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Tumor markers for cancer detection. II.

Updated results of a prospective study assessing the value of tumor marker determinations in a supposedly healthy population (2,000) for identification of a group at risk for cancer are reported. With observation periods varying from 1 to 6 years (mean 3.5 years), repeated determinations by RIA were routinely carried out for CEA, AFP, beta-HCG, beta 2-M, ferritin, and, more recently, beta 1-SP. Preliminary data on TPA, CA 12-5, and CA 19-9 were also obtained. A comparative study of methods for CEA determination using monoclonal and polyclonal antibodies revealed that preference should be given to polyclonal antibodies. In the group considered to be "at risk" (ie, having at least one abnormal marker value) (N = 481), the cancer detection rate was 29 per 1,000 against 3.2 per 1,000 in the normal group (N = 1,519). These figures were significant, even if the number of malignancies detected was small (N = 27). By associating general tumor markers such as CEA, TPA, and CA 19-9 with site-specific markers such as PAP and CA 12-5, it seemed that marker determinations played a useful role in risk assessment in cancer detection programs.

Adolescent↗

Monoclonal antibodies in cancer detection and therapy.

Anticancer antibodies have had a long history in the management of cancer, with major applications having been shown in the immunohistochemistry and immunoassay of tumor-associated antigen markers. With the advent of hybridoma-derived monoclonal antibodies, attempts to use these more reproducible reagents in vivo for cancer detection and therapy have intensified. Radiolabeled monoclonal antibodies appear to be gaining a role in the management of cancer by means of imaging methods to detect sites of increased radioactivity, and several products have been developed and tested clinically. In the area of radioimmunotherapy, a number of problems still need to be solved, including low tumor uptake of the radioimmunoconjugate, dose-limiting myelotoxicity, and the induction of an immune response to repeated doses of murine (foreign) immunoglobulins. Similar problems exist for toxin and drug immunoconjugates, but these also fail to benefit from the "bystander" effect of the ionizing radiation delivered with radioimmunoconjugates, and plant and bacterial toxin molecules appear to have additional immunogenicity that restricts repeated injections. Despite these limitations, recombinant engineering and other chemical approaches are making progress in developing second-generation immunoconjugates that may be more efficacious and less immunogenic as cancer-selective therapeutics. Although nonconjugated, "naked", murine monoclonal antibodies have shown limited success in the therapy of human neoplasms, human and "humanized" forms may be more effective, particularly in lymphatic tumors. Some evidence also suggests that anti-idiotype antibodies (antiantibodies) may serve as surrogate antigens in cancer vaccines. Thus, a number of promising immunologic approaches for cancer diagnosis, detection, and therapy have made important progress in recent years.

Animals↗

Features of early gastric cancer detected by modern diagnostic technique.

To ascertain how the clinicopathologic features of early gastric cancer detected by current diagnostic tools had changed clinical features, we compared 711 early gastric cancer patients with 933 advanced gastric cancer patients regarding age, sex, and tumor location. We found that the proportion of early gastric cancer cases did not change according to age. However, the proportion of early gastric cancer cases in the proximal part was significantly lower than that observed in the distal part (p < 0.01). We conclude that recent diagnostic improvements have rendered age no longer a major deterrent for early detection of gastric cancer. However, a careful examination of the proximal stomach is called for because it is so hard to detect small lesions in that area.

Adult↗

Social work role in an early ovarian cancer detection program.

Social Work intervention in an early ovarian cancer detection program has helped women who are at high risk for the disease because of family history, make full use of the clinic's medical resources. It has provided an enabling component for their participation in required medical procedures; has assisted them in dealing with unresolved emotions precipitated by their relative's death from cancer earlier in their lives; and has helped them move into the next indicated stages of medical intervention.

Adaptation, Psychological↗

The incremental contribution of clinical breast examination to invasive cancer detection in a mammography screening program.

OBJECTIVE: The objective of this study was to determine the potential added contribution of clinical breast examination (CBE) to invasive breast cancer detection in a mammography screening program, by categories of age and breast density. SUBJECTS AND METHODS: We prospectively followed 61,688 women aged 40 years or older who had undergone at least one screening examination with mammography and CBE between January 1, 1996, and December 31, 2000, for 1 year after their mammogram for invasive cancer. We computed the incremental sensitivity, specificity, and positive predictive value of CBE over mammography alone for combinations of age and breast density (predominantly fatty or dense). RESULTS: Mammography sensitivity was 78% and combined mammography-CBE sensitivity was 82%, thus CBE detected an additional 4% of invasive cancers. CBE detected a minority of invasive cancers compared with mammography for all age groups and all breast densities. Sensitivity increased from adding CBE to screening mammography for all ages, from 6.8% in women ages 50-59 with dense breasts to 1.8% in women ages 60-69 years with fatty breasts. CBE generally added incrementally more to sensitivity among women with dense breasts. Specificity and positive predictive value declined when CBE was used in conjunction with mammography, and this decrement was more pronounced in women with dense breasts. CONCLUSION: CBE had modest incremental benefit to invasive cancer detection over mammography alone in a screening program, but also led to greater risk of false-positive results. These risks and benefits were greater in women with dense breasts. The balance of risks and benefits must be weighed carefully when evaluating the inclusion of CBE in a screening examination.

Adult↗

Sensitivity of sputum cytology after homogenization with dithiothreitol in lung cancer detection. Two years of experience.

OBJECTIVE: To compare the sensitivity of sputum cytology using the dithiothreitol homogenization method (DTT) with that of the standard pick-and-smear (PS) method in lung cancer detection. STUDY DESIGN: In a two-year period, 2,428 sputum specimens were examined. Standard PS smears were prepared as controls; the remainder of the specimens were homogenized with DTT before smears were prepared. The sensitivity of the two methods in detecting positive cases was compared. RESULTS: Among 260 positive cases, the DTT method detected 256, while the PS method detected only 212, representing a difference of 17%. The DTT method also detected 28 more suspicious cases and permitted definitive typing of the tumor in a further 11 cases. CONCLUSION: Homogenization of sputum with DTT is not only a simple and versatile method but also a more sensitive method as compared to the PS method in lung cancer detection.

Dithiothreitol↗

Can complexed prostate specific antigen and prostatic volume enhance prostate cancer detection in men with total prostate specific antigen between 2.5 and 4.0 ng./ml.

PURPOSE: We assessed whether complexed prostate specific antigen (PSA) and complexed PSA referenced variables would enhance prostate cancer detection in men with serum total PSA between 2.5 and 4.0 ng./ml. MATERIALS AND METHODS: Transition zone and total prostate gland volumes were determined in 151 men who underwent prostate biopsy using an 11 core biopsy strategy. In addition to measuring the Bayer section sign complexed PSA assay, we also calculated 2 computed complexed PSA values (Hybritech parallel total PSA--Hybritech free PSA and Bayer total PSA--Hybritech free PSA). We calculated 8 volume referenced variables using total and complexed PSA, and 2 computed complexed PSA values by dividing each value by the total prostate and transition zone volumes. RESULTS: Of the 151 patients 37 (24.5%) had cancer. In 10 of the 37 men with cancer (27%) a positive core was present in only 1 or more of the 5 alternate regions not sampled by conventional sextant biopsies. At 92% sensitivity a cutoff value of 2.3 ng./ml. for complexed and 31% for free-to-total PSA provided 42% and 11% specificity, respectively (p <0.001). In the 116 men with a total prostate volume of 30 cc or greater at 92% sensitivity the specificity of complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (52%) were better than that of complexed (40%) and free-to-total (11%) PSA. In the 35 men with a total prostate volume of less than 30 cc at 92% sensitivity the specificity of complexed PSA (50%), complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (55%) were significantly better than that of free-to-total PSA (8%, p <0.001). The area under the curve of complexed PSA was almost identical to that of the 2 computed complexed PSA calculations. CONCLUSIONS: A substantial proportion of men with total PSA values between 2.5 and 4.0 ng./ml. had prostate cancer. Complexed and computed complexed PSA were more specific than the free-to-total PSA ratio when total PSA was between 2.5 and 4.0 ng./ml. A 2.3 ng./ml. threshold for complexed and computed complexed PSA appears to stratify prostate biopsy results in men with total PSA between 2.5 and 4.0 ng./ml. The computed complexed PSA calculation appears to be equivalent to the complexed PSA serum assay for detecting cancer. Volume referenced complexed PSA performed better than complexed PSA in men with a total prostate volume of 30 cc or greater compared to men with a total prostate volume of less than 30 cc.

Adult↗

Lung cancer detection. Results of a randomized prospective study in Czechoslovakia.

A randomized prospective study of lung cancer detection was begun in 1976 to evaluate semiannual screening by radiologic and sputum cytologic study in comparison to screening at a 3-year interval, and to no screening. In a high-risk population of 6364 men (aged 40 to 64 years), the initial prevalence of lung cancer was 0.28% (18 cases), the annual incidence was 0.35% per year (66 cases during 3 years), the proportion of Stage I cases was 31% (26/84), and Stage II was 17% (14/84), "curative" resections were 27% (23/84), and 5-year survival was 23% (19/84). The study confirmed the ability of radiologic screening to detect lung cancer at an earlier stage when treatment by resection can be accomplished. The fate of a high-risk population submitted to screening was better than that of a population with no screening where lung cancer was discovered by symptoms, accidental x-rays, or at autopsy. A matter of lesser importance was the frequency of screening. The absolute numbers of 5-year survivors detected by screening were practically the same for either compared screening frequency.

Adult↗

Age of uptake of early cancer detection facilities by low-risk and high-risk patients with familial breast and ovarian cancer.

INTRODUCTION: Some 5-10% of all cases of breast cancer and ovarian cancer have a hereditary genesis. In the setting of an interdisciplinary cancer genetics clinic, a study of the age at which patients first take advantage of early cancer detection (ECD) facilities was conducted in order to assess the influence of familial risk on health issues. METHODS: The study included 556 women who fulfilled the inclusion criteria (IC) for genetic analysis of the BRCA1 and BRCA2 genes, as well as 205 who did not meet these criteria but attended the primary consultation. RESULTS: Consulters who met the inclusion criteria took advantage of nearly all methods of ECD at an earlier time than women who did not. A comparison of consulters with or without breast cancer showed that those without breast cancer participated in all methods of ECD at an earlier time. CONCLUSION: Methods of improving and increasing participation in ECD facilities, and of encouraging women who are at risk to start on such programs at a younger age, need to be discussed. In this study, familial risk already resulted in a younger age of uptake of ECD facilities.

Adult↗

Monoclonal antibodies: new agents for cancer detection and targeted therapy.

Antibodies directed against markers on cancer cells are gaining in importance for the purpose of targeting diagnostic and therapeutic agents. In the past, this approach has had very limited success principally because the classical methods for producing antibodies from blood serum of animals immunized with cancer cells or extracts were unsatisfactory. The situation has changed dramatically since 1975 following the design of procedures for "immortalizing" antibody-producing cells (lymphocytes) by fusing them with cultured myeloma cells to form hybridomas which continuously secrete antibodies. Since these hybridomas produce antibodies coded for by a single antibody-producing cell, the antibodies are called monoclonal. Building on these advances in biomedical research, it is now possible to reproducibly manufacture monoclonal antibodies on a scale suitable for use in cancer detection and therapy.

Antibodies, Monoclonal↗

Early lung cancer detection based on registered perfusion MRI.

Lung cancer remains the most common fatal malignancy in both men and women in the United States and elsewhere around the world among people who have been exposed passively or actively to tobacco smoke. Technological advances have produced imaging modalities that are proving to be useful for the early detection of lung cancer. In the usual modes, computed tomography (CT) and magnetic resonance imaging (MRI) can identify suspicious lesions, but further work is needed to detect cancer in its early stage. Tumor angiogenesis assessed by perfusion-sensitive MRI is a promising method for early and accurate identification of lung cancer that avoids patient stress and the potential progression to a less treatable stage inherent in serial imaging. However, compensating for the respiratory and anatomical structure motion is a challenge. In order to use perfusion MRI in a signal imaging session to define metabolic and vascular characteristics of tumors, we present a novel affine registration method for perfusion MRI that can register points of interest by tracking image intensity changes around the target point. The registration results are used to generate accurate time intensity curves (TIC) of different regions of interest (ROI). The patterns of different TICs are mapped on the cancer and other structures. The method is computationally efficient and performs well in our perfusion MRI sequence analysis.

Artifacts↗

Knowledge of testicular cancer risk and need for self-examination in college students: a call for equal time for men in teaching of early cancer detection techniques.

College athletes were surveyed about their knowledge and practice of early cancer detection techniques. Males were almost completely unaware of their risk for testicular cancer (87%). Only 9.6% had been taught testicular self-examination and only half of these by their physician. Six percent actually examined themselves regularly. In comparison, more than 60% of women had been taught breast self-examination (75% by a physician) and about one third were doing regular examinations. More than 90% of the young men and women had been seen by physicians for a physical examination within the past 3 years. Physicians need to begin educating males about testicular cancer and its early detection.

Adolescent↗

A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.

In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.

Colorectal Neoplasms↗

[Differential traits of prostatic cancer detected through an early screening program versus the one detected during urologic consultation].

OBJECTIVE: To compare some features of prostate cancers (PCa) detected in a screening program, versus cancers diagnosed in an outpatient clinic. MATERIAL AND METHODS: Retrospective study of 393 patients with biopsy evidence of PCa: 93 (23.7%) from a screening campaign, and 300 (76.3%) detected in an outpatient Urology clinic. Features studied at the moment of diagnosis were age, PSA, digital rectal examination (DRE), transrectal ultrasound (TRUS) characteristics and volume stimation, PSA density (PSAD), clinical stage and Gleason score. A comparison was established between the two groups of patients taking into account the mentioned parameters. RESULTS: A higher age, PSA and DPSA values were found among cancers detected out of the screening program. A greater probability of abnormal DRE and a more advanced clinical stage was also noted. In the screening group, 78.5% of the cancers were localized and 8.6% metastatic. In the outpatient clinic group, the proportions were 50.7% and 26%, respectively. No differences were found with respect to TRUS findings, prostate volume, or Gleason score. CONCLUSIONS: Cancers detected in screening programs are found in earlier stages. Nevertheless, results from long term randomized studies are necessary to verify if these data really mean that a disease-specific mortality reduction can be achieved.

Aged↗

Plasma epigenetic markers for cancer detection and prenatal diagnosis.

Successful detection of circulating nucleic acids has opened up new possibilities in cancer testing and prenatal diagnosis. Circulating DNA markers are useful in cancer detection, prognostication and monitoring. Cancer-associated molecular changes which can be detected include gene mutations, chromosomal rearrangements, microsatellite alterations, viral sequences, and, to be discussed in more detailed, gene promoter hypermethylation. Methylation analysis is commonly performed by DNA digestion with methylation-sensitive restriction endonucleases followed by polymerase chain reaction (PCR), or bisulfite modification followed by methylation-specific PCR (MSP). The detection of fetal DNA in maternal plasma has opened up new possibilities for noninvasive prenatal diagnosis. However, circulating fetal DNA detection has been based on exploiting gender and polymorphic differences between the fetus and mother. The recent discovery of epigenetic differences between the maternal and the fetal DNA detectable in maternal plasma has launched a hunt for fetal-derived epigenetic markers in maternal plasma. It is hoped that this type of universally applicable markers would be made available in a clinical diagnostic setting in the near future.

DNA↗

T1c prostate cancer detection rate and pathologic characteristics: comparison between patients with serum prostate-specific antigen range of 3.0 to 4.0 ng/mL and 4.1 to 10.0 ng/mL in Korean population.

OBJECTIVES: To prospectively evaluate the Stage T1c prostate cancer detection rate and pathologic characteristics of patients with a serum prostate-specific antigen (PSA) level of 3.0 to 4.0 ng/mL and compare this with the rate of patients who had a PSA level of 4.1 to 10.0 ng/mL. METHODS: We analyzed the data of patients who had PSA levels of 3.0 to 10.0 ng/mL, benign findings on digital rectal examination, and no specific lesion identified on transrectal ultrasonography. The clinical characteristics, cancer detection rate, and pathologic findings of the biopsy and prostatectomy specimen were compared between the low (3.0 to 4.0 ng/mL) and intermediate (4.1 to 10.0 ng/mL) PSA groups. RESULTS: A total of 450 patients met our criteria. Of these 450 patients, 85 and 365 had a low or an intermediate PSA level, respectively. Prostate cancer was diagnosed in 26% of the low and 19% of the intermediate PSA group. No significant difference was found between the two groups in the pathologic biopsy findings, including the mean Gleason score and percentage of patients with a Gleason score of 7 or more. The pathologic findings of the prostatectomy specimens also showed no significant differences between the two groups, including the mean Gleason score, pathologic stage, and percentage of insignificant prostate cancer. CONCLUSIONS: No statistically significant difference was found in the incidence of Stage T1c prostate cancer or pathologic characteristics in comparison between the low and intermediate PSA groups. These results suggest that a lower PSA cutoff should be considered as an indication for prostate biopsy in the Korean population.

Biopsy, Needle↗

11C-acetate PET imaging of prostate cancer: detection of recurrent disease at PSA relapse.

UNLABELLED: Patients with rising prostate-specific antigen (PSA) levels after definitive local therapy of prostate carcinoma present a diagnostic dilemma. A local recurrence would be amenable to additional local therapy with curative intent, whereas metastatic disease would require palliative androgen ablation therapy. In this study, we evaluated the effectiveness of PET with (11)C-acetate (AC PET) for evaluation of patients with rising PSA after radical prostatectomy or radiation therapy. We also compared the reliability of AC PET in detecting recurrent prostate cancer with that of PET with (18)F-FDG. METHODS: Two groups of patients with PSA recurrence were enrolled in this study: group A, 30 patients after prostatectomy, and group B, 16 patients after radiation therapy. After administration of 1,110 MBq (30 mCi) of (11)C-acetate, whole-body PET images were obtained. After allowing for (11)C decay, 555 MBq (15 mCi) of (18)F-FDG were administered and repeated whole-body imaging was performed. The PET findings were scored as positive or negative in each of the following regions: prostatic bed, pelvic nodes, paraaortic nodes, and other sites (bone or soft tissue). PET findings were correlated with those of CT, bone scintigraphy, and biopsy. RESULTS: Twenty-seven of 46 AC PET studies (59%) had positive findings, whereas only 8 (18)F-FDG PET studies had positive findings (17%). Limiting the analysis to patients with findings confirmed by CT, bone scintigraphy, or biopsy or considered highly likely to represent tumor, 14 (30%) had disease identified by AC PET, whereas only 4 (9%) had disease identified by (18)F-FDG PET. CT was performed on 22 patients and had positive findings in 3 (14%). Thirteen of 22 patients (59%) with serum PSA > 3 ng/mL had positive AC PET findings, whereas only 1 of 24 patients (4%) with serum PSA levels < or = 3 ng/mL had positive findings. CONCLUSION: AC PET demonstrates marked uptake in prostate cancer and has higher sensitivity than (18)F-FDG PET. These preliminary data show that (11)C-acetate is a promising tracer for detection of recurrent prostate cancer.

Acetates↗

Mode of breast cancer detection: a study from the German part of the Maas-Rhine-EUREGIO.

Cancer screening programmes differ throughout the European Union with regard to their content as well as their acceptance by the population. In Germany, mammography is not yet part of the recommended screening programme, although its routine use is recommended by several national and international institutions. We were interested in the present methods of breast cancer detection and the correlation to tumour stage, histology and prognosis. Patients with breast cancer, presenting in our department between January 1990 and December 1994 (1,050 cases), were asked whether the suspicious finding was first detected by themselves, their physician, or in routine mammography. Seventy-two per cent of tumours were detected by patients themselves, 12% by the physician at routine cancer screening or for other reasons, and 16% were found in mammography performed without clinical suspicion of cancer. Tumours found by physicians or by mammography were treated much sooner than those first recognized by the patient and, thus, were of lower T and N stages. Surgery could more often be breast-conserving in these cases. Of the T2 stages, as far as can be determined after the short follow-up, patients with tumours detected by screening showed a better survival rate. In spite of the introduction of cancer screening programmes most breast carcinomas are still detected by patients themselves. Therapy is often started after a great delay, so that the tumours are found to be at more advanced stages and show a worse prognosis than those detected by clinical examination or mammography.

Adult↗