Showing papers in "Journal of the National Cancer Institute in 1997"

Changing Views of the Role of Matrix Metalloproteinases in Metastasis

Abstract: Metastatic spread of cancer continues to be the greatest barrier to cancer cure. Understanding the molecular mechanisms of metastasis is crucial for the design and effective use of novel therapeutic strategies to combat metastases. One class of molecules that has been repeatedly implicated in metastasis is the matrix metalloproteinases (MMPs). In this review, we re-examine the evidence that MMPs are associated with metastasis and that they make a functional contribution to the process. Initially, it was believed that the major role of MMPs in metastasis was to facilitate the breakdown of physical barriers to metastasis, thus promoting invasion and entry into and out of blood or lymphatic vessels (intravasation, extravasation). However, recent evidence suggests that MMPs may have a more complex role in metastasis and that they may make important contributions at other steps in the metastatic process. Studies using intravital videomicroscopy, as well as experiments in which levels of MMPs or their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are manipulated genetically or pharmacologically, suggest that MMPs are key regulators of growth of tumors, at both primary and metastatic sites. On the basis of this evidence, a new view of the functional role of MMPs in metastasis is presented, which suggests that MMPs are important in creating and maintaining an environment that supports the initiation and maintenance of growth of primary and metastatic tumors. Further clarification of the mechanisms by which MMPs regulate growth of primary and metastatic tumors will be important in the development of novel therapeutic strategies against metastases.

A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting Highlights and Bethesda Guidelines

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is a distinct autosomal dominant syndrome accounting for approximately 5%–6% of the total colorectal cancer burden with clinical and pathologic features caused by defective mismatch repair genes(1). Germline mutations in hMSH2, hMLH1, hPMS1, hPMS2, and MSH6/GTBP have been identified in affected individuals(2,3).HNPCC is characterized by early-onset colorectal cancer (median age at diagnosis 45 years); right-sided predominance; excess synchronous and metachronous colorectal neoplasms; and an increased incidence of extracolonic neoplasms, including endometrial, small-bowel, gastric, renal pelvis and ureter, and ovarian tumors and skin lesions, such as sebaceous adenomas, carcinomas, and keratoacanthomas (4–10). In 1991, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (11) established minimal clinical criteria for recruiting HNPCC patients for collaborative studies. These criteria, also known as the Amsterdam Criteria, include the following: 1) at least three relatives with histologically verified colorectal cancer, one of them a first-degree relative of the other two (familial adenomatous polyposis excluded); 2) at least two successive generations affected; and 3) in one of the individuals, diagnosis of colorectal cancer before the age of 50. These criteria were pivotal in identifying kindreds that eventually led to the association of the HNPCC syndrome with germline mismatch repair gene mutations (MMR). However, the criteria do not account for extracolonic cancers or for small kindreds. On November 11 and 12, 1996, the Early Detection Branch of the National Cancer Institute convened an international workshop in Bethesda, MD, entitled ‘‘The Intersection of Pathology and Genetics in the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome.’’ The purpose of the workshop was to clarify the role of genetics in the pathology of HNPCC. Discussions centered on genomic instability, multistep carcinogenesis and the role of mismatch repair genes in HNPCC, histopathology of HNPCCs and possible relationships to molecular genetic changes, markers of cell proliferation and their relationship to HNPCC as well as their potential use in early diagnosis and prognosis, and, lastly, clinicopathologic criteria that could lead to the identification of additional HNPCC patients. The keynote speaker was Dr. Alfred Knudson (Fox Chase Cancer Center, Philadelphia), who discussed the tumor spectrum of the HNPCC syndrome. Issues that arose during the workshop are discussed below.

Hereditary Pancreatitis and the Risk of Pancreatic Cancer

Abstract: BACKGROUND Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene. Acute attacks of abdominal pain begin early in life and the disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types of chronic pancreatitis, the frequency of pancreatic cancer in the inherited type of pancreatitis is uncertain. PURPOSE The aim of this study was to assess the frequency of pancreatic cancer and other tumors in patients with hereditary form of pancreatitis. METHODS To determine the natural history of hereditary pancreatitis, we invited all members of the American Pancreatic Association and the International Association of Pancreatology to participate in a longitudinal study of this rare form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (< or = 30 years) at onset of symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries contributed medical records of 246 (125 males and 121 females) patients thought to have hereditary pancreatitis as the most likely diagnosis. This group included 218 patients where the diagnosis appeared to be highly probable and 28 additional patients where the diagnosis of hereditary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients with onset of disease before age 30 years but with an uncertain family history. We reviewed all causes of death and compared the observed to the expected frequency of cancer in this historical cohort of patients with hereditary pancreatitis. The strength of the association between pancreatitis and pancreatic cancer was estimated by the standardized incidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the background population, adjusted for age, sex, and country. RESULTS The mean age (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, eight pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years of follow-up, yielding an SIR of 53 (95% confidence interval [CI] = 23-105). The frequency of other tumors was not increased: SIR = 0.7 (95% CI = 0.3-1.6). Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort have already been tested for the defective hereditary pancreatitis gene: all 30 carry a mutated copy of the trypsinogen gene. The transmission pattern of hereditary pancreatitis was known for 168 of 238 patients without pancreatic cancer and six of eight with pancreatic cancer. Ninety-nine of the 238 patients without pancreatic cancer and six of the patients with pancreatic cancer inherited the disease through the paternal side of the family. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approaches 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. CONCLUSIONS Patients with hereditary pancreatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern increases the probability of developing pancreatic cancer.

Green Tea Constituent Epigallocatechin-3-Gallate and Induction of Apoptosis and Cell Cycle Arrest in Human Carcinoma Cells

Abstract: Background and Purpose: The polyphenolic compounds present in green tea show cancer chemopreventive effects in many animal tumor models. Epidemiologic studies have also suggested that green tea consumption might be effective in the prevention of certain human cancers. We investigated the effect of green tea polyphenols and the major constituent, epigallocatechin-3-gallate, on the induction of apoptosis (programmed cell death) and regulation of cell cycle in human and mouse carcinoma cells. Methods: Human epidermoid carcinoma cells (cell line A431), human carcinoma keratinocyte (cell line HaCaT), human prostate carcinoma cells (cell line DU145), mouse lymphoma cells (cell line L5178Y), and normal human epidermal keratinocytes (NHEKs) were used. Apoptosis was assessed by 1) the formation of internucleosomal DNA fragments by agarose gel electrophoresis, 2) confocal microscopy, and 3) flow cytometry after tagging the DNA fragments by fluorescence label. The distribution of cells in different phases of the cell cycle was analyzed by flow cytometry. Results: Treatment of A431 cells with green tea polyphenols and its components, epigallocatechin-3-gallate, epigallocatechin, and epicatechin-3-gallate, resulted in the formation of internucleo-somal DNA fragments, characteristic of apoptosis. Treatment with epigallocatechin-3-gallate also resulted in apoptosis in HaCaT, L5178Y, and DU145 cells, but not in NHEK. Confocal microscopy and flow cytometry confirmed the findings. The DNA cell cycle analysis showed that in A431 cells, epigallocatechin-3-gallate treatment resulted in arrest in the G 0 -G 1 phase of the cell cycle and a dose-dependent apoptosis. Conclusions: Green tea may protect against cancer by causing cell cycle arrest and inducing apoptosis. It needs to be evaluated in human trials.

Participation in Colorectal Cancer Screening: A Review

Abstract: The purpose of this review is to evaluate the published literature on adherence to colorectal cancer (CRC) screening with fecal occult blood testing (FOBT) and sigmoidoscopy. Specifically, the review addresses the following: 1) prevalence of FOBT and sigmoidoscopy; 2) interventions to increase adherence to FOBT and sigmoidoscopy; 3) correlates or predictors of adherence to FOBT and sigmoidoscopy; and 4) reasons for nonadherence. Other objectives are to put the literature on CRC screening adherence in the context of recently reported findings from experimental interventions to change prevention and early detection behaviors and to suggest directions for future research on CRC screening adherence. CRC screening offers the potential both for primary and for secondary prevention. Data from the 1992 National Health Interview Survey show that 26% of the population more than 49 years of age report FOBT within the past 3 years and 33% report ever having had sigmoidoscopy. The Year 2000 goals set forth in Healthy People 2000 are for 50% of the population more than 49 years of age to report FOBT within the past 2 years and for 40% to report that they ever had sigmoidoscopy. Thus, systematic efforts to increase CRC screening are warranted. To date, attempts to promote CRC screening have used both a public health model that targets entire communities, e.g., mass media campaigns, and a medical model that targets individuals, e.g., general practice patients. Most of these efforts, however, did not include systematic evaluation of strategies to increase adherence. The data on FOBT show that the median adherence rate to programmatic offers of FOBT is between 40% and 50%, depending on the type of population offered the test, e.g., patients or employees. Approximately, 50% of those initially offered testing in unselected populations will respond to minimal prompts or interventions. A salient issue for FOBT, however, is whether or not the behavior can be sustained over time. Fewer studies examined adherence to sigmoidoscopy. Adherence was highest in relatives of CRC cases and in employer-sponsored programs offered to workers at increased risk of CRC. At present, we know very little about the determinants of CRC screening behaviors, particularly as they relate to rescreening.

Gene Therapy for Cancer: What Have We Done and Where Are We Going?

Abstract: Gene-based therapies for cancer in clinical trials include strategies that involve augmentation of immunotherapeutic and chemotherapeutic approaches. These strategies include ex vivo and in vivo cytokine gene transfer, drug sensitization with genes for prodrug delivery, and the use of drug-resistance genes for bone marrow protection from high-dose chemotherapy. Inactivation of oncogene expression and gene replacement for tumor suppressor genes are among the strategies for targeting the underlying genetic lesions in the cancer cell. A review of clinical trial results to date, primarily in patients with very advanced cancers refractory to conventional treatments, indicates that these treatments can mediate tumor regression with acceptably low toxicity. Vector development remains a critical area for future research. Important areas for future research include modifying viral vectors to reduce toxicity and immunogenicity, increasing the transduction efficiency of nonviral vectors, enhancing vector targeting and specificity, regulating gene expression, and identifying synergies between gene-based agents and other cancer therapeutics.

Cancer Incidence in a Population-Based Cohort of Patients Hospitalized With Diabetes Mellitus in Denmark

Abstract: Background: Diabetes has been associated with an increased risk of several cancers, notably cancers of the pancreas, liver, endometrium, and kidney. Since most previous studies have involved a limited sample size or focused on specific cancer sites, we conducted a comprehensive assessment of the risk of cancer in a nationwide cohort of diabetics in Denmark. Methods: Discharge records of 109581 individuals hospitalized with a diagnosis of diabetes from 1977 through 1989 were linked with national cancer registry records through 1993. Standardized incidence ratios (SIRs) were calculated for specific cancer sites. Results: The SIRs for primary liver cancer were 4.0 (95% confidence interval [CI] = 3.5-4.6) in males and 2.1 (95% CI = 1.6-2.7) in females. These SIRs remained elevated with increasing years of follow-up and after exclusion of patients with reported risk factors (e.g., cirrhosis and hepatitis) or patients whose cancers were diagnosed at autopsy. Kidney cancer risk was also elevated, with SIRs of 1.4 (95% CI = 1.2-1.6) in males and 1.7 (95 % CI = 1.4-1.9) in females. For both sexes combined, the SIR for pancreatic cancer was 2.1 (95% CI = 1.9-2.4), with a follow-up time of 1-4 years; this SIR declined to 1.3 (95% CI = 1.1-1.6) after 5-9 years of follow-up. Excess risks were also observed for biliary tract and endometrial cancers. The SIRs for kidney and endometrial cancers declined somewhat after exclusion of diabetics with reported obesity. Conclusions: Patients hospitalized with a diagnosis of diabetes appear to be at higher risk of developing cancers of the liver, biliary tract, pancreas, endometrium, and kidney. The elevated risks of endometrial and kidney cancers, however, may be confounded by obesity.

Association of Prostate Cancer Risk With Genetic Polymorphisms in Vitamin D Receptor and Androgen Receptor

Abstract: Background: Prostate cancer is an increasingly common disease for which there are few well-established risk factors. Family history data suggest a genetic component; however, the majority of prostate cancer cases cannot be explained by a single-gene model. Prostate cell division is influenced by two steroid hormones, testosterone and vitamin D, the action of each being mediated by its respective receptor. The genes for the two receptors are candidates in a multigenic model for prostate cancer susceptibility. Purpose: We examined genetic polymorphisms in two steroid receptors, the androgen receptor (AR) and the vitamin D receptor (VDR), in a case-control pilot study of prostate cancer. Methods: Fifty-seven non-Hispanic white case patients with prostate cancer and 169 non-Hispanic white control subjects were genotyped for a previously described microsatel-lite (CAG repeats) in the AR gene and for a newly discovered poly-A micro-satellite in the 3'-untranslated region (3'UTR) of the VDR gene. To compare genotypes with respect to prostate cancer risk, we estimated odds ratios (ORs) by using logistic regression. ORs were also estimated separately for advanced and localized cases of disease. All P values resulted from two-sided tests. Results: Both the AR and the VDR polymorphisms were associated, individually and after mutual adjustment, with prostate cancer. Adjusted ORs (95% confidence intervals [CIs]) for prostate cancer were 2.10 (95% CI = 1.11-3.99) for individuals carrying an AR CAG allele with fewer than 20 repeats versus an allele with 20 or more repeats and 4.61 (95% CI = 1.34-15.82) for individuals carrying at least one long (A 18 to A 22 ) VDR poly-A allele versus two short (A 14 to A 17 ) poly-A alleles. For both the AR and VDR genes, the at-risk genotypes were more strongly associated with advanced disease than with localized disease. Conclusions : In this pilot study, genetic variation in both the VDR and the AR genes was associated with prostate cancer, and both genes appear to preferentially confer risk for advanced disease. These two genetic risk factors, if confirmed, are among the strongest risk factors yet identified for prostate cancer. Implications: These results are consistent with a multigenic model of prostate cancer susceptibility. On the basis of the joint effect of several genetic loci, one might ultimately be able to construct a risk profile to predict advanced disease, so that men whose disease is unlikely to progress to an advanced stage can possibly be spared aggressive treatment.

Accelerated Titration Designs for Phase I Clinical Trials in Oncology

Abstract: Background: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity. Purpose: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained. Methods: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of three to six patients, with 40% dose-step increments. Designs 2 through 4 used intrapatient dose escalation if the worst toxicity is grade 0-1 in the previous course for that patient. Results: Only three of the actual trials demonstrated cumulative toxic effects of the chemotherapeutic agents in patients. The average number of patients required for a phase I trial was reduced from 39.9 for design 1 to 24.4, 20.7, and 21.2 for designs 2, 3, and 4, respectively. The average number of patients who would be expected to have grade 0-1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only 7.9, 3.9, and 4.8 for designs 2, 3, and 4, respectively. The average number of patients with grade 3 toxicity as their worst toxicity increases from 5.5 for design 1 to 6.2, 6.8, and 6.2 for designs 2, 3, and 4, respectively. The average number of patients with grade 4 toxicity as their worst toxicity increases from 1.9 for design 1 to 3.0, 4.3, and 3.2 for designs 2, 3, and 4, respectively. Conclusion: Accelerated titration (i.e., rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are undertreated, speed the completion of phase I trials, and provide a substantial increase in the information obtained. [J Natl Cancer Inst 1997;89:1138-47]

Tobacco, Alcohol, and Socioeconomic Status and Adenocarcinomas of the Esophagus and Gastric Cardia

Abstract: Background: Incidence rates for adenocarcinomas of the esophagus and gastric cardia have risen steeply over the last few decades. To determine risk factors for these tumors, we conducted a multicenter, population-based, case‐control study. Methods: The study included 554 subjects newly diagnosed with esophageal or gastric cardia adenocarcinomas, 589 subjects newly diagnosed with esophageal squamous cell carcinoma or other gastric adenocarcinomas, and 695 control subjects. Estimates of risk (odds ratios [ORs] and corresponding 95% confidence intervals [CIs]) were calculated for the four tumor types separately and for esophageal and gastric cardia adenocarcinomas combined. Results: Risk of esophageal and gastric cardia adenocarcinomas combined was increased among current cigarette smokers (OR = 2.4; 95% = 1.7‐3.4), with little reduction observed until 30 years after smoking cessation; this risk rose with increasing intensity and duration of smoking. Risk of these tumors was not related to beer (OR = 0.8; 95% CI = 0.6‐1.1) or liquor (OR = 1.1; 95% CI = 0.8‐1.4) consumption, but it was reduced for drinking wine (OR = 0.6; 95% CI = 0.5‐0.8). Similar ORs were obtained for the development of noncardia gastric adenocarcinomas in relation to tobacco and alcohol use, but higher ORs were obtained for the development of esophageal squamous cell carcinomas. For all four tumor types, risks were higher among those with low income or education. Conclusions: Smoking is a major risk factor for esophageal and gastric cardia adenocarcinomas, accounting for approximately 40% of cases. Implications: Because of the long lag time before risk of these tumors is reduced among exsmokers, smoking may affect early stage carcinogenesis. The increase in smoking prevalence during the first two thirds of this century may be reflected in the rising incidence of these tumors in the past few decades among older individuals. The recent decrease in smoking may not yet have had an impact. [J Natl Cancer Inst 1997;89:1277‐84] The incidence rates for adenocarcinomas of the esophagus and gastric cardia have risen steeply in the United States and Europe during the past few decades, whereas the incidence of squamous cell carcinoma of the esophagus and of adenocarci

Prognostic Significance of Vascular Endothelial Growth Factor Protein in Node-Negative Breast Carcinoma

Abstract: Background: The clinical outcome is generally positive for patients with node-negative breast carcinoma (i.e., those who do not have detectable metastases in the lymph nodes) who have been treated with surgery or surgery plus radiation therapy. In about 30% of the patients, however, the disease recurs, and they are at risk of death. Determination of valid new prognostic indicators would improve the ability to identify patients at high risk of recurrence. Breast cancer can entail substantial development of new blood vessels within the tumor tissue, and it is known that the growth and metastasis of solid tumors are dependent on such angiogenesis. The conversion of tumor cells to an angiogenic phenotype may be preceded by a change in the balance of angiogenic growth factors and angiogenesis inhibitors. Purpose: This study was conducted to determine if the levels of vascular endothelial growth factor (VEGF) protein, a potent endothelial growth factor and mediator of vascular permeability and angiogenesis, measured in the primary tumors of women with node-negative breast cancer are associated with known prognostic factors and patient survival. Methods: By use of a selective enzymatic immunoassay, levels of VEGF protein were measured in cytosolic extracts of primary tumor tissue surgically obtained from 260 women with node-negative breast carcinoma who had been treated with surgery with or without radiation therapy but not with adjuvant therapy and who had been followed for a median time of 66 months. The relationships between VEGF concentrations and other prognostic dichotomous variables or clinical outcome were tested by the use of the Kolmogorov-Smirnov test and univariate and multivariate Cox analyses, respectively. The relationship between VEGF and hormone receptors (i.e., those for estrogen and progesterone) was examined by the use of Spear-man's correlation analyses. All P values resulted from the use of two-sided statistical tests. Results: Tumors from 247 (95%) of the 260 patients had detectable VEGF, ranging in concentration from 5.0 to 6523 pg/mg protein (median, 126.25 pg/mg protein). No statistically significant associations were found between VEGF and the other prognostic factors (e.g., age, menopausal status, histologic tumor type, tumor size, and hormone receptors) examined. Levels of VEGF were found to be prognostic for both relapse-free and overall survival in univariate and multivariate analyses (likelihood ratio tests; all four P values <.001). In the multivariate analysis, the first-order interaction term of VEGF and estrogen receptor was also prognostic for overall survival (likelihood ratio test; P =.05). Conclusions: The results show that cytosolic levels of VEGF in tumor tissue samples are indicative of prognosis for patients with node-negative breast carcinoma.

Biology of Cachexia

Abstract: About half of all cancer patients show a syndrome of cachexia, characterized by loss of adipose tissue and skeletal muscle mass. Such patients have a decreased survival time, compared with the survival time among patients without weight loss, and loss of total body protein leads to substantial impairment of respiratory muscle function. These changes cannot be fully explained by the accompanying anorexia, and nutritional supplementation alone is unable to reverse the wasting process. Despite a falling caloric intake, patients with cachexia frequently show an elevated resting energy expenditure as a result of increases in Cori cycle (i.e., catalytic conversion of lactic acid to glucose) activity, glucose and triglyceride-fatty acid cycling, and gluconeogenesis. A number of cytokines, including tumor necrosis factor-apha, interleukins 1 and 6, interferon gamma, and leukemia-inhibitory factor, have been proposed as mediators of the cachectic process. However, the results of a number of clinical and laboratory studies suggest that the action of the cytokines alone is unable to explain the complex mechanism of wasting in cancer cachexia. In addition, cachexia has been observed in some xenograft models even without a cytokine involvement, suggesting that other factors may be involved. These probably include catabolic factors, which act directly on skeletal muscle and adipose tissue and the presence of which has been associated with the clinical development of cachexia. A polyunsaturated fatty acid, eicosapentaenoic acid, attenuates the action of such catabolic factors and has been shown to stabilize the process of wasting and resting energy expenditure in patients with pancreatic cancer. Such a pharmacologic approach may provide new insights into the treatment of cachexia.

Cigarette Smoking and Changes in the Histopathology of Lung Cancer

Abstract: Background: Adenocarcinoma of the lung, once considered minimally related to cigarette smoking, has become the most common type of lung cancer in the United States. The increased incidence of this cancer might be explained by advances in diagnostic technology (i.e., increased ability to perform biopsies on tumors in smaller, more distal airways), changes in cigarette design (e.g., the adoption of filtertips), or changes in smoking practices. We examined data from the Connecticut Tumor Registry and two American Cancer Society studies to explore these possibilities. Methods: Connecticut Tumor Registry data from 1959 through 1991 were analyzed to determine whether the increase in lung adenocarcinoma observed during that period could be best described by birth cohort effects (i.e., generational changes in cigarette smoking) or calendar period effects (i.e., diagnostic advances). Associations between cigarette smoking and death from specific types of lung cancer during the first 2 years of follow-up in Cancer Prevention Study I (CPS-I), initiated in 1959) and Cancer Prevention Study II (CPS-II, initiated in 1982) were also examined. Results: Adenocarcinoma incidence in Connecticut increased nearly 17-fold in women and nearly 10-fold in men from 1959 through 1991. The increases followed a clear birth cohort pattern, paralleling gender and generational changes in smoking more than diagnostic advances. Cigarette smoking became more strongly associated with death from lung adenocarcinoma in CPS-II compared with CPS-I, with relative risks of 19.0 (95% confidence interval [CI] = 8.3‐47.7) for men and 8.1 (95% CI = 4.5‐14.6) for women in CPS-II and 4.6 (95% CI = 1.7‐12.6) for men and 1.5 (0.3‐7.7) for women in CPS-I. Conclusions: The increase in lung adenocarcinoma since the 1950s is more consistent with changes in smoking behavior and cigarette design than with diagnostic advances. [J Natl Cancer Inst 1997;89:1580‐6]

Tamoxifen and Chemotherapy for Lymph Node-Negative, Estrogen Receptor-Positive Breast Cancer

Abstract: Background The B-20 study of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was conducted to determine whether chemotherapy plus tamoxifen would be of greater benefit than tamoxifen alone in the treatment of patients with axillary lymph node-negative, estrogen receptor-positive breast cancer. Methods Eligible patients (n = 2306) were randomly assigned to one of three treatment groups following surgery. A total of 771 patients with follow-up data received tamoxifen alone; 767 received methotrexate, fluorouracil, and tamoxifen (MFT); and 768 received cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT). The Kaplan-Meier method was used to estimate disease-free survival, distant disease-free survival, and survival. Reported P values are two-sided. Results Through 5 years of follow-up, chemotherapy plus tamoxifen resulted in significantly better disease-free survival than tamoxifen alone (90% for MFT versus 85% for tamoxifen [P = .01]; 89% for CMFT versus 85% for tamoxifen [P = .001]). A similar benefit was observed in both distant disease-free survival (92% for MFT versus 87% for tamoxifen [P = .008]; 91% for CMFT versus 87% for tamoxifen [P = .006]) and survival (97% for MFT versus 94% for tamoxifen [P = .05]; 96% for CMFT versus 94% for tamoxifen [P = .03]). Compared with tamoxifen alone, MFT and CMFT reduced the risk of ipsilateral breast tumor recurrence after lumpectomy and the risk of recurrence at other local, regional, and distant sites. Risk of treatment failure was reduced after both types of chemotherapy, regardless of tumor size, tumor estrogen or progesterone receptor level, or patient age; however, the reduction was greatest in patients aged 49 years or less. No subgroup of patients evaluated in this study failed to benefit from chemotherapy. Conclusions Findings from this and other NSABP studies indicate that patients with breast cancer who meet NSABP protocol criteria, regardless of age, lymph node status, tumor size, or estrogen receptor status, are candidates for chemotherapy.

Molecular Damage in the Bronchial Epithelium of Current and Former Smokers

Abstract: Background: Most lung cancers are attributed to smoking. These cancers have been associated with multiple genetic alterations and with the presence of preneoplastic bronchial lesions. In view of such associations, we evaluated the status of specific chromosomal loci in histologically normal and abnormal bronchial biopsy specimens from current and former smokers and specimens from nonsmokers. Methods: Multiple biopsy specimens were obtained from 18 current smokers, 24 former smokers, and 21 nonsmokers. Polymerase chain reaction-based assays involving 15 polymorphic microsatellite DNA markers were used to examine eight chromosomal regions for genetic changes (loss of heterozygosity [LOH] and microsatellite alterations). Results: LOH and microsatellite alterations were observed in biopsy specimens from both current and former smokers, but no statistically significant differences were observed between the two groups. Among individuals with a history of smoking, 86% demonstrated LOH in one or more biopsy specimens, and 24% showed LOH in all biopsy specimens. About half of the histologically normal specimens from smokers showed LOH, but the frequency of LOH and the severity of histologic change did not correspond until the carcinoma in situ stage. A subset of biopsy specimens from smokers that exhibited either normal or preneoplastic histology showed LOH at multiple chromosomal sites, a phenomenon frequently observed in carcinoma in situ and invasive cancer. LOH on chromosomes 3p and 9p was more frequent than LOH on chromosomes 5q, 17p (17p13; TP53 gene), and 13q (13q14; retinoblastoma gene). Microsatellite alterations were detected in 64% of the smokers. No genetic alterations were detected in nonsmokers. Conclusions: Genetic changes similar to those found in lung cancers can be detected in the nonmalignant bronchial epithelium of current and former smokers and may persist for many years after smoking cessation.

Clonal Genetic Alterations in the Lungs of Current and Former Smokers

Abstract: Background and Purpose: Genetic damage has been identified at multiple chromosomal sites (i.e., loci) in lung cancer cells. We questioned whether similar damage could be detected in the bronchial epithelial cells of chronic smokers who do not have this disease. Methods: Biopsy specimens from six different bronchial regions were obtained from 54 chronic smokers (40 current smokers and 14 former smokers). The presence of squamous metaplasia and dysplasia (abnormal histologic changes) in the specimens was documented by examination of hematoxylin-eosin-stained sections, and a metaplasia index ([number of biopsy specimens with metaplasia/total number of biopsy specimens] x 100%) was calculated for each subject. Loss of heterozygosity (i.e., loss of DNA sequences from one member of a chromosome pair) involving microsatellite DNA at three specific loci-chromosome 3p14, chromosome 9p21, and chromosome 17p13-was evaluated by means of the polymerase chain reaction. Fisher's exact test and logistic regression analysis were used to assess the data. Reported P values are two-sided. Results: Data on microsatellite DNA status at chromosomes 3p14, 9p21, and 17p13 were available for 54, 50, and 44 subjects, respectively. The numbers of individuals who were actually informative (i.e., able to be evaluated for a loss of heterozygosity) at the three loci were 36 (67%), 37 (74%), and 34 (77%), respectively. DNA losses were detected in 27 (75%), 21 (57%), and six (18%) of the informative subjects at chromosomes 3p14, 9p21, and 17p13, respectively. Fifty-one subjects were informative for at least one of the three loci, and 39 (76%) exhibited a loss of heterozygosity. Forty-two subjects were informative for at least two of the loci, and 13 (31%) exhibited losses at a minimum of two loci. Loss of heterozygosity at chromosome 3p14 was more frequent in current smokers (22 [88%] of 25 informative) than in former smokers (five [45%] of 11 informative) (P = .01) and in subjects with a metaplasia index greater than or equal to 15% (21 [91%] of 23 informative) than in subjects with a metaplasia index of less than 15% (six [46%] of 13 informative) (P = .003). In five informative individuals among nine tested nonsmokers, a loss of heterozygosity was detected in only one subject at chromosome 3p14 (P =.03), and no losses were detected at chromosome 9p21 (P = .05). Conclusions: Genetic alterations at chromosomal sites containing putative tumor-suppressor genes (i.e., 3p14 and the FHIT gene, 9p21 and the p16 gene [also known as CDKN2], and 17p13 and the p53 gene [also known as TP53]) occur frequently in the histologically normal or minimally altered bronchial epithelium of chronic smokers.

Risk of Second Malignant Neoplasms Among Long-term Survivors of Testicular Cancer

Abstract: Background We have quantified the site-specific risk of second malignant neoplasms among nearly 29,000 survivors (> or = 1 year) of testicular cancer, taking into account the histologic type of initial cancer and the primary therapy used to treat it. Methods The study cohort consisted of 28,843 men identified within 16 population-based tumor registries in North America and Europe; over 3300 men had survived more than 20 years. New invasive cancers were identified through a search of registry files. Results Second cancers were reported in 1406 men (observed-to-expected ratio [O/E] = 1.43; 95% confidence interval = 1.36-1.51), with statistically significant excesses noted for acute lymphoblastic leukemia (O/E = 5.20), acute nonlymphocytic leukemia (O/E = 3.07), melanoma (O/E = 1.69), non-Hodgkin's lymphoma (O/E = 1.88), and cancers of the stomach (O/E = 1.95), colon (O/E = 1.27), rectum (O/E = 1.41), pancreas (O/E = 2.21), prostate (O/E = 1.26), kidney (O/E = 1.50), bladder (O/E = 2.02), thyroid (O/E = 2.92), and connective tissue (O/E = 3.16). Overall risk was similar after seminomas (O/E = 1.42) or nonseminomatous tumors (O/E = 1.50). Risk of solid tumors increased with time since the diagnosis of testicular cancer, yielding an O/E = 1.54 (O = 369) among 20-year survivors (two-sided P for trend = .00002). Secondary leukemia was associated with both radiotherapy and chemotherapy, whereas excess cancers of the stomach, bladder, and, possibly, pancreas were associated mainly with radiotherapy. Conclusions Men with testicular cancer continue to be at significantly elevated risk of second malignant neoplasms for more than two decades following initial diagnosis. Patterns of excess second cancers suggest that many factors may be involved, although the precise roles of treatment, natural history, diagnostic surveillance, and other influences are yet to be clarified.

Lung Cancer Risk From Residential Radon: Meta-analysis of Eight Epidemiologic Studies

Abstract: estimated RR of 1.14 (95% CI = 1.0-1.3) at 150 Bq/m 3 was found. An influence analysis indicated that no single study dominated the combined results. The exposure-response trend was similar to model-based extrapolations from miners and to RRs computed directly from miners with low cumulative exposures. However, there were significant differences in the study-specific estimates of the exposure response (two-sided P<.001), which were not explained by study differences in percent of the defined exposure interval covered by radon measurements, mean number of residences per subject, and other factors. Conclusions: Meta-analyses are valuable for identifying differences among studies and for summarizing results, but they should be interpreted cautiously when expected RRs are low as with indoor radon

Multidrug resistance in breast cancer: A meta-analysis of MDR1/gp170 expression and its possible functional significance

Abstract: Background: P-glycoprotein (gp170; encoded by the MDR1 gene [also known as PGY1]) is a membrane protein capable of exporting a variety of anticancer drugs from cells. MDR1/ gp170 expression has been studied in breast cancer, but the prevalence of this expression and its role in breast tumor drug resistance are unclear. Purpose: We conducted a critical review and meta-analysis of studies examining MDR1/ gp170 expression in breast cancer to estimate the likely prevalence and clinical relevance of this expression. We also explored reasons for differences in the findings from individual studies. Methods: Published papers on MDR1/gp170 expression in breast cancer were identified by searching several literature databases and reviewing the bibliographies of identified papers. Variability across the studies in the proportion of tumors expressing MDR1/gp170 was assessed by use of chi-squared tests of homogeneity, weighted means, and weighted linear regression. Pooled relative risks (RRs) for the association between the induction of MDR1/gp170 expression and prior chemotherapy and associations between MDR1/gp170 expression and several clinical outcomes were estimated by use of Mantel-Haenszel methods. Heterogeneity among the pooled RRs was explored by use of chi-squared tests. Reported P values are two-sided. Results: Thirty-one studies were identified and evaluated. The proportion of breast tumors expressing MDR1/gp170 in all of the studies was 41.2%, but there was substantial heterogeneity in the values across individual studies (P<.0001). Regression analyses demonstrated that a considerable portion of the observed heterogeneity was a consequence of the change, over time, from RNA hybridization-based assays to immunohistochemistry-based assays of MDR1/gp170 expression. Measuring MDR1/gp170 expression before versus after chemotherapy and use of cytotoxic drugs that are not substrates for gp170 also contributed to the heterogeneity. Treatment with chemotherapeutic drugs or hormonal agents was associated with an increase in the proportion of tumors expressing MDR1/gp170 (RR = 1.77; 95% confidence interval [CI] = 1.46-2.15). Patients with tumors expressing MDRl/gpl70 were three times more likely to fail to respond to chemotherapy than patients whose tumors were MDR1/ gp170 negative (RR = 3.21; 95% CI = 2.28-4.51); this RR increased to 4.19 (95% CI = 2.71-6.47) when considering only patients whose tumor expression of MDR1/gp170 was measured after chemotherapy. MDR1/gp170 expression was not associated with lymph node metastases, estrogen receptor status, tumor size, tumor grade, or tumor histology. Conclusions and Implications: MDR1/gp170 expression in breast tumors is associated with treatment and with a poor response to chemotherapy. The data are consistent with a contributory role for MDR1/gp170 in the multidrug resistance in some breast tumors.

Leisure-Time Physical Activity, Body Size, and Colon Cancer in Women

Abstract: Background: Physical inactivity and high body mass index (weight in kilograms divided by height in square meters) have been linked to increased risk of colon cancer. However, none of the few prospective studies in women has shown a statistically significant reduction in colon cancer incidence or mortality associated with increased leisure-time physical activity. Purpose: In this prospective study, we asked whether leisure-time physical activity, body mass index, or body fat distribution could significantly influence the risk of colon cancer in women. Methods: The participants in this study were enrolled in the Nurses’ Health Study, which began in 1976. Every 2 years, the women provided additional personal information and information on medical risk factors and major medical events. The time spent per week at a variety of leisure-time physical activities was determined, and the time spent at each activity was multiplied by its typical energy expenditure, expressed in terms of metabolic equivalents or METs. The resulting values for each woman were added to yield an MET-hours-per-week score. Reported diagnoses of colon cancer were confirmed by review of hospital records and pathology reports. Relative risks and associated 95% confidence intervals were calculated. Results: In multivariate analyses that included body mass index, women who expended more than 21 MET-hours per week on leisure-time physical activity had a relative risk of colon cancer of 0.54 (95% confidence interval [CI] = 0.330.90) in comparison with women who expended less than 2 MET-hours per week. Women who had a body mass index greater than 29 kg/m 2 had a relative risk of colon cancer of 1.45 (95% CI = 1.02-2.07) in comparison with women who had a body mass index less than 21 kg/m 2 . A tendency toward higher colon cancer risk was observed for increasing waist-to-hip ratio (relative risk = 1.48 [95% CI = 0.88-2.49] for comparison of the highest quintile ratio [>0.833] to the lowest [<0.728]). Conclusions and Implications: The significant inverse association between leisure-time physical activity and incidence of colon cancer in women in this study is consistent with what has been found in men. Recommendations to increase physical activity and maintain lean body weight should receive greater emphasis as part of a feasible approach to the prevention of colon cancer. [J Natl Cancer Inst 1997;89:948-55]

Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers

Abstract: Background: Cigarette smoking has been shown to increase oxidative DNA damage in human sperm cells. Assessment of the role of cigarette smoking in the etiology of childhood cancer has focused primarily on the effect of maternal smoking. Similar studies in relation to paternal smoking, however, have been inconclusive. Few studies have evaluated the effect of paternal smoking in the preconception period, and most of these could not disentangle the effects of paternal from maternal smoking. Purpose: We investigated the relationship of paternal smoking, particularly in the preconception period, with childhood cancer among offspring of the nonsmoking mothers. Methods: We conducted a population-based, case-control study in Shanghai, People's Republic of China, where the prevalence of smoking is high among men but extremely low among women. The study included 642 childhood cancer case patients (<15 years of age) and their individually matched control subjects. Information concerning parental smoking, alcohol drinking, and other exposures of the index child was obtained by direct interview of both parents of the study subjects. Odds ratios (ORs), derived from conditional logistic regression models, were used to measure the association between paternal smoking and risk of childhood cancers. Results and Conclusions: Paternal preconception smoking was related to a significantly elevated risk of childhood cancers, particularly acute leukemia and lymphoma. The risks rose with increasing pack-years of paternal preconception smoking for acute lymphocytic leukemia (ALL) (P for trend =.01), lymphoma (P for trend =.07), and total cancer (P for trend =.006). Compared with children whose fathers had never smoked cigarettes, children whose fathers smoked more than five pack-years prior to their conception had adjusted ORs of 3.8 (95% confidence interval [CI] = 1.3-12.3) for ALL, 4.5 (95% CI = 1.2-16.8) for lymphoma, 2.7 (95% CI = 0.8-9.9) for brain tumors, and 1.7 (95% CI = 1.2-2.5) for all cancers combined. Statistically significant increased risks of cancer were restricted to children under the age of 5 years at diagnosis or those whose fathers had smoked during all of the 5 years prior to conception. Implications: Further studies are needed to confirm the association of paternal smoking with increased risk of cancer in offspring, to clarify the pattern of risks in relation to the timing of cigarette smoking, and to elucidate the biologic mechanism involved in predisposing the offspring to cancer. For example, it may be that paternal smoking induces prezygotic genetic damage that, in turn, acts as the predisposing factor.

Body Size and Prostate Cancer: A 20-Year Follow-up Study Among 135006 Swedish Construction Workers

Abstract: Background: Obesity is associated with endocrine changes (e.g., increased estrogen and decreased testosterone in the blood) that have been implicated in the cause of prostate cancer and, therefore, ...

Probability of Carrying a Mutation of Breast-Ovarian Cancer Gene BRCA1 Based on Family History

Abstract: Background: Heritable mutations of the breast cancer gene BRCA1 are rare, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovarian cancers. Nevertheless, the presence of such mutations is highly predictive of the development of these cancers. Purpose: We developed and applied a mathematic model for calculating the probability that a woman with a family history of breast and/or ovarian cancer carries a mutation of BRCA1. Methods and Results: As a basis for the model, we use Mendelian genetics and apply Bayes’ theorem to information on the family history of these diseases. Of importance are the exact relationships of all family members, including both affected and unaffected members, and ages at diagnosis of the affected members and current ages of the unaffected members. We used available estimates of BRCA1 mutation frequencies in the general population and age-specific incidence rates of breast and ovarian cancers in carriers and noncarriers of mutations to estimate the probability that a particular member of the family carries a mutation. This probability is based on cancer statuses of all first- and second-degree relatives. We first describe the model by considering single individuals: a woman diagnosed with breast and/or ovarian cancer and also a woman free of cancer. We next considered two artificial and two actual family histories and addressed the sensitivity of our calculations to various assumptions. Particular relationships of family members with and without cancer can have a substantial impact on the probability of carrying a susceptibility gene. Ages at diagnosis of affected family members and their types of cancer are also important. A woman with two primary cancers can have a probability of carrying a mutation in excess of 80%, even with no other information about family history. The number and relationships of unaffected members, along with their current ages or ages at death, are critical determinants of one’s carrier probability. An affected woman with several cancers in her family can have a probability of carrying a mutation that ranges from close to 100% to less than 5%. Conclusion: Our model gives informative and specific probabilities that a particular woman carries a mutation. Implications: This model focuses on mutations in BRCA1 and assumes that all other breast cancer is sporadic. With the cloning of BRCA2, we now know that this assumption is incorrect. We have adjusted the model to include BRCA2, but the use of this version must await publication of penetrance data for BRCA2, including those for male breast cancer that are apparently associated with BRCA2 but not with BRCA1. The current model is, nevertheless, appropriate and useful. Of principal importance is its potential and that of improved versions for aiding women and their health care providers in assessing the need for genetic testing. [J Natl Cancer Inst 1997;89:227-37] There are approximately 180 000 new cases of breast cancer diagnosed each year in the United States. Approximately 45 000 women die of the disease annually. Although only about 26 000 cases of ovarian cancer are diagnosed each year, proportionately more women (14 000 annually) die of ovarian cancer (1). It is estimated that 2% of all breast cancers and 10% of ovarian cancers occur in women who carry a mutation in the BRCA1 susceptibility gene for breast cancer (2). The prevalence of mutations at BRCA1 has been estimated to be 0.04%-0.20% in the general population (3), but prevalence may vary, depending on racial or ethnic group (4). Approximately 85% of female carriers will develop breast cancer and 63% will develop ovarian cancer by the age of 70 years (2). Moreover, these two cancers seem to be statistically independent (2). In particular, based on these estimates, for female carriers who live to age 70 years, about 95% [o r1˛( 1 ˛0.85) (1 ˛ 0.63)] have developed one or the other cancer and about 54% (or 0.85 ◊ 0.63) have both cancers. The high penetrances of breast and ovarian cancers among women with BRCA1 mutations mean that family history of these diseases is a strong indicator of whether a mutation is present in the family. This article presents a method for finding the probability that a particular family member carries a mutation at BRCA1 on the basis of her family’s history of these two diseases.

Protective Effects of Silymarin Against Photocarcinogenesis in a Mouse Skin Model

Abstract: Background: Nonmelanoma skin cancer is the most common cancer among humans; solar UV is its major cause. Therefore, it is important to identify agents that can offer protection against this cancer. Purpose: We evaluated the protective effects of silymarin, a flavonoid compound isolated from the milk thistle plant, against UVB radiation-induced nonmelanoma skin cancer in mice and delineated the mechanism(s) of its action. Methods: For long-term studies, three different protocols of treatment were employed, each evaluating protection by silymarin at a different stage of carcinogenesis. Female SKH-I hairless mice were subjected to 1) UVB-induced tumor initiation followed by phorbol ester-mediated tumor promotion, 2) 7,12-dimethylbenz[a]anthracene-induced tumor initiation followed by UVB-mediated tumor promotion, and 3) UVB-induced complete carcinogenesis. Forty mice were used in each protocol and were divided into control and treatment groups. Silymarin was applied topically at a dose of 9 mg per application before UVB exposure, and its effects on tumor incidence (% of mice with tumors), tumor multiplicity (number of tumors per mouse), and average tumor volume per mouse were evaluated. In short-term studies, the following parameters were measured: formation of sunburn and apoptotic cells, skin edema, epidermal catalase and cyclooxygenase (COX) activities, and enzymatic activity and messenger RNA (mRNA) expression for ornithine decarboxylase (ODC), a frequently observed marker at tumor promotion stage. Fisher's exact test was used to evaluate differences in tumor incidence, two-sample Wilcoxon rank sum test was used for tumor multiplicity and tumor volume, and Student's t test was used for all other measurements. All statistical tests were two-sided. Results: In the protocol with UVB-induced tumor initiation, silymarin treatment reduced tumor incidence from 40% to 20% (P = .30), tumor multiplicity by 67% (P = .10), and tumor volume per mouse by 66% (P = .14). In the protocol with UVB-induced tumor promotion, silymarin treatment reduced tumor incidence from 100% to 60% (P<.003), tumor multiplicity by 78% (P<.0001), and tumor volume per mouse by 90% (P<.003). The effect of silymarin was much more profound in the protocol with UVB-induced complete carcinogenesis, where tumor incidence was reduced from 100% to 25% (P<.0001), tumor multiplicity by 92% (P<.0001), and tumor volume per mouse by 97% (P<.0001). In short-term experiments, silymarin application resulted in statistically significant inhibition in UVB-caused sunburn and apoptotic cell formation, skin edema, depletion of catalase activity, and induction of COX and ODC activities and ODC mRNA expression. Conclusions and Implication: Silymarin can provide substantial protection against different stages of UVB-induced carcinogenesis, possibly via its strong antioxidant properties. Clinical testing of its usefulness is warranted.

Helicobacter pylori cagA + Strains and Dissociation of Gastric Epithelial Cell Proliferation From Apoptosis

Abstract: Background: Infection with Helicobacter pylori induces chronic gastritis in virtually all infected persons, and such gastritis has been associated with an increased risk of developing gastric cancer. This risk is further enhanced with cagA + (positive for cytotoxin-associated gene A) H. pylori strains and may be a consequence of induced gastric cell proliferation and/or alteration in apoptosis (programmed cell death) in the gastric epithelium. Purpose: To determine whether the H. pylori cagA genotype and another virulence-related characteristic, the vacA (vacuolating cytotoxin A) s1a genotype, differentially affect epithelial cell proliferation, apoptosis, and the histologic parameters of inflammation and injury, we quantitated these characteristics in infected and uninfected persons. Methods : Fifty patients underwent upper gastrointestinal endoscopy, and biopsy specimens were taken. Apoptotic cells in the specimens were quantitated after terminal deoxynucleotidyl transferase labeling of DNA fragments with digoxigenin-deoxyuridine triphosphate; epithelial cell proliferation was scored by immunohistochemical analysis of the proliferation-associated antigen Ki-67. Antibodies directed against H. pylori and CagA protein were measured in the serum of patients by means of enzyme-linked immunosorbent assays. Analysis of H. pylori genomic DNA, by use of the polymerase chain reaction, was performed to determine the cagA and vacA genotypes. Acute and chronic inflammation, epithelial cell degeneration, mucin depletion, intestinal metaplasia, glandular atrophy, and vacuolation were each scored in a blinded manner. Reported P values are two-sided. Results: Persons harboring cagA + strains (n = 20) had significantly higher gastric epithelial proliferation scores than persons infected with cagA - strains (n = 9) or uninfected persons (n = 21) (P = .025 and P<.001, respectively), but the difference in cell proliferation between the latter two groups was not statistically significant. The number of apoptotic cells per 100 epithelial cells (apoptotic index) in persons infected with cagA + strains was lower than in persons infected with cagA - strains (P =.05). Apoptotic indices in the cagA + group were similar to those in the uninfected group (P =.2). Epithelial cell proliferation was significantly correlated with acute gastric inflammation, but only in the cagA + group (r =.44; P =.006). The cagA + and vacA s1a genotypes were found to be concordant, confirming the close relationship between these virulence-related genotypes. Conclusions: Gastric mucosal proliferation was significantly correlated with the severity of acute gastritis in persons infected with cagA + vacA s1a strains of H. pylori. This increased proliferation was not accompanied by a parallel increase in apoptosis. Implications: Increased cell proliferation in the absence of a corresponding increase in apoptosis may explain the heightened risk for gastric carcinoma that is associated with infection by cagA + vacA s1a strains of H. pylori.

Controlled Trial of Pretest Education Approaches to Enhance Informed Decision-Making for BRCA1 Gene Testing

Abstract: BACKGROUND In response to the isolation of the BRCA1 gene, a breast-ovarian cancer-susceptibility gene, biotechnology companies are already marketing genetic tests to health care providers and to the public. Initial studies indicate interest in BRCA1 testing in the general public and in populations at high risk. However, the optimal strategies for educating and counseling individuals have yet to be determined. PURPOSE Our goal was to evaluate the impact of alternate strategies for pretest education and counseling on decision-making regarding BRCA1 testing among women at low to moderate risk who have a family history of breast and/or ovarian cancer. METHODS A randomized trial design was used to evaluate the effects of education only (educational approach) and education plus counseling (counseling approach), as compared with a waiting-list (control) condition (n = 400 for all groups combined). The educational approach reviewed information about personal risk factors, inheritance of cancer susceptibility, the benefits, limitations, and risks of BRCA1 testing, and cancer screening and prevention options. The counseling approach included this information, as well as a personalized discussion of experiences with cancer in the family and the potential psychological and social impact of testing. Data on knowledge of inherited cancer and BRCA1 test characteristics, perceived risk, perceived benefits, limitations and risks of BRCA1 testing, and testing intentions were collected by use of structured telephone interviews at baseline and at 1-month follow-up. Provision of a blood sample for future testing served as a proxy measure of intention to be tested (in the education and counseling arms of the study). The effects of intervention group on study outcomes were evaluated by use of hierarchical linear regression modeling and logistic regression modeling (for the blood sample outcome). All P values are for two-sided tests. RESULTS The educational and counseling approaches both led to significant increases in knowledge, relative to the control condition (P < .001 for both). The counseling approach, but not the educational approach, was superior to the control condition in producing significant increases in perceived limitations and risks of BRCA1 testing (P < .01) and decreases in perceived benefits (P < .05). However, neither approach produced changes in intentions to have BRCA1 testing. Prior to and following both education only and education plus counseling, approximately one half of the participants stated that they intended to be tested; after the session, 52% provided a blood sample. CONCLUSIONS Standard educational approaches may be equally effective as expanded counseling approaches in enhancing knowledge. Since knowledge is a key aspect of medical decision-making, standard education may be adequate in situations where genetic testing must be streamlined. On the other hand, it has been argued that optimal decision-making requires not only knowledge, but also a reasoned evaluation of the positive and negative consequences of alternate decisions. Although the counseling approach is more likely to achieve this goal, it may not diminish interest in testing, even among women at low to moderate risk. Future research should focus on the merits of these alternate approaches for subgroups of individuals with different backgrounds who are being counseled in the variety of settings where BRCA1 testing is likely to be offered.

Thrombospondin-1 Expression in Bladder Cancer: Association With p53 Alterations, Tumor Angiogenesis, and Tumor Progression

Abstract: Background Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an important component of the extracellular matrix and is known to be a potent inhibitor of angiogenesis (ie, formation of new blood vessels) both in vitro and in vivo Several reports suggest that TSP possesses tumor suppressor function, possibly through its ability to inhibit tumor neovascularization It has recently been shown that TSP expression is enhanced by the product of the p53 gene (also known as TP53) Purpose We examined the role of TSP expression in tumor recurrence and overall survival in patients with invasive bladder cancer We also examined the relationship between alterations in p53 protein expression, TSP expression, and tumor angiogenesis Methods Tumors from 163 patients (with a median follow-up of 77 years) who underwent radical cystectomy for invasive transitional cell carcinoma of the bladder (63 patients with organ-confined disease and no lymph node involvement, 48 patients with extravesical extension of the disease and no lymph node involvement, and 52 patients with metastasis to regional lymph nodes) were examined for TSP expression by immunohistochemistry, utilizing monoclonal antibody MA-II, which recognizes an epitope in the amino-terminal region of TSP For each tumor, microvessel density counts and p53 protein expression status (via immunohistochemistry) were also determined TSP expression was graded as low, moderate, or high without knowledge of clinical outcome, p53 status, and microvessel density count; tumors with moderate and high TSP levels were considered as one group Groups of patients were compared by Kaplan-Meier product limit estimates of overall survival, the complement of cumulative incidence curves for recurrence-free survival, and the stratified logrank test Reported P values are two-sided Results TSP expression was significantly associated with disease recurrence (P = 009) and overall survival (P = 023) Patients with low TSP expression exhibited increased recurrence rates and decreased overall survival TSP expression was an independent predictor of disease recurrence (P = 002) and overall survival (P = 01) after stratifying for tumor stage, lymph node status, and histologic grade, but it was not independent of p53 status TSP expression was significantly associated with p53 expression status (P = 001) and microvessel density counts (P = 001) Tumors with p53 alterations were significantly more likely to demonstrate low TSP expression, and tumors with low TSP expression were significantly more likely to demonstrate high microvessel density counts Results of an analysis of variance were compatible with the hypothesis that p53 affects tumor angiogenesis by regulating the level of TSP expression Conclusions and implications These data support the concept that TSP may possess a tumor-inhibitory function TSP may act, in part, through the regulation of tumor neovascularity These results may also provide insight into one mechanism by which p53 exerts its tumor suppressor effects, ie, through the control of tumor angiogenesis

Benzene and the dose-related incidence of hematologic neoplasms in China. Chinese Academy of Preventive Medicine--National Cancer Institute Benzene Study Group.

Abstract: Background: Benzene is a widely distributed environmental contaminant known to cause leukemia, particularly acute nonlymphocytic leukemia, and perhaps other hematologic neoplasms and disorders. Few epidemiologic studies, however, have been able to address relationships between the extent of benzene exposure and the level of risk. Purpose : A large cohort study was carried out in China to evaluate the risks of developing specific hematologic neoplasms and selected related disorders in relationship to quantitative estimates of occupational benzene exposure. Methods: A cohort of 74828 benzene-exposed and 35805 unexposed workers employed from 1972 through 1987 in 12 cities in China was identified and followed to determine the incidence of hematologic neoplasms and related disorders. Estimates of benzene exposure were derived from work histories and available historic benzene measurements. Existing pathologic material and supporting medical records were reviewed to establish diagnoses of disease. Relative risks (RRs) (i.e., ratios of incidence rates for specific hematologic neoplasms and related disorders in the benzene-exposed group to incidence rates in the unexposed group) were determined by use of Poisson regression analysis, with stratification by age and sex. Results: For workers historically exposed to benzene at average levels of less than 10 parts per million (ppm), the RR for all hematologic neoplasms combined was 2.2 (95% confidence interval [CI] = 1.1-4.2), and, for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes, the RR was 3.2 (95% CI = 1.0-10.1). For individuals who were occupationally exposed to benzene at constant levels of 25 ppm or more, the RR for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes was 7.1 (95% CI = 2.1-23.7). Workers with 10 or more years of benzene exposure had an RR of developing non-Hodgkin's lymphoma of 4.2 (95% CI = 1.1-15.9), and the development of this neoplasm was linked most strongly to exposure that had occurred at least 10 years before diagnosis (i.e., distant exposure) (P for trend = .005, two-sided). In contrast, the risk for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes was significantly increased among those with more recent benzene exposure (P for trend = .003, two-sided), but it was not linked to distant exposure (P for trend = .51, two-sided). Conclusions: The results of this study suggest that benzene exposure is associated with a spectrum of hematologic neoplasms and related disorders in humans. Risks for these conditions are elevated at average benzene-exposure levels of less than 10 ppm and show a tendency, although not a strong one, to rise with increasing levels of exposure. The temporal pattern of benzene exposure appears to be important in determining the risk of developing specific diseases.

Prooxidant-Antioxidant Shift Induced by Androgen Treatment of Human Prostate Carcinoma Cells

Abstract: Background: Prostate cancer is a disease associated with aging. Also commonly associated with increasing age is a shift in the prooxidant‐antioxidant balance of many tissues toward a more oxidative state, i.e., increased oxidative stress. We hypothesize that androgen exposure, which has long been associated with the development of prostate cancer, may be a means by which the prooxidant‐antioxidant balance of prostate cells is altered. Purpose: Using established prostate carcinoma cell lines, we studied the effect of androgens on various parameters of oxidative state (e.g., generation of hydrogen peroxide and hydroxyl radicals, lipid peroxidation, and oxygen consumption) and antioxidant defense mechanisms (e.g., the glutathione system and catalase). Methods: The androgen-responsive LNCaP and the androgen-independent DU145 prostate carcinoma cell lines were exposed to 5a-dihydrotestosterone (DHT) and to the synthetic androgen R1881. The cellular proliferation responses were measured by use of a fluorometric assay to quantitate the amount of DNA. The generation of reactive oxygen species was measured by use of 2*,7*-dichlorofluorescin diacetate, a dye that fluoresces in the presence of hydrogen peroxide or hydroxyl radicals. Lipid peroxidation was quantitated by use of a chromogen specific for malonaldehyde and 4-hydroxy-2(E)-nonenal. General mitochondrial activity was determined by assaying 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) reduction. A Clarktype electrode was used to assess oxygen consumption per cell. Intracellular glutathione concentrations and the activities of catalase and g-glutamyl transpeptidase were measured spectrophotometrically. All P values resulted from two-sided tests. Results: DHT at less than 1 to 100 nM (a concentration range encompassing the physiologic levels of DHT considering all ages) and R1881 at 0.1-1 nM concentrations were effective in inducing in LNCaP cells comparable proliferative responses and changes in oxidative stress. In contrast, neither DHT nor R1881 had any effect on the oxidative stress in DU145 cells. The mitochondrial activity in LNCaP cells, as measured by MTT reduction, was significantly elevated above the levels of the untreated controls by DHT (0.1-1000 nM) and R1881 (0.05-1 nM )( P<.001 in both). Oxygen consumption and catalase activity were increased in LNCaP cells in the presence of 1 nM R1881 by 60% and 40%, respectively, over the values in the untreated control cells (P<.03 and P<.01, respectively). The same concentration of R1881 resulted in a decrease in intracellular glutathione concentrations and an increase in g-glutamyl transpeptidase activity in LNCaP ells. Treatment with the oxidizing agents H2O2 and menadione produced an increase in g-glutamyl transpeptidase activity in LNCaP cells, whereas treatment with the antioxidant compound ascorbic acid (100 mM) reduced the oxidative stress produced in LNCaP cells by 1 nM R1881 and completely blocked the g-glutamyl transpeptidase activity. Conclusions: Physiologic levels of androgens are capable of increasing oxidative stress in androgenresponsive LNCaP prostate carcinoma cells. The evidence suggests that this result is due in part to increased mitochondrial activity. Androgens also alter intracellular glutathione levels and the activity of certain detoxification enzymes, such as g-glutamyl transpeptidase, that are important for maintenance of the cellular prooxidant‐antioxidant balance. [J Natl Cancer Inst 1997;89:40-8]

Cure of Helicobacter pylori Infection and Duration of Remission of Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Abstract: Background Low-grade B-cell lymphomas arising in mucosa-associated lymphoid tissue (MALT) are most frequently localized in the gastrointestinal tract. More than 90% of gastric MALT lymphomas are diagnosed in patients with chronic, Helicobacter pylori-associated gastritis. High remission rates for these lymphomas have been observed after the cure of H. pylori infection. Data are lacking, however, with regard to the duration of the remissions. To address this question of remission duration, we have followed 50 patients in whom H. pylori infections were eradicated, and we determined whether the patients in complete remission displayed evidence of residual monoclonal B cells during follow-up. Methods Patients were treated with amoxycillin and omeprazole for 2 weeks in an attempt to cure H. pylori infections. Follow-up included endoscopic investigations with biopsy sampling. Monoclonal B cells in biopsy specimens were detected by means of a polymerase chain reaction (PCR)-based assay. Results H. pylori infections were cured in all 50 patients. The median follow-up for the 50 patients is currently 24 months (729 days; range, 135-1411 days). Forty patients achieved complete remission of their lymphomas, but five have subsequently relapsed. The median time of continuous complete remission for the 40 patients was 15.4 months (468 days; range, 0-1198 days). Among six patients whose Iymphomas did not respond to H. pylori eradication, four revealed high-grade lymphomas upon surgery. PCR indicated the presence of monoclonal B cells during follow-up in 22 of 31 assessable patients in complete remission. Conclusions Complete remissions of low-grade gastric MALT Iymphomas after the cure of H. pylori infection appear to be stable, although most patients display evidence of monoclonal B cells during follow-up. Whether these patients are truly cured of their Iymphomas remains to be determined.