Showing papers in "International Journal of Cancer in 1993"

Estimates of the worldwide incidence of eighteen major cancers in 1985.

Abstract: The annual incidence rates (crude and age-standardized) and numbers of new cases of 18 different cancers have been estimated for the year 1985 in 24 areas of the world. The total number of new cancer cases (excluding non-melanoma skin cancer) was 7.6 million, 52% of which occur in developing countries. The most common cancer in the world today is lung cancer, accounting for 17.6% of cancers of men worldwide, and 22% of cancers in men in the developed countries. Stomach cancer is now second in frequency (it was slightly more common than lung cancer in 1980) and breast cancer—by far the most important cancer of women (19.1% of the total)—is third. There are very large differences in the relative importance of the different cancers by world area. The major cancers of developed countries (other than the 3 already named) are cancers of the colon-rectum and prostate, and, in developing countries, cancers of the cervix uteri, mouth and pharynx, liver and oesophagus. The implications of these patterns for cancer control, and specifically prevention, are discussed. Tobacco smoking and chewing are almost certainly the major prevent able causes of cancer today.

Estimates of the worldwide mortality from eighteen major cancers in 1985. Implications for prevention and projections of future burden

Abstract: This report presents worldwide estimates of annual mortality from all cancers and for 18 specific cancer sites around 1985. Crude and age-standardized mortality rates and numbers of deaths were computed for 24 geographical areas. Of the estimated 5 million deaths from cancer (excluding non-melanoma skin cancer), 56% occurred in developing countries. The most frequent neoplasm is lung cancer, accounting for 22% of cancer deaths in men. Among women breast cancer is the leading malignancy, accounting for 16% and 11% of all cancer deaths in developed and developing countries, respectively. In developing countries, cancer of the cervix uteri ranks first, breast cancer second. The second most frequent cause of death from cancer in both sexes is cancer of the stomach, followed by liver cancer in men and by colon/rectum cancer in women. Cancers of the colon/rectum and prostate maintain a high rank in men living in developed countries, while cancers of the lung, ovary and pancreas occupy similar ranks among women. In developing countries, cancers of the oesophagus and mouth/pharynx follow those previously mentioned in both sexes. If the estimated rates continue to prevail, increases in the numbers of deaths of 20.4% in developed and 18.1% in developing countries are expected by the year 2000, simply as a consequence of demographic trends towards ageing and population growth. Our results provide an indication of the potential impact of preventive practices. It is estimated that 20% of all cancer deaths (1 million) could be prevented by eliminating tobacco smoking. Mortality from cancers of the liver and uterine cervix, both major problems in developing countries, could be substantially reduced by immunization against hepatitis B virus infection and early detection through Pap smears, respectively.

Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53-independent pathway: Implications for the possible role of dietary fibre in the prevention of large-bowel cancer

Abstract: The purpose of this study was to determine whether cultured colonic adenoma and carcinoma cells undergo apoptosis (programmed cell death) in vitro and whether specific growth and dietary factors, thought to be involved in the control of growth and differentiation of human colonic cells, could induce cell death through apoptosis. In cell lines originating from 6 colorectal adenomas and 7 carcinomas, spontaneous apoptosis was observed. Sodium butyrate, a naturally occurring fatty acid, is present in the human large bowel in millimolar amounts as a result of bacterial fermentation of dietary fibre. Sodium butyrate, at physiological concentrations, induced apoptosis in 2 adenoma cell lines, RG/C2 and AA/Cl, and in the carcinoma cell line PC/JW/FI. In contrast, transforming growth factor beta 1, which is thought to have an important role in the control of growth in colonic epithelium, did not induce apoptosis. Neither RG/C2 nor PC/JW/FI contain wild-type p53, therefore this tumour-suppressor gene is not required to mediate signals for the induction of apoptosis in colonic tumour cells. Our studies report the induction of apoptosis in colonic tumour cells by the naturally occurring fatty acid sodium butyrate. Since sodium butyrate is produced by bacterial fermentation of dietary fibre, the observation that this fatty acid can induce apoptosis could, in part, explain why a high-fibre diet appears to be protective against colon cancer. Escape from the induction of programmed cell death may be an important event in colorectal carcinogenesis.

Review article: Epidemiology of male breast cancer. A meta‐analysis of published case‐control studies and discussion of selected aetiological factors

Abstract: Male breast cancer is a rare tumour in all parts of the world. About 1% of all breast cancers occur in men, but the male/female ratio is higher among black than among white populations. This effect can be seen in US cancer registries and even more markedly in African data. A positive correlation exists on a population scale between male breast cancer and prostate cancer. Seven case-control studies of male breast cancer are available, and a pooled analysis was conducted of the most commonly suspected risk factors. Male breast cancer appears to be associated with marital status: Mantel-Haenszel exposure odds ratio (EOR) for never married = 1.6; 95% confidence limits (CL) = 1.1, 2.3, religion (EOR for being Jewish = 2.1; 95% CL = 1.4, 3.2), previous breast pathology (EOR for positive history of benign breast disease = 2.7; 95% CL = 1.7, 4.2), gynaecomastia (EOR for positive history = 6.2, 95% CL = 3.4, 11.4), previous testicular pathology (EOR for positive history = 2.2; 95% CL = 1.5, 3.3), previous liver diseases (EOR for positive history = 1.6; 95% CL = 1.0, 2.4) and family history of breast cancer (EOR for first-degree relative with breast cancer = 2.5; 95% CL = 1.7, 3.7). No association is found with smoking history. Other potential risk factors such as reproductive history, education, occupation, anthropometric variables, association with various diseases, and specific exposures such as drug use, were not systematically evaluated in all studies and provide sometimes contradictory results, possibly due to small numbers of exposed subjects. Overall, the analytical epidemiology of male breast cancer presents similarities with the epidemiology of female breast cancer, with a potential role of factors related to hormonal status, relative hyperoestrogeny in men being potentially linked to increased risk of disease. Genetics may also play a role, with high risk linked to a familial history of breast cancer, and with a major risk in patients with Klinefelter's syndrome.

Role of aminopeptidase N (CD13) in tumor-cell invasion and extracellular matrix degradation

Abstract: We have investigated the effect of monoclonal antibodies (MAbs) specific for aminopeptidase N/CD13 on the invasion of human metastatic tumor cells into reconstituted basement membrane (Matrigel). The invasion of human metastatic tumor cells (SN12M renal-cell carcinoma, HT1080 fibrosarcoma and A375M melanoma) into Matrigel-coated filters was inhibited by an anti-CD13 MAb, WM15, in a concentration-dependent manner. However, this MAb did not have any effect on tumor-cell adhesion and migration to the extracellular matrices, which may be involved in tumor-cell invasion. MAb WM15 inhibited the degradation of type-IV collagen by tumor cells in a concentration-dependent manner. We also found that WM15 inhibited hydrolysing activities towards substrates of aminopeptidases in 3 different tumor cells. Since our previous study indicated that bestatin, an aminopeptidase inhibitor, was able to inhibit tumor-cell invasion, as well as aminopeptidase activities of murine and human metastatic tumor cells, cell-surface amino-peptidase N/CD13 may be partly involved in the activation mechanism for type-IV collagenolysis to achieve tumor-cell invasion, and anti-CD13 MAb WM15 may inhibit tumor-cell invasion through a mechanism involving its inhibitory action on the aminopeptidase N in tumor cells.

Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and-neck squamous-cell carcinoma.

Abstract: Squamous-cell carcinoma of the head and neck includes a heterogeneous group of tumours of the upper air and food passages for which prognosis is difficult to assess. In fact, patients in comparable stages may have diverse clinical courses and responses to similar treatments. In order to better define the prognosis of each patient there is therefore a need to identify novel biological markers which reflect more accurately growth rate, progression and metastatic potential of each tumour. We assessed whether metastases correlate with micro-vessel counts (i.e. intratumoral vascularity) using the CD-31 monoclonal antibody (MAb) and p53 mutant protein expression, determined in the primary by immunocytochemical methods in 70 patients with locally advanced head and neck cancer. Patients were treated with concurrent chemo-radiotherapy; 50 of these presented loco-regional node metastasis at diagnosis whereas 3 cases, initially node-negative, developed distant metastasis during the period of observation. No feature was predictive for objective response to treatment. The overall mean and median blood vessel density at “hot spots” was 37.42 and 36, respectively, and 57% of the tumours expressed p53 mutant proteins. These 2 biological markers were significantly associated. Patients with metastases (loco-regional and distant) had a significantly higher mean blood-vessel density than those without tumour spread. Also, patients with p53-positive (+/ + +) tumours had a significantly higher incidence of metastasis than those with negative ones. Multivariate analysis showed that both vascularity and stage, but not p53 expression, are significant and independent predictors of metastasis in this series.

Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma.

Abstract: Clinical importance of tumor angiogenesis, especially its significance as a prognostic indicator, was examined in 125 primary breast-cancer patients The grade of neovascularization was assessed by the vessel density which was obtained by immunocytochemical staining for factor VIII antigen Postoperative survey demonstrated that the vessel density is a statistically significant predictor of relapse-free survival (median follow-up period: 62 months) Patients with over 100 counts of factor-VIII antigen-positive cells per 200 x field in the most active areas of neovascularization showed significantly poorer prognosis than those with less than 100 counts The prognostic value of the vessel density was also confirmed by another evaluation method using immunocytochemical staining to CD-31 which is a platelet/endothelial cell adhesion molecule A significant difference in relapse-free survival rate was shown between patients having higher counts of CD-31 positive cells and those having lower counts Breakdown analysis stratified by nodal status showed that the vessel density was a significant prognostic indicator in node-negative and node-positive patients Multivariate analysis indicated that the vessel density is an independent prognostic indicator in primary breast-cancer patients

Cancer in Kampala, Uganda, in 1989–91: Changes in incidence in the era of aids

Abstract: Re-establishment of the cancer registry in Kyadondo County, Uganda, has allowed estimation of incidence rates for the period September 1989 to December 1991. The results are compared with earlier data from the same area, and from other African cancer registries. The most striking feature is the emergence of Kaposi's sarcoma as the leading cancer in males (almost half of all registered cases) and the second most frequent (17.9%) in females. This parallels the evolution of the epidemic of AIDS. There were also marked increases in the incidence of both oesophageal and prostatic carcinoma, while the incidence of cancer of the penis and the urinary bladder declined, possibly as a result of improved standards of hygiene. In females, the incidence of cancer of the cervix has more than doubled since the 1950s, and is now among the highest recorded in the African continent.

Trends in non-melanocytic skin cancer treated in Australia : the second national survey

Abstract: An Australia-wide survey in 1985 recorded the highest rates of medically treated non-melanocytic skin cancer (NMSC) ever reported We report the findings of a repeat survey conducted in 1990 This second survey confirmed the differences, by age, sex, body site, latitude, country of birth and skin reaction to strong sunlight, that were observed in 1985 Over the 5-year period certain changes were noted: the incidence of NMSCs increased by 19%, of basal-cell carcinomas (BCC) by 11% and of squamous-cell carcinomas (SCC) by 51% With advancing age, men and women differed in their incidence, and this difference was greater for SCC than for BCC Log-linear modelling, however, failed to detect either a cohort or a survey effect between the 2 surveys The proportional distribution of BCCs and SCCs by body site indicated an increase in BCCs on the trunk in both men and women, and half the proportion of SCCs on the head and neck in women as compared with men The latitudinal gradients observed in 1985 were even stronger in 1990; the population living north of 37 degrees S experienced a 30% increase in the incidence of treated NMSC between 1985 and 1990, while the population living south of 37 degrees S had a 25% decrease The implications of these findings for cancer-control initiatives are discussed

Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression.

Abstract: Recent data indicate a major role for IL-10 in suppressing immune and inflammatory reactions. To date, expression of human IL-10 has been attributed primarily to helper T lymphocytes, activated monocytes, and neoplastic B cells, and was often found to be associated with IL-6 expression. In this study we sought to determine whether non-hematopoietic human tumor cell lines produce IL-10 and, if so, what is the relationship between IL-10 and IL-6. Using ELISA, we determined IL-10 and IL-6 levels in culture supernatants of 48 cell lines established from carcinomas of the kidney, colon, breast and pancreas, malignant melanomas and neuroblastomas. IL-6 protein was secreted by 28 of the tumor cell lines; IL-10 was measurable in 15 cell lines. IL-6 secretion was maximal and most frequent in renal-cancer cell lines, while IL-10 production was found to be highest and most common among cell lines derived from colon carcinomas. IL-10 in conditioned medium of one of the colon carcinoma cell lines (CCL222) was bio-active, as demonstrated in the mouse MC/9 mast-cell-line assay and in human mixed-lymphocyte reactions. In both assays, IL-10 bio-activity was neutralized by an anti-IL-10 monoclonal antibody. Expression of IL-6 and IL-10 was confirmed by RNA analysis using message amplification by PCR and sequencing of amplified cDNA. LPS, IL-1 alpha, and TNF-alpha strongly enhanced the release of IL-6 by RCC cells, but only marginally affected IL-10 production in colon-carcinoma cells. IL-10 secretion by colon-carcinoma cells was moderately stimulated by IFN-gamma and IL-4. Dexamethasone suppressed the release of IL-6, but had no inhibitory effect on IL-10 secretion. Our results demonstrate that tumor cell lines established from certain types of human carcinomas are capable of expressing and releasing IL-6 and/or IL-10, suggesting a role of these cytokines in solid-tumor development and anti-tumor immunity.

Over‐expression of p53 nuclear oncoprotein in transitional‐cell bladder cancer and its prognostic value

Abstract: Two hundred and twelve archival bladder-cancer biopsy specimens were analyzed immunohistochemically to detect over-expression of p53 protein. The results of immunohistochemical analysis were correlated to established histological and quantitative prognostic factors and survival of patients during a mean follow-up period of more than 10 years. Twentynine percent of tumours were positive for p53 protein, and over-expression was associated with high histological grade, non-papillary growth architecture, dense inflammatory cell reaction, DNA aneuploidy, high S-phase fraction, high mitotic frequency and high SD of nuclear area. Progression in T, N and M categories was significantly related to over-expression of p53 protein. In univariate survival analysis, over-expression of p53 predicted poor outcome in the entire cohort, in papillary tumours and in muscle-invasive tumours but not in superficial tumours. In a multivariate survival analysis, over-expression of p53 oncoprotein had no independent prognostic value over clinical stage and mitotic index. The results confirm that p53 is involved in the growth regulation of bladder cancer and is certainly a subject for detailed analysis of specific mutations.

Amplification and over‐expression of the EGFR and erbB‐2 genes in human esophageal adenocarcinomas

Abstract: Esophageal cancer is one of the 10 most prevalent human cancers worldwide. The incidence of esophageal adenocarcinoma is on the rise and patients with this disease typically have very poor prognosis. Informative biomarkers would benefit the clinical management of this disease. We examined 13 cases with esophageal adenocarcinomas and 5 cases with Barrett's esophagus for amplification of the EGFR and erbB-2 genes. We detected multiple copies of the EGFR gene in 30.8% of the tumors and multiple copies of the erbB-2 gene in 15.4% of the tumors. Of the cases with amplification of the erbB-2 gene, co-amplification of the EGFR gene was found. Multiple copies of the EGFR gene were also found in one case of Barrett's esophagus. Immunohistochemical staining of the tissues revealed increased expression of the erbB-2 protein in Barrett's mucosa and adenocarcinoma, but no associations between staining intensity and degree of EGFR or erbB-2 gene amplification, histology, or tumor stage were found. Differential polymerase chain reaction was examined as a method for pre-operative detection of gene amplification in esophageal tumors and Barrett's mucosa.

Expression of MaTu-MN protein in human tumor cultures and in clinical specimens.

Abstract: MaTu is a novel agent which may be of relevance in human oncogenesis, and has 2 components. One of them, the exogenous MX (coding for protein p58X), is transmissible to human fibroblasts, to HeLa and to HeLa x fibroblast (H/F) hybrids. The other component, MN, is a cellular gene. Its product, the protein p54/58N, is inducible by infecting HeLa cells with MX or by growing them in dense cultures. This p54/58N appears to be a tumor-associated antigen: it is expressed in HeLa and in tumorigenic cells (H/F-T), but not in fibroblasts or in nontumorigenic hybrid cells (H/F-N). Proteins related to p54/58N were also found on immunoblots prepared from human carcinomas of ovary, endometrium and uterine cervix, but not from normal tissues from corresponding organs or from placenta. Using genetically engineered MN protein, we developed a radioimmunoassay for MN-specific antibodies, and for quantitative determination of MN proteins in cell extracts. In HeLa cells infected with MX we observed conspicuous ultrastructural alterations: formation of abundant filaments on the cell surface and amplification of mitochondria. Using immunogold-staining, we visualized the p54/58N on the surface microvilli and in the nucleus, particularly in nucleoli.

Increased accumulation of p53 protein in cisplatin-resistant ovarian cell lines.

Abstract: We have examined p53 protein levels in cell lines selected for resistance to the chemotherapeutic drug cis-diamminedichloroplatinum (II), cisplatin. The majority of the independent cisplatin-resistant clones isolated by a single selection with cisplatin from the ovarian tumour cell line A2780 showed increased levels of p53 protein compared to the parental cell line. Elevated p53 protein levels were also observed in cisplatin-resistant ovarian human tumour lines isolated after multiple exposures to cisplatin (A2780/cp70 and OVIP/DDP). Direct PCR sequencing of p53 cDNAs showed that both the A2780/cp70 and the parental A2780 cell lines had a wild-type p53 gene sequence. The OVIP and OVIP/DDP lines both had a heterozygous mutation at codon 126. Cell-cycle analysis after gamma-irradiation or cisplatin treatment showed evidence of a G1/S and G2/M cell-cycle checkpoint in both A2780/cp70 and the sensitive parental cell lines. However, the resistant cell line A2780/cp70 showed less inhibition of DNA synthesis after gamma-irradiation than the sensitive cell line. Transfection of a mutant p53 gene construct (containing a mutation at codon 143, val to ala) into the A2780/cp70 resistant cells conferred a significantly increased sensitivity to cisplatin, suggesting that p53 is a direct determinant of cisplatin resistance in these cells. However, expression of this mutant p53 in the A2780 cells did not affect sensitivity.

p53 mutation in gastric cancer: a genetic model for carcinogenesis is common to gastric and colorectal cancer.

Abstract: Mutation of the p53 tumour-suppressor gene in exons 5 through 8 was examined in 118 cases of gastric cancer (59 early gastric cancers and 59 advanced gastric cancers) using PCR-SSCP (polymerase-chain-reaction-single-strand-conformation polymorphism) analysis and direct sequencing. In early gastric cancer, mutations were found in 15 of 41 (37%) cases of the cohesive type, i.e., papillary adenocarcinoma, well to moderately differentiated tubular adenocarcinoma, and poorly differentiated adenocarcinoma with solid nests or focal tubular structures, but were not detected in 18 cases of the non-cohesive type, i.e., signet-ring-cell carcinoma and poorly differentiated adenocarcinoma growing in a scattered manner. In advanced gastric cancer, 25 of 59 (42%) cases of the cohesive type had p53 mutation. No significant association was found between p53 mutation and other histopathological parameters such as macroscopic classification, lymph-node involvement and depth of tumour invasion. Fifteen of 25 (60%) mutations in the advanced gastric-cancer group were accompanied by allele loss at the p53 gene locus. Eighty-three percent of mutations in early gastric cancer and 52% of mutations in advanced gastric cancer showed G:C-to-A:T transition, almost exclusively at CpG dinucleotide mutational hot spots, indicating that the spectrum of p53 mutation was similar to that of colorectal cancer. These data suggest that the p53 mutation occurs selectively in gastric cancer of the cohesive type from the intramucosal cancer stage.

A monoclonal antibody detects heterogeneity in vascular endothelium of tumours and normal tissues

Abstract: A new murine monoclonal antibody (MAb), E-9, has been raised using tissue-cultured human umbilical vein endothelial cells. The antigen recognized by this MAb is a peptide of 170 kDa under non-reducing conditions and 96 kDa under reducing conditions. MAb E-9 showed marked heterogeneity in its distribution in various tissues. The antigen recognized by it was present in vascular endothelial cells of all tumours, foetal organs and in regenerating and inflamed tissues. It stained a few normal tissues. However, with the exception of tonsils, staining tended to be weak and limited to a few blood vessels, as revealed by double staining using pan-endothelial antibody (CD31) and antibody to von Willebrand factor, another marker of vascular endothelium. Surprisingly, blood vessels within the placental villi were completely negative. The function of the antigen recognized by MAb E-9 is not known, but its evaluation and use should increase our understanding of angiogenesis.

Bcl-2 proto-oncogene expression in Epstein-Barr-virus-associated nasopharyngeal carcinoma.

Abstract: The bcl-2 proto-oncogene product inhibits apoptosis. Increased levels of bcl-2 protein are associated with prolonged B-cell survival and have been demonstrated in a high proportion of follicular B-cell lymphoma. Recent studies have shown that bcl-2 protein expression in B cells immortalized by Epstein-Barr virus (EBV) in vitro is up-regulated by the EBV-latency-associated antigen, latent membrane protein (LMP) I. The epithelial malignancy, undifferentiated nasopharyngeal carcinoma (UNPC), has a well-established association with EBV and the tumour cells characteristically display a restricted latent viral phenotype including LMP I. This study has investigated the relationship between the presence of EBV DNA, EBV phenotypic profiles and bcl-2 protein expression in conventionally processed and cryopreserved samples of NPC using in situ hybridization, immunocytochemical and immunoblotting techniques. bcl-2 was detected in most (80%) samples of UNPC as well as in 1/3 samples of keratinizing NPC and 2/2 samples of nasopharyngeal adenocarcinoma. However, no close correlation was found between the presence of EBV DNA, and profiles for LMP I and bcl-2 protein expression in 45 UNPC. In addition, bcl-2 protein was shown to be selectively expressed in the basal compartment of normal nasopharyngeal epithelia. bcl-2 protein expression has not been reported previously in malignant tumours of epithelial origin. The findings in this study implicate a role for bcl-2 both in normal keratinocyte differentiation and in the pathogenesis of epithelial malignancy.

Diet and risk of gastric cancer. A population-based case-control study in Sweden.

Abstract: A case-control study to evaluate risk factors of gastric cancer was carried out in areas with contrasting incidence rates in Sweden. Face-to-face interviews were conducted with 338 of 456 eligible histologically confirmed gastric-cancer cases and 669 of 880 eligible control subjects, sampled from population registers and frequency-matched by age and gender. We focused on 2 periods, adolescence and 20 years prior to interview. The association of gastric-cancer risk with dietary habits during adolescence were similar to that found for the period 20 years before interview; high consumption of wholemeal bread, fruit and vegetables was associated with reduced gastric-cancer risk. In addition, cheese, fish and tea had a protective effect during adolescence. Increased gastric-cancer risk was related to whole-milk consumption, but this association decreased substantially in a multivariate analysis including vegetables. There was a positive relationship between gastric-cancer risk and the age at which the interviewees started using refrigerators. This population-based study confirmed the protective effect of a high consumption of vegetables and fruit in the development of gastric cancer, but failed to find any association between intake of meat, sausage, cold cuts, liver, salt, coffee, the habit of frying, smoking or grilling foods, and risk of gastric cancer.

Diet and colorectal adenomas: a case-control study in Majorca.

Abstract: A case-control study on dietary factors and colorectal adenomas was conducted in the island of Majorca, Spain, from April 1987 to February 1990 Subjects were interviewed using a food frequency questionnaire Nutrient and caloric intake was estimated using local food composition tables The risk of colorectal adenomas was related to the consumption of sugar and pastries Consumption of vegetables was highly protective, irrespective of the cooking procedures Analyses by nutrients identified as protective factors fiber from fruits and vegetables, magnesium and zinc, and vitamins C, B 6 and folic acid No excess risk was found for alcohol drinking, intake of saturated fats or animal protein Of the non-dietary factors, sedentariness in the work-place and urban residence were the only risk factors identified

Effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain-tumour biopsies in vitro

Abstract: Spheroids initiated directly from human primary gliomas were used to investigate the effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferation, migration and invasion into foetal rat brain tissue. EGF increased tumour spheroid volume in 10 of 13 glioblastomas studied, whereas 5 of 11 tumours responded to bFGF. NGF increased the spheroid volume in 2 of 5 tumours. In 8 tumours, PDGF(bb) had no effect on tumour spheroid volume. An increase in BUdR-labelling indices confirmed that cell proliferation was responsible for the volume increase observed in stimulated spheroids. EGF stimulated cell migration in 5 and bFGF in 3 of 8 tumours studied. NGF stimulated cell migration in 1 of 5 glioblastomas, whereas 1 of 3 glioblastomas responded to PDGF(bb). The effects of growth factors on the invasion of spheroids prepared from the glioblastoma biopsy specimens were also studied in vitro using foetal rat brain aggregates as target tissue. EGF stimulated invasion in 7 of 8 glioblastomas studied, whereas bFGF stimulated invasion in 2 of these tumours. NGF or PDGF(bb) did not increase the invasiveness of the glioblastoma tissue. Our results represent the net effect of the growth factors on a complex tumour-cell population. We conclude that exogenously administered growth factors, EGF in particular, increase the cell proliferation as well as migratory and invasive capacities of cultured primary brain tumour biopsies in vitro.

E‐cadherin expression in head and neck squamous‐cell carcinoma is associated with clinical outcome

Abstract: The cell-cell adhesion molecule E-cadherin has been shown to suppress invasive growth of epithelial cells in vitro, and loss of its expression is thought to be important in invasion and metastatic potential of epithelial tumors in vivo. We retrospectively studied the level of E-cadherin expression in 50 primary head and neck squamous-cell carcinomas (HNSCC) by immunohistochemical methods, on frozen sections, using anti-E-cadherin monoclonal antibody (MAb) 6F9. It concerned patients with different stages of carcinoma of larynx or oral cavity who had been treated with curative intention 30 months or more before. Percentages of membranous stained tumor cells were scored in 1 of 5 categories. Scores were generally low, as in 11/50 lesions or = 30 months without evidence of disease had significantly higher levels of membranous E-cadherin expression in their primary tumors than 10 patients with unfavorable clinical course clearly related to recurrent and/or metastatic HNSCC. Moreover, this could only partially be explained by distinctions in differentiation grade between both groups. Our results suggest that membranous E-cadherin expression has prognostic importance in patients with HNSCC.

Increasing incidence of both major histological types of esophageal carcinomas among men in Sweden.

Abstract: Although a rare tumor form, there is evidence that the incidence of esophageal adenocarcinomas is increasing in Western Europe and the US. The aim of this nationwide population-based study was to describe the secular trends in the incidence rates of adenocarcinoma and squamous-cell carcinoma of the esophagus over a 28-year period from 1960 to 1987. The Swedish Cancer Registry, complete to more than 95%, was used to identify the cases. The percentage verified by histology rose from 89% to 98%. The age-standardized incidence rate of adenocarcinoma increased in males from 0.5 per 10(5) in 1960-63 to 1.1 per 10(5) in 1984-87, corresponding to an average annual increase of 1.5%. In females the incidence remained stable around 0.2 per 10(5). The age-standardized incidence rate of squamous-cell carcinoma in males increased from 2.9 to 4.0 per 10(5), corresponding to an average annual increase of 1.0%. In females the rate decreased from 1.4 to 1.2 per 10(5), corresponding to an annual average decrease of 0.5%. The male/female ratio was 4.6 for adenocarcinoma and 2.7 for squamous-cell carcinoma of the esophagus. Since the incidence rates of squamous-cell carcinoma of the esophagus and of adenocarcinoma seem to be rising, there is a great need for well-planned analytical epidemiological studies of these tumor locations, taking the histological type into consideration.

Sex differences in lung‐cancer risk associated with cigarette smoking

Abstract: The importance of cigarette smoking as a risk factor for specific histologic types of lung cancer in men and women has been examined in a case-control analysis of data from the Cancer Surveillance Program of Orange County, a population-based registry. Smoking habits were abstracted from medical records for 1153 men and 833 women diagnosed with primary lung cancer in 1984-1986 and 1851 men and 1656 women aged 30 or older diagnosed with cancers not associated with smoking. Ninety-six percent of men and 89% of women with lung cancer were current or former cigarette smokers, as compared with 55% of men and 34% of women with other cancers. The age and ethnicity-adjusted odds ratios (OR) for ever-smoking were 19.7 for men and 15.0 for women. Men and women who smoked 2 or more packs per day experienced nearly equal risks. Comparison of the most common cell types showed that women smokers had equal or lower ORs for squamous-cell carcinoma and adenocarcinoma, but higher OR for small-cell carcinoma, as compared with men smokers. While the smoking-associated OR were equal for small-cell and squamous-cell carcinomas in men, the OR for women were significantly higher for small-cell carcinoma than for squamous-cell carcinoma.

Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression.

Abstract: RB-protein status as determined by immunohistochemical analysis was compared with loss of heterozygosity (LOH) at the RB locus in 68 primary transitional-cell carcinomas of the bladder. Absence of RB-protein expression was found in 15 of 17 tumors in which LOH at the RB locus was identified, whereas 31 of 36 tumors from informative patients which showed no LOH had a normal RB-protein pattern ( p < 0.001). Altered RB-protein expression was also more frequently seen in muscle-invasive and high-grade tumors ( p < 0.003 and <0.005, respectively). Our results indicate that LOH at the RB locus is highly correlated with loss of RB-protein expression in primary bladder carcinomas and further strengthens the notion that loss of RB function may be associated with more aggressive bladder tumors.

Amplification of fgfr4 gene in human breast and gynecological cancers

Abstract: We have investigated gene amplification of fibroblast growth factor receptor-4 (FGFR4) gene in 30 primary breast tumor samples and 15 gynecological tumor samples. Ten percent of the breast tumors showed 2- to 4-fold amplification. Amplification was found more frequently in estrogen- and progesterone-receptor-positive tumors and in tumors with high lymph-node involvement. Breast tumor samples were also analyzed for the amplification of fgfr3 and erbB2 genes and the chromosome 11q13 located genes hst1/int2/bcl1/sea. erbB2 gene was amplified 2- to 13-fold in 13% of the cases, but no amplification of int2/hst1/bcl1/sea amplicon was found. Gynecological tumors were also analyzed for the amplification of fgfr4 and fgfr3 genes and for int2 and hst1 oncogenes. Eleven of the 15 gynecological tumors were ovarian neoplasms including 2 benign tumors; the remainder comprised 1 ovarian metastasis of breast cancer; 1 endometrial cancer; 1 uterine leiomyosarcoma and 1 carcinosarcoma of the fallopian tube. In gynecological tumors, fgfr4 gene was found to be amplified in 2 ovarian tumors. Amplification of hst1 was found in 1 benign ovarian tumor. Thus, the fgfr4 gene may be involved in breast and ovarian tumorigenesis.

Cytogenetic analysis of epithelial renal‐cell tumors: Relationship with a new histopathological classification

Abstract: Renal-cell carcinomas (RCC) are clinically, histologically and cytogenetically very heterogeneous. The present histological WHO classification shows no clear correlation between histologic subtypes and specific chromosomal abnormalities. In 1986, a new classification was proposed by Thoenes and Storkel based on the cell type from which the tumor arises. They distinguish S cell types: clear-cell, chromophilic, chromophobic, ductus Bellini and oncocytic. Results of 105 primary tumors show that, in this new classification, there is a correlation between different subtypes of renal-cell tumor and specific chromosomal abnormalities at a microscopic and/or molecular level. The clear-cell compact type shows structural aberrations of chromosomes 1, 3, 4, 5q, 6, 10q, 11q and 12q, together with polysomy of chromosomes X, 4, 5, 7, 10, 12, 15, 16, 19, 20, 21 and 22, monosomy of chromosomes 3, 8, 9, 13, 14, and loss of Y. The main characteristics of the chromophilic tubulo-papillary type are trisomies 7 and 17, and loss of the Y-chromosome. Chromophobic carcinoma seems to be correlated with, inter alia, polysomy 7, trisomies 12, 16, 18, 19, structural abnormalities of 11q, and telomeric associations. Oncocytomas do not reveal any specific chromosomal anomaly, except for trisomy 7. Loss of heterozygosity on 3p is only found in the clear-cell compact type. Some specific chromosomal abnormalities correlate with a particular grade of the tumor. These correlations support the hypothesis that specific chromosomal abnormalities play a role in the histogenesis and oncogenesis of RCC. They may be important for tumor diagnosis and clinical prognosis. (C) 1993 Wiley-Liss, Inc.

Ganglioside expression on human malignant melanoma assessed by quantitative immune thin-layer chromatography.

Abstract: The ganglioside composition of 20 human malignant melanomas and 5 normal tissues (muscle, spleen, kidney, liver and brain) was analyzed by high-performance thin-layer chromatography (HPTLC) and immune HPTLC using a panel of antiganglioside monoclonal antibodies, and quantified by photodensitometry. The most prominent gangliosides were GM3 and GD3, present in all 20 melanomas; however these were expressed in the 5 normal tissues as well. GD2, GM2, GT3 and 9-O-Ac-GD3 were each expressed in at least 17 of 20 melanomas, but distribution on the normal tissues examined was largely restricted to brain. The detection of several additional glycolipids was studied. GMI was highly expressed in normal brain tissue, but was not detected in any melanoma biopsies, and SGPG was detected in neither. Fuc-GMI was identified in 3 melanoma specimens and a base-sensitive ganglioside, not previously identified in melanoma, was detected in 4 of 20 melanomas with the anti-GD2 MAb 3F8. This compound is most likely O-acetylated GD2. GD3 lactones were identified in 16 of 20 melanoma biopsies, however the proportion that are naturally occurring rather than artifacts of extraction is unclear. The total expression of the more restricted gangliosides (GM2, GD2, GT3 and 9-O-Ac-GD3) in these 20 melanomas ranged between 2.4 and 102.5 micrograms/g, representing 8 x 10(6) to 3 x 10(8) ganglioside molecules per cell. This number of tumor-surface antigens provides the rationale for a polyvalent anti-melanoma vaccine containing GM2, GD2, GT3 and 9-O-Ac-GD3.

Expression of MMP‐7(pump‐1) mRNA in human colorectal cancers

Abstract: The expression of MMP-7 (pump-1) gene was examined in 10 cases of colorectal cancer by utilizing RT-PCR. In 9 out of 10 cases, MMP-7 mRNA was detected in cancerous tissue, whereas none was detected in adjacent normal colon tissue. However, this message was detected in only 1 out of 6 colon-cancer cell lines. In colonic mucosa from 3 patients with ulcerative colitis it was not detected. The expression of MMP-2 (72-kDa type-IV collagenase) mRNA was also investigated in the same tissue samples, and was detected in all samples, including cancerous and non-cancerous tissue. Our data suggest that MMP-7 is expressed in a tumor-associated manner in colorectal cancers and may play a role in tumor progression.

K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos.

Abstract: We investigated point mutational activation of the ras genes (K-ras codons 12, 13 and 61; N-ras codons 12, 13 and 61; H-ras codons 12 and 61) in primary, resected lung cancer by dot blotting and oligonucleotide hybridization. K-ras mutations were found in 14 (29%) of the 48 lung tumour specimens examined, but no N-ras or H-ras mutations were found. The highest frequency of K-ras mutation was observed in adenocarcinoma: 12 of the 21 samples studied (57%) had a mutation, which is one of the highest frequencies reported for lung adenocarcinoma. The commonest type of mutation in these lung tumour samples consisted of transversions: we observed 11, of which 8 (57% of all mutations) were G to T transversions. Most of the 48 patients studied had a history of heavy smoking, either with or without evidence of occupational exposure to asbestos. Statistical analysis revealed--in addition to the highly significant association between the adenocarcinoma type of lung cancer and K-ras mutation--a clear association of K-ras mutations with heavy life-time smoking (> or = 50 pack-years of cigarette smoking; odds ratio (OR) 4.9, 90% CI 1.2-19.5, multivariate analysis). In addition, occupational asbestos exposure showed an elevated, but non-significant, OR of 2.2 (90% CI 0.6-8.7) with the presence of K-ras mutation. We conclude that the occurrence of K-ras mutations in adenocarcinoma of the lung is frequent, and that such mutations are associated with heavy life-time exposure to tobacco smoke, possibly in combination with occupational exposure to asbestos fibres.