serological tests. No difference in the prevalence of HSV-2 antibody between the patients and controls was revealed by either test. Various combinations of the results from the two tests also failed to show any difference between patients and controls. Moreover, no significant differences were observed in the prevalence of HSV-2 antibody between patients suffering from the various pathological conditions and those diagnosed at enrollment and later in the course of the study. These results do not provide any support for the hypothesis of the involvement of HSV-2 in cervical neoplasia.
TL;DR: The excess risk of sino‐nasal cancer with exposure to paint, lacquer and glue remained statistically elevated after adjustment for contemporary exposure to wood‐dust and formaldehyde.
Abstract: A comprehensive data linkage system for the detailed investigation of occupational cancer has newly been established in the Danish Cancer Registry, providing employment histories back until 1964. Based on this system a study of 839 cases of cancer of the nasal cavities, sinuses and rhinopharnyx and 2,465 cancer controls diagnosed in Denmark during the period 1970-1982 was conducted. Histories of exposure to formaldehyde, wood-dust and 10 other specified compounds or procedures, were assessed by industrial hygienists unaware of the case-control status of the cancer patients under study. Some 4.2% of the male and 0.1% of the female controls had been exposed to formaldehyde. A statistically significant excess risk (p less than 0.05) for carcinoma of the nasal cavity and sinuses among males with a history of exposure to formaldehyde (RR = 2.8), wood-dust (RR = 2.5) and paint lacquer and glue (RR = 2.1) was found. When adjustment was made for wood-dust exposure the relative risk associated with formaldehyde was reduced to 1.6, which is not significantly in excess of 1.0, although still compatible with a 3- to 4-fold increase in risk using conventional 95% confidence limits. The joint action of exposure to wood-dust and formaldehyde was in accordance with an additive effect. The excess risk of sino-nasal cancer with exposure to paint, lacquer and glue remained statistically elevated after adjustment for contemporary exposure to wood-dust and formaldehyde.
TL;DR: It is suggested that expression of H‐2K molecules on the 3LL clones, immunogenicity and the metastatic phenotype are causally related in this system.
Abstract: Two clones of the 3LL Lewis lung carcinoma, a low-metastatic clone A9 and a high-metastatic clone D122, were studied for MHC expression and immunogenic properties. Using monoclonal antibodies, we demonstrated that the A9 clone expresses both the H-2Kb and the H-2Db, whereas the D122 expresses only the H-2Db, and lacks the expression of the H-2Kb encoded molecules. Cells of the low-metastatic clone A9 grew progressively in syngeneic (C57BL/6J) or in F1 mice, but were rejected in allogeneic recipients. The high-metastatic D122 grew progressively in all mouse strains tested, yet metastases were formed only in syngeneic recipients. When H-2 recombinant mice were used, the A9 again manifested a significantly greater immunogenic potency than the metastatic D122, which grew in all 4 recombinants tested. Metastases, however, were formed in B10HTG and to a lesser extent in B10A(4R), thus indicating that metastasis formation is restricted by both C57BL background and H-2Db sub region. We subsequently tested whether the higher immunogenicity of the H-2Kb-positive A9 cells is expressed also in syngeneic mice, to examine whether this could account for its low metastatic phenotype. We found that immunization by A9 cells significantly inhibited the growth of a subsequent A9 graft and even of D122, yet D122 did not retard the growth of secondary D122 or A9 cells. The increased immunogenic effect was expressed also in the generation of syngeneic cytotoxic lymphocytes by A9 but not by D122 cells. We suggest that expression of H-2K molecules on the 3LL clones, immunogenicity and the metastatic phenotype are causally related in this system.
TL;DR: It is found that primary but not metastatic DR+ melanoma cells are able to activate the proliferation and cytotoxicity of autologous peripheral blood lymphocytes, suggesting a potential role of DR antigens in regulating tumor‐host relationships in melanoma patients.
Abstract: Lymphocytes from melanoma patients were stimulated in mixed culture with autologous tumor cells (MLTC) in order to evaluate lymphocyte proliferation and subsequent cytotoxicity on autologous melanoma cells. It was found that melanoma cells from lymph node metastases were unable to induce autologous tumor-cytotoxic cells in 21 cases examined, in 15 of which MLTC also failed to induce lymphocyte proliferation. Patients' lymphocytes, however, were significantly stimulated by allogeneic irradiated lymphocytes and by interleukin 2. To investigate whether the lack of autologous stimulation was restricted to metastatic cells, the immune response of patients with only primary lesions of malignant melanoma was evaluated. It was found that primary melanoma cells were able to induce proliferation in 7 out of 9 (77%) patients, whereas positive cytotoxicity was obtained in 2 out of 4 patients tested. In order to see whether the presence of DR molecules was important for the stimulatory activity, melanoma cells were examined for the expression of DR antigens by indirect immunofluorescence with monoclonal antibodies. Positive autologous MLTC was found in all of six DR+ primary melanomas, whereas the two DR-tumors were unable to stimulate autologous lymphocytes. An anti-DR but not an anti-DC monoclonal antibody was able to block the proliferation of lymphocytes induced by an autologous primary melanoma. Neither MLTC nor cell-mediated killing was obtained with either DR+ or DR-metastatic melanoma. In 60% of the cases tested, however, DR+ metastatic melanoma cells were able to stimulate allogeneic lymphocytes of normal individuals. Increased expression of DR antigens was induced by in vitro treatment with human gamma-interferon in metastatic tumor cells; this caused an increase in the proliferation of allogeneic but not autologous lymphocytes. These findings indicate that primary but not metastatic DR+ melanoma cells are able to activate the proliferation and cytotoxicity of autologous peripheral blood lymphocytes, suggesting a potential role of DR antigens in regulating tumor-host relationships in melanoma patients.
TL;DR: Comparison of M2 expression with the display of the 3‐fucosyl‐N‐acetyllactosamine determinant, the structure recognized by most of the anti‐myeloid monoclonal antibodies reported so far, shows that more AMLs are M2‐positive and the proportion of M1‐positive blast cells in individual AML samples is higher.
Abstract: The selectivity of a novel myelomonocytic cell surface antigen, designated M2, has been assessed in a series of 208 leukemias. The M2 antigen is defined by a monoclonal antibody (VIM-2) of the IgM class. Its expression within the normal hemopoietic system is restricted to myelomonocytic cells. Lymphocytes, erythrocytes, thrombocytes and their morphologically recognizable precursors are negative. Sixty of the 66 acute myeloblastic leukemias (= 91%) and 28 of the 30 myeloid blast crises of CML patients (= 93%) were M2-positive. As expected from our findings with normal myeloid cells, the myeloid cells found in stable phase of CML were also in all instances, M2-positive. Quite in contrast, lymphoid cells from patients with B-CLL, T-CLL, prolymphocytic leukemia, hairy-cell leukemia, lymphoblastic lymphoma, Sezary syndrome, from CML patients in lymphoid blast crisis and from the majority of patients with ALL, were completely M2-negative. Also negative were the blast cells of patients with acute megakaryoblastic leukemia and acute erythroleukemia. A direct comparison of M2 expression with the display of the 3-fucosyl-N-acetyllactosamine determinant, the structure recognized by most of the anti-myeloid monoclonal antibodies reported so far, shows that more AMLs are M2-positive and the proportion of M2-positive blast cells in individual AML samples is higher.