Showing papers in "International Journal of Cancer in 1988"

Estimates of the worldwide frequency of sixteen major cancers in 1980.

Abstract: The numbers of new cancer cases in 16 common sites occurring in 1980 have been estimated for 24 areas of the world for which the United Nations produces population estimates. For the world as a whole, the total number of new cases was 6.35 million, almost exactly evenly divided between the developed and developing countries. In males, the most important sites were lung, stomach, colon/rectum, mouth/pharynx, prostate and oesophagus, and in females breast, cervix, colon/rectum, stomach, corpus uteri and lung. When the two sexes are combined, stomach cancer emerges as the most common cancer in 1980 (669,400 new cases per year), but this estimate is only slightly greater than that of lung cancer (660,500 new cases), and comparisons with earlier estimates for 1975 suggest that, with declining incidence rates for stomach cancer and the continuing rise for lung cancer, the latter would become the most common cancer in the world by the end of 1981. The implications for cancer control in the developed and developing countries of the world are discussed.

The international incidence of childhood cancer

Abstract: The International Agency for Research on Cancer has coordinated a worldwide study of the incidence of cancer in childhood. Contributors from over 50 countries have provided data. This paper presents a summary of some of the major results. The incidence rates and relative frequencies of childhood cancers are described according to 12 diagnostic groups, defined mainly in terms of tumour morphology. Variations in the risk of those tumours between different countries and different ethnic groups provide important information on the relative importance of environmental and genetic factors in their aetiology.

Establishment of a human cell line (mono mac 6) with characteristics of mature monocytes

Abstract: A monocytic cell line, termed Mono Mac, was established from peripheral blood of a patient with monoblastic leukemia. Two clones, designated Mono Mac I and Mono Mac 6, were isolated and both were assigned to the monocyte lineage on the basis of morphological, cytochemical and immunological criteria. Most importantly, the clones express NaF-sensitive non-specific-esterase, produce reactive oxygen and stain with MAb My4. Mono Mac 6, in addition, constitutively exhibits phagocytosis of antibody-coated erythrocytes in 80% of the cells and reacts with a panel of MAbs that are specific for mature monocytes, i.e., M42, LeuM3, 63D3, Mo2 and UCHMI. By contrast, the monoblastic cell lines U937 and THP-I are negative for all these markers. Only expression of My4 could be detected after differentiation induced by interferon-gamma (IFN-gamma). Similar treatment of Mono Mac I, however, resulted in staining with all the monocyte-specific MAbs mentioned above, while IFN-gamma treatment of Mono Mac 6 enhanced antigen expression. In addition, the cells showed an increased frequency of multinucleated cells with a rise from 4.8% to 21.9%. Mono Mac 6 appears to be the only one of the cell lines studied to constitutively express phenotypic and functional features of mature monocytes.

P53 expression in breast cancer

Abstract: Immunohistochemical evaluation of 200 primary breast cancers with the anti-p53 mouse monoclonal antibody (MAb) PAb421 showed positivity in nuclei of malignant cells in 31 cases (15.5%). PAb421+ cases were significantly more frequently epidermal growth factor receptor (EGF-R)-positive (67.7%; p less than 0.001) and estrogen receptor (ER)-negative (73.3%; p less than 0.001); they displayed surface histocompatibility class-1 (80.6%; p less than 0.01) and 11 (74.2%; p less than 0.05) antigens. Low values for progesterone receptor (mean 67.20 +/- 25.2 fmol/mg; p less than 0.05) and a high number of cells positive for the proliferation-associated antigen Ki-67 (log mean 6.88 +/- 0.33; p less than 0.01) were found in PAb421+ tumors as well as a high number of grade-3 infiltrating duct carcinomas (70%; p = 0.01). Of the 200 cases of mammary carcinoma, 88 were further analyzed using another human specific anti-p53 MAb PAb1801, and 40 (45.5%) were found positive. This MAb stained all the PAb421+ cases and was significantly associated with negative ER status (39.5%; p less than 0.05) and high Ki-67 scores (log mean 6.93 +/- 0.24; p = 0.001). Analysis of PAb1801+/Pab421- cases for HLA antigens, EGF-R and ER showed a phenotype similar to that of the p53-ve/ER+ carcinomas, except for the high Ki-67 score. No differences in age of the patient, number of involved nodes, tumor size, ploidy or labelling index scores were evident between p53+ and carcinomas. We concluded that p53 in mammary carcinomas is associated with ER-negative, growth factor receptor-positive, high-grade tumors, and is a promising new parameter to evaluate the cellular biology and prognosis of breast cancer.

Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma.

Abstract: Expression of the Epstein-Barr virus (EBV) encoded nuclear antigens (EBNA 1 to 6) and membrane-associated protein (LMP) was investigated by immunoblotting in 83 nasopharyngeal carcinoma (NPC) biopsies and 25 other tumor and normal tissue specimens from the head and neck region. Fifty-eight of the 83 NPC biopsies were large enough to yield parallel data on virus DNA and viral expression. All 16 cases of clinically diagnosed and histologically confirmed NPCs from North Africa contained EBV DNA and expressed EBNA-1. Of 31 clinically diagnosed NPCs from China, 29 contained EBV DNA and 25 of these expressed EBNA-1. One control tissue biopsy from the oropharynx of NPC patients contained EBV DNA, but none expressed EBNA-1. The latent membrane protein (LMP) was detected in 22/31 of the Chinese and in 10/16 of the North African NPC biopsies. None of the NPC biopsies or control tissues expressed detectable amounts of EBNA 2 or any of the other 4 nuclear antigens which are invariably expressed in EBV-transformed B cells. A smaller number of tumors from Malaysia and East Africa exhibited a similar pattern of expression. EBV was rescued from a nude-mouse-passaged North African NPC tumor by co-cultivation of the tumor cells with umbilical cord blood lymphocytes. The tumor expressed EBNA 1 and LMP, but not EBNA 2 or the other 4 EBNAs. The resulting LCLs expressed all 6 nuclear antigens, EBNA 1 to 6 and LMP. Our data suggest that expression of the EBV genome is regulated in a tissue-specific fashion.

Cancer of the larynx/hypopharynx, tobacco and alcohol: IARC international case-control study in Turin and Varese (Italy), Zaragoza and Navarra (Spain), Geneva (Switzerland) and Calvados (France).

Abstract: A case-control study on larynx and hypopharynx cancer was carried out in 6 populations including the city of Turin and the province of Varese (Italy), the provinces of Navarra and Zaragoza (Spain), the canton of Geneva (Switzerland), and the departement of Calvados (France). This report presents an analysis of the risk associated with alcohol and tobacco consumption based on 1,147 male cases and 3,057 male population controls. Special attention was given to the study of the risk at various sites of larynx and hypopharynx. The effect of tobacco is similar for all sites and the risk associated with ever smoking is on the order of 10. The risks from alcohol drinking depend on site. They are similar for epilarynx and hypopharynx (RR = 4.3, for more than 80 g/day) and lower for endolarynx (RR = 2.1, for more than 80 g/day). For all sites the risk decreases after quitting (RR = 0.3 after 10 years); exclusive use of filter cigarettes is protective (RR = 0.5 relative to smokers of plain cigarettes only) as is exclusive use of blond tobacco (RR = 0.5 relative to smokers of black tobacco only). Inhalation increases the risk of endolaryngeal cancer but not that of hypopharynx or epilarynx. The relative risks for joint exposure to alcohol and tobacco are consistent with a multiplicative model.

The Danish case-control study of cutaneous malignant melanoma. II. Importance of UV-light exposure.

Abstract: A population-based case-control study of 474 patients with cutaneous malignant melanoma and 926 population controls, conducted in East Denmark over a 3-year period, included an evaluation of the relationship of UV-light exposure to cutaneous melanoma risk. Patients with lentigo maligna melanoma were not included. Significantly increased risk was associated with severe sunburn before age 15 (RR = 2. 7 for 5 + vs. never), sunbathing (RR = 1. 6), boating (RR = 1. 4) and vacations spent in the sun (RR = 1. 4 for very sunny vs. never). A significant decrease in risk was associated with occupational exposure during the summer in males (RR = 0. 7), and no association with cutaneous microtopography was seen. These findings were independent of the effects of constitutional risk factors (naevi, freckles and light hair colour). No association was found between the risk of cutaneous melanoma and exposure to artificial UV-light (fluorescent light, sun lamps, or sun beds). No significant difference was found between superficial spreading melanoma and nodular melanoma with regard to any of the sun exposure variables. Our data indicate that exposure to intermittent intense sunlight is an important risk factor for cutaneous malignant melanoma, while long-term continuous exposure does not appear to be a risk factor for cutaneous malignant melanoma, while long-term continuous exposure does not appear to be a risk factor.

Smooth‐muscle differentiation in stromal cells of malignant and non‐malignant breast tissues

Abstract: A mouse monoclonal antibody (MAb) recognizing α-smooth-muscle actin has been used to study smooth-muscle differentiation features in the stromal cells of desmoplastic reactions accompanying mammary tumors. We have studied, by the same immunohistochemical technique, a series of malignant and non-malignant human breast tissues. Cells composing the desmoplastic reaction were found to express α-smooth-muscle actin in all the 11 breast carcinomas examined, whereas no immunostain was demonstrated in the stromal cells of 7 breast tissue samples histologically defined as normal. Three of 9 cases of fibrocystic disease showed a minority of positively stained stromal cells, generally in association with epithelial hyperplasia. All the 7 cases of sclerosing adenosis, 3 of 4 cases of diffuse papillomatosis and all 3 intraductal papillomas exhibited a majority of immunoreactive stromal cells. Numerous stromal cells in 3 of 11 circumscribed fibroadenomas analyzed expressed low amounts of α-smooth-muscle actin. The factor(s) responsible for smooth-muscle differentiation in stromal cells are presently unknown, but the detection of this previously unsuspected stromal cell phenotype in non-malignant mammary tissues might help in characterizing the variant morphological aspects designated under the label “fibrocystic disease” and in understanding the biology of pre-malignant or early malignant lesions of the breast.

Isolation of simian immunodeficiency virus from african green monkeys and seroepidemiologic survey of the virus in various non‐human primates

Abstract: Sixteen isolates of simian retrovirus closely related to human immunodeficiency virus (HIV) were obtained from healthy African green monkeys (AGM) (Cercopithecus aethiops). The first isolate was obtained from a monkey seropositive for HIV, and the others were isolated from monkeys harboring antibodies to the first isolate. These simian retro-viruses were referred to as simian immunodeficiency virus from AGM, SIV[AGM], due to their cross-reactivities with HIV structural proteins. These SIV[AGM] isolates were found by Western blotting analysis to have virus-specific proteins of 120, 66, 55, 32–40, 24 and 17 kDa, which were all similar in size to the analogous proteins of HIV. Putative gas proteins of p55, p24 and pl7 were recognized by sera of human AIDS patients, but the corresponding env proteins of 32–40 and 120 kDa showed only weak cross-reactivity with those of HIV. The transmembrane glycoproteins of these 3 SIV[AGM] isolates showed size heterogeneity, being 32, 35 and 40 kDa. This virus had particles that were morphologically similar to those of HIV, and had Mg2+ -dependent reverse transcriptase. Furthermore, the SIV[AGM] showed tropism and cytopathic effects on CD4-positive human cell tines. In a sero-epidemiological survey of SIV[AGM] in various non-human primates, 2 other African monkey species, the mandrill and de Brazza's monkey, were also found to have antibodies to SIV[AGM]. These HIV-related simian retroviruses will be important in determining the origin and transmission of HIV group viruses, and may provide useful animal models for studies on the infection and pathogenesis of HIV and AIDS.

Monoclonal antibody JSB-1 detects a highly conserved epitope on the P-glycoprotein associated with multi-drug-resistance.

Abstract: Resistance to multiple chemotherapeutic agents is a common clinical problem in the treatment of cancer. This resistance may occur before primary therapy or be acquired during treatment. We have generated a monoclonal antibody (MAb) (JSB-I), specific for a conserved epitope on the plasma membrane 170- to 180-kDa glycoprotein, the expression of which is strongly correlated with the degree of multi-drug resistance (MDR). JSB-I strongly binds to both Chinese-hamster-derived MDR cell lines and human MDR cell lines, including cell lines derived from lung and ovary. A drug-sensitive revertant line, and the corresponding drug-sensitive parent lines, showed only weak reactivity or none at all. JSB-I reacts strongly to air-dried or acetone-fixed cells and therefore has potential value for diagnostic detection of MDR cells in human tumor samples.

Remission of oral leukoplakias and micronuclei in tobacco/betel quid chewers treated with beta-carotene and with beta-carotene plus vitamin A.

Abstract: Fishermen from Kerala (India) who chewed tobacco-containing betel quids daily (17.2 +/- 9.6 quids per day) and had well-developed oral leukoplakias with elevated frequencies of micronucleated cells participated in a short-term intervention trial. Beta-carotene (180 mg/week) (Group I), beta-carotene (180 mg/week) plus vitamin A (100,000 IU/week) (Group II), and placebo (Group III) capsules were given twice weekly for 6 months under strict supervision. The remission of oral leukoplakias, the inhibition of new leukoplakias, and the reduction of micronucleated oral mucosal cells were recorded at the 3rd and 6th months of the trial period. After 3 months, the frequency of micronucleated cells was significantly reduced in Group I (from 4.09% to 1.1% in areas of leukoplakia, and from 4.1% to 1.0% in the normal mucosa). At this time, remission of oral leukoplakias did not differ significantly from that observed in the placebo group. After 6 months of treatment, remission of leukoplakias in Group I (14.8%) and Group II (27.5%) differed significantly from that seen in Group III (3.0%). The development of new leukoplakias during the 6-month period was strongly inhibited in Group II (7.8%), and to a lesser degree in Group I (14.8%), as compared to Group III (21.2%). During the trial period, all participants continued to chew tobacco-containing betel quids in their accustomed manner. Thus, remission and inhibition of new oral leukoplakias and reduction of micronucleated mucosal cells occurred in the groups receiving beta-carotene and beta-carotene plus vitamin A during the continuous presence of carcinogens derived from tobacco and areca nut.

Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: Relevance for early detection of ovarian cancer

Abstract: To investigate the sensitivity of the CA 125 immunoradiometric assay for occult ovarian neoplasia, serum CA 125 levels were retrospectively determined "blind" in specimens collected from 105 women who subsequently developed ovarian neoplasia, and from 323 matched controls. The distribution of CA 125 levels was very different between the case and control populations (p = 0.0001) over the entire collection-to-diagnosis interval (range 1-143 months). Median CA 125 levels for all cases, and for those collected more than 24, 36 or even 60 months prior to diagnosis, were always 18 U/ml or greater, compared with a median of 10.9 U/ml for controls. Half of the cases collected within the 18 months preceding diagnosis had CA 125 levels of more than 30 U/ml and one-third had levels greater than 65 U/ml. About one-fourth of those collected prior to 60 months before diagnosis had levels above 30 U/ml. In contrast, approximately 7% and 0.9% of controls had levels in excess of 30 or 65 U/ml, respectively. Elevations occurred in cases eventually diagnosed with localized or advanced cancer, and with borderline or obviously malignant disease. These results provide an insight into the preclinical biology of ovarian neoplasia that may help in designing methods for early detection of this disease, and demonstrate the usefulness of the JANUS serum bank as a resource in evaluating serum tests.

Case-control study of proximal and distal colon cancer and diet in Wisconsin.

Abstract: The relationship between diet and subsite-specific colon cancer was investigated using dietary histories obtained from a statewide, population-based sample of 152 proximal colon cancer patients, 201 distal colon cancer patients and 618 general population controls. The results do not support hypotheses that (1) dietary fat and cholesterol are more strongly related to proximal colon cancer and (2) vegetables and other dietary sources of fiber are more strongly associated with distal colon cancer. Vegetable consumption over lifetime was consistently protective for both proximal and distal colon cancer. Odds ratios and 95% confidence intervals for the most significant dietary factors (based on high vs. low consumption) for proximal colon cancer were: salad, 0.29 (0.17, 0.48); miscellaneous vegetables, 0.58 (0.35, 0.97); cruciferous vegetables, 0.59 (0.35, 0.97); processed lunchmeat, 2.04 (1.31, 3.17); pan-fried foods, 1.79 (1.15, 2.80); eggs, 1.75 (1.02, 2.99) and for distal colon cancer they were: salad, 0.43 (0.28, 0.67); cruciferous vegetables, 0.44 (0.28, 0.71); cheese, 0.62 (0.40, 0.96); processed lunchmeat, 1.79 (1.17, 2.73); pan-fried foods, 1.55 (1.03, 1.27). The results support recommendations that the "prudent diet" (low-fat, high-vegetable) may reduce colon cancer risk.

Establishment and characterization of three transplantable EBV‐containing nasopharyngeal carcinomas

Abstract: Three transplantable nasopharyngeal carcinoma (NPC) tumors, designated C15, C17 and C18, have been obtained and characterized. C15, derived from a primary NPC tumor, has been propagated in nude mice for 30 passages. C17 and C18, derived from metastatic NPC tissue, have been passaged 10 times. Desmosomes, present in every case, provided confirmation of the epithelial origin of all 3 tumors. The Epstein-Barr virus (EBV) genome is contained in C15, C18 and C17 tumor cells with 30, 12 and 3 copies, respectively. The Epstein-Barr virus nuclear antigen (EBNA) was stained by the classical anti-complement immunofluorescence (ACIF) technique. Fluorescence intensity was strong in C15, moderate in C18, and hardly detectable in C17 cells. No expression of the EA and VCA antigens was detected. Flow cytometry analysis performed on monocellular suspensions showed the absence of detectable CR2 molecules (the EBV receptor on B lymphocytes) in all 3 tumors, and the constitutive expression of HLA class-II antigens in C15 and C17 cells. IL-1 activity was demonstrated in the supernatant of C15 and C17 cells cultivated in vitro for 3 days. These data confirm that the constitutive synthesis of MHC class-II molecules and the release of IL-1-like activities are frequent features of NPC cells. These characteristics could be of importance in relation with the T-cell infiltrate found in NPC primary tumors.

Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis.

Abstract: The role of host mast cells in tumor-associated angiogenesis was investigated by comparing the angiogenic response of genetically mast-cell-deficient W/Wv mice and mast-cell-sufficient +/+ littermate mice to s.c. growing B16-BL6 tumors. The angiogenic response was found to be slower and initially less intense in W/Wv mice than in +/+ mice. Fewer W/Wv mice than +/+ mice developed spontaneous lung metastases and W/Wv mice exhibited fewer lung metastases per mouse. Bone-marrow repair of the mast-cell deficiency restored the angiogenic response of W/Wv mice and also restored the incidence of hematogenous metastases to approach that of +/+ mice. Differences in lymphatic metastasis were not detected between W/Wv and +/+ mice. These results demonstrate a role for mast cells in vivo during tumor angiogenesis, and suggest a role also for host mast cells in hematogenous metastasis.

Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark.

Abstract: In order to evaluate the influence of sex hormones on breast cancer risk, a population-based case-control study was conducted in Denmark, including 1,486 cases diagnosed over a one-year period. These were identified from the files of the nation-wide clinical trial of the Danish Breast Cancer Cooperative Group and the Danish Cancer Registry. The control group was an age-stratified random sample of 1,336 women from the general population. Data on risk factors were collected by self-administered (mailed) questionnaires. The major findings included a trend (p = 0.001) toward decreasing risk with increasing age at menarche in pre-menopausal women, trends toward increasing risk with continued menstrual cycles after the age of 50 in pre- and post-menopausal women (p-values of 0.01 and 0.002 respectively), and a trend (p = 0.002) toward increasing risk with increasing duration of non-contraceptive sex hormone usage in post-menopausal women. Information on brand names made it possible to examine types of hormones used, which showed an RR of 1.36 (95% CI 0.98–1.87) for sequential therapy with oestrogen and progestagen and RR = 2.31 (95% CI 1.37–3.88) for combined oestrogen-androgen treatment. These results should be interpreted with caution, however, needing verification from other studies. No significant association was observed between breast cancer and self-reported height and weight.

A case-control study of diet and colo-rectal cancer in northern Italy.

Abstract: The relation between dietary factors and the risk of colo-rectal cancer was investigated in a case-control study conducted in Northern Italy on 339 cases of colon cancer, 236 cases of rectal cancer and 778 controls admitted to hospital for acute, non-neoplastic or digestive disorders. Consistent positive associations were observed with more frequent consumption of starchy foods (pasta or rice) (relative risk, RR = 3.0 for colon and I.S for rectum (or highest vs. lowest fertile) and beef/veal meats (RR = 2.1 for colon, 2.1 for rectum), whereas reduced relative risks were observed in subjects reporting more frequent green vegetable consumption (RR = 0.5 for highest vs. lowest tertile), a few specific vegetable or fruit items, and coffee (RR = 0.6 for highest vs. lowest tertile). Various fats in seasonings were positively, but inconsistently, related to intestinal cancer risk, whereas no association was evident with measures of whole grain foods or alcohol intake. For both intestinal sites, a 4- to 5-fold difference in risk was evident between the extreme quintiles of a simple score obtained by algebraic sum of the A major groups of foods. These findings could not be explained in terms of confounding by socio-economic status or other major potential distorting factors, are in agreement with the results from previous studies of colo-rectal cancer in Southern Europe, and are consistent with various aspects of the descriptive epidemiology of intestinal cancer in Italy.

Biological characterization and oncogene expression in human colorectal carcinoma cell lines.

Abstract: To establish well-characterized cellular reagents for the study of colon carcinoma, we have examined 19 human colorectal carcinoma cell lines with regard to morphology, ultrastructure, expression of tumor-associated antigens, proliferative capacity in vitro, anchorage-independent growth, oncogene expression, tumorigenicity and malignant potential. Cell lines examined were cultured under identical conditions, and in vitro and in vivo analyses were performed in parallel on replicate cultures. Three classes of colorectal cell lines were defined according to their tumorigenicity in nude mice. Class-1 lines formed rapidly progressing tumors in nearly all mice at an inoculum of 10(6) cells. Cell lines belonging to class-2 were less tumorigenic, producing tumors later and at a slower growth rate. Class-3 lines were non-tumorigenic under all experimental conditions tested. By Northern analysis, the oncogenes c-myc, H-ras, K-ras, N-ras, myb, fos and p53 were expressed in nearly all cell lines examined. In contrast, transcripts for abl, src and ros were not detected. The best in vitro predictor of tumorigenicity was colony formation in soft agar. There was no detectable correlation between tumorigenicity and metastatic potential, doubling time in vitro, production of tumor-associated markers, xenograft histology or expression of specific oncogenes.

Interaction between epidermal growth factor and its receptor in progression of human gastric carcinoma.

Abstract: The expressions of epidermal growth factor (EGF) and its receptor were studied immunohistochemically in a total of 156 gastric carcinomas; 26 early and 130 advanced. No EGF immunoreactivity was found in early carcinomas, while EGF-positive tumor cells were detected in 38 (29.2%) of the 130 advanced carcinomas. EGF receptor immunoreactivity was detected in one (3.8%) of the 26 early carcinomas and in 44 (33.8%) of the 130 advanced carcinomas, the incidence being significantly different (p<0.01). Out of the 130 advanced carcinomas, 17 (13.1%) had synchronous expression of EGF and its receptor and most of the tumors with strong expression of EGF were positive to EGF receptor. A significant correlation was observed between the depth of tumor invasion and EGF or its receptor immunoreactivity in tumor cells (p<0.05). Furthermore, a good correlation was demonstrated between the synchronous expression of EGF and its receptor and the depth of tumor invasion or the tumor staging. The incidence of cases with EGF in metastatic tumors was significantly higher than that in primary tumors (p<0.05). Patients with synchronous expression of EGF and its receptor had a far poorer prognosis than those without EGF and receptor.

A unifying concept of the aetiology of breast cancer.

Abstract: A number of risk factors for breast cancer are considered jointly in one pathogenetic framework which relates to the formation of pre-cancerous lesions. Energy-rich diet during puberty and adolescence enhances the occurrence of pre-cancerous lesions in the breast. This process is counteracted by full-term pregnancies, and the earlier they come the fewer the number of such lesions. Energy-rich diet later in life contributes to the occurrence of obesity which, after menopause, enhances the growth of existing subclinical and clinical breast cancer. In both periods of life the nutritional factor exerts its effect through endocrine mechanisms in which oestrogens play a major part.

Human papillomavirus DNA in normal, metaplastic, preneoplastic and neoplastic epithelia of the cervix uteri.

Abstract: Colposcopically directed cervical punch biopsies from 362 patients were screened by Southern blot hybridization for the presence of DNA of human papillomavirus (HPV) 6, 10, 11, 16, 18, 31 and 33. The biopsies represented original squamous epithelium, epithelium of metaplastic origin, different stages of cervical intraepithelial neoplasia (CIN) and invasive carcinomas. HPV6/11, 16, 18 and 31 were detected in 2.9% to 13.7% of histologically normal epithelia. HPV6/11 prevailed in CIN I. HPV16 was clearly more abundant than other HPV types in high-grade CIN and invasive cancers (50%-60%), compared with healthy epithelium. Restriction enzyme cleavage analysis of DNA from primary cancers and corresponding metastases proved the stable association of HPV16 DNA with invasive tumor cells. Preliminary follow-up studies of CIN II patients suggested that HPV16-associated lesions are relatively more likely to persist or to progress. Taken together, the data support the notion of a higher oncogenic potential of HPV16.

Amplification of the EGF receptor and c-myc genes in human esophageal cancers.

Abstract: The incidence of esophageal cancer is extremely high in Linxian County and certain other regions of the People's Republic of China. Epidemiologic and laboratory studies suggest that N-nitroso carcinogens and other environmental factors play a causative role. In the present study, employing over 100 DNA samples obtained from Lin-xian patients who underwent surgery for esophageal cancer, we have found a significant frequency of amplification of either the human epidermal growth factor receptor (HER-I) gene or the c-myc oncogene. These changes were found not only in tumor specimens, but also in adjacent non-tumor (grossly normal) tissue specimens obtained from patients with esophageal cancer. RNA samples were also obtained from over 30 tissue samples. These revealed considerable variation in the abundance of HER-I and c-myc transcripts in both the tumor and adjacent non-tumor specimens. A few samples revealed extremely high levels of these transcripts. Thus, changes in gene copy number or level of expression of HER-I or c-myc DNA sequences may play an important role in the pathogenesis of esophageal cancer in this high-risk region.

The Danish case-control study of cutaneous malignant melanoma. I. Importance of host factors.

Abstract: The relationship between cutaneous malignant melanoma and possible host factors was investigated in a population-based case-control study from East Denmark over a 3-year period. A total of 474 melanoma patients and 926 population controls aged 20-79 years were interviewed. Patients with lentigo maligna melanoma were not included. The major constitutional risk factors were: number of raised naevi on the arms (RR = 5.1 for 5+ vs. none), degree of freckling (RR = 2.9 for many vs. none), and light hair colour (RR = 1.7 for blond/fair vs. dark brown/black), which were independent of one another. An apparent synergy between number of raised naevi on the arms and degree of freckling was found. Thus, persons at high risk of melanoma may be identified by a simple assessment of naevi and degree of freckling. No significant difference was found between superficial spreading melanoma and nodular melanoma with regard to the most important host factors.

Monoclonal antibody mapping of keratins 8 and 17 and of vimentin in normal human mammary gland, benign tumors, dysplasias and breast cancer.

Abstract: The distribution of keratins 8 and 17 and of vimentin in 28 normal human mammary tissue samples, 16 benign tumors, 26 fibrocytic diseases and 52 malignant breast tumors have been studied using monoclonal antibodies HI, E3 and NT30, respectively. Three cell populations in normal mammary epithelium have been identified: luminal epithelium containing keratin 8, myoepithelium of the lobular structures positive for vimentin, and myoepithelium of extralobular ducts positive for keratin 17. In different kinds of benign tumor and dysplastic proliferation a mosaic of cells with all normal phenotypes has been observed. The majority of cells co-expressed keratins 8 and 17 or vimentin. In the overwhelming majority of carcinomas, cells did not contain myoepithelial markers (keratin 17 and vimentin) but expressed only keratin 8 specific to normal luminal epithelium.

Epidemiologic evidence of an association between body iron stores and risk of cancer.

Abstract: Biologic evidence suggests that high body iron stores could promote development of cancer. Because a previous study had shown an association between prescribed iron medication and lung cancer risk in men, we examined recent iron use as well as 2 additional indirect measures of body iron stores, anemia and the total iron-binding capacity (TIBC) of plasma, in relation to subsequent risk of cancer in a larger cohort of 174,507 persons. Women, but not men, who reported recent iron use had a lower risk of lung cancer than those who did not [RR = 0.60, 95% confidence limits (CL) 0.37, 0.97] after adjustment for age and cigarette smoking. Women who had used iron appeared to remain relatively iron-depleted. Risk for other cancers was slightly, but not significantly, lower in women who used iron. Anemia (hemoglobin less than 12 g) was also associated with lower risk of lung cancer in women (RR = 0.61, 95% CL 0.61, 0.98), but not in men. TIBC, which is inversely related to body iron stores, was inversely related to risk of lung cancer in women in a graded fashion (RR = 0.41, 95% CL 0.23, 0.73 comparing highest with lowest quartile). In men, a protective effect of higher TIBC against lung cancer was suggested, but did not reach statistical significance. These indirect measures of body iron stores appeared to reflect iron stores better in women than in men, probably because variability in iron stores is greater in women and iron deficiency more prevalent. A possible alternative explanation for our findings is incomplete adjustment for the confounding effects of cigarette smoking. This could apply to iron use and hemoglobin level which were related to smoking, but not to TIBC, which was not. These data, which indicate lower risk of cancer in iron-depleted women, lend epidemiologic support to the hypothesis that high iron stores may increase cancer risk, at least for lung cancer.

Inflammatory cell infiltrates in human melanoma at different stages of tumor progression

Abstract: Progression of human melanoma is associated with changes in antigenic phenotypes of tumor cells. To establish whether inflammatory infiltrates in progressing melanoma also change, we studied 146 cutaneous melanomas at different stages of progression. Monoclonal antibodies (MAbs) against lymphocyte and macrophage subpopulations, interleukin-2 receptor (IL-2 R), immune interferon (IFN-gamma), and the IFN-gamma-inducible, progression-associated melanoma antigens HLA-DR and gp89 were applied in situ. During the course of melanoma progression, decreased amounts of peritumoral T cells, IL-2 R-expressing lymphocytes and dermal T6+ dendritic cells were found, while increased numbers of intratumoral T cells, inflammatory (27E10+) and mature (25F9+) macrophages were associated with local progression of primary melanomas. In metastases, most infiltrate components except 25F9+ macrophages were rare. Positive correlations were observed between: (1) dermal T6+ cells and IL-2 R+ lymphocytes, and (2) presence of IFN-gamma in the infiltrate and HLA-DR and gp89 antigens on tumor cells. In all stages, HLA-DR expression on tumor cells was correlated with: (1) a shift towards T8+ lymphocytes in the infiltrates and (2) a loss of IL-2 R expression. Our data suggest mutual influences between melanoma cells and mononuclear cell infiltrates in situ.

Enhancement of the antiproliferative effect of cis-diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C.

Abstract: Quercetin (3, 3′, 4′, 5, 7-pentahydroxyflavone) has been shown to inhibit a variety of enzymes including the calcium- and phospholipid-dependent protein kinase (protein kinase C) in vivo and in vitro. We show that this compound synergistically enhances the antiproliferative activity of cis-diamminedichlo-roplatinum(II) (cis-DDP) and nitrogen mustard. Quercetin does not affect the repair of DNA interstrand cross-links introduced by cis-DDP. Long-term exposure to 12-O-tetradeca-noylphorbol-13-acetate (TPA), which reduces total protein kinase C activity, also amplifies the growth-inhibitory effect of cis-DDP and acts synergistically with quercetin. A synergism is also observed if tamoxifen or staurosporine are combined with cis-DDP. For both drugs the dose-effect curves for the inhibition of protein kinase C closely resemble the dose-effect curves for the antiproliferative activities. Although alternative mechanisms cannot be definitively excluded, the effects of quercetin, TPA, tamoxifen and staurosporine may result from the inhibition of protein kinase C.

Regulation of growth and epidermal growth factor receptor levels of LNCaP prostate tumor cells by different steroids.

Abstract: The growth of LNCaP cells, derived from a lymph-node carcinoma of the human prostate, was stimulated by different hormones. Optimal growth (3- to 4-fold increase in DNA content per culture versus controls) was observed at 0.1 nM R1881 (a synthetic androgen), 1 nM progesterone or 10 nM estradiol. Triamcinolone acetonide had no effect. Dihydrotestosterone maximally stimulated cell growth at 10 nM. When the culture medium was changed 4 times in 6 days instead of twice, optimal growth was observed at 1 nM dihydrotestosterone. This indicates that a rapid metabolism of dihydrotestosterone influenced growth response. LNCaP cells contained considerable amounts of androgen receptors (920 fmol/mg cytosol protein) while progestagen, estrogen and glucocorticoid receptors were absent. The affinity of steroids for the androgen receptor decreased in the order of: R1881 (relative binding affinity: 100.0) greater than dihydrotestosterone (67.7) greater than progesterone (29.4) greater than testosterone (23.8) greater than estradiol (4.3) greater than triamcinolone acetonide (less than 0.1). Effects on cell growth of these steroids paralleled their affinity for the androgen receptor. The number of EGF receptors per cell increased in a dose-dependent manner upon treatment with various hormones. Again the amount of steroid needed for maximal effects reflected the affinity of the steroid for the androgen receptor. An approximately 2-fold increase in EGF receptor number was observed within 24 hr and before an increase in growth could be detected. Actinomycin-D and cycloheximide inhibited the hormonally induced increase in EGF receptor numbers.

Utilization of human hematopoietic cell lines for the propagation and characterization of HBLV (human herpesvirus 6).

Abstract: Details of the productive infection of established human cell lines of diverse origin by HBLV (also designated Human Herpesvirus 6) are described in this report. The infection and replication of HBLV in several T and B lymphoid and other cell lines was observed by electron microscopic examination, by the detection of viral antigen expression by indirect immunofluorescence assay (IFA) and by the presence of HBLV DNA by Southern blot hybridization. Several of these cell lines produced large amounts of virus. For this reason and because of the absence of other human herpesviruses, these lines have provided a valuable resource for the preparation of reagents and the development of assays for the detection and characterization of HBLV. The isolation and characterization of new HBLV isolates from patients with chronic fatigue syndrome were also facilitated by using some of the cell lines reported here. The host range of HBLV in established cell lines, therefore, does not appear to be limited to the B lymphocytes, as initially suggested by in vivo studies. The infection of T and B lymphocytes, megakaryocytes and neuronal cells in vitro suggests a need for the evaluation of diverse hematological and neurological disorders to shed light on a possible HBLV involvement.

The glioblastoma-derived T-cell suppressor factor/transforming growth factor beta 2 inhibits the generation of lymphokine-activated killer (LAK) cells.

Abstract: Glioblastoma cells release factors (G-TsF) which inhibit T-cell proliferation. The G-TsF is a novel member of the transforming growth factor beta family and is identical to TGF beta 2. The effect of G-TsF and TGF beta 2 on the induction of LAK cell activity was investigated by culturing PBL obtained from normal blood donors and brain tumour patients in varying concentrations (50-500 U/ml) of interleukin 2 (IL2) alone or IL2 plus G-TsF/TGF beta 2 (1 ng/ml) for 4 days. Subsequent cytolytic activity was measured against autologous and allogeneic glioblastoma targets, fresh NK-resistant melanoma cells and K562 cells. G-TsF/TGF beta 2 purified from glioblastoma cell cultures and TGF beta 2 isolated from porcine platelets significantly suppressed the generation of LAK cell activity, and the inhibitory effect could be reduced by higher concentrations of IL2. The suppressive effect of TGF beta 2 was most significant during the early stages of LAK cell generation and no inhibitory effect was seen when TGF beta 2 was added directly to the cytotoxicity assay. These results suggest that human glioblastomas may exert an inhibitory influence on the generation of an immune response in vivo through the production of G-TsF/TGF beta 2, and that the inhibitory effect may be modified by IL2.