Showing papers on "Cancer published in 1999"

Global cancer statistics

Abstract: The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.

Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.

Abstract: Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case. A class discovery procedure automatically discovered the distinction between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) without previous knowledge of these classes. An automatically derived class predictor was able to determine the class of new leukemia cases. The results demonstrate the feasibility of cancer classification based solely on gene expression monitoring and suggest a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.

Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

Abstract: Background: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. Methods: Women (N = 13 388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35‐59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years. Gail’s algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50‐59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles’), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35‐4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease. [J Natl Cancer Inst 1998;90:1371‐88]

Cancer statistics, 1999.

Abstract: The Surveillance Research Program of the American Cancer Society's Department of Epidemiology and Surveillance Research reports its 33rd annual compilation of cancer frequency, incidence, mortality, and survival data for the United States.

Estimates of the worldwide incidence of 25 major cancers in 1990

Abstract: The annual incidence rates (crude and age-standardized) and numbers of new cases of 25 different cancers have been estimated for the year 1990 in 23 areas of the world. The total number of new cancer cases (excluding non-melanoma skin cancer) was 8.1 million, just over half of which occur in the developing countries. The most common cancer in the world today is lung cancer, accounting for 18% of cancers of men worldwide, and 21% of cancers in men in the developed countries. Stomach cancer is second in frequency (almost 10% of all new cancers) and breast cancer, by far the most common cancer among women (21% of the total), is third. There are large differences in the relative frequency of different cancers by world area. The major cancers of developed countries (other than the 3 already named) are cancers of the colon-rectum and prostate, and in developing countries, cancers of the cervix uteri and esophagus. The implications of these patterns for cancer control, and specifically prevention, are discussed. Tobacco smoking and chewing are almost certainly the major preventable causes of cancer today.

Tobacco Smoke Carcinogens and Lung Cancer

Abstract: The complexity of tobacco smoke leads to some confusion about the mechanisms by which it causes lung cancer. Among the multiple components of tobacco smoke, 20 carcinogens convincingly cause lung tumors in laboratory animals or humans and are, therefore, likely to be involved in lung cancer induction. Of these, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This review focuses on carcinogens in tobacco smoke as a means of simplifying and clarifying the relevant information that provides a mechanistic framework linking nicotine addiction with lung cancer through exposure to such compounds. Included is a discussion of the mechanisms by which tobacco smoke carcinogens interact with DNA and cause genetic changes--mechanisms that are reasonably well understood--and the less well defined relationship between exposure to specific tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes. Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer--an approach that has not yet reached its full potential--are also discussed, as are inhalation studies of tobacco smoke in laboratory animals and the potential role of free radicals and oxidative damage in tobacco-associated carcinogenesis. By focusing in this review on several important carcinogens in tobacco smoke, the complexities in understanding tobacco-induced cancer can be reduced, and new approaches for lung cancer prevention can be envisioned.

Estimates of the worldwide mortality from 25 cancers in 1990.

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

Rising incidence of renal cell cancer in the United States

Abstract: ContextClinical surveys have revealed that incidental detection of renal cell carcinoma is rising because of increased use of imaging procedures.ObjectiveTo examine incidence, mortality, and survival trends of renal cell and renal pelvis cancers by age, sex, race, and tumor stage at diagnosis.DesignCalculation of age-adjusted incidence and mortality rates, along with 5-year relative survival rates, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program.Setting and ParticipantsPatients diagnosed as having kidney cancer from 1975 through 1995 in the 9 geographic areas covered by tumor registries in the SEER program, which represent about 10% of the US population.Main Outcome MeasuresIncidence, mortality, and 5-year relative survival rates by time periods.ResultsThe age-adjusted incidence rates for renal cell carcinoma between 1975 and 1995 for white men, white women, black men, and black women were 9.6, 4.4, 11.1, and 4.9 per 100,000 person-years, respectively. The corresponding rates for renal pelvis cancer were 1.5, 0.7, 0.8, and 0.5 per 100,000 person-years. Renal cell cancer incidence rates increased steadily between 1975 and 1995, by 2.3% annually among white men, 3.1% among white women, 3.9% among black men, and 4.3% among black women. Increases were greatest for localized tumors but were also seen for more advanced and unstaged tumors. In contrast, the incidence rates for renal pelvis cancer declined among white men and remained stable among white women and blacks. Although 5-year relative survival rates for patients with renal cell cancer improved among whites but not among blacks, kidney cancer mortality rates increased in all race and sex groups.ConclusionsIncreasing detection of presymptomatic tumors by imaging procedures, such as ultrasonography, computed tomography, and magnetic resonance imaging, does not fully explain the upward incidence trends of renal cell carcinoma. Other factors may be contributing to the rapidly increasing incidence of renal cell cancer in the United States, particularly among blacks.

Extended Lymph-Node Dissection for Gastric Cancer

Abstract: Background Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery. Methods Between August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results. Results Patients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 2...

The role of cyclooxygenases in inflammation, cancer, and development

Abstract: The cyclooxygenase (COX) enzymes catalyze a key step in the conversion of arachidonate to PGH2, the immediate substrate for a series of cell specific prostaglandin and thromboxane synthases. Prostaglandins play critical roles in numerous biologic processes, including the regulation of immune function, kidney development, reproductive biology, and gastrointestinal integrity. There are two COX isoforms, which differ mainly in their pattern of expression. COX-1 is expressed in most tissues, whereas COX-2 usually is absent, but is induced by numerous physiologic stimuli. Surprisingly, disruption of Cox1 (Ptgs1) in the mouse did not result in gastrointestinal abnormalities. cox-2 (Ptgs2) null mice show reproductive anomalies and defects in kidney development. Epidemiologic, animal, and human data indicate that NSAIDs, inhibitors of cyclooxygenase, are chemopreventive for colon cancer. COX-2 is overexpressed in 50% of benign polyps and 80-85% of adenocarcinomas. Offspring from cox-2 null by Apcdelta716 matings exhibit an 86% reduction in polyp number when compared to offspring from control animals, thus providing genetic evidence that COX-2 contributes to tumor formation or growth. The in vivo mechanism by which COX-2 affects tumor growth has not been determined. It is possible that both tumor and stromally derived COX-2 could influence tumor angiogenesis and/ or immune function.

Cancer risks in BRCA2 mutation carriers

Abstract: BACKGROUND: Carriers of germline mutations in the BRCA2 gene are known to be at high risk of breast and ovarian cancers, but the risks of other cancers in mutation carriers are uncertain. We investigated these risks in 173 breast-ovarian cancer families with BRCA2 mutations identified at 20 centers in Europe and North America.METHODS: Other cancer occurrence was determined in a final cohort of 3728 individuals, among whom 681 persons had breast or ovarian cancer and 3047 persons either were known mutation carriers, were first-degree relatives of known mutation carriers, or were first-degree relatives of breast or ovarian cancer patients. Incidence rates were compared with population-specific incidence rates, and relative risks (RRs) to carriers, together with 95% confidence intervals (CIs), were estimated by use of a maximum likelihood approach. Three hundred thirty-three other cancers occurred in this cohort.RESULTS: Statistically significant increases in risks were observed for prostate cancer (estimated RR = 4.65; 95% CI = 3.48-6.22), pancreatic cancer (RR = 3.51; 95% CI = 1. 87-6.58), gallbladder and bile duct cancer (RR = 4.97; 95% CI = 1. 50-16.52), stomach cancer (RR = 2.59; 95%CI = 1.46-4.61), and malignant melanoma (RR = 2.58; 95% CI = 1.28-5.17). The RR for prostate cancer for men below the age of 65 years was 7.33 (95% CI = 4.66-11.52). Among women who had already developed breast cancer, the cumulative risks of a second, contralateral breast cancer and of ovarian cancer by the age of 70 years were estimated to be 52.3% (95% CI = 41.7%-61.0%) and 15.9% (95% CI = 8.8%-22.5%), respectively.CONCLUSIONS: In addition to the large risks of breast and ovarian cancers, BRCA2 mutations may be associated with increased risks of several other cancers. (Less)

Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal

Abstract: Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.

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

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

Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.

Abstract: The incidence of pancreatic cancer still seems to be increasing, and it is the fifth most common cause of cancer death in the United States. The prognosis is one of the most dismal of all cancers: approximately 95% of all patients diagnosed with pancreatic cancer will die within 1 year. 1 To date, the only potentially curative therapy is radical surgical resection. After potentially curative resection for cancer of the pancreatic head, the 1-year survival estimate is 50% to 60%, 2-year survival is 15% to 35%, and 5-year survival is 5% to 20%. In patients with periampullary carcinoma in the ampulla of Vater, distal common bile duct, or duodenum, a much better survival rate is obtained after surgical resection, with a 5-year survival rate of 40% to 60%. 2–7 After radical resection, pancreatic cancer recurs primarily within the abdominal cavity; most failures are locoregional and in the liver. Distant metastases in the lung or peritoneal cavity are seldom seen without local tumor recurrence and are characteristic of late recurrence. Therefore, a treatment approach combining local and systemic adjuvant treatment in pancreas and periampullary cancer seems interesting. Radiation therapy with or without chemotherapy has been extensively studied in locoregional advanced disease, especially the combination of external radiotherapy combined with 5-fluorouracil (5-FU). 8–11 The possible benefit of chemoradiotherapy resulted in the use of radiotherapy combined with 5-FU as adjuvant treatment in a prospective randomized multicenter study performed by the Gastrointestinal Tumor Study Group (GITSG), in which 14 institutes participated. 12 The high incidence of pancreatic cancer and the relatively large group of participating institutions was intended to guarantee sufficient patient accrual. Radiotherapy consisted of a split course of 40 Gy—two courses of 20 Gy with an interval of 2 weeks. 5-FU was given concomitantly during the first week of radiotherapy and during 2 years thereafter. The 21 patients who received adjuvant treatment had a 2-year survival rate of 43%, significantly better than the 18% found in the control group (p < 0.03). The trial was prematurely closed because the interim analysis showed a statistically significant difference in favor of the treatment arm. Another 30 patients were treated with the same adjuvant treatment and studied by the GITSG with similar results (2-year survival rate 46%). This trial demonstrated for the first time that prolonged survival could be obtained with adjuvant treatment after surgical resection of pancreatic cancer, although this was demonstrated in only a small number of patients. 13 However, a nonrandomized study showed no significant difference in survival after adjuvant treatment as given in the GITSG trial. 14 At present, no other prospective randomized trial in pancreatic or periampullary cancers has been reported in the United States or Europe. Recently, Yeo et al 15 described the beneficial effect of adjuvant radiotherapy and 5-FU treatment. However, in that nonrandomized study, there seemed to be a selection of patients. Patients who had a satisfactory recovery by postoperative day 60 were encouraged to accept adjuvant therapy. Patients declining radiotherapy were significantly older and had a significantly longer postoperative stay, more intensive care therapy, and a significantly greater incidence of postoperative complications. The GITSG trial led to the use of standard adjuvant radiotherapy with 5-FU in the United States. In 1987, we initiated a prospective randomized clinical trial in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) to study the effect of adjuvant radiotherapy and 5-FU.

Adjuvant Radiotherapy and 5-Fluorouracil After Curative Resection of Cancer of the Pancreas and Periampullary Region

Abstract: ObjectiveThe survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers.Summary Background DataA previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastr

Cyclosporine induces cancer progression by a cell-autonomous mechanism

Abstract: Malignancy is a common and dreaded complication following organ transplantation. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipient's immune-surveillance system. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-beta (TGF-beta). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID-beige mice; anti-TGF-beta monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells, and that cyclosporine-induced TGF-beta production is involved in this.

Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3

Abstract: Background: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. Methods: Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. Results: IGFBP-3 levels correlated with IGF-I levels (r = .64) and with IGF-II levels (r = .90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m] 2 ), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR] = 2.51; 95% confidence interval [CI] = 1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR = 0.28; 95% CI = 0.12-0.66 ; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. Conclusions: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer.

Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice

Abstract: Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer.

Detection of Aberrant Promoter Hypermethylation of Tumor Suppressor Genes in Serum DNA from Non-Small Cell Lung Cancer Patients

Abstract: Recent evidence suggests that tumor cells may release DNA into the circulation, which is enriched in the serum and plasma, allowing detection of ras and p53 mutations and microsatellite alterations in the serum DNA of cancer patients. We examined whether aberrant DNA methylation might also be found in the serum of patients with non-small cell lung cancer. We tested 22 patients with non-small cell lung cancer using methylation-specific PCR, searching for promoter hypermethylation of the tumor suppressor gene p16, the putative metastasis suppressor gene death-associated protein kinase, the detoxification gene glutathione S-transferase P1, and the DNA repair gene O6-methylguanine-DNA-methyltransferase. Aberrant methylation of at least one of these genes was detected in 15 of 22 (68%) NSCLC tumors but not in any paired normal lung tissue. In these primary tumors with methylation, 11 of 15 (73%) samples also had abnormal methylated DNA in the matched serum samples. Moreover, none of the sera from patients with tumors not demonstrating methylation was positive. Abnormal promoter methylation in serum DNA was found in all tumor stages. Although these results need to be confirmed in larger studies and in other tumor types, detection of aberrant promoter hypermethylation of cancer-related genes in serum may be useful for cancer diagnosis or the detection of recurrence.

Fractionation and protraction for radiotherapy of prostate carcinoma

Abstract: Purpose: To investigate whether current fractionation and brachytherapy protraction schemes for the treatment of prostatic cancer with radiation are optimal, or could be improved. Methods and Materials: We analyzed two mature data sets on radiotherapeutic tumor control for prostate cancer, one using EBRT and the other permanent seed implants, to extract the sensitivity to changes in fractionation of prostatic tumors. The standard linear-quadratic model was used for the analysis. Results: Prostatic cancers appear significantly more sensitive to changes in fractionation than most other cancers. The estimated α/β value is 1.5 Gy [0.8, 2.2]. This result is not too surprising as there is a documented relationship between cellular proliferative status and sensitivity to changes in fractionation, and prostatic tumors contain exceptionally low proportions of proliferating cells. Conclusions: High dose rate (HDR) brachytherapy would be a highly appropriate modality for treating prostate cancer. Appropriately designed HDR brachytherapy regimens would be expected to be as efficacious as low dose rate, but with added advantages of logistic convenience and more reliable dose distributions. Similarly, external beam treatments for prostate cancer can be designed using larger doses per fraction; appropriately designed hypofractionation schemes would be expected to maintain current levels of tumor control and late sequelae, but with reduced acute morbidity, together with the logistic and financial advantages of fewer numbers of fractions.

Colorectal Cancer: Molecules and Populations

Abstract: The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.

beta-catenin signaling and cancer.

Abstract: Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.

Cancer cell lines

Abstract: 17. Ovarian Cancer A.P. Wilson, C.M. Garner. 18. Cervical Cancer S.Y. Sharp, L.R. Kelland. 19. Endometrial Cancer P.G. Satyaswaroop. 20. Breast Cancer R.L. Sutherland, et al. 21. Paired Breast Cancer Cell Lines I.I. Wistuba, et al. 22. Ovarian Germ Cell Tumors M. Sawada, T. Miki. 23. Testicular Germ Cell Tumors M.F. Pera. 24. Choriocarcinoma V. Ganapathy, et al. 25. Thymomas and Thymic Cancers H.K. Muller-Hermelink, A. Marx. 26. Kaposi's Sarcoma C. Boshoff. 27. Brain Tumors F. Ali-Osman. 28. Head and Neck Cancers C.D. Lansford, et al. 29. Gastric Cancer T. Suzuki, M. Sekiguchi. 30. Colorectal Cancer M.G. Brattain, et al. 31. Prostate Cancer J.M. Kozlowski, J.A. Sensibar. 32. Liver Cancer M. Namba, et al. 33. Wilms' Tumor and Other Childhood Renal Neoplasms N.A. Brownlee, et al. 34. Retinoblastoma B.L. Gallie, et al.