Showing papers in "International Journal of Cancer in 1996"
TL;DR: The International Classification of Childhood Cancer (ICCC) updates the widely used Birch and Marsden classification scheme to accommodate important changes in recognition of different types of neoplasms, while preserving continuity with the original classification.
Abstract: The International Classification of Childhood Cancer (ICCC) updates the widely used Birch and Marsden classification scheme. ICCC is based on the second edition of the International Classification of Diseases for Oncology (ICD-O-2). The purpose of the new classification is to accommodate important changes in recognition of different types of neoplasms, while preserving continuity with the original classification. The grouping of neoplasms into 12 main diagnostic groups is maintained. The major changes are: (1) intracranial and intraspinal germ-cell tumours now constitute a separate subgroup within germ-cell tumours; (2) histiocytosis X (Langerhans-cell histiocytosis) is excluded from ICCC; (3) Kaposi's sarcoma is a separate subgroup within soft-tissue sarcomas; (4) skin carcinoma is a separate subgroup within epithelial neoplasms; (5) "other specified" and "unspecified" neoplasms are now usually separate sub-categories within the main diagnostic groups. Draft copies of the ICCC were distributed to some 200 professionals with interest and expertise in the field and their comments are considered in this final version. This classification will be used for presentation of data in the second volume of the IARC Scientific Publication "International Incidence of Childhood Cancer." A computer programme for automated classification of childhood tumours coded according to ICD-O-1 or ICD-O-2 is now available from IARC.
969 citations
TL;DR: It is concluded that temporally, proliferation and migration are mutually exclusive behaviors and cell density or non‐permissive substrates that inhibit cell motility favor a more proliferative phenotype.
Abstract: Astrocytomas often show high rates of local invasion that lead to local recurrence of the disease. Histologically, the most highly invasive astrocytoma cells are detected in isolation rather than as nests of tumor. Our study attempted to determine whether the migratory response to extracellular substrates influences the proliferative behavior of these highly invasive cells. The preferential and specific migratory response of human astrocytoma cells to extracellular matrix proteins was assessed by a microliter scale migration assay. Growth curve studies on protein ligands permissive (merosin) for cell migration indicated that the lag phase was protracted compared with cells seeded on non-permissive proteins (vitronectin). Once a certain cell density was reached, logarithmic proliferation was indistinguishable on the different proteins. The proliferation index of populations of cells migrating on merosin and vitronectin was measured by both BrdU incorporation and MIB-1 immunocytochemistry labeling. Cells seeded on vitronectin showed higher proliferation throughout the population than cells seeded on merosin. On merosin, the more migratory cells at the periphery were less proliferative than non-migratory cells in the central region of that population. The integrin-associated signal transduction protein, p125FAK, was heavily localized in the membrane of non-migrating cells and largely absent in migrating astrocytoma cells. We conclude that temporally, proliferation and migration are mutually exclusive behaviors. Cell density or non-permissive substrates that inhibit cell motility favor a more proliferative phenotype. Conversely, active migration suppresses cell proliferation.
386 citations
TL;DR: Hormone replacement increases the endometrial‐cancer risk after unopposed estrogens and the breast‐ cancer risk—notably after estrogen‐progestin combined therapy—and tentatively suggest that it exerts a protective effect against colon and liver cancer risks.
Abstract: We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow-up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen-progestin combined brand was associated with an increasing relative risk of breast cancer with follow-up time, the SIR reaching 1.4 (95% CI 1.1-1.8) after 10 years of follow-up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6-5.9) in women prescribed estrogens alone, whereas those given an estrogen-progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol-progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow-up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow-up time. We conclude that hormone replacement increases the endometrial-cancer risk after unopposed estrogens and the breast-cancer risk-notably after estrogen-progestin combined therapy-and tentatively suggest that it exerts a protective effect against colon and liver cancer risks.
324 citations
TL;DR: It is concluded that systemic GM‐CSF enhances immune responses to melanoma‐associated peptides and supports CTL‐mediated tumor rejection in vivo.
Abstract: Peptide epitopes derived from differentiation antigens of the melanocyte lineage were recently identified in human melanomas as targets for MHC-restricted cytotoxic T lymphocytes (CTL). The characterization of multiple CTL-defined antigenic determinants has opened possibilities of development of antigen-targeted vaccines. In the present study, we determined CTL reactivity against melanoma-associated peptides derived from Melan A/MART-1, tyrosinase, and gp100/Pmel17 in 3 HLA-A2+ melanoma patients. Then, we assessed the immune responses to synthetic melanoma-associated peptides injected intradermally. After 3 cycles of immunization with peptide alone, we used systemic GM-CSF as an adjuvant during the fourth cycle of immunization. Enhanced DTH reactions and CD8+ CTL responses were observed after treatment with systemic GM-CSF. Immunohistochemical characterization of DTH-constituting elements revealed infiltrates of CD4+ and CD8+ T lymphocytes and strong expression of IL-2 and gammaIFN, suggesting the activation of CD4+ ThI and CD8+ CTL by peptides presented by MHC-class-I molecules of dermal APC. Objective tumor regression was documented in all patients. We conclude that systemic GM-CSF enhances immune responses to melanoma-associated peptides and supports CTL-mediated tumor rejection in vivo.
316 citations
TL;DR: Contrary to expectations, moderate/strong staining for cyclin D1 was associated with improved relapse‐free and overall survival relative to patients whose tumours stained weakly or negatively, and tumours that were considered negative for cycl in D1 staining had an adverse prognosis.
Abstract: We have used immunohistochemical staining to assess the expression of cyclin D1 in formalin-fixed sections of 345 breast carcinomas, dating back 20 years. Clinical follow-up data were available on all patients. Approximately 50% of the tumours showed excessive nuclear staining for cyclin D1 as compared with normal epithelium. Some tumours showed strong cytoplasmic staining in the absence of nuclear staining, and around 25% of the tumours were judged to be negative for nuclear cyclin D1. Contrary to expectations, moderate/strong staining for cyclin D1 was associated with improved relapse-free and overall survival relative to patients whose tumours stained weakly or negatively. Conversely, tumours that were considered negative for cyclin D1 staining had an adverse prognosis, and the poor outcome was further accentuated if the tumours were also oestrogen receptor-negative. A possible explanation for our findings is that tumours in which cyclin D1 levels are abnormally low may have sustained mutations in other genes, such as RBI and that it is this abnormality that has the more significant impact on survival from breast cancer.
315 citations
TL;DR: The findings underscore the different etiology and pathogenesis of SCC vs. ADC and suggest that the genetic alterations observed may represent molecular fingerprints of critical risk involved in the development of these 2 cancers.
Abstract: Cancer of the esophagus exists in 2 main forms with different etiological and pathological characteristics—squamous cell carcinoma (SCC) and adenocarcinoma (ADC). This review focuses on the occurrence of genetic alterations in SSC and ADC of the esophagus and on their possible implications for the elucidation of the etiology and pathogenesis of these cancers. The most common alterations found in esophageal cancers include allelic losses at chromosomes 3p, 5q, 9p, 9q, 13q, 17p, 17q and 18q, as well as mutations of p53 (mostly missense). Rb (deletions), cyclin DI (amplifications) and c-myc (amplifications). The sequence of occurrence of these alterations with respect to histopathological tumor progression is discussed. Our findings underscore the different etiology and pathogenesis of SCC vs. ADC and suggest that the genetic alterations observed may represent molecular fingerprints of critical risk involved in the development of these 2 cancers. © 1996 Wiley-Liss, Inc.
309 citations
TL;DR: Examination of expression of Melan A/MART‐1, tyrosinase and gp100/Pmel17 in fresh melanoma tissues of HLA‐A2+ patients and the spontaneous CTL reactivity against antigenic peptides derived from these antigens concludes that CTL responses against melanocyte differentiation antigENS may mediate regression of antigen‐positive tumors and select for antigen‐loss variants in vivo.
Abstract: Antigenic peptides derived from differentiation antigens of the melanocyte lineage were recently identified in human melanomas as targets for MHC-restricted cytotoxic T lymphocytes (CTL). CTL directed against peptides derived from the Melan A/MART-1, tyrosinase and gp100/Pmel17 antigens can be detected in melanoma patients and in healthy controls. The presence of defined antigenic peptides and corresponding precursor CTL in patients with metastatic melanoma opens perspectives for the development of antigen-specific tumor vaccines. In this study, we examined the expression of Melan A/MART-1, tyrosinase and gp100lPmel17 in fresh melanoma tissues of HLA-A2+ patients and the spontaneous CTL reactivity against antigenic peptides derived from these antigens. Our results demonstrate an inverse correlation of antigen expression and CTL response to Melan A/MART-1 and tyrosinase in patients with metastatic melanoma. In 2 patients with advanced disease, CTL responses against Melan A/MART-1 and tyrosinase were induced by intradermal immunization with synthetic nona- or deca-peptides derived from these antigens. Metastases increasing in size over time showed a loss of Melan A/MART-1 expression in the presence of CTL in one patient. The regression of a metastasis with persistent tyrosinase expression was observed in the other patient after the induction of CTL, reactive against tyrosinase. We conclude that CTL responses against melanocyte differentiation antigens may mediate regression of antigen-positive tumors and select for antigen-loss variants in vivo.
289 citations
TL;DR: It is demonstrated that peptide alone injected intradermally may generate antigen‐specific DTH reactions and an increase of antigen‐ specific CTL reactivity.
Abstract: Peptide epitopes derived from differentiation antigens of the melanocyte lineage have been identified in human melanomas and normal cultured melanocytes as targets for MHC-restricted cytotoxic T lymphocytes (CTL). Characterization of multiple CTL-defined antigenic determinants and the presence of corresponding precursor CTL open perspectives for the development of antigen-based vaccines. In the present study, we determined the CTL reactivity against melanoma-associated peptides derived from Melan A/MART-1, tyrosinase and gp100/Pmel17 in 10 HLA-A2+ melanoma patients and 10 healthy individuals. Then, we examined the immunological effects and toxicity of intradermal inoculation of synthetic melanoma-associated peptides. Six patients with advanced melanoma received weekly intradermal injections of 6 melanoma-associated peptides and the influenza matrix peptide as a control for 4 consecutive weeks. DTH reactions were observed in 5/6 patients at the injections sites of the tyrosinase signal peptide and of the influenza matrix peptide. No toxic side effects were observed. Changes in CTL reactivity after peptide vaccination were assessed by an MLPC assay for each peptide. Generation of peptide-specific CTL was documented against Melan A/MART-1-derived peptide epitopes, the tyrosinase signal peptide and the influenza matrix peptide after vaccination. A decreasing CTL response against the internal tyrosinase peptide was documented in 1 patient through the course of vaccination and a decrease in DTH reactions. No major tumor regressions were observed. Two patients with rapidly progressive disease before vaccination have shown disease stabilization since vaccinations started. In conclusion, our results demonstrate that peptide alone injected intradermally may generate antigen-specific DTH reactions and an increase of antigen-specific CTL reactivity.
258 citations
TL;DR: Viral persistence and the development of high‐grade lesions were found to be closely associated with HPV16; 56% of HPV16 isolates were persistent compared to 7% of other HPV types, and all 4 subsequent CIN 3 lesions were in women with persistent infection.
Abstract: Women referred for colposcopy with mild and moderate dyskaryosis and found to have only minor cervical abnormalities were screened for oncogenic human papilloma virus (HPV) types. The natural development of these abnormalities in 42 HPV-positive women was assessed by cytology and colposcopy at 6-month intervals for up to 2 years. As is the case with cancers and high-grade cervical intra-epithelial neoplasia (CIN), minor cervical abnormalities were frequently found to be associated with HPV16, -18, -31 and -33. Viral persistence and the development of high-grade lesions were found to be closely associated with HPV16; 56% of HPV16 isolates were persistent compared to 7% of other HPV types, and all 4 subsequent CIN 3 lesions were in women with persistent infection. A striking association of persistence with a variant of HPV16 having a base change at nucleotide 350 was observed. Ten of 12 women with this variant had persistent infection compared to only 1 of 16 women infected with the HPV16 prototype. © 1996 Wiley-Liss, Inc.
250 citations
TL;DR: It is suggested that environmental aflatoxin exposure may enhance the hepatic carcinogenic potential of hepatitis B virus and a large‐scale study will be needed to evaluate the effect of a flatoxin exposure on HBsAg non‐carriers.
Abstract: To investigate the carcinogenic effect of environmental aflatoxin exposure, 56 cases of hepatocellular carcinoma (HCC) diagnosed between 1991 and 1995 were identified and individually matched by age, sex, residence and date of recruitment to 220 healthy controls from the same large cohort in Taiwan. Blood samples were analyzed for hepatitis B and C viral markers and for aflatoxin-albumin adducts; urine was tested for aflatoxin metabolites. We obtained information about sociodemographic characteristics, habitual alcohol drinking, cigarette smoking and diet in a structured interview. Hepatitis B virus surface antigen (HBsAg) carriers had a significantly increased risk for HCC. After adjustment for HBsAg serostatus, the matched odds ratio (ORm) was significantly elevated for subjects with high levels of urinary aflatoxin metabolites. When stratified into tertiles, a dose-response relationship with HCC was observed. The ORm for detectable aflatoxin-albumin adducts was not significant after adjustment for HBsAg serostatus. HBsAg-seropositive subjects with high aflatoxin exposure had a higher risk than subjects with high aflatoxin exposure only or HBsAg seropositivity only. In male HBsAg-seropositive subjects, adjusted ORs were 2.8 (95% confidence interval [CI] = 0.9-9.1) for detectable compared with non-detectable aflatoxin-albumin adducts and 5.5 (CI = 1.3-23.4) for high compared with low urinary aflatoxin metabolite levels. Our results suggest that environmental aflatoxin exposure may enhance the hepatic carcinogenic potential of hepatitis B virus. A large-scale study will be needed to evaluate the effect of aflatoxin exposure on HBsAg non-carriers.
246 citations
TL;DR: The view that the interval between successive smears in cervical‐cancer screening can be increased considerably for women with cytomorphologically normal and high‐risk HPV‐negative cervical smears as determined by PCR is supported.
Abstract: Cervical-cancer screening programmes using cytomorphological criteria could be more efficient if the screening included objective individual risk factors for women with normal cytology, such as a test for high-risk human papillomavirus (HPV). The value of a PCR-based test for high-risk HPV types was studied in a cohort of 1622 women presenting in a routine triannual population-based screening programme. Women were included in the study when they had no previous history of cervical dysplasia; and their initial Pap smear was read as normal (Pap 1 or 2). The mean age of the women was 42 years (range 34-54 years) and mean follow-up time was 40 months (range 5-73 months). Women were referred for colposcopically directed biopsies if they had had 2 successive cervical smears read as Pap 3a (mild to moderate dyskaryosis) or one read as > or = Pap 3b (severe dyskaryosis). Women with histologically confirmed cervical intraepithelial neoplasia grade III (CIN III) were considered positive cases. All women were tested for 14 high-risk HPV genotypes. Of the 86 high-risk HPV-positive women, 6 developed CIN III, whereas only 1 of the 1536 HPV-negative women did. The women with normal Pap smears containing high-risk HPV genotypes were 116 times (95% CI, 13-990) more at risk of developing CIN III, in contrast to women without high-risk HPV. These results support the view that the interval between successive smears in cervical-cancer screening can be increased considerably for women with cytomorphologically normal and high-risk HPV-negative cervical smears as determined by PCR.
TL;DR: Results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.
Abstract: pp125FAK, a protein tyrosine kinase (PTK) co-localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.
TL;DR: As a first attempt towards a specific and differentiated immunohistochemical classification of human tumors, a number of human recombinant S100 proteins are produced, purified and characterized and raised specific polyclonal antibodies.
Abstract: The S100 Ca2+-binding proteins recently became of major interest because of their differential expression in neoplastic tissues, their involvement in metastatic processes, and the clustered organization of at least 10 S100 genes on human chromosome 1q21, a region frequently rearranged in several tumors. As a first attempt towards a specific and differentiated immunohistochemical classification of human tumors, we produced, purified and characterized a number of human recombinant S100 proteins and raised specific polyclonal antibodies. Their distinct cellular and intracellular localization was examined by immunohistochemical methods in normal and cancerogenic human tissues and cell lines. S100A1 and S100A2 can be detected in a few normal tissues only, whereas S100A4, S100A6, and S100B are expressed at higher levels in cancer tissues. In the future, these S100 antibodies will potentially be of great value in cancer diagnosis and therapy. © 1996 Wiley-Liss, Inc.
TL;DR: Evidence is provided of the involvement of endothelial‐cell‐associated CD44 in angiogenesis, which is essential for tumor growth and metastasis and abolishes the stimulating effect of hyaluronan polysaccharides on endothelial cell migration and proliferation.
Abstract: Angiogenesis is essential for tumor growth and metastasis. In the process of angiogenesis, the interaction between adhesive proteins of endothelial cells and extracellular matrix components plays an important role by mediating cell attachment, which is indispensable for their motility, and by transmitting the regulatory signals for cell locomotion and proliferation. In this study, we examined the hypothesis that CD44 expressed on the endothelial cell surface is involved in the angiogenesis process. The experiments using calf pulmonary artery endothelial cells (CPAE) and a human microvascular endothelial cell line (HMEC-1) show that a monoclonal antibody against CD44 (clone J 173) inhibits endothelial cell proliferation by about 30% and migration by 25-50%, and abolishes the stimulating effect of hyaluronan polysaccharides on endothelial cell migration and proliferation. This antibody also suppresses the capillary formation of CPAE in an in vitro model of angiogenesis using fibrin matrix. These results provide evidence of the involvement of endothelial-cell-associated CD44 in angiogenesis.
TL;DR: The high prevalence of MRP and LRP expression observed in this large set of cell lines, which have not been subjected to laboratory drug selection, suggests that MDR mechanisms associated with these proteins may be widespread in human malignancies.
Abstract: In addition to P-glycoprotein (Pgp), 2 proteins related to multidrug resistance (MDR) have recently been described The Multidrug-Resistance-associated protein (MRP) is one of the ATP-binding-cassette (ABC) transporters The Lung-Resistance Protein (LRP) is the major component of human vaults, which are newly described cellular organelles and thought to mediate intracellular transport processes Using immunocytochemical methods, we have examined the expression of MRP and LRP among panels of human cancer-cell lines not selected for drug resistance which have been previously characterized for expression of Pgp, and in vitro response to a variety of anti-cancer drugs Expression of MRP and LRP was observed in 47/55 (87%) and 46/59 (78%) cell lines, respectively Statistically significant correlations were observed between expression of each of these 3 proteins and in vitro sensitivity to at least one drug classically associated with MDR LRP showed the greatest individual predictive value, which also applied to several non-classical MDR drugs Co-expression of 2-3 MDR-related proteins was observed in 64% of the lines and was, in general, associated with high relative levels of drug resistance Previously identified "classic" MDR lines as well as "pan-resistant" lines concurrently expressed all 3 MDR-related proteins Some highly drug-resistant cell lines without detectable MDRI/Pgp were found to express relatively high levels of MRP and LRP The high prevalence of MRP and LRP expression observed in this large set of cell lines, which have not been subjected to laboratory drug selection, suggests that MDR mechanisms associated with these proteins may be widespread in human malignancies Moreover, the overlapping of these more recently recognized MDR phenotypes with Pgp-type MDR results in a complex phenotype, the understanding of which may be of importance in the development of new drugs and design of clinical treatment protocols, particularly those seeking to employ strategies to reverse the MDR phenotype
TL;DR: The results suggest that Ad‐p53 is capable of infecting and killing cancer cells of diverse tissue origins (including multi‐drug resistant cancer cells), that p21WAF1/CIP1 may be a useful marker of p53 infectivity and that there may be synergy between Ad‐ p53 and either mitomycin C or Adriamycin induced cell death in tumors with p53 mutations.
Abstract: Deficiency in p53-mediated cell death is common in human cancer, contributing to both tumorigenesis and chemoresistance. In an attempt to restore p53, we evaluated in vitro infectivity and cytotoxicity of a wild type (w.t.) p53-expressing adenovirus (Ad-p53) toward a panel of human cancer cell lines (n = 19). At a multiplicity of infection of 30, both Ad-p53 and adenovirus expressing β-galactosidase (Ad-LacZ) infected greater than 99% of cells derived from brain, lung, breast, ovarian, colon, and prostate cancer, but failed to infect leukemia or lymphoma cells. Ad-p53, but not Ad-LacZ, infection of cancer cells was followed by nuclear accumulation of the CDK inhibitor p21WAF1/CIP1, cell cycle arrest and loss of viability. Ad-p53 induced apoptotic death in cancer cells that express mutant p53, including multi-drug resistant cells, but fewer deaths were observed in some w.t. p53 expressing cells. Ad-p53-infected SKBr3 breast cancer cells were more sensitive to cytotoxicity of the DNA damaging drugs mitomycin C or Adriamycin, but not the M-phase specific drug vincristine. Our results suggest that Ad-p53 is capable of infecting and killing cancer cells of diverse tissue origins (including multi-drug resistant cancer cells), that p21WAF1/CIP1 may be a useful marker of p53 infectivity and that there may be synergy between Ad-p53 and either mitomycin C or Adriamycin induced cell death in tumors with p53 mutations. © 1996 Wiley-Liss, Inc.
TL;DR: New findings in the pathology of HNPCC, particularly an increased frequency of interval cancers and the likely accelerated rate of the adenoma to cancer sequence, indicate the need for more frequent colonoscopic surveillance with an option for prophylactic subtotal colectomy in germ‐line‐positive individuals.
Abstract: Hereditary non-polyposis colorectal cancer (HNPCC) pre-disposes to cancers of the colon, endometrium and several other extra-colonic sites in the absence of premonitory physical stigmata (Muir-Torre syndrome excepted). Discovery of the several DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2) holds the potential for determining the cancer destiny of patients, theoretically in utero. Pre-symptomatic DNA testing is now possible in patients from HNPCC families and will be clinically available once inexpensive and simple tests for these germ-line mutations have been effected. Genetic counseling will be mandatory, given the myriad socio-psychological, insurance, and potentially other personal issues which may impact this knowledge. New findings in the pathology of HNPCC, particularly an increased frequency of interval cancers and the likely accelerated rate of the adenoma to cancer sequence, indicate the need for more frequent colonoscopic surveillance with an option for prophylactic subtotal colectomy in germ-line-positive individuals. © 1996 Wiley-Liss, Inc.
TL;DR: There is some evidence that total energy intake is a risk factor for prostate cancer, and a weak positive association between intake of retinol and advanced cancer was observed.
Abstract: The role of diet in the etiology of prostate cancer remains unclear, because results from several case-control and cohort studies on fat intake and risk of prostate cancer have been inconsistent; few of the studies have adjusted the results for caloric intake. To examine the relationship between energy, intake of several nutrients and risk of prostate cancer (all stages combined and advanced stages separately), we conducted a population-based case-control study in Orebro County, Sweden, from 1989 through 1994. A total of 526 patients with newly diagnosed prostate cancer and 536 controls, randomly selected from the population register and frequency-matched by age, were included in the analyses. Information about dietary intake was obtained from a self-administered semi-quantitative food frequency questionnaire. Odds ratios with 95% confidence intervals were estimated by unconditional logistic regression. In age-adjusted analyses, there were positive associations of prostate cancer (all stages combined) risk with total energy intake as well as intake of total fat (saturated and monounsaturated), protein, retinol and zinc. The positive association with energy intake was stronger for advanced cancer, with an excess risk of 70% for the highest quartile vs. the lowest. After adjustment for energy intake, there was no apparent association of prostate cancers (all stages combined) with any of the investigated nutrients. However, a weak positive association between intake of retinol and advanced cancer was observed. We conclude that our results provide some evidence that total energy intake is a risk factor for prostate cancer.
TL;DR: It is suggested that RT‐PCR amplification of CEA mRNA is an efficient means of detecting circulating solid cancer cells in the peripheral blood, although long‐term clinical studies should be done to evaluate its usefulness; not only breast cancer but also gastrointestinal cancer might be better regarded as a systemic disease even in early stages of carcinoma.
Abstract: Detection of the mRNA of selected genes by reverse transcriptase-polymerase chain reaction (RT-PCR) is a sensitive and powerful tool for detecting cancer cells in bone-marrow or peripheral-blood samples. In this study, we determined whether carcinoembryonic antigen (CEA) mRNA is detectable in the peripheral blood of patients with gastrointestinal or breast cancer. In addition, we studied selected patients undergoing surgical procedures to assess whether tumor manipulation during operation enhances cancer-cell dissemination. Peripheral blood from 55 patients with gastrointestinal or breast cancer and from 22 control cases was analysed for CEA mRNA using RT-PCR. For 15 selected cases undergoing curative surgery for cancer, samples were also obtained during and after surgery. The lower limit of detection was 1 to 10 CEA-positive cells diluted among 1 × 107 blood mononuclear cells. The test was positive for 20 of the 55 patients with cancer (36%). None of the 22 control samples were positive. An increase in positivity was observed with increasing stage of disease; however, even some patients with early-stage cancer showed positive results. In addition, CEA mRNA could be detected in the peripheral blood during operation in 3 of 13 patients whose pre-operative CEA mRNA in the peripheral blood had been negative. These findings suggest that, (1) RT-PCR amplification of CEA mRNA is an efficient means of detecting circulating solid cancer cells in the peripheral blood, although long-term clinical studies should be done to evaluate its usefulness; (2) not only breast cancer but also gastrointestinal cancer might be better regarded as a systemic disease even in early stages of carcinoma; and (3) surgical manipulation can provoke cancer-cell dissemination. ©1996 Wiley-Liss, Inc.
TL;DR: The dramatic increase of childhood KS implies that the prevalence of causative factors is rising in Uganda, and a newly described herpes‐like virus is implicated as the cause of KS (KSHV), and DNA sequences of this virus were present in all of 8 childhood cases tested.
Abstract: During 1989-94 clinicians had treated 100 cases of histologically or clinically confirmed Kaposis sarcoma (KS) in children under 15 years of age (median age 4 years) at the Uganda Cancer Institute in Kampala. The male/female ratio was 1.7/1. 78% of the children tested positive for HIV while 69% of all mothers were HIV positive. 81% of the mothers with an HIV-infected child also tested HIV positive. There were seven discordant child-mother pairs among the 34 pairs tested for HIV. Five children were HIV positive; yet their mothers were HIV negative. There were no child-mother pairs with KS even though the prevalence of KS in HIV-seropositive adults (7-10%) would predict two mothers with KS. 39% of patients had an infection in a site later involved with KS. The most prominent KS-related findings were lymphadenopathy and mucocutaneous lesions. Scientists have implicated a newly described herpes-like virus as the cause of KS (KSHV). All eight children tested for DNA sequences of this virus had these DNA sequences in archival tissues. The areas of the body most affected by KS were orofacial (79%) and inguinal/genital (13%) areas sites that favor the entry of a causative agent e.g. KSHV. The median age of onset of KS symptoms was 33 months for HIV-positive child-mother pairs and 34 months for HIV-negative child-mother pairs suggesting that exposure to a potentially infectious agent occurred at birth or early infancy. It was 36 months for those of unknown HIV status. The high concordancy of child-mother HIV seropositivity suggests that the KS agent could be spread perinatally or during breast feeding. The dramatic increase in the incidence of KS in children (>40-fold increase) since the emergence of AIDS suggests that the prevalence of causative factors is also increasing.
TL;DR: Data suggest that elF‐4E‐induced VPF expression may be an important factor in some forms of tumor angiogenesis and development and strongly suggest that enhancedVPF expression is achieved through translational regulation rather than transcriptional regulation in cells overexpressing elF•4E.
Abstract: Studies aimed at elucidating the function of the protein synthesis factor eukaryotic initiation factor 4E (elF-4E) have demonstrated that overexpression of this protein results in marked cell phenotypic and proliferative changes, including neoplastic transformation of cells. These data suggest that elF-4E may somehow participate in the development and progression of tumors in vivo. In order to determine how elF-4E exerts its transforming effects, we examined vascular permeability factor (VPF) levels in cells transfected with an elF-4E vector. Cells overexpressing elF-4E showed an increase in intracellular, and an average 130-fold increase in secreted VPF protein levels (CHO 0.13 ± 0.12 ng/ml; CHO-4E 20.5 ± 12.5 ng/ml) over control cells. HUVEC growth induction revealed these VPF levels to be biologically active. Northern analysis revealed no difference in VPF transcript between the 2 cell lines. Polysome analysis showed that the VPF message in elF-4E-transfected cells was associated with the heavy polysomal regions, whereas the VPF message was associated with light polysomes in control cells. These data strongly suggest that enhanced VPF expression is achieved through translational regulation rather than transcriptional regulation in cells overexpressing elF-4E. This indicates that elF-4E-induced VPF expression may be an important factor in some forms of tumor angiogenesis and development. © 1996 Wiley-Liss, Inc.
TL;DR: Cervical HPV infection was by far the most significant risk factor for cervical squamous intraepithelial lesions and the importance of the previously identified epidemiological risk factors for cervical neoplasia was also demonstrated.
Abstract: Sexual behavior has been consistently identified as a major risk factor for cervical cancer. Population-based studies have demonstrated that risk related to sexual activity is mediated by human papillomavirus (HPV) infection. We conducted a case-control study of 199 cases with low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions as defined by cytology and 1000 control women selected from an ongoing prospective cohort study in Copenhagen, Denmark. Furthermore, 131 women with equivocal smears (atypical squamous cells of undetermined significance) were examined as a separate borderline case group. At enrollment, all women had a personal interview and a gynecological examination including cervical swabs for HPV testing and a Pap smear. HPV testing was performed using a combination of general primer 5/6-mediated and type-specific polymerase-chain-reaction-based methods. Cervical HPV infection was by far the most significant risk factor for cervical squamous intraepithelial lesions. The relationship with HPV was observed for all grades, while strength of association was greater for more severe lesions. The importance of the previously identified epidemiological risk factors for cervical neoplasia was also demonstrated. However, most of the effect of these factors could be explained by taking HPV infection into account, except for schooling and smoking. Non-use of barrier contraceptives and smoking were the only significant risk factors in HPV-positive women. In HPV-negative women, a residual effect existed for different measures of sexual activity, and use of oral contraceptives and smoking constituted significant risk determinants Overall, 66% of cases could be attributed to HPV; however, if the results were restricted to histologically confirmed high-grade lesions, the proportion of cases that could be attributed to HPV infection increased to 80%.
TL;DR: Observing the role of duodenal and gastric reflux in the absence of exogenous carcinogens in esophageal carcinogenesis demonstrates that refluxed duodenosquamous contents per se are responsible for esophagesis carcinogenesis.
Abstract: Esophageal adenocarcinoma arises from Barrett's esophagus, which is induced by gastro-esophageal reflux. This refluxate often contains duodenal contents, whose backflow triggers gastric carcinoma, suggesting the hypothesis that refluxed duodenal contents cause esophageal carcinoma. This study examines the role of duodenal and gastric reflux in the absence of exogenous carcinogens in esophageal carcinogenesis. Wistar male rats, 120 in all, each weighing approximately 250 g, were used. Three experimental procedures were performed to produce gastro-duodeno-esophageal reflux, duodeno-esophageal reflux and gastro-esophageal reflux, for comparison with 2 control procedures, Roux-en-Y reconstruction and a sham operation. The animals were fed a standard diet and were examined 50 weeks after surgery. While no carcinoma was found among the 16 gastro-esophageal-reflux, 11 Roux-en-Y and 12 sham-operation animals, 10 of the 12 animals with gastro-duodeno-esophageal reflux (83%) and 10 of the 13 with duodeno-esophageal reflux (77%) developed esophageal carcinoma. The difference between groups was significant (p < 0.001). Two animals with gastro-duodeno-esophageal reflux had esophageal double and triple carcinomas respectively. Of the 23 carcinomas, 16 were adenocarcinoma, 4 adenosquamous carcinoma, and 3 squamous-cell carcinoma. Adenocarcinoma developed from the columnar-lined epithelium near the esophago-jejunostoma, while adenosquamous and squamous-cell carcinoma arose from the squamous esophagitis. These observations demonstrate that refluxed duodenal contents per so are responsible for esophageal carcinogenesis.
TL;DR: Horticulture and pesticide indicators were associated with all cancers at ages 0 to 4 years, Wilms' tumour, non‐Hodgkin's lymphoma, eye cancer and neuroblastoma, and chicken farming was associated with some common cancers of adolescence, and was strongest for osteosarcoma and mixed cellular type of Hodgkin's disease.
Abstract: In this study of cancer in offspring we demonstrate that factors linked to horticulture and use of pesticides are associated with cancer at an early age, whereas factors in animal husbandry, in particular poultry farming, are associated with cancers in later childhood and young adulthood. Incident cancer was investigated in offspring born in 1952-1991 to parents identified as farm holders in agricultural censuses in Norway in 1969-1989. In the follow-up of 323,292 offspring for 5.7 million person-years, 1,275 incident cancers were identified in the Cancer Registry for 1965-1991. The standardized incidence for all cancers was equal to the total rural population of Norway, but cohort subjects had an excess incidence of nervous-system tumours and testicular cancers in certain regions and strata of time that could imply that specific risk factors were of importance. Classification of exposure indicators was based on information given at the agricultural censuses. Risk factors were found for brain tumours, in particular non-astrocytic neuroepithelial tumours: for all ages, pig farming tripled the risk [rate ratio (RR), 3.11; 95% confidence interval (CI), 1.89-5.13]; indicators of pesticide use had an independent effect of the same magnitude in a dose-response fashion, strongest in children aged 0 to 14 years (RR, 3.37; 95% CI, 1.63-6.94). Horticulture and pesticide indicators were associated with all cancers at ages 0 to 4 years, Wilms' tumour, non-Hodgkin's lymphoma, eye cancer and neuroblastoma. Chicken farming was associated with some common cancers of adolescence, and was strongest for osteosarcoma and mixed cellular type of Hodgkin's disease. The main problem in this large cohort study is the crude exposure indicators available; the resulting misclassification is likely to bias any true association towards unity.
TL;DR: The data suggest that cyclin D1 activation determines the evolution of a particular subset of estrogen‐responsive tumors, and distinct pathways of cyclin activation in human breast and ovarian cancer are suggested.
Abstract: Evidence of the involvement of cyclin genes in genetic alterations in human cancer is growing. In the present study, we investigated the amplification, in human breast and ovarian cancer, of 5 cyclin genes; cyclin A, cyclin D1, cyclin D2, cyclin D3 and cyclin E. For this purpose, a series of 1,171 breast and 237 ovarian tumors tested for DNA amplification by Southern blotting and a subset of 132 breast and 22 ovarian cancers were analyzed for RNA expression levels by slot-blot and Northern blotting. In breast tumors, only cyclin D1 was found to be activated in a sizeable fraction of the tumors (amplification 12.6%, overexpression 19%). Cyclin A, D2, D3, and E genes never, or only on rare occasions, showed increased DNA copy numbers and were never found overexpressed at the RNA level. Amplification of cyclin D1 correlated with ER+ breast cancer and the presence of lymph-node metastasis. Interestingly, we were also able to determine an association with invasive lobular carcinoma. Our data suggest that cyclin D1 activation determines the evolution of a particular subset of estrogen-responsive tumors. Data obtained in ovarian tumors contrasted with observations in breast cancer. Cyclin D1 DNA amplification was much less frequent in ovarian than in breast tumors (3.3% vs. 12.6%), whereas cyclin E amplification and overexpression were observed in a significant number of cases (12.5% and 18.0% respectively). Cyclin A, cyclin D2 and D3 rarely showed anomalies at the DNA level and were never overexpressed. No clear correlation could be observed between amplification of the cyclin E gene and tumor type, stage or grade in ovarian cancer. Data presented here suggest distinct pathways of cyclin activation in human breast and ovarian cancer.
TL;DR: The isolation of human antibody fragments against the human ED‐B domain that bind to human, mouse and chicken B‐FN is described and, by immunohistochemistry, the antibody fragments stain human neoplastic tissues and the human, mice and chicken neovasculature.
Abstract: Fibronectin (FN) exists in several polymorphic forms due to alternative splicing. The B-FN isoform (with ED-B domain inserted by splicing) is present in the stroma of foetal and neoplastic tissues and in adult and neoplastic blood vessels during angiogenesis but is undetectable in mature vessels. This isoform, therefore, represents a promising marker for angiogenesis, as already shown using the mouse monoclonal antibody (MAb) BC-1 directed against an epitope on human B-FN. However, this MAb does not directly recognise the human ED-B domain nor does it recognise B-FN of other species; therefore, it cannot be used as a marker of angiogenesis in animal models. In principle, antibodies directed against the human ED-B domain should provide pan-species markers for angiogenesis as the sequence of this domain is highly conserved in different species (and identical in humans and mice). As it has proved difficult to obtain such antibodies by hybridoma technology, we used phage display technology. Here, we describe the isolation of human antibody fragments against the human ED-B domain that bind to human, mouse and chicken B-FN. As shown by immunohistochemistry, the antibody fragments stain human neoplastic tissues and the human, mouse and chicken neovasculature.
TL;DR: It is concluded that low plasma levels of the vitamins C, E, retinol and carotene are related to increased risk of subsequent overall and lung‐cancer mortality and that low levels of vitamin E in smokers arerelated to an increase risk of prostate‐ cancer mortality.
Abstract: Plasma vitamins C, E, retinol and carotene were measured in 1971-1973 in 2,974 men working in Basel Switzerland. In 1990, the vital status of all participants was assessed. A total of 290 men had died from cancer during the 17 years of follow-up, including 87 with lung cancer, 30 with prostate cancer, 28 with stomach cancer and 22 with colon cancer. Overall mortality from cancer was associated with low mean plasma levels of carotene (adjusted for cholesterol) and of vitamin C. Lung and stomach cancers were associated with low mean plasma carotene level. After calculation of the relative risk, using the Cox model, with exclusion of mortality during the first 2 years of follow-up, simultaneously low levels of plasma carotene (below quartile I) and lipid-adjusted retinol were related to a significantly increased mortality risk for all cancers and for lung cancer. Simultaneously, low levels of plasma vitamin C and lipid-adjusted vitamin E also were associated with a significantly increased risk for lung cancer. Additionally, low vitamin E levels in smokers were related to an increased risk for prostate cancer. It is concluded that low plasma levels of the vitamins C, E, retinol and carotene are related to increased risk of subsequent overall and lung-cancer mortality and that low levels of vitamin E in smokers are related to an increased risk of prostate-cancer mortality.
TL;DR: Human head and neck cancers have a multiplicity of non‐mutually exclusive mechanisms of immune suppression that are most prominently associated with reduced CD8+ cell influx and reduced influx and altered function of intratumoral CD4+ cells.
Abstract: Freshly excised human head and neck cancers (219 primary cancers; 64 metastatic lymph node cancers) were analyzed for the immune inhibitory mediators released from the cancer tissues and the immune infiltrate within the tumor. Significant levels of the immune inhibitory mediators transforming growth factor-beta (TGF-beta), prostaglandin E2 (PGE2) and interleukin-10 (IL-10) were released from these cancers. Also released was granulocyte-macrophage colony-stimulating factor (GM-CSF), whose secretion was associated with an intratumoral presence of CD34+ cells. We have previously shown that CD34+ cells within human head and neck cancers are immune inhibitory granulocyte-macrophage progenitor cells. The presence of TGF-beta, PGE2 and IL-10 was associated with a reduced content of CD8+ T-cells within the cancers. The CD4+ cell content appeared to be less affected by these immune inhibitory mediators. Instead, parameters indicative of CD4+ cell function (p55 IL-2 receptor expression, release of IL-2 and IFN-gamma) were diminished in cancers that released higher levels of TGF-beta, IL-10 and GM-CSF and had a higher CD34+ cell content. Furthermore, metastatic cancers released higher levels of the soluble immune inhibitory mediators and lower levels of IFN-gamma and IL-2 than did primary cancers, although CD34+ cells were similarly present in both primary and metastatic cancers. Our results show that human head and neck cancers have a multiplicity of non-mutually exclusive mechanisms of immune suppression that are most prominently associated with reduced CD8+ cell influx and reduced influx and altered function of intratumoral CD4+ cells.
TL;DR: Both testicular cancer and cryptorchidism tended to occur more frequently in first‐born men and in sons of older women, but these associations were not statistically significant.
Abstract: To explore risk factors for testicular cancer and cryptorchidism, 2 parallel case-control studies were conducted in Denmark. The testicular-cancer study was population-based and included 514 cases and 720 controls. The cryptorchidism study included 387 cases and 416 controls and was based on 2 hospital series of men treated for cryptorchidism and a control group sampled among residents in the Copenhagen area. The 2037 men were interviewed by telephone, and self-administered questionnaires were sent to their mothers. A strong association was seen between low social class and cryptorchidism, with sons of unskilled workers having a 3-fold higher risk of cryptorchidism than sons of self-employed men. Testicular cancer was only moderately associated with high-social-class indicators, and only with such indicators pertaining to the mother. Both testicular cancer and cryptorchidism tended to occur more frequently in first-born men and in sons of older women, but these associations were not statistically significant. Late puberty was associated with reduced risk of testicular cancer. The effect of age at puberty may be due both to advanced age at diagnosis and to the existence of common determinants of age at puberty and testicular cancer. Men who had been treated for cryptorchidism entered puberty later than other men, possibly because of impaired hormonal function of the testes. There was no indication of increased risk of testicular cancer or cryptorchidism in sons of mothers who smoked around the time of conception or during the pregnancy. © 1996 Wiley-Liss, Inc.
TL;DR: The authors' observations suggest that gp96 and perhaps other HSPs are anchored to the cell surface as part of larger molecular complexes, which also transport them to theCell surface expression of gp96 is enhanced by heat shock and exposure to reducing agents.
Abstract: Heat shock protein (HSP) gp96/grp94 contains a signal peptide at the amino terminus and a -KDEL sequence at the carboxy terminus and is a major component of the lumen of the mammalian endoplasmic reticulum (ER). We show, by a number of immunolocalization methods using light and electron microscopy, that a significant proportion of intact gp96 molecules is also expressed on the cell surface. Surface gp96 molecules truly represent surface expression and do not result from adventitious deposition of gp96 released by dead cells on to the live cells in culture. Cell surface expression of gp96 is enhanced by heat shock and exposure to reducing agents. Gp96 molecules are not released from plasma membranes by repeated salt washes, and gp96 is not an integral membrane protein. Our observations suggest that gp96 and perhaps other HSPs are anchored to the cell surface as part of larger molecular complexes, which also transport them to the cell surface.