Showing papers on "Cancer published in 1998"

Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families

Abstract: The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Cancer Treatment by Targeted Drug Delivery to Tumor Vasculature in a Mouse Model

Abstract: In vivo selection of phage display libraries was used to isolate peptides that home specifically to tumor blood vessels. When coupled to the anticancer drug doxorubicin, two of these peptides-one containing an alphav integrin-binding Arg-Gly-Asp motif and the other an Asn-Gly-Arg motif-enhanced the efficacy of the drug against human breast cancer xenografts in nude mice and also reduced its toxicity. These results indicate that it may be possible to develop targeted chemotherapy strategies that are based on selective expression of receptors in tumor vasculature.

Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma

Abstract: The cloning of the genes encoding cancer antigens has opened new possibilities for the treatment of patients with cancer. In this study, immunodominant peptides from the gp100 melanoma-associated antigen were identified, and a synthetic peptide, designed to increase binding to HLA-A2 molecules, was used as a cancer vaccine to treat patients with metastatic melanoma. On the basis of immunologic assays, 91% of patients could be successfully immunized with this synthetic peptide, and 13 of 31 patients (42%) receiving the peptide vaccine plus IL-2 had objective cancer responses, and four additional patients had mixed or minor responses. Synthetic peptide vaccines based on the genes encoding cancer antigens hold promise for the development of novel cancer immunotherapies.

A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995

Abstract: BACKGROUND The National Cancer Data Base (NCDB) represents a national electronic registry system now capturing nearly 60% of incident cancers in the U. S. In combination with other Commission on Cancer programs, the NCDB offers a working example of voluntary, accurate, cost-effective "outcomes management" on a both a local and national scale. In addition, it is of particular value in capturing clinical information concerning rare cancers, such as those of the thyroid. METHODS For the accession years 1985-1995, NCDB captured demographic, patterns-of-care, stage, treatment, and outcome information for a convenience sample of 53,856 thyroid carcinoma cases (1% of total NCDB cases). This article focuses on overall 10-year relative survival and American Joint Committee on Cancer (AJCC) (3rd/4th edition) stage-stratified 5-year relative survival for each histologic type of thyroid carcinoma. Care patterns also are discussed. RESULTS The 10-year overall relative survival rates for U. S. patients with papillary, follicular, Hurthle cell, medullary, and undifferentiated/anaplastic carcinoma was 93%, 85%, 76%, 75%, and 14%, respectively. For papillary and follicular neoplasms, current AJCC staging failed to discriminate between patients with Stage I and II disease at 5 years. Total thyroidectomy ± lymph node sampling/dissection represented the dominant method of surgical treatment rendered to patients with papillary and follicular neoplasms. Approximately 38% of such patients receive adjuvant iodine-131 ablation/therapy. At 5 years, variation in surgical treatment (i.e., lobectomy vs. more extensive surgery) failed to translate into compelling differences in survival for any subgroup with papillary or follicular carcinoma, but longer follow-up is required to evaluate this. NCDB data appeared to validate the AMES prognostic system, as applied to papillary cases. Younger age appeared to influence prognosis favorably for all thyroid neoplasms, including medullary and undifferentiated/anaplastic carcinoma. NCDB data also revealed that unusual patients diagnosed with undifferentiated/anaplastic carcinoma before age of 45 years have better survival. CONCLUSIONS The NCDB system permits analysis of care patterns and survival for large numbers of contemporaneous U. S. patients with relatively rare neoplasms, such as thyroid carcinoma. In this context, it represents an unsurpassed clinical tool for analyzing care, evaluating prognostic models, generating new hypotheses, and overcoming the volume-related drawbacks inherent in the study of such neoplasms. [See editorial on pages 2434-6, this issue.] Cancer 1998;83:2638-2648. © 1998 American Cancer Society.

Doxorubicin-Induced Cardiomyopathy

Abstract: Doxorubicin (Adriamycin) has been used in oncologic practice since the late 1960s. It held promise as a powerful drug in the fight against cancer. The tumors most commonly responding to doxorubicin when it is given as a single agent or in combination with other antitumor agents include breast and esophageal carcinomas; osteosarcoma, Kaposi's sarcoma, and soft-tissue sarcomas; and Hodgkin's and non-Hodgkin's lymphomas. Other cancers that are less responsive to doxorubicin but that are still treated with the drug because of its overall benefits include gastric, liver, bile-duct, pancreatic, and endometrial carcinomas. However, reports of fatal cardiotoxic effects of doxorubicin have . . .

The National Cancer Data Base Report on Cutaneous and Noncutaneous Melanoma A Summary of 84,836 Cases from the Past Decade

Abstract: BACKGROUND. This study reviews the case-mix characteristics, management, and outcomes of melanoma cases occuring in the U. S. within the last decade. METHODS. Analyses of the National Cancer Data Base (NCDB) were performed on cases diagnosed between 1985 through 1994. A total of 84,836 cases comprised of cutaneous and noncutaneous melanomas were evaluated. RESULTS. The percentages of melanomas that were cutaneous, ocular, mucosal, and unknown primaries were 91.2%, 5.2%, 1.3%, and 2.2%, respectively. For cutaneous melanomas, the proportion of patients presenting with American Joint Committee on Cancer Stages 0, I, II, III, and IV were 14.9%, 47.7%, 23.1%, 8.9%, and 5.3%, respectively. Factors associated with decreased survival included more advanced stage at diagnosis, nodular or acral lentiginous histology, increased age, male gender, nonwhite race, and lower income. Multivariate analysis identified stage, histology, gender, age, and income as independent prognostic factors. For ocular melanomas, 85.0% were uveal, 4.8% were conjunctival, and 10.2% occurred at other sites. During the study period, there was a large increase in the proportion of ocular melanoma patients treated with radiation therapy alone. For mucosal melanomas, the distribution of head and neck, female genital tract, anal/rectal, and urinary tract sites was 55.4%, 18.0%, 23.8%, and 2.8%, respectively. Patients with lymph node involvement had a poor prognosis. For unknown primary melanomas, the distribution of metastases as localized to a region or multiple sites at presentation was 43.0% and 57.0%, respectively. Surgical treatment of patients with unknown primary site of the melanoma resulted in better survival compared with no treatment. CONCLUSIONS. Treatment of early stage cutaneous melanoma resulted in excellent patient outcomes. In addition to conventional prognostic factors, socioeconomic factors were found to be associated with survival. Cancer 1998;83:1664 ‐78. © 1998 American Cancer Society.

Relationship Between Cancer Patients' Predictions of Prognosis and Their Treatment Preferences

Abstract: Context.— Previous studies have documented that cancer patients tend to overestimate the probability of long-term survival. If patient preferences about the trade-offs between the risks and benefits associated with alternative treatment strategies are based on inaccurate perceptions of prognosis, then treatment choices may not reflect each patient’s true values. Objective.— To test the hypothesis that among terminally ill cancer patients an accurate understanding of prognosis is associated with a preference for therapy that focuses on comfort over attempts at life extension. Design.— Prospective cohort study. Setting.—Five teaching hospitals in the United States. Patients.—A total of 917 adults hospitalized with stage III or IV non‐small cell lung cancer or colon cancer metastatic to liver in phases 1 and 2 of the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). Main Outcome Measures.— Proportion of patients favoring life-extending therapy over therapy focusing on relief of pain and discomfort, patient and physician estimates of the probability of 6-month survival, and actual 6-month survival. Results.— Patients who thought they were going to live for at least 6 months were more likely (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.8-3.7) to favor lifeextending therapy over comfort care compared with patients who thought there was at least a 10% chance that they would not live 6 months. This OR was highest (8.5; 95% CI, 3.0-24.0) among patients who estimated their 6-month survival probability at greater than 90% but whose physicians estimated it at 10% or less. Patients overestimated their chances of surviving 6 months, while physicians estimated prognosis quite accurately. Patients who preferred life-extending therapy were more likely to undergo aggressive treatment, but controlling for known prognostic factors, their 6-month survival was no better. Conclusions.— Patients with metastatic colon and lung cancer overestimate their survival probabilities and these estimates may influence their preferences about medical therapies.

A Preoperative Nomogram for Disease Recurrence Following Radical Prostatectomy for Prostate Cancer

Abstract: Background: Few published studies have combined clinical prognostic factors into risk profiles that can be used to predict the likelihood of recurrence or metastatic progression in patients following treatment of prostate cancer. We developed a nomogram that allows prediction of disease recurrence through use of preoperative clinical factors for patients with clinically localized prostate cancer who are candidates for treatment with a radical prostatectomy. Methods: By use of Cox proportional hazards regression analysis, we modeled the clinical data and disease follow-up for 983 men with clinically localized prostate cancer whom we intended to treat with a radical prostatectomy. Clinical data included pretreatment serum prostate-specific antigen levels, biopsy Gleason scores, and clinical stage. Treatment failure was recorded when there was clinical evidence of disease recurrence, a rising serum prostate-specific antigen level (two measurements of 0.4 ng/mL or greater and rising), or initiation of adjuvant therapy. Validation was performed on a separate sample of 168 men, also from our institution. Results: Treatment failure (i.e., cancer recurrence) was noted in 196 of the 983 men, and the patients without failure had a median follow-up of 30 months (range, 1-146 months). The 5-year probability of freedom from failure for the cohort was 73% (95% confidence interval = 69%-76%). The predictions from the nomogram appeared accurate and discriminating, with a validation sample area under the receiver operating characteristic curve (i.e., comparison of the predicted probability with the actual outcome) of 0.79. Conclusions: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among men with clinically localized prostate cancer treated with radical prostatectomy.

Incidence of Hereditary Nonpolyposis Colorectal Cancer and the Feasibility of Molecular Screening for the Disease

Abstract: Background Genetic disorders that predispose people to colorectal cancer include the polyposis syndromes and hereditary nonpolyposis colorectal cancer. In contrast to the polyposis syndromes, hered...

Tamoxifen in the Treatment of Breast Cancer

Abstract: Breast cancer is the most common cancer in women in the Western world. Because breast cancer is estrogen-dependent, reducing estrogen secretion by oophorectomy, hypophysectomy, or adrenalectomy can cause the cancer to regress. The need for these surgical procedures was reduced by the introduction of tamoxifen, which acts as an antiestrogen by inhibiting the binding of estrogen to estrogen receptors. Tamoxifen was approved by the Food and Drug Administration in 1977 for the treatment of women with advanced breast cancer and several years later for adjuvant treatment of primary breast cancer.1 Pharmacology and Endocrinology Pharmacologic and Pharmacokinetic Properties The compound administered . . .

Use of the Percentage of Free Prostate-Specific Antigen to Enhance Differentiation of Prostate Cancer From Benign Prostatic Disease: A Prospective Multicenter Clinical Trial

Abstract: Context.—The percentage of free prostate-specific antigen (PSA) in serum has been shown to enhance the specificity of PSA testing for prostate cancer detection, but earlier studies provided only preliminary cutoffs for clinical use.Objective.—To develop risk assessment guidelines and a cutoff value for defining abnormal percentage of free PSA in a population of men to whom the test would be applied.Design.—Prospective blinded study using the Tandem PSA and free PSA assays (Hybritech Inc, San Diego, Calif).Setting.—Seven nationwide university medical centers.Participants.—A total of 773 men (379 with prostate cancer, 394 with benign prostatic disease) 50 to 75 years of age with a palpably benign prostate gland, PSA level of 4.0 to 10.0 ng/mL, and histologically confirmed diagnosis.Main Outcome Measures.—A percentage of free PSA cutoff that maintained 95% sensitivity for prostate cancer detection, and probability of cancer for individual patients.Results.—The percentage of free PSA may be used in 2 ways: as a single cutoff (ie, perform a biopsy for all patients at or below a cutoff of 25% free PSA) or as an individual patient risk assessment (ie, base biopsy decisions on each patient's risk of cancer). The 25% free PSA cutoff detected 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients, and generally were less threatening in terms of tumor grade and volume. For individual patients, a lower percentage of free PSA was associated with a higher risk of cancer (range, 8%-56%). In the multivariate model used, the percentage of free PSA was an independent predictor of prostate cancer (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.5-4.1; P<.001) and contributed significantly more than age (OR, 1.2; 95% CI, 0.92-1.55) or total PSA level (OR, 1.0; 95% CI, 0.92-1.11) in this cohort of subjects with total PSA values between 4.0 and 10.0 ng/mL.Conclusions.—Use of the percentage of free PSA can reduce unnecessary biopsies in patients undergoing evaluation for prostate cancer, with a minimal loss in sensitivity in detecting cancer. A cutoff of 25% or less free PSA is recommended for patients with PSA values between 4.0 and 10.0 ng/mL and a palpably benign gland, regardless of patient age or prostate size. To our knowledge, this study is the largest series to date evaluating the percentage of free PSA in a population representative of patients in whom the test would be used in clinical practice.

Levels of TGF-α and EGFR Protein in Head and Neck Squamous Cell Carcinoma and Patient Survival

Abstract: Background: The most accurate predictor of disease recurrence in patients treated for head and neck squamous cell carcinoma is, at present, the extent of regional lymph node metastasis. Since elevated levels of epidermal growth factor receptor (EGFR) and of its ligand, transforming growth factor-a (TGF-a), have been detected in primary tumors of patients with head and neck squamous cell carcinoma, we determined whether tumor levels of these proteins were of prognostic importance. Methods: Monoclonal antibodies specific for EGFR and TGF-a were used for immunohistochemical detection of each protein in tissue sections of primary tumors from 91 patients who were treated by surgical resection. Levels of immunoreactive EGFR and TGF-a were quantified by use of a computerized image analysis system and were normalized to appropriate standards. The logrank test and proportional hazards regression analysis were used to calculate the probability that EGFR and TGF-a levels were associated with disease-free survival (i.e., no recurrence of cancer) and cause-specific survival (i.e., patients do not die of their disease). All P values were two-sided. Results: When tumor levels of EGFR or TGF-a were analyzed as continuous variables, disease-free survival and cause-specific survival were reduced among patients with higher levels of EGFR (both P = .0001) or TGF-a (both P = .0001). In a multivariate analysis, tumor site, tumor level of EGFR, and tumor level of TGF-a were statistically significant predictors of disease-free survival; in a similar analysis, regional lymph node stage and tumor levels of EGFR and of TGF-a were significant predictors of cause-specific survival. Conclusion: Quantitation of EGFR and TGF-a protein levels in primary head and neck squamous cell carcinomas may be useful in identifying subgroups of patients at high risk of tumor recurrence and in guiding therapy. [J Natl Cancer Inst 1998; 90:824‐32]

Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study.

Abstract: OBJECTIVE: In 1986 a prospective multicenter observation trial in patients with resected gastric cancer was initiated in Germany. An analysis of prognostic factors based on the 10-year survival data is now presented. PATIENTS AND METHODS: A total of 1654 patients treated for gastric cancer between 1986 and 1989 at 19 centers in Germany and Austria were included. The resected specimen were evaluated histopathologically according to a standardized protocol. The extent of lymphadenectomy was classified after surgery based on the number of removed lymph nodes on histopathologic assessment (25 or fewer removed nodes, D1 or standard lymphadenectomy; >25 removed nodes, D2 or extended lymphadenectomy). Endpoint of the study was death. Follow-up is complete for 97% of the included patients (median follow-up of the surviving patients is 8.4 years). Prognostic factors were assessed by multivariate analysis. RESULTS: A complete macroscopic and microscopic tumor resection (R0 resection according to the UICC 1997) could be achieved in 1182 of the 1654 patients (71.5%). The calculated 10-year survival rate in the entire patient population was 26.3% +/- 4.7%; it was 36.1% +/- 1.6% after an R0 resection. In the total patient population there was an independent prognostic effect of the ratio between invaded and removed lymph nodes, the residual tumor (R) category, the pT category, the presence of postsurgical complications, and the presence of distant metastases. Multivariate analysis in the subgroup of patients who had a UICC R0 resection confirmed the nodal status, the pT category, and the presence of postsurgical complications as the major independent prognostic factors. The extent of lymph node dissection had a significant and independent effect on the 10-year survival rate in patients with stage II tumors. This effect was present in the subgroups with (pT2N1) and without (pT3N0) lymph node metastases on standard histopathologic assessment. The beneficial effect of extended lymph node dissection for stage II tumors persisted when patients with insufficient lymph node dissection (<15 nodes) were excluded from the analysis. There was no difference in the postsurgical morbidity and mortality rates between patients with standard and extended lymph node dissection. CONCLUSIONS: Lymph node ratio and lymph node status are the most important prognostic factors in patients with resected gastric cancer. In experienced centers, extended lymph node dissection does not increase the mortality or morbidity rate of resection for gastric cancer but markedly improves long-term survival in patients with stage II tumors. This effect appears to be independent of the phenomenon of stage migration.

Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis.

Abstract: The p16INK4a (p16) tumor suppressor gene can be inactivated by promoter region hypermethylation in many tumor types including lung cancer, the leading cause of cancer-related deaths in the U.S. We have determined the timing of this event in an animal model of lung carcinogenesis and in human squamous cell carcinomas (SCCs). In the rat, 94% of adenocarcinomas induced by the tobacco specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone were hypermethylated at the p16 gene promoter; most important, this methylation change was frequently detected in precursor lesions to the tumors: adenomas, and hyperplastic lesions. The timing for p16 methylation was recapitulated in human SCCs where the p16 gene was coordinately methylated in 75% of carcinoma in situ lesions adjacent to SCCs harboring this change. Moreover, the frequency of this event increased during disease progression from basal cell hyperplasia (17%) to squamous metaplasia (24%) to carcinoma in situ (50%) lesions. Methylation of p16 was associated with loss of expression in both tumors and precursor lesions indicating that both alleles were functionally inactivated. The potential of using assays for aberrant p16 methylation to identify disease and/or risk was validated by detection of this change in sputum from three of seven patients with cancer and 5 of 26 cancer-free individuals at high risk. These studies show for the first time that an epigenetic alteration, aberrant methylation of the p16 gene, can be an early event in lung cancer and may constitute a new biomarker for early detection and monitoring of prevention trials.

Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial

Abstract: Background: Epidemiologic studies have suggested that vitamin E and b-carotene may each influence the development of prostate cancer. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a controlled trial, we studied the effect of a-tocopherol (a form of vitamin E) and b-carotene supplementation, separately or together, on prostate cancer in male smokers. Methods: A total of 29 133 male smokers aged 50‐69 years from southwestern Finland were randomly assigned to receive a-tocopherol (50 mg), b-carotene (20 mg), both agents, or placebo daily for 5‐8 years (median, 6.1 years). The supplementation effects were estimated by a proportional hazards model, and two-sided P values were calculated. Results: We found 246 new cases of and 62 deaths from prostate cancer during the follow-up period. A 32% decrease (95% confidence interval [CI] = ˛47% to ˛12%) in the incidence of prostate cancer was observed among the subjects receiving a-tocopherol (n = 14 564) compared with those not receiving it (n = 14 569). The reduction was evident in clinical prostate cancer but not in latent cancer. Mortality from prostate cancer was 41% lower (95% CI = ˛65% to ˛1%) among men receiving a-tocopherol. Among subjects receiving b-carotene (n = 14 560), prostate cancer incidence was 23% higher (95% CI = ˛4%‐59%) and mortality was 15% higher (95% CI = ˛30%‐89%) compared with those not receiving it (n = 14 573). Neither agent had any effect on the time interval between diagnosis and death. Conclusions: Long-term supplementation with a-tocopherol substantially reduced prostate cancer incidence and mortality in male smokers. Other controlled trials are required to confirm the findings. [J Natl Cancer Inst 1998;90:440‐6]

Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer.

Abstract: Purpose: Three-dimensional conformal radiation therapy (3D-CRT) is a technique designed to deliver prescribed radiation doses to localized tumors with high precision, while effectively excluding the surrounding normal tissues. It facilitates tumor dose escalation which should overcome the relative resistance of tumor clonogens to conventional radiation dose levels. The present study was undertaken to test this hypothesis in patients with clinically localized prostate cancer. Methods and Materials: A total of 743 patients with clinically localized prostate cancer were treated with 3D-CRT. As part of a phase I study, the tumor target dose was increased from 64.8 to 81 Gy in increments of 5.4 Gy. Tumor response was evaluated by post-treatment decrease of serum prostate-specific antigen (PSA) to levels of ≤1.0 ng/ml and by sextant prostate biopsies performed ≥2.5 years after completion of 3D-CRT. PSA relapse-free survival was used to evaluate long-term outcome. The median follow-up was 3 years (range: 1–7.6 years). Results: Induction of an initial clinical response was dose-dependent, with 90% of patients receiving 75.6 or 81.0 Gy achieving a PSA nadir ≤1.0 ng compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy, respectively ( p p p p Conclusions: The data provide evidence for a significant effect of dose escalation on the response of human prostate cancer to irradiation and defines new standards for curative radiotherapy in this disease.

Somatic mutations of the mitochondrial genome in human colorectal tumours

Abstract: Alterations of oxidative phosphorylation in tumour cells were originally believed to have a causative role in cancerous growth1. More recently, mitochondria have again received attention with regards to neoplasia, largely because of their role in apoptosis and other aspects of tumour biology2,3,4,5,6,7,8. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generation in this organelle, coupled with a low level of DNA repair9,10,11,12. However, no detailed analysis of mitochondrial DNA in human tumours has yet been reported. In this study, we analysed the complete mtDNA genome of ten human colorectal cancer cell lines by sequencing and found mutations in seven (70%). The majority of mutations were transitions at purines, consistent with an ROS-related derivation. The mutations were somatic, and those evaluated occurred in the primary tumour from which the cell line was derived. Most of the mutations were homoplasmic, indicating that the mutant genome was dominant at the intracellular and intercellular levels. We showed that mitochondria can rapidly become homogeneous in colorectal cancer cells using cell fusions. These findings provide the first examples of homoplasmic mutations in the mtDNA of tumour cells and have potential implications for the abnormal metabolic and apoptotic processes in cancer.

Reovirus Therapy of Tumors with Activated Ras Pathway

Abstract: Human reovirus requires an activated Ras signaling pathway for infection of cultured cells. To investigate whether this property can be exploited for cancer therapy, severe combined immune deficient mice bearing tumors established from v-erbB-transformed murine NIH 3T3 cells or human U87 glioblastoma cells were treated with the virus. A single intratumoral injection of virus resulted in regression of tumors in 65 to 80 percent of the mice. Treatment of immune-competent C3H mice bearing tumors established from ras-transformed C3H-10T1/2 cells also resulted in tumor regression, although a series of injections were required. These results suggest that, with further work, reovirus may have applicability in the treatment of cancer.

A Survey of the Humoral Immune Response of Cancer Patients to a Panel of Human Tumor Antigens

Abstract: Evidence is growing for both humoral and cellular immune recognition of human tumor antigens. Antibodies with specificity for antigens initially recognized by cytotoxic T lymphocytes (CTLs), e.g., MAGE and tyrosinase, have been detected in melanoma patient sera, and CTLs with specificity for NY-ESO-1, a cancer-testis (CT) antigen initially identified by autologous antibody, have recently been identified. To establish a screening system for the humoral response to autoimmunogenic tumor antigens, an enzyme-linked immunosorbent assay (ELISA) was developed using recombinant NY-ESO-1, MAGE-1, MAGE-3, SSX2, Melan-A, and tyrosinase proteins. A survey of sera from 234 cancer patients showed antibodies to NY-ESO-1 in 19 patients, to MAGE-1 in 3, to MAGE-3 in 2, and to SSX2 in 1 patient. No reactivity to these antigens was found in sera from 70 normal individuals. The frequency of NY-ESO-1 antibody was 9.4% in melanoma patients and 12.5% in ovarian cancer patients. Comparison of tumor NY-ESO-1 phenotype and NY-ESO-1 antibody response in 62 stage IV melanoma patients showed that all patients with NY-ESO-1+ antibody had NY-ESO-1+ tumors, and no patients with NY-ESO-1− tumors had NY-ESO-1 antibody. As the proportion of melanomas expressing NY-ESO-1 is 20–40% and only patients with NY-ESO-1+ tumors have antibody, this would suggest that a high percentage of patients with NY-ESO-1+ tumors develop an antibody response to NY-ESO-1.

Kirsten ras Mutations in Patients With Colorectal Cancer: the Multicenter “RASCAL” Study

Abstract: Background: Kirsten ras (Ki-ras) gene mutations occur early in the progression of colorectal adenoma to carcinoma. The aim of this collaborative study was to clarify the association between Ki-ras mutations, patient outcome, and tumor characteristics by use of data from colorectal cancer patients worldwide. Methods: Investigators who had published data on Ki-ras and colorectal cancer were invited to complete a questionnaire for each patient entered into a database. Twosided statistical tests were used to analyze data. Results: Patients (n = 2721) were recruited from 22 groups in 13 countries. Mutations of Ki-ras codon 12 (wild type = GGT = glycine) or codon 13 (wild type = GGC = glycine) were detected in 37.7% of the tumors; 80.8% (584 of 723) of all the specified mutations occurred in codon 12, and 78.1% (565 of 723) of all the specified mutations were at the second base of either codon. Mutations were not associated with sex, age, tumor site, or Dukes’ stage. Mutation rates seen in patients with sporadic tumors were comparable to those observed in patients with a predisposing cause for their cancer. Poorly differentiated tumors were less frequently mutated (P = .002). Multivariate analysis suggested that the presence of a mutation increased risk of recurrence (P<.001) and death (P = .004). In particular, any mutation of guanine (G) to thymine (T) but not to adenine (A) or to cytosine (C) increased the risk of recurrence (P = .006) and death (P<.001). When individual, specific mutations were evaluated, only valine codon 12 was found to convey an independent, increased risk of recurrence (P = .007) and death (P = .004). Conclusions: Ki-ras mutations are associated with increased risk of relapse and death, but some mutations are more aggressive than others. [J Natl Cancer Inst 1998;90:675‐84]

Inhibition of Apoptosis by Survivin Predicts Shorter Survival Rates in Colorectal Cancer

Abstract: Deregulated inhibition of apoptosis (programmed cell death) may facilitate the insurgence of neoplasia, but whether it also influences the outcome of common cancers has remained controversial. In this study, we investigated the expression of a novel inhibitor of apoptosis, survivin, in colorectal cancer and its relationship with tumor cell apoptosis and overall prognosis. By immunohistochemistry, survivin was expressed in 91 of 171 (53.2%) cases of colorectal carcinomas of histological stages 0 to IV. In contrast, normal colon epithelium did not express survivin. Although survivin expression did not correlate with p53 abnormalities (46.5% versus 58.0%; P = 0.18), survivin-positive cases were strongly associated with bcl-2 expression (72.5% versus 27.4%; P < 0.0001) and reduced apoptotic index (0.76% +/- 0.39% versus 1.17% +/- 0.62%; P < 0.0001). Expression of survivin alone in bcl-2-negative (discordant) cases also resulted in reduced apoptotic index (0.82% +/- 0.57% versus 1.16% +/- 0.66%; P = 0.0046). When analyzed for prognostic significance, patients with low apoptotic index (< 0.97%) had worse survival rates than the group with high apoptosis (P < 0.001), and a multivariate Cox proportional hazard model identified reduced apoptosis as an independent predictive factor for overall survival (P < 0.0001). These data demonstrate that apoptosis inhibition by survivin, alone or in cooperation with bcl-2, is an important predictive/prognostic parameter of poor outcome in colorectal carcinoma and identify survivin as a new diagnostic/therapeutic target in cancer.

Determining Carrier Probabilities for Breast Cancer–Susceptibility Genes BRCA1 and BRCA2

Abstract: Breast cancer-susceptibility genes BRCA1 and BRCA2 have recently been identified on the human genome. Women who carry a mutation of one of these genes have a greatly increased chance of developing breast and ovarian cancer, and they usually develop the disease at a much younger age, compared with normal individuals. Women can be tested to see whether they are carriers. A woman who undergoes genetic counseling before testing can be told the probabilities that she is a carrier, given her family history. In this paper we develop a model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCA2, on the basis of her family history of breast and ovarian cancer in first- and second-degree relatives. Of special importance are the relationships of the family members with cancer, the ages at onset of the diseases, and the ages of family members who do not have the diseases. This information can be elicited during genetic counseling and prior to genetic testing. The carrier probabilities are obtained from Bayes's rule, by use of family history as the evidence and by use of the mutation prevalences as the prior distribution. In addressing an individual's carrier probabilities, we incorporate uncertainty about some of the key inputs of the model, such as the age-specific incidence of diseases and the overall prevalence of mutations. There is some evidence that other, undiscovered genes may be important in explaining familial breast cancer. Users of the current version of the model should be aware of this limitation. The methodology that we describe can be extended to more than two genes, should data become available about other genes.

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Abstract: Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.

Detection and characterization of carcinoma cells in the blood

Abstract: A highly sensitive assay combining immunomagnetic enrichment with multiparameter flow cytometric and immunocytochemical analysis has been developed to detect, enumerate, and characterize carcinoma cells in the blood. The assay can detect one epithelial cell or less in 1 ml of blood. Peripheral blood (10–20 ml) from 30 patients with carcinoma of the breast, from 3 patients with prostate cancer, and from 13 controls was examined by flow cytometry for the presence of circulating epithelial cells defined as nucleic acid+, CD45−, and cytokeratin+. Highly significant differences in the number of circulating epithelial cells were found between normal controls and patients with cancer including 17 with organ-confined disease. To determine whether the circulating epithelial cells in the cancer patients were neoplastic cells, cytospin preparations were made after immunomagnetic enrichment and were analyzed. Epithelial cells from patients with breast cancer generally stained with mAbs against cytokeratin and 3 of 5 for mucin-1. In contrast, no cells that stained for these antigens were observed in the blood from normal controls. The morphology of the stained cells was consistent with that of neoplastic cells. Of 8 patients with breast cancer followed for 1–10 months, there was a good correlation between changes in the level of tumor cells in the blood with both treatment with chemotherapy and clinical status. The present assay may be helpful in early detection, in monitoring disease, and in prognostication.