Showing papers in "International Journal of Cancer in 1999"

Estimates of the worldwide incidence of 25 major cancers in 1990

Abstract: The annual incidence rates (crude and age-standardized) and numbers of new cases of 25 different cancers have been estimated for the year 1990 in 23 areas of the world. The total number of new cancer cases (excluding non-melanoma skin cancer) was 8.1 million, just over half of which occur in the developing countries. The most common cancer in the world today is lung cancer, accounting for 18% of cancers of men worldwide, and 21% of cancers in men in the developed countries. Stomach cancer is second in frequency (almost 10% of all new cancers) and breast cancer, by far the most common cancer among women (21% of the total), is third. There are large differences in the relative frequency of 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 and esophagus. The implications of these patterns for cancer control, and specifically prevention, are discussed. Tobacco smoking and chewing are almost certainly the major preventable causes of cancer today.

Estimates of the worldwide mortality from 25 cancers in 1990.

Abstract: We present here worldwide estimates of annual mortality from all cancers and for 25 specific cancer sites around 1990. Crude and age-standardised mortality rates and numbers of deaths were computed for 23 geographical areas. Of the estimated 5.2 million deaths from cancer (excluding non-melanoma skin cancer), 55% (2.8 million) occurred in developing countries. The sex ratio is 1.33 (M:F), greater than that of incidence (1.13) due to the more favourable prognosis of cancer in women. Lung cancer is still the most common cause of death from cancer worldwide with over 900,000 deaths per year, followed by gastric cancer with over 600,000 deaths and colorectal and liver cancers accounting for at least 400,000 deaths each. In men, deaths from liver cancer exceed those due to colo-rectal cancer by 38%. Over 300,000 deaths of women are attributed to breast cancer, which remains the leading cause of death from cancer in women, followed by cancers of the stomach and lung with 230,000 annual deaths each. In men, the risk of dying from cancer is highest in eastern Europe, with an age-standardised rate for all sites of 205 deaths per 100,000 population. Mortality rates in all other developed regions are around 180. The only developing area with an overall rate of the same magnitude as that in developed countries is southern Africa. All of eastern Asia, including China, has mortality rates above the world average, as do all developed countries. The region of highest risk among women is northern Europe (age-standardised rate = 125.4), followed by North America, southern Africa and tropical South America. Only south-central and western Asia (Indian subcontinent, central Asia and the middle-eastern countries) and Northern Africa are well below the world average of 90 deaths per 100,000 population annually. Our results indicate the potential impact of preventive practices. It is estimated that 20% of all cancer deaths (1 million) could be prevented by eliminating tobacco smoking. Infectious agents account for a further 16% of deaths.

Cancer risk in mutation carriers of DNA-mismatch-repair genes.

Abstract: Excessive incidence of various cancers is a challenging feature of the hereditary-non-polyposis-colorectal-cancer (HNPCC) syndrome. This study estimated the cancer incidences in HNPCC compared with the general population. Individuals in a cohort of 1763 members of 50 genetically diagnosed families were categorized according to their genetic status as mutation carriers, non-carriers, or individuals at 50 or 25% risk of being a carrier. Incidences of cancers in these groups were compared with those in the Finnish population overall. In 360 mutation carriers, standardized incidence ratios (SIR) were significantly increased for colorectal [68; 95% confidence intervals (CI), 56 to 81], endometrial (62; 95% CI, 44 to 86), ovarian (13; 95% CI, 5.3 to 25), gastric (6.9; 95% CI, 3.6 to 12), biliary tract (9.1; 95% CI, 1.1 to 33), uro-epithelial (7.6; 95% CI, 2.5 to 18) and kidney (4.7; 95% CI, 1 to 14) cancers and for central-nervous-system tumours (4.5; 95% CI, 1.2 to 12). The SIR increased with increasing likelihood of being a mutation carrier. The cumulative cancer incidences were 82, 60, 13 and 12% for colorectal, endometrial, gastric and ovarian cancers respectively. For other tumours associated with increased risk, corresponding incidences were below 4%. Interestingly, the incidence of endometrial cancer (60%) exceeded that for colorectal cancer in women (54%). The tumour spectrum associated with germline mutations of DNA-mismatch-repair genes involves 8 or more organ sites, suggesting a need to develop methods to screen for extra-colonic cancer also. Int. J. Cancer 81:214–218, 1999. © 1999 Wiley-Liss, Inc.

Erratum: Estimates of the worldwide mortality from 25 cancers in 1990. Int. J. Cancer, 83, 18-29 (1999).

Abstract: Pisani, P., Parkin, D.M., Bray, F. and Ferlay, J. Estimates of the worldwide mortality from 25 cancers in 1990. Int. J. Cancer, 83, 18-29 (1999). Due to a printer's error, incorrect table headings were entered in Tables II-IV after the proofs of the article had been approved by the author. The correct tables are reprinted on the following pages. The publisher regrets this error.

Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1

Abstract: Thirty-nine tumor-bearing patients with metastatic melanoma were treated with 3 subcutaneous injections of the MAGE-3.A1 peptide at monthly intervals. No significant toxicity was observed. Of the 25 patients who received the complete treatment, 7 displayed significant tumor regressions. All but one of these regressions involved cutaneous metastases. Three regressions were complete and 2 of these led to a disease-free state, which persisted for more than 2 years after the beginning of treatment. No evidence for a cytolytic T lymphocyte (CTL) response was found in the blood of the 4 patients who were analyzed, including 2 who displayed complete tumor regression. Our results suggest that injection of the MAGE-3.A1 peptide induced tumor regression in a significant number of the patients, even though no massive CTL response was produced.

Rho GTPases are over‐expressed in human tumors

Abstract: Small GTPases of the Rho family are involved in the regulation of a variety of cellular processes, such as the organization of the microfilamental network, cell-cell contact and malignant transformation. To address the question of whether Rho proteins are involved in carcinogenesis in man, we compared their expression in tumors from colon, breast and lung with that of the corresponding normal tissue originating from the same patient. As shown by Rho-specific 32P-ADP-ribosylation, as well as Western-blot analysis, the amount of RhoA protein was largely increased in all 3 types of tumors tested. The most dramatic differences in the expression of Rho GTPases were observed in breast tissue. All breast tumors analyzed showed high levels of RhoA, Rac and Cdc42 proteins, whereas in the corresponding normal tissue these Rho proteins were hardly or not detectable. Progression of breast tumors from WHO grade I to grade III was accompanied by a significant average increase in RhoA protein. Overall, increase in the amount of Rho GTPases, in particular RhoA, appears to be a frequent event in different types of human tumors. This supports the view that Rho GTPases are involved in human carcinogenesis. Int. J. Cancer 81:682–687, 1999. © 1999 Wiley-Liss, Inc.

Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy.

Abstract: While use of hormone-replacement therapy (HRT) effectively alleviates menopausal symptoms and prevents osteoporosis and possibly cardiovascular disease, there is concern of a detrimental impact on breast-cancer risk. There is a particular lack of data regarding the effect of long-term use of oestrogen-progestin combinations on breast-cancer risk. We conducted a large epidemiological study in Sweden, where combined oestrogen-progestin treatment has been predominant, to examine the influence of different regimens of menopausal hormone therapy on breast-cancer risk. In this population-based case-control study, 3,345 women aged 50 to 74 years with invasive breast cancer (84% of all eligible) and 3,454 controls of similar age (82% of all selected) were included. Mailed questionnaires and telephone interviews were used to collect detailed information on use of hormone replacement and on potential confounding factors. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through multiple logistic regression. There was a trend of increasing breast-cancer risk with duration of oestrogen/oestrogen-progestin use (OR for women treated at least 10 years, 2.43; 95% CI, 1.79-3.30, as compared to never-users), with statistically significant estimates only for women with BMI<27 kg/m2. Excess risks were observed to current use and use that ceased more than 10 years ago (OR for women treated at least 5 years, OR was 2.68, 95% CI, 2.09-3.42, and OR 2.57, 95% CI, 1.28-5.15, as compared with never-users, respectively). A positive association which was noted for use of oestrogen combined with testosterone-derived progestins appeared especially pronounced with continuously combined regimens. Long-term use of replacement oestrogens with or without progestins may substantially increase the incidence of post-menopausal breast cancer, particularly among non-obese women.

Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity.

Abstract: Stress and surgery have been suggested to compromise host resistance to infectious and malignant diseases in experimental and clinical settings. Because stress affects numerous physiological systems, the role of the immune system in mediating such effects is unclear. In the current study, we assessed the degree to which stress-induced alterations in natural killer (NK) cell activity underlie increased susceptibility to tumor development in F344 rats. Two stress paradigms were used: forced swim and abdominal surgery. Host resistance to tumor development was studied using 3 tumor models syngeneic to inbred F344 rats: CRNK-16 leukemia and the MADB106 mammary adenocarcinoma, both sensitive to NK activity, and the NK-insensitive C4047 colon cancer. Swim stress increased CRNK-16-associated mortality and metastatic development of MADB106 but not metastasis of C4047 cells. In both stress paradigms, stress suppressed NK activity (NKA) for a duration that paralleled its metastasis-enhancing effects on the MADB106 tumor. In vivo depletion of large granular lymphocyte/NK cells abolished the metastasis-enhancing effects of swim stress but not of surgical stress. Our findings indicate that stress-induced suppression of NKA is sufficient to cause enhanced tumor development. Under certain stressful conditions, suppression of NKA is the primary mediator of the tumor-enhancing effects of stress, while under other conditions, additional factors play a significant role. Clinical circumstances in which surgical stress may induce enhanced metastatic growth are discussed.

Widespread intraspecies cross-contamination of human tumor cell lines arising at source.

Abstract: We present a panoptic survey of cell line cross-contamination (CLCC) among original stocks of human cell lines, investigated using molecular genetic methods. The survey comprised 252 consecutive human cell lines, almost exclusively tumor-derived, submitted by their originators to the DSMZ and 5 additional cell repositories (CRs), using a combination of DNA profiling (4-locus minisatellite and multilocus microsatellite probes) and molecular cytogenetics, exploiting an interactive database (http://www.dsmz.de/). Widespread high levels of cross-contaminants (CCs) were uncovered, affecting 45 cell lines (18%) supplied by 27 of 93 originators (29%). Unlike previous reports, most CCs (42/45) occurred intraspecies, a discrepancy attributable to improved detection of the more insidious intraspecies CCs afforded by molecular methods. The most prolific CCs were classic tumor cell lines, the numbers of CCs they caused being as follows: HeLa (n = 11), T-24 (n = 4), SK-HEP-1 (n = 4), U-937 (n = 4) and HT-29 (n = 3). All 5 supposed instances of spontaneous immortalization of normal cells were spurious, due to CLCC, including ECV304, the most cited human endothelial cell line. Although high, our figure for CCs at the source sets a lower limit only as (i) many older tumor cell lines were unavailable for comparison and (ii) circulating cell lines are often obtained indirectly, rather than via originators or CRs. The misidentified cell lines reported here have already been unwittingly used in several hundreds of potentially misleading reports, including use as inappropriate tumor models and subclones masquerading as independent replicates. We believe these findings indicate a grave and chronic problem demanding radical measures, to include extra controls over cell line authentication, provenance and availability. Int. J. Cancer 83:555–563, 1999. © 1999 Wiley-Liss, Inc.

Molecular effects of paclitaxel: myths and reality (a critical review).

Abstract: Recent studies on paclitaxel (Taxol), a microtubule-stabilizing agent and effective anti-cancer drug, have identified numerous cellular and molecular effects, such as induction of cytokines and tumor-suppressor genes, indirect cytotoxicity due to secretion of tumor necrosis factor, vast activation of signal-transduction pathways and selective activity against cells lacking functional p53. Some of these results, including the immediate activation of signaling pathways and gene expression, have been observed only with paclitaxel concentrations 1,000-fold higher than those required for mitotic arrest and apoptosis. The effects of loss of p53 on paclitaxel cytotoxicity depend on cell type (normal murine fibroblasts vs. human cancer cells) and duration of exposure to paclitaxel; p53 status marginally affects paclitaxel sensitivity in human cancer. Although the biochemistry of mitosis and meiosis has been studied independently of research on the mechanism of action of anti-cancer drugs, it eventually provided insight into the effects of paclitaxel. For example, serine protein phosphorylation, which occurs during mitotic arrest or meiosis, explains paclitaxel-induced hyperphosphorylation of Bcl-2 and Bcl-xL. Although some observations are disputed, such mitotic arrest correlates with paclitaxel cytotoxicity, while there is currently no evidence that any paclitaxel effect at clinically relevant concentrations is independent of its tubulin-binding properties. Thus, paclitaxel exerts two types of effect: mitotic arrest with coincidental serine protein phosphorylation and cytotoxicity at clinically relevant concentrations as well as immediate activation of tyrosine kinase pathways and activation of gene expression at much higher concentrations.

Nasopharyngeal carcinoma cell line (C666‐1) consistently harbouring Epstein‐Barr virus

Abstract: We have established a cell line (C666-1) from undifferentiated nasopharyngeal carcinoma (NPC). This cell line consistently carries the Epstein-Barr virus (EBV) in long-term cultures. C666-1 is a subclone of its parental cell line, C666, derived from an NPC xenograft of southern Chinese origin. It grows as an adherent culture and lacks contact inhibition. In addition, it is tumorigenic in athymic nude mice. The cells consistently express EBV-encoded RNAs and are positively stained for cytokeratin, an epithelial marker. In addition, they express EBNA1 protein, LMP1 and LMP2 transcripts and thus resemble the EBV latency II pattern. The virus genotype is EBV-1 with the latent membrane protein 1 gene showing a 30-bp deletion at the carboxyl terminus, both consistent with findings in southern Chinese NPC tumours. Cytogenetic analysis revealed a sub-diploid status with a chromosomal modal number of 45. C666-1 is unique among NPC cell lines in that it carries EBV. These cells may serve as a good investigative tool as the viral latency pattern and genotype are observed in the majority of primary NPC biopsies from Chinese patients.

Independent and joint effects of tobacco smoking and alcohol drinking on the risk of esophageal cancer in men and women

Abstract: To estimate the independent and joint effects of tobacco smoking and alcohol drinking, we analyzed data from a series of 5 hospital-based case-control studies of squamous-cell carcinoma of the esophagus conducted in high-risk areas in South America. A total of 830 case subjects and 1779 control subjects were included in the pooled analysis. All exposure characteristics of amount, duration, cessation and type of alcohol and tobacco consumed were strongly related to esophageal-cancer risk in both sexes. Women had the same exposure profile as men, but the magnitudes of the associations were lower than were those among men. Black-tobacco smoking was associated with a 2-fold increased risk as compared with the smoking of blond or mixed tobacco. Quitting either of the 2 habits significantly reduced esophageal-cancer risk. Alcohol and tobacco alone were strongly related to the risk of esophageal cancer, even in the absence of the other exposure. A history of simultaneous exposure to cigarette smoking and alcohol drinking had a strong multiplicative effect on risk. Concomitant exposure to heavy alcohol drinking and black-tobacco smoking identified the group with the highest risk for developing esophageal cancer (odds ratio = 107). A synergistic interaction was found between the 2 habits, particularly in women and in moderately exposed men. Moderate cigarette smoking without drinking and moderate alcohol drinking without smoking had a negligible effect on esophageal-cancer risk. However, simultaneous exposure to the same moderate amounts increased the risk 12- to 19-fold in men and in women respectively. The overall public-health implications of these findings are obvious for a tumor that depends on preventive strategies for its control.

Induction of inflammatory angiogenesis by monocyte chemoattractant protein‐1

Abstract: Almost any growth of tumors is to some extent associated with an inflammatory reaction which may be anti-tumorigenic by acting directly on tumor cells or protumorigenic cells presumably by inducing tumor-associated angiogenesis. In this study, we have analyzed the angiogenesis-inducing capacity of monocyte chemoattractant protein-1 (MCP-1), a key regulatory molecule of monocyte trafficking to sites of inflammation. MCP-1 was found to be potently angiogenic when implanted into rabbit cornea, exerting potency similar to the specific angiogenic vascular endothelial growth factor (VEGF)-A121. MCP-1-induced angiogenesis in the cornea is associated with prominent recruitment of macrophages, whereas VEGF-A121-induced corneal angiogenesis is devoid of inflammatory cell recruitment. Based on these findings, we studied MCP-1 expression and macrophage recruitment in human invasive ductal mammary carcinomas in comparison with the physiological angiogenic processes in bovine ovarian corpus luteum. Macrophage recruitment was always associated with MCP-1 expression. High macrophage counts in mammary tumors corresponded with poor prognosis. In contrast, physiological ovarian angiogenesis was associated with only minimal inflammatory recruitment of macrophages. Our data show that MCP-1 is an indirect inflammation-associated inducer of angiogenesis and demonstrate distinct qualitative differences between tumor angiogenesis in human mammary tumors and physiological angiogenesis in the ovary. Int. J. Cancer 82:765–770, 1999. © 1999 Wiley-Liss, Inc.

Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA

Abstract: We conducted a study to estimate the current incidence rates of basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC) of the skin in the population of New Hampshire (NH), USA, and to quantify recent changes in the incidence rates of these malignancies. BCCs and SCCs diagnosed among NH residents were identified through physician practices and central pathology laboratories in NH and bordering regions from June 1979 through May 1980 and from July 1993 through June 1994. For each diagnosis period, we estimated the age-adjusted incidence rates for both BCC and SCC among both men and women and for separate anatomic sites. Between 1979-1980 and 1993-1994, incidence rates of SCC increased by 235% in men and by 350% in women. Incidence rates of BCC increased by more than 80% in both men and women. While the absolute increase was greatest for tumors of the head and neck, the relative change was most pronounced for tumors on the trunk in men and on the lower limb in women. Thus, there has been a marked rise in the incidence rates of BCC and SCC skin cancers in NH in recent years. The anatomic pattern of increase in BCC and SCC incidence is consistent with an effect of greater sunlight exposure. Studies of BCC and SCC occurrence are needed to identify possible behavioral and environmental factors and to assess possible changes in diagnostic practices that might account for the rise in incidence of these common malignancies.

Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis

Abstract: Angiogenesis is a possible target in the treatment of human gliomas. To evaluate the role of 3 growth factors, vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF) and basic fibroblast growth factor (bFGF), in the angiogenic cascade, we determined their levels in extracts of 71 gliomas by enzyme-linked immunosorbent assay (ELISA). The levels of bFGF were only marginally different between gliomas of World Health Organization (WHO) grade II (low grade) and grades III and IV (high grade). In contrast, the mean concentrations of VEGF were 11-fold higher in high-grade tumors and those of HGF/SF 7-fold, respectively. Both were highly significantly correlated with microvessel density (p < 0.001) as determined by immunostaining for factor VIII-related antigen. In addition, VEGF and HGF/SF appeared to be independent predictive parameters for glioma microvessel density as determined by multiple regression analysis. We measured the capacity of all 3 factors to induce endothelial tube formation in a collagen gel. In this assay, bFGF was found to be an essential cofactor with which VEGF as well as HGF/SF were able to synergize independently. According to the concentrations of angiogenic factors, extracts from high-grade tumors were significantly more potent in the tube formation assay than the low-grade extracts (p = 0.02). Adding neutralizing antibodies to bFGF, VEGF and HGF/SF together with the extracts, tube formation was inhibited by up to 98%, 62% and 54%, respectively. Our findings suggest that bFGF is an essential cofactor for angiogenesis in gliomas, but in itself is insufficient as it is present already in the sparsely vascularized low-grade tumors. Upon induction of angiogenesis in high-grade tumors, bFGF may synergize with rising levels of not only VEGF but possibly also with HGF/SF, which appears here to be an independent angiogenic factor. Int. J. Cancer (Pred. Oncol.) 84:10–18, 1999. © 1999 Wiley-Liss, Inc.

Risk of colorectal and other gastro-intestinal cancers after exposure to nitrate, nitrite and N-nitroso compounds: a follow-up study.

Abstract: N-nitroso compounds are potent carcinogens detected in foodstuffs. The importance of dietary nitrosamines in relation to human cancer development is, however, uncertain. We studied the relationship between intake of nitrates, nitrites and N-nitrosodimethylamine (NDMA) and risk of cancers of the gastro-intestinal tract in a cohort of 9,985 adult Finnish men and women. During a follow-up period of up to 24 years, 189 gastro-intestinal cancer cases were diagnosed in the cohort, initially free from cancer. Intake of nitrate, nitrite and NDMA were estimated, based on food-consumption data from a 1-year dietary history interview covering the total diet of the participants. A significant positive association was observed between intake of NDMA and subsequent occurrence of colorectal cancer with a relative risk (RR) between the highest and lowest quartiles of intake of 2.12 [95% confidence interval (CI) 1.04-4.33]. Of various sources of N-nitroso compounds, intake of smoked and salted fish was significantly (RR = 2.58, 95% CI 1.21-5.51) and intake of cured meat was non-significantly (RR = 1.84, 95% CI 0.98-3.47) associated with risk of colorectal cancer. No similar association was observed for intake of other fish or other meat. No significant associations were observed between NDMA intake and cancers of the head and neck combined or of the stomach or between nitrate or nitrite intake and risk of cancers of the gastro-intestinal tract. Our results are in line with the idea that N-nitroso compounds can induce colorectal cancer in humans.

Carcinoma In situ of the testis: Review of biological and clinical features

Abstract: Carcinoma in situ of the testis (CIS) is the uniform precursor of testicular germ-cell tumours. Morphologically, CIS consists of large, intratubular, gonocyte-like cells with large nuclei and abundant glycogen. CIS cells are probably derived from primordial germ cells and are supposed to be present in the testis of a future testis cancer patient at the time of birth. CIS cells appear to spread inside the seminiferous tubules until CIS progresses to invasive cancer. Diagnosis is best achieved by surgical biopsy of the testis and subsequent immunohistological staining of placental alkaline phosphatase (PlAP). This enzyme is present in embryonal germ cells, CIS and seminoma as well as several other types of germ-cell tumour but usually not in normal germ cells. CIS is found in testicular tissue adjacent to testicular germ-cell tumours in about 90% of cases, and it is observed in all clinical groups known to be at risk for testicular cancer: cryptorchidism (2% to 4%), infertility (0% to 1%), ambiguous genitalia (25%) and contralateral testis of patients with testicular cancer (5%). Conversely, CIS is found in less than 1% of the normal male population, and this prevalence corresponds well to the life-time risk of testicular cancer in males. If CIS is left untreated, there is a 50% probability of progressing to frank germ-cell neoplasm within 5 years. Localised low-dose radiotherapy to the testis eradicates CIS and germ cells, while Leydig cells are preserved. The patient can thus be spared orchiectomy and hormone supplementation. Currently, dose-reduction studies are looking for the optimal radiation dose, which is expected to be around 14 to 16 Gy. After chemotherapy, there is a cumulative risk of 42% for recurrence of CIS within 10 years. The concept of CIS offers the chance of very early detection of testicular cancer and organ-preserving early treatment.

Humoral immune responses of cancer patients against "Cancer-Testis" antigen NY-ESO-1: correlation with clinical events.

Abstract: Humoral immune responses against the "Cancer-Testis" (CT) antigen NY-ESO-1 are frequently observed in patients with NY-ESO-1 expressing tumors. This is in contrast to other known tumor antigens (TA) defined by antibody or cytotoxic T cell (CTL) reactivity, i.e., MAGE-1, MAGE-3, SSX2, Melan A, and tyrosinase. No NY-ESO-1 antibody has been detected in healthy controls and patients with NY-ESO-1 negative tumors. In this study, we have assessed the NY-ESO-1 serum antibody response in patients with NY-ESO-1 positive tumors of different histological types and stages using Western blotting and an ELISA. Of the 12 patients analyzed, 10 had demonstrable NY-ESO-1 antibodies at the start of the study. All patients were followed for changes in NY-ESO-1 antibody titers during the course of tumor treatment and clinical evolution. In 4 patients, an increase of NY-ESO-1 antibody titer was observed with progression of disease or extensive tumor necrosis under treatment. One patient showed a stable NY-ESO-1 antibody titer over 3 years along with gradual regression of a large tumor mass. In 5 patients, a decrease of NY-ESO-1 antibody was detected: in 1 patient after curative tumor resection, in 3 patients with partial regression of metastatic disease under chemo- and immunotherapy, and in another patient with a NY-ESO-1 negative tumor relapse. Our results indicate that the induction and maintenance of NY-ESO-1 antibody is dependent on the presence of NY-ESO-1 expressing tumors. Furthermore, changes in NY-ESO-1 antibody titers correlate with the evolution of NY-ESO-1 positive disease.

Role of medical history in brain tumour development. Results from the international adult brain tumour study.

Abstract: In an international population-based case-control study carried out in 8 centres in 6 countries, we investigated the role of specific medical conditions in the aetiology of brain tumours in adults. Recruited were 1,178 glioma and 331 meningioma cases and 2,493 age- and gender-matched population controls. Only medical conditions occurring at least 2 years before brain tumour diagnosis were considered. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a conditional logistic regression model. Heterogeneity between centres was tested. No association between meningioma and previous medical conditions was observed. For glioma, there was an increased risk associated with epilepsy (RR = 6.55, 95% CI 3.40-12.63), but this was considerably weaker for epilepsy of more than 20 years duration. The risk remained elevated after adjustment for use of anti-epileptic drugs. There was a statistically significant inverse association between glioma and all allergic diseases combined (RR = 0.59, 95% CI 0.49-0.71); this was also observed for specific allergic conditions, namely, asthma and eczema. Subjects who reported a history of infectious diseases (e.g., colds, flu) showed a 30% reduction in risk (RR = 0.72, 95% CI 0.61-0.85). The decreased risks for glioma in subjects reporting a history of allergic conditions or infectious diseases may indicate an influence of immunological factors on the development of glioma. The association between glioma and epilepsy has to be interpreted cautiously and needs further investigation.

Health-related quality of life in childhood cancer: discrepancy in parent-child reports.

Abstract: The purpose of our study was to describe reports of parents and of children with cancer on items taken from 4 domains of health-related quality of life (HRQL), bodily pain/distress, general health perceptions, physical functioning and limitations in role/social functioning as a result of physical health, and to examine whether differences in parent-child reports varied as a function of the child's health condition (cancer vs. healthy). Twenty-seven child-parent dyads with cancer and 27 child-parent dyads who were healthy (child ages 8 to 18 inclusive) completed measures of child HRQL [Child Health Questionnaire-Parent Form (CHQ-PF50) and Child Health Questionnaire (CHQ-CF87)] and demographic information at a scheduled out-patient general pediatric or pediatric oncology clinic appointment. Sixteen items included on both the CHQ-CF87 and CHQ-PF50 were examined to compare parent and child reports of child HRQL. As hypothesized, greater discrepancies were evident in the reports of parents of children with cancer than parents of children who are healthy [F(16,31) = 3.98, p < 0.0001]. Statistically significant discrepancies emerged in parent and child responses on 50% of the items in the sample of children with cancer, with parents reporting that their children experience more limitations in their lives than did the children themselves. In the healthy group, statistically significant discrepancies emerged on only 1 of the 16 items (6.3%).

Effect of organised screening on cervical cancer incidence and mortality in Finland, 1963–1995: Recent increase in cervical cancer incidence

Abstract: A nation-wide screening programme for cervical cancer started in Finland gradually from 1963 onwards. By the beginning of the 1990s, there had been a decrease of 80% both in the age-adjusted incidence of and mortality from cervical cancer. To describe the recent patterns in cervical cancer incidence and mortality and evaluate their differentials in relation with the organised screening activities, we have updated the material on the cervical cancer incidence and mortality as well as mass-screening activities up to the year 1995. Based on the files of the Finnish Cancer Registry, there is a striking increase of about 60% in the incidence of cervical cancer during the last 4 years of the study period among women below 55 years of age. The mortality rates are still decreasing. There is no overall decrease over recent years in the coverage of the programme invitations or smears taken. Incidence of invasive cancer and of moderate and severe dysplasia as detected in mass screening have increased. As to the interpretation, changes in the risk factors, such as in sexual behaviour and smoking habits, over the decades might partly explain increasing trends in cervical cancer incidence. As the change in incidence was relatively abrupt, inadequacies or changes in the effectiveness in the screening programme, particularly among young women, may also have contributed. Expanding the coverage of and attendance in the pap-screening programme among women in young target ages would still be effective. Increasing emphasis on quality assessment in screening is also needed.

Antigens recognized by autologous antibody in patients with renal-cell carcinoma

Abstract: The screening of cDNA expression libraries derived from human tumors with autologous antibody (SEREX) is a powerful method for defining the structure of tumor antigens recognized by the humoral immune system. Sixty-five distinct antigens (NY-REN-1 to NY-REN-65) reactive with autologous IgG were identified by SEREX analysis of 4 renal cancer patients and were characterized in terms of cDNA sequence, mRNA expression pattern, and reactivity with allogeneic sera. REN-9, -10, -19, and -26 have a known association with human cancer. REN-9 (LUCA-15) and REN-10 (gene 21) map to the small cell lung cancer tumor suppressor gene locus on chromosome 3p21.3. REN-19 is equivalent to LKB1/STK11, a gene that is defective in Peutz-Jeghers syndrome and cancer. REN-26 is encoded by the bcr gene involved in the [t(9:22)] bcr/abl translocation. Genes encoding 3 of the antigens in the series showed differential mRNA expression; REN-3 displays a pattern of tissue-specific isoforms, and REN-21 and REN-43 are expressed at a high level in testis in comparison to 15 other normal tissues. The other 62 antigens were broadly expressed in normal tissues. With regard to immunogenicity, 20 of the 65 antigens reacted only with autologous sera. Thirty-three antigens reacted with sera from normal donors, indicating that their immunogenicity is not restricted to cancer. The remaining 12 antigens reacted with sera from 5-25% of the cancer patients but not with sera from normal donors. Seventy percent of the renal cancer patients had antibodies directed against one or more of these 12 antigens. Our results demonstrate the potential of the SEREX approach for the analysis of the humoral immune response against human cancer.

Elevated expression of endoglin, a component of the TGF‐β‐receptor complex, correlates with proliferation of tumor endothelial cells

Abstract: Endoglin/CD105 is a membrane protein involved in the TGF-beta receptor signalling pathway. Endoglin expression has been reported to be selective for a few cell types, in particular endothelial cells, although a number of conflicting reports have been published. In this study, we performed a detailed analysis of endoglin expression in human lung tumors and different tumor and endothelial cell lines, employing reverse-transcriptase-polymerase-chain reaction as well as immunoblotting and immunohistochemistry using verified antibodies to endoglin. Our data show a clearly preferential expression of both endoglin mRNA and protein in endothelial cells. In tumors, endoglin expression was strongly elevated in the angiogenic endothelium at the tumor edges. In agreement with this observation, we find a clear correlation between endoglin expression and markers of proliferation, such as cyclin A and Ki-67, suggesting that endoglin expression is linked to cell-cycle regulation. These findings not only resolve some of the discrepancies in the literature, but also provide the basis for further applications making use of its selective localization and expression in the tumor vasculature.

Betulinic acid: A new cytotoxic agent against malignant brain-tumor cells

Abstract: Malignant brain tumors are the most common solid tumors in children. The overall prognosis for this group of patients is still poor, emphasizing the importance of more effective therapies. Betulinic acid (Bet A) has been described as a novel cytotoxic compound active against melanoma and neuroblastoma cells. Here we report that Bet A was active against medulloblastoma and glioblastoma cell lines. In addition, Bet A exerted cytotoxic activity against primary tumor cells cultured from patients in 4 of 4 medulloblastoma-tumor samples tested and in 20 of 24 glioblastoma-tumor samples. Since a small percentage of primary-glioblastoma-tumor cells (4/24) did not respond to Bet-A treatment, resistance to Bet A might occur. Induction of apoptosis by Bet A involved mitochondrial perturbations, since inhibition of the mitochondrial permeability transition by the mitochondrion-specific inhibitor bongkrekic acid (BA) reduced Bet-A-induced apoptosis. In addition, mitochondria undergoing Bet-A-induced permeability transition triggered DNA fragmentation in isolated nuclei. Cytochrome c was released from mitochondria of Bet-A-treated cells, and might be involved in activation of caspases. Following treatment with Bet A, caspase-8, caspase-3 and PARP were proteolytically processed. Inhibition of caspase cleavage by the broad-range caspase inhibitor zVAD.fmk strongly reduced Bet-A-induced apoptosis, indicating that apoptosis was mediated by activation of caspases. Since Bet A did not exhibit cytotoxicity against murine neuronal cells in vitro, these findings suggest that Bet A may be a promising new agent for the treatment of medulloblastoma and glioblastoma cells that clearly warrants further pre-clinical and clinical evaluation.

Hypoxia‐mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression

Abstract: Tumor hypoxia and high levels of expression of the urokinase-type plasminogen activator (uPA) receptor (uPAR) represent a poor clinical outcome for patients with various cancers. Here, we examined the effect of hypoxia on in vitro invasion of extracellular matrix and uPAR expression by human carcinoma cells. Compared with culture under 20% O2, culture for up to 24 hr under 1% or 4% O2 resulted in increased cell surface uPAR. However, the highest uPAR levels were observed in cells cultured under 1% O2. Culture of MDA-MB-231 breast carcinoma cells under hypoxia also resulted in increased uPAR mRNA levels. Furthermore, incubation with cobalt chloride or with an iron chelator also resulted in elevated uPAR expression, while presence of 30% carbon monoxide in the hypoxic atmosphere reduced the hypoxia-mediated uPAR mRNA upregulation. Increased uPAR expression was paralleled by higher cell-associated uPA levels and lower levels of secreted uPA as determined by gel zymography performed on cell extracts and culture-conditioned media. In addition, the in vitro invasiveness of MDA-MB-231 breast carcinoma cells was significantly higher when the invasion assay was performed under hypoxic conditions. This effect of hypoxia on invasion was abrogated by including in the assay a monoclonal, function-blocking anti-uPAR antibody or by the presence of 30% carbon monoxide in the hypoxic atmosphere. Our findings indicate that hypoxia stimulates carcinoma cell invasiveness by upregulating uPAR expression on the cell surface through a mechanism that requires a putative heme protein. Through a similar mechanism, hypoxia may stimulate tumor invasion and metastasis in vivo. Int. J. Cancer 80:617–623, 1999. © 1999 Wiley-Liss, Inc.

Health-related quality of life in pediatric bone marrow transplant survivors: according to whom?

Abstract: Historically, health-related quality of life (HRQL) assessment in pediatrics, including the few validated instruments in pediatric oncology, has been based on proxy reporting, relying primarily on parental assessment. Children have been deemed incapable of providing consistent and reliable information about their level of functioning or state of well-being. Previous studies have been hampered by either limited or poor correlation among the proxy reporters, i.e., teachers, parents and physicians, and in comparisons to disease severity. Simply stated, proxy reporters have greater agreement about what the child can do vs. what the child thinks or feels. Comparisons among proxy reporters have been hindered also by a lack of parallel content in the instruments used, which may result in poorly congruent assessments simply because the instruments measure different constructs. In addition to the measurement issues, the emotional milieu of the parent, particularly the mother, has been shown to influence assessments of the child's functioning. Maternal distress, marital adjustment and health locus of control all co-vary with reports of the child's behavior. What, then, is the proxy reporter telling us about the child? We conducted a cross-sectional study of school-aged pediatric bone marrow transplant (BMT) patients at our institution to evaluate children's self-reported HRQL and functional status. We formally tested the Child Health Rating Inventories (CHRIs), a recently developed generic health-status measure, with its companion measure, the Disease Impairment Inventories-Bone Marrow Transplant (DSII-BMT). Separate questionnaires were administered to patients, parents and physicians at a scheduled outpatient visit after BMT. The questionnaires were designed to have parallel content. All responses were confidential. The psychometric properties of the CHRIs and DSII-BMT are reported elsewhere. In brief, the responses of all raters were reliable, based on measurements of internal consistency. The children's self-reported health status was correlated significantly with the physicians' disease severity rating (DSR) across all generic and disease-specific domains. In contrast, parental reports of child health status were not correlated significantly with the DSR for disease-specific problems or the child's pain. Parental ratings deviated most from the children's ratings within the dimensions of mental health and quality of life (p 12 months after transplant", with the exception of mental health and quality of life, parental scores were the same as or higher than the children's ratings. Our results confirm previous studies that the parental reporting of children's health status is a complex construct and that valuable information can be elicited directly from the children. Further research is needed to substantiate these findings, particularly in longitudinal applications with adequate sample sizes.

GATA-3 is expressed in association with estrogen receptor in breast cancer.

Abstract: To better understand the molecular basis for the hormone-responsive phenotype in breast cancer, we have used a human cDNA array to compare patterns of gene expression between breast carcinoma cell lines discordant for estrogen receptor (ER) expression. These experiments indicated abundant expression of the transcription factor GATA-3 in the ER-positive cell lines MCF7 and T-47D, with minimal or no expression in the ER-negative cells lines MDA-MB-231 and HBL-100. Northern blot analysis of a panel of human breast carcinoma cell lines demonstrated a correlation between ER and GATA-3 expression. Studies of MCF7 cells grown in the absence or presence beta-estradiol indicated that GATA-3 expression was not responsive to estradiol. Protein immunoprecipitation and gel shift analysis confirmed the presence of functional GATA-3 protein in MCF7 but not in HBL-100 nuclear extracts. A panel of 47 primary breast cancers was characterized for expression of ER and GATA-3 using immunoperoxidase assay. In primary tumors, a statistically significant correlation between ER and GATA-3 expression was established (p < 0.0001, chi2). Our results indicate that GATA-3, in association with ER, is likely to regulate genes critical to the hormone-responsive breast cancer phenotype.

Sodium selenite-induced oxidative stress and apoptosis in human hepatoma HepG2 cells.

Abstract: The mechanisms involved in the anti-carcinogenic activity of selenium remain to be elucidated. In the present study, we examined sodium selenite-induced oxidative stress and apoptosis in a human hepatoma cell line (HepG2). Sodium selenite (10 microM) exerted clear cytotoxic effect, as shown by the significant increase of lactate dehydrogenase leakage. Selenite-induced DNA alterations in apoptosis were studied by: 1. comet assay; 2. TdT-mediated dUTP nick end-labeling assay. In addition, characteristic apoptotic morphological alterations were also observed in selenite-treated cells. Our results clearly show that Se-induced cell death occurs predominantly in the form of apoptosis. Selenite-induced oxidative stress was evaluated by the measurement of reactive oxygen species production using lucigenin-dependent chemiluminescence. The involvement of glutathione in selenite-induced oxidative stress was further demonstrated by the concurrent decline of intracellular reduced glutathione and increase of oxidized glutathione contents in Se-treated cells. Moreover, the finding that selenite-induced oxidative stress and apoptosis was significantly attenuated by superoxide dismutase, catalase and deferoxamine provides additional evidence to suggest that Se-induced oxidative stress mediates the induction of apoptosis, a mechanism related to the anti-carcinogenic and chemopreventive effect of Se.

Platinum organ toxicity and possible prevention in patients with testicular cancer.

Abstract: Advances in the management of metastatic testicular cancer are attributed mainly to the introduction of cisplatin into combination chemotherapy. In parallel with the development of effective chemotherapy resulting in long-term survival for the majority of patients, possible adverse effects of treatment have been systematically investigated. Besides acute side effects of cisplatin, such as gastro-intestinal toxic effects and moderate myelosuppression, reduction in glomerular filtration rate occurs in 20% to 30% of patients despite prophylactic intensive hydration and forced diuresis. Such changes in glomerular function are essentially irreversible. Persistent effects on tubular renal function occur less commonly, but hypomagnesemia due to hypermagnesiuria is often seen. Neurotoxicity, mainly sensory peripheral neuropathy, is common during treatment but disappears in the majority of patients after its completion. However, persistent paresthesias are found in 20% to 60% of patients. A typical audiometric abnormality affecting up to 50% of patients is bilateral loss of hearing at 4 to 8 kHz. A correlation between the cumulative cisplatin dose applied and the frequency of neuro- and nephrotoxicity has been demonstrated in some studies. The administration schedule additionally appears to influence the extent of toxicity, whereby single-day infusion schedules are associated with pronounced neural and renal toxicity, possibly due to higher peak plasma levels of cisplatin. Other long-term abnormalities after treatment with cisplatin-based combination regimens are a weak predisposition to secondary malignancies, infertility and chronic vascular toxicity. Several strategies have been developed to reduce such side effects. Ongoing trials are investigating the role of the aminothiol amifostine as a nephro- and neuroprotectant.

IGF‐I and IGF‐II in relation to colorectal cancer

Abstract: Recent data suggest that the IGF system plays an important role in the pathogenesis of several forms of human cancer, and there is evidence that IGFs acting in an autocrine and paracrine manner may also affect colorectal cancer risk. We have conducted a case-control study on the island of Crete, Greece, to examine the potential relation between circulating IGF-I and -II and their major binding protein (IGF-BP3), on the one hand, and colorectal cancer, on the other. IGF-I, IGF-II and IGF-BP3 were determined in the serum from 41 patients with colorectal cancer and 50 healthy controls; data were analyzed using unconditional multiple logistic regression, adjusting for age, gender, education, height and BMI, as well as mutually. Both IGF-I and IGF-II were positively, while IGF-BP3 was inversely, associated with risk for colorectal cancer, though none of these relations reached statistical significance. However, individuals with IGF-I and -II values in the upper 2 tertiles of the respective distributions had a significantly elevated odds ratio for colorectal cancer (OR = 5.2, 95% confidence interval 1.0-26.8) compared with those in the lower tertile in both distributions. Our results provide evidence that high levels of circulating IGF-I and -II might be associated with colorectal cancer.