RESUMO
Certain transformed subclones of the mouse cell line BALB/3T3 release 5 to 15 times more type C virus per cell than the parent cell line after treatment with 5-bromodeoxyuridine. Virus release begins within 8 hours and exponentially increases for the first 24 to 48 hours. Superinducibility is associated with the transformed phenotype.
Assuntos
Bromodesoxiuridina/farmacologia , Gammaretrovirus/efeitos dos fármacos , Vírus de RNA/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Transformação Celular Neoplásica , Células Clonais , Cinética , Camundongos , DNA Polimerase Dirigida por RNA/análise , Retroviridae/efeitos dos fármacos , Retroviridae/enzimologiaRESUMO
Reverse transcripts of the rna genome of the bovine leukemia virus (BLV) as well as 125I-labeled BLV RNA hybridize to the DNA of tissues from leukemic cattle with the adult form of the disease but not to bovine thymic lymphoma or normal bovine tissues.
Assuntos
Doenças dos Bovinos/microbiologia , Vírus da Leucemia Bovina , Leucemia/veterinária , Retroviridae , Animais , Bovinos , Linhagem Celular , DNA Viral/análise , Leucemia/análise , Leucemia/microbiologia , Vírus da Leucemia Bovina/análise , Linfoma/microbiologia , Linfoma/veterinária , Hibridização de Ácido Nucleico , Retroviridae/análise , Neoplasias do Timo/microbiologia , Neoplasias do Timo/veterináriaRESUMO
Cell cultures commonly used in animal cell research, both cell strains and continuous cell lines from various mammalian species, spontaneously produce type C RNA viruses.
Assuntos
Células Cultivadas , Vírus Oncogênicos/isolamento & purificação , Vírus de RNA/isolamento & purificação , Animais , Carcinoma 256 de Walker , Gatos , Linhagem Celular , Cricetinae , Células Epiteliais , Feminino , Feto , Idoxuridina/farmacologia , Rim , Tumor de Células de Leydig , Masculino , Microscopia Eletrônica , Ovário , Cavidade Peritoneal , DNA Polimerase Dirigida por RNA/análise , Radioimunoensaio , Ratos , Retroviridae/enzimologia , Retroviridae/isolamento & purificação , Sarcoma Experimental , Suínos , Neoplasias Testiculares , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Chromosome 8 alterations, including loss of 8p21-22 and gain of 8q24, are commonly observed in prostate carcinoma. We examined whether these alterations are associated with poor prognosis in prostate cancer. METHODS: We used dual-probe fluorescence in situ hybridization and DNA probes for 8p22 (lipoprotein lipase gene), centromere 8 (8cen), and 8q24 (c-myc gene) to determine the corresponding copy numbers in tumor samples from 144 patients with high-grade, advanced (stage III) prostate carcinoma. Cox models were used for multivariate analysis of systemic progression or patient death from prostate cancer. All statistical tests are two-sided. RESULTS: We classified the 8p22, 8cen, and c-myc copy number as normal, loss, and gain. An additional increase (AI) category of c-myc relative to the centromere copy number (i.e., overrepresentation and amplification of c-myc) was also used. Alterations of 8p22 were not statistically significantly associated with either systemic progression or patient death. Alterations of c-myc were associated with both systemic progression (P =.024) and patient death (P =.039); AI of c-myc showed the poorest outcome. We also evaluated the prognostic relevance of the combined 8p22-8cen-c-myc loci anomaly pattern for the following six patterns: normal-normal-normal, loss-any 8cen-normal, loss-gain-gain, gain-gain-gain, non-loss-any 8cen-AI, and loss-any 8cen-AI, where any 8cen is normal, loss, or gain of the chromosome 8 centromere. Patients with the loss-any 8cen-AI pattern had earlier systemic progression (P =.009) and earlier cause-specific death (P =.013) than did patients with other patterns. Multivariate analyses demonstrated that the loss-any 8cen-AI pattern was an independent risk factor for systemic progression (P<.001) and cause-specific death (P =.002). CONCLUSIONS: Genetic alterations of chromosome 8 appear to accumulate in parallel with the progression of prostate carcinomas. AI of the c-myc gene, especially with loss of 8p22, appears to be associated with poor patient prognosis.
Assuntos
Cromossomos Humanos Par 8/genética , Genes myc/genética , Lipase Lipoproteica/genética , Neoplasias da Próstata/genética , Centrômero/genética , Sondas de DNA , Progressão da Doença , Humanos , Hibridização in Situ Fluorescente , Masculino , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/patologia , Risco , Análise de SobrevidaRESUMO
The role of c-myc in prostatic carcinogenesis is poorly understood. The pathogenetic relationship between high-grade prostatic intraepithelial neoplasia (PIN), prostatic carcinoma, and metastases is not well-defined. We used fluorescence in situ hybridization (FISH) with a region-specific probe for c-myc (band 8q24) and chromosome enumeration probes for chromosomes 7, 8, 10, 12, and Y to evaluate genetic changes in matched PIN (48 foci), localized prostatic carcinoma (71 foci), and lymph node metastases (23 foci) in 25 totally embedded whole-mount stage D1 (T2-3 N1-3 M0) radical prostatectomy and pelvic lymphadenectomy specimens. The c-myc protein expression in these lesions was evaluated by immunohistochemistry. Foci with extra copies of c-myc could be divided into three groups: (a) those with simple gain of a whole chromosome 8 (no increase in c-myc copy number relative to the chromosome 8 centromere), which was identified in 42, 25, and 46% of foci of PIN, carcinoma, and metastases, respectively; (b) those with an intermediate increase in c-myc copy number relative to the chromosome 8 centromere, which was found in 8, 11, and 25% of foci of PIN, carcinoma, and metastases, respectively; and (c) those with substantial amplification of c-myc (large increases in c-myc copy number relative to the chromosome 8 centromere), which was detected in 0, 8, and 21% of foci of PIN, carcinoma, and metastases, respectively. Substantial amplification of c-myc was strongly correlated with increasing cancer nuclear grade and immunohistochemical evidence of c-myc protein overexpression. Numeric chromosomal anomalies were found in 67, 68, and 96% of foci of PIN, carcinoma, and metastases, respectively. The most frequent anomaly in PIN and carcinoma was a gain of chromosome 8, and the presence of this anomaly strongly correlated with Gleason score. Carcinoma foci usually contained more FISH anomalies than paired PIN foci, but three prostates contained one or more PIN foci with more anomalies than carcinoma. Thirteen primary tumor foci exhibited intratumor genetic heterogeneity by FISH. One or more foci of the primary tumor usually shared FISH anomalies with the matched metastases. Our FISH results indicate that: (a) gain of chromosome 8 and amplification of c-myc are potential markers of prostate carcinoma progression; (b) PIN is likely a precursor of carcinoma; (c) intraglandular and intratumoral genetic heterogeneity is relatively common; and (d) usually a single focus of cancer gives rise to metastases.
Assuntos
Aberrações Cromossômicas , Amplificação de Genes , Genes myc , Hibridização in Situ Fluorescente , Neoplasias da Próstata/genética , Idoso , Cromossomos Humanos Par 8 , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasia Prostática Intraepitelial/genética , Proteínas Proto-Oncogênicas c-myc/análise , Valores de ReferênciaRESUMO
While colony formation assays provide sensitive indices of tumor cell proliferation and growth inhibition imposed by many chemotherapeutic agents, drugs which require metabolic activation lack activity in such assays. In the present study, we have utilized freshly isolated rat hepatocytes for the activation of drugs which are metabolized by hepatic microsomal as well as extra-microsomal enzymes. Hepatocytes in fluid medium are placed over soft-agarose matrix containing tumor-derived cells (e.g., A204, A549) within 35-mm culture dishes; drug and/or drug vehicle is added directly to the hepatocyte layer, and cultures are incubated for 24 hr prior to removal of the hepatocyte layer. Tumor cell colony formation is assessed following 7 to 10 days of incubation. Cyclophosphamide was used as a prototype agent to assess utility of the coculture methodology. In vivo treatment of rats with phenobarbital prior to hepatocyte isolation enhances cyclophosphamide toxicity in vitro, whereas pretreatment with carbon tetrachloride markedly reduced subsequent in vitro cyclophosphamide cytotoxicity. Hepatocyte:tumor cell cocultures provide an efficient means to detect metabolic activation and inactivation of several selected cancer chemotherapeutic agents as well. In the presence of hepatocytes, the 50% growth-inhibitory concentrations for cyclophosphamide, indicine N-oxide, and procarbazine are markedly decreased, whereas the 50% growth-inhibitory concentrations for [2,5-bis(1-aziridinyl)-3,6-diazo-1,4-cyclohexadiene-1,4-diyl]bis(c arbamic acid)diethyl ester, 1,3-bis-chloro(2-chloroethyl)-1-nitrosourea, dacarbazine, 5-fluorouracil, ftorafur, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, and vincristine are significantly increased. By contrast, the 50% growth-inhibitory concentrations for actinomycin D, mitomycin C, 6-mercaptopurine, and other agents are unaffected by hepatocyte presence. Cryopreserved hepatocytes exhibit detectable levels of drug activation, although inadequate for routine use. Results suggest that hepatocyte:tumor cell cocultures may be well-suited for assessing the degree to which hepatic metabolism may activate or inactivate new anticancer drugs.
Assuntos
Antineoplásicos/metabolismo , Ensaio de Unidades Formadoras de Colônias , Fígado/metabolismo , Neoplasias Pulmonares/metabolismo , Rabdomiossarcoma/metabolismo , Ensaio Tumoral de Célula-Tronco , Animais , Tetracloreto de Carbono/farmacologia , Sobrevivência Celular , Ciclofosfamida/metabolismo , Congelamento , Humanos , Fenobarbital/farmacologia , Ratos , Preservação de TecidoRESUMO
Fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 7, 8, 11, and 12 was used to evaluate multiple 18-gauge needle biopsy cores from 50 randomly selected radical prostatectomy specimens. FISH analysis detected 26 diploid (52%), 7 tetraploid (14%), and 17 aneuploid tumors (34%). The FISH results were concordant with flow cytometric (FCM) DNA content measurements of the corresponding prostatectomy specimens for 31 tumors. For the 19 FISH/FCM discordant tumors, FISH was more sensitive than FCM for detecting ploidy anomalies. Common numerical chromosome alterations were gains of chromosomes 7 and 8, which were found in 13 (76%) and 10 (59%) aneuploid tumors, respectively. Gain of chromosome 7 was strongly associated with higher Gleason score (> or = 8) (P < 0.0001) and with advanced tumor pathological stages (stages T3 + T4; P < 0.01). Gain of chromosome 8 also correlated with higher Gleason score (P < 0.01). FISH showed intratumoral ploidy heterogeneity in 3 of 41 (7%) studied tumors. Among 17 noncancerous adjacent tissue specimens, chromosome alterations were observed in one, which contained high-grade prostatic intraepithelial neoplasia. Combined FISH and fluorescent leukocyte common antigen staining showed that infiltrating leukocytes do not contribute to the observed gains of chromosomes 7 and 8 in prostate cancer tissue. These results demonstrate that (a) FISH analysis of prostate needle biopsy-sized specimens can be a practical, sensitive method for determination of nuclear ploidy and numerical chromosome alterations; and (b) gains of chromosomes 7 and 8 are common numerical alterations of prostate cancer cells and may be potential markers of tumor behavior and patient prognosis.
Assuntos
Centrômero , Aberrações Cromossômicas , Ploidias , Neoplasias da Próstata/genética , Biópsia por Agulha , Marcadores Genéticos , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Masculino , Próstata/patologia , Neoplasias da Próstata/patologiaRESUMO
Fluorescence in situ hybridization is a new methodology which can be used to detect cytogenetic anomalies within interphase tumor cells. We used this technique to identify nonrandom numeric chromosomal alterations in tumor specimens from the poorest prognosis patients with pathological stages T2N0M0 and T3N0M0 prostate carcinomas. Among 1368 patients treated by radical prostatectomy, 25 study patients were ascertained who died most quickly from progressive prostate carcinoma within 3 years of diagnosis and surgery. Tumors from 25 control patients who survival for more than 5 years and who were matched for age, tumor histological grade, and pathological stage also were evaluated. The tumors from all 25 (100%) poor prognosis patients and from 11 of 25 (44%) control patients were found to be aneuploid by fluorescence in situ hybridization (P < 0.0001). Alterations of chromosome 7 were observed in 24 of the tumors (96%) from the poor prognosis patients versus 3 tumors (12%) from the control group (P < 0.0001). Moreover, a characteristic aneuploidy pattern with multiple abnormal chromosomes and a hypertetrasomic population was generally found in tumors from the poor prognosis patients. This preliminary study suggests that fluorescence in situ hybridization studies of prostate cancer specimens may help to identify those patients at highest risk for early cancer death.
Assuntos
Aneuploidia , Cromossomos Humanos Par 7 , Neoplasias da Próstata/genética , Idoso , Estudos de Casos e Controles , Cromossomos Humanos Par 17 , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Ploidias , Prognóstico , Hiperplasia Prostática/genética , Neoplasias da Próstata/mortalidade , Valores de Referência , Cromossomos SexuaisRESUMO
The pathogenetic relationship between high-grade prostatic intraepithelial neoplasia (PIN), prostatic carcinoma, and metastases is poorly understood. We used fluorescence in situ hybridization (FISH) with centromere-specific probes for chromosomes 7, 8, 10, 12, and Y to evaluate numeric chromosomal anomalies in PIN (68 foci), localized prostatic carcinoma (78 foci), and lymph node metastases (8 foci) in 40 whole-mount radical prostatectomy and pelvic lymphadenectomy specimens. Chromosomal anomalies were found in 50, 51, and 100% of the foci of PIN, carcinoma, and metastases, respectively. The mean numbers of abnormal chromosomes per focus were 0.66 in PIN, 1.09 in carcinoma, and 3.75 in metastases. The most frequent anomaly in PIN was a gain of chromosome 8 (32% of foci), followed by gains of chromosomes 10 (13%), 7 (10%), 12 (4%), and Y (4%). The most frequent anomalies in foci of carcinoma were gains of chromosomes 7 and 8 (28% and 30% of foci, respectively), followed by gains of chromosomes 10 (23%), 12 (9%), and Y (9%). There was a positive correlation of the gain of chromosome 8 with the pathological stage and Gleason score (both P < 0.05). Usually, carcinoma foci contained more anomalies than paired PIN foci, but five prostates contained one or more foci of PIN with more anomalies than carcinoma. Among the cases with metastases, usually one or more foci of the primary tumor shared chromosomal anomalies with the matched metastases. Our results indicate that PIN and prostatic carcinoma foci have similar proportions of chromosomal anomalies, but foci of carcinoma usually have more alterations. This observation supports the hypothesis that PIN is often a precursor of carcinoma, although there are some carcinoma foci that have few or no apparent chromosomal alterations, whereas concurrent PIN foci have multiple alterations. A gain of chromosome 8 was the most common numerical alteration and was associated with increasing cancer stage and grade, suggesting that it may play a role in the initiation and progression of prostatic carcinoma. Usually, one or more foci of the primary tumor shared chromosomal anomalies with associated lymph node metastases, suggesting that, often, just a single focus of carcinoma gives rise to metastases.
Assuntos
Aberrações Cromossômicas , Hibridização in Situ Fluorescente , Neoplasia Prostática Intraepitelial/genética , Neoplasias da Próstata/genética , Idoso , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/patologiaRESUMO
Cytogenetic analyses have demonstrated that chromosome region 7q22-32 is commonly altered in prostate adenocarcinomas. In addition, in recent fluorescence in situ hybridization studies, we have observed that aneusomy of chromosome 7 is frequent in prostate cancer and is associated with higher tumor grade, advanced pathological stage, and early prostate cancer death. These findings suggest that genetic alterations of chromosome 7 play a significant role in the development of prostate cancer. To better define the chromosome 7 alterations, PCR analysis of 21 microsatellite loci was performed on 54 paired prostate cancer and control DNAs. Overall, chromosome 7 allelic imbalance was identified in 16 of 54 cases (30%). Allelic imbalances of loci mapped to 7q were observed in 15 of the 16 cases. The allelic imbalances were classified as losses in 15 tumors (28%) and as gains in 1 (2%) by comparative multiplex PCR analysis. The most common site of allelic loss included loci D7S523 and D7S486 at 7q31.1. A comparison with clinicopathological features of the tested tumors revealed that the allelic loss of 7q31.1 correlated with higher tumor grade (P = 0.012) and lymph node metastasis (P = 0.017). These results indicate that 7q31 may be the site of a putative suppressor gene(s) important for the pathogenesis of prostate carcinoma, and that the genetic alterations at 7q31.1 may participate in tumor progression and metastasis.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7 , Neoplasias da Próstata/genética , Alelos , Mapeamento Cromossômico , Humanos , Masculino , Reação em Cadeia da Polimerase , Neoplasias da Próstata/patologiaRESUMO
Gains of chromosome 7 and alterations of the 7q-arm have been frequently observed in multiple cancers using various cytogenetic and molecular genetic techniques. Using PCR analysis of microsatellite markers, we have previously reported that allelic imbalance of 7q31 is common in prostate cancer and is associated with higher tumor grade and advanced pathological stage. In an effort to better understand the chromosome 7 alterations in prostate cancer, we undertook a molecular cytogenetic study of 25 prostate specimens using fluorescence in situ hybridization (FISH) with DNA probes for the chromosome 7 centromere and for 5 loci mapped to 7q31 (D7S523, D7S486, D7S522, D7S480, and D7S490) and 1 locus at 7q11.23 (ELN). Six tumors had no apparent anomaly for any chromosome 7 probe. Nine tumors showed apparent simple gain of a whole chromosome 7, whereas one tumor had apparent simple loss of a whole chromosome 7. Four tumors had gain of the chromosome 7 centromere and additional overrepresentation of the 7q-arm. One tumor had overrepresentation of 7q31 without any apparent anomaly of the chromosome 7 centromere, and one tumor had apparent loss of the chromosome 7 centromere with no apparent anomaly of the 7q-arm. Three tumors had gain of the chromosome 7 centromere and loss of the 7q31 region. Gain of 7q31 was strongly correlated with tumor Gleason score. Multiplex PCR studies of these specimens supported these FISH observations. Mutation screening and DNA sequencing of the MET gene, which is mapped to 7q31, revealed only the presence of simple sequence polymorphisms but no apparent acquired disease-associated mutations. FISH analysis of metaphases from an aphidicolin-induced, chromosome 7 only, somatic cell hybrid demonstrated that the DNA probe for D7S522 spans the common fragile site FRA7G at 7q31. Our data indicate that the 7q-arm, particularly the 7q31 region, is genetically unstable in prostate cancer, and some of the gene dosage differences observed may be due to fragility at FRA7G.
Assuntos
Aberrações Cromossômicas , Fragilidade Cromossômica , Cromossomos Humanos Par 7 , Neoplasias da Próstata/genética , Quebra Cromossômica , Deleção Cromossômica , Sítios Frágeis do Cromossomo , Análise Mutacional de DNA , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Masculino , Monossomia , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas/genética , TrissomiaRESUMO
The applicability of a human tumor colony-forming assay to drug screening was investigated in terms of feasibility, validity, and potential for discovering new antitumor drugs. Feasibility was addressed in a pilot study during which basic methods, appropriate assay quality controls, and a standardized protocol for screening were developed. Considerable variability was noted in the availability and colony growth of different tumor types. The majority of the evaluable experiments utilized breast, colorectal, kidney, lung, melanoma, or ovarian tumors. For many tumor types, little evidence of growth was observed, or only rare specimens formed colonies. Colony-forming efficiencies ranged from 0.05 to 0.11% for the six most useful tumors listed above. A set of quality control measures was developed to address technical problems inherent in the assay. Testing of standard agents in the pilot study established that most of these agents could be detected as active. However, it also identified three assay limitations: compounds requiring systemic metabolic activation are inactive; medium constituents may block the activity of certain antimetabolites; and compounds without therapeutic efficacy may be positive in the assay. The assay categorized nontoxic clinically ineffective agents as true negatives with 97% accuracy. Of 79 compounds which were negative in the current National Cancer Institute prescreen (leukemia P388), 14 were active in the assay. Several demonstrated outstanding in vitro activity and are structurally unrelated to compounds already in development or in clinical trials. A subset of these active compounds were found to lack activity in a P388 in vitro colony-forming assay. This indication of differential cytotoxicity to human tumor cells makes this subset of compounds particularly interesting as antitumor drug leads. The demonstrated sensitivity to most standard agents, discrimination of nontoxic compounds, reproducibility of survival values within assays and between laboratories, and evidence of ability to identify active compounds which were negative in the in vivo prescreen suggest that the human tumor colony-forming assay may be a valuable tool for antitumor drug screening. However, because of technical limitations inherent in the current assay methodology, this must be confined to selected tumor types and limited to screening on a moderate scale.
Assuntos
Antineoplásicos/farmacologia , Ensaio de Unidades Formadoras de Colônias , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaio Tumoral de Célula-Tronco , Células Cultivadas , Humanos , Controle de QualidadeRESUMO
PURPOSE: To determine the efficacy and complication rate of radical prostatectomy (RP) as a treatment option for clinically localized prostate cancer (clinical stage < or = T2c). METHODS: The study was a retrospective analysis of 1,143 consecutive patients (median age, 64 years; range, 38 to 79 y) who underwent RP at one institution (mean follow-up time, 9.7 years). Complications for this study population were compared with those of a contemporary group of 1,000 consecutive patients. RESULTS: Of 1,143 patients, 83 (7%) had a low clinical stage (T1) and 160 (14%) had a low histologic grade (Gleason score < or = 3); 648 (57%) had a high clinical stage (T2b or T2c) and 204 (18%) had a high histologic grade (Gleason score > or = 7). Only 113 (10%) died of prostate cancer, and 177 (15%) developed metastasis. Adjuvant treatment (androgen deprivation or radiation therapy) was given in 197 (17%) patients (> or = pT3) and provided virtually identical results as without adjuvant treatment. The 10- and 15-year crude survival rates for 1,143 patients were 75% +/- 1.5% (SE) and 60% +/- 2.2%, respectively; the cause-specific survival rates were 90% +/- 1.1% and 83% +/- 1.9%, respectively; and the metastasis-free survival rates were 83% +/- 1.3% and 77% +/- 1.9%, respectively (398 men at risk at 10 years and 138 men at risk at 15 years). The 10-year survival rate for patients with Gleason score > or = 7 was 74% +/- 3.9%. Only tumor grade was a significant predictor for disease outcome. The hospital mortality rate decreased from 0.7% for the 1,143 study patients to 0% for the more recent 1,000 patients. Severe incontinence declined to 1.4% for the more recent 1,000 patients. Most patients who underwent RP were healthy (Charlson comorbidity index). CONCLUSION: Survival at 15 years was similar to the expected survival rate. Current morbidity and mortality rates associated with RP were extremely low. Thus, RP has been a viable management option for men with clinically localized prostate cancer who have a life expectancy of more than 10 years.
Assuntos
Prostatectomia , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Quimioterapia Adjuvante , Comorbidade , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prostatectomia/efeitos adversos , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Análise de Sobrevida , Fatores de TempoRESUMO
In an attempt to identify new prognostic markers, we performed fluorescence in situ hybridization (FISH) ploidy analysis of tumor tissue from patients with a targeted stage and histological grade of prostate carcinoma. We identified all 227 patients from the Mayo Clinic radical prostatectomy data base who had a high histological grade pathological stage C (pT3N0M0) tumor removed between 1966 and 1987. After histological review of the paraffin-embedded specimen blocks, 181 cases were suitable for FISH analysis using chromosome enumeration probes for chromosomes 7, 8, 10, 12, X, and Y. FISH detected 80 (44%) diploid, 22 (12%) tetraploid, and 79 (44%) aneuploid tumors. The common aneusomies were of chromosomes 7 and 8, which were present in 51 (28%) and 46 (25%) tumors, respectively. Aneusomies of chromosomes 10, 12, X, and Y were observed in 11 (6%), 15 (8%) 12 (7%) and 16 (9%) tumors, respectively. FISH aneuploid tumors showed a trend of more frequent systemic prostate cancer progression than nonaneuploid tumors (P = 0.060). For individual chromosome anomalies, gains of chromosome 8, aneusomy of chromosome 8, and aneusomy of chromosome Y correlated highly with systemic cancer progression (P = 0.006, 0.013, and 0.021, respectively). Gains of chromosome Y and aneusomy of chromosome Y were associated with an increased prostate cancer death rate (P < 0.001 for both). Multivariate analysis showed that gains of chromosome 8 and aneusomy of chromosome Y were significant independent "predictors" of systemic cancer progression (P = 0.008) and cancer death (P < 0.001), respectively. These results demonstrate that aneuploidy and specific aneusomies detected by FISH are potential markers for a poor prognosis in histological high-grade pathological stage C (pT3N0M0) prostate carcinoma.
Assuntos
Aneuploidia , Cromossomos Humanos Par 8 , Hibridização in Situ Fluorescente , Neoplasias da Próstata/genética , Cromossomo Y , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: The Agency for Health Care Policy and Research (AHCPR) recently released the clinical practice guidelines for the diagnosis and treatment of benign prostatic hyperplasia. Prevalence estimates from a population-based cross-sectional study, the baseline component of a cohort study of the natural history of prostatism, were used to assess their potential impact in the United States. METHODS: The study group comprised a population-based sample of white men aged 50 to 79 years who were randomly selected within age- and residence-specific strata from the Olmsted County, Minnesota, population (1990 census, 105,720). These 1317 men completed symptom assessments and diagnostic evaluations that paralleled the AHCPR guidelines, including the measurement of urinary flow rates and, for a subset (n = 303), ultrasonic determination of postvoiding residual urine volume. RESULTS: The application of the AHCPR benign prostatic hyperplasia diagnostic guidelines to the study cohort (American Urologic Association Symptom Index > 7 and peak urinary flow rate < 15 mL/s) suggests that 17% of men aged 50 to 59 years, 27% of men aged 60 to 69 years, and 35% of men aged 70 to 9 years are eligible to discuss treatment options. Application of these percentages to the 1990 US white population suggests that approximately 5.6 million men aged 50 to 79 years are eligible to discuss treatment options. This number will double by the year 2020 owing to the aging of the population. CONCLUSION: The projected number of men potentially meeting AHCPR guidelines to discuss treatment options for benign prostatic hyperplasia could have a substantial impact on the health care system; this will be compounded by the aging of the population.
Assuntos
Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/terapia , Adulto , Árvores de Decisões , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Hiperplasia Prostática/fisiopatologia , Estados Unidos , UrodinâmicaRESUMO
BACKGROUND: Most studies that have described the sensitivity and specificity of prostate-specific antigen (PSA) as a screening test have been conducted in urology practice settings or in media-based screening programs. The control patients from these settings may have a higher prevalence of urologic disorders that increase serum PSA levels than that of the general population in which screening efforts might take place, leading to biased estimates of sensitivity and specificity. OBJECTIVE: To determine the sensitivity and specificity of serum PSA levels for the early detection of prostate cancer in a population-based setting. PATIENTS AND METHODS: This population-based case-control study was conducted in Olmsted County, Minnesota, where the Rochester Epidemiology Project could identify all incident cases of prostate cancer through passive surveillance of medical care provided to local residents. Case patients were all 177 men (age range, 50-79 years) who were newly diagnosed as having prostate cancer from 1990 through 1992 and had a prediagnostic serum PSA determination (90% of all incident cases). Control patients were randomly selected from the Olmsted County population and had undergone a clinical examination to exclude prostate cancer. RESULTS: The median (25th and 75th percentiles) of serum PSA levels was 9.4 ng/mL (5.4 and 18.6 ng/mL, respectively) for case patients and 1.2 ng/mL (0.7 and 2.1 ng/mL, respectively) for control patients (P < .001). When sensitivity was plotted against 1-specificity, the area under the receiver operating characteristic curve was 0.94 (SE, 0.01). The predictive power declined somewhat with age, with areas under the curve of 0.96, 0.94, and 0.90 for men in their 50s, 60s, and 70s, respectively. When cases were restricted to the 155 men with clinically localized disease, the area under the curve was essentially unchanged (0.94; SE, 0.01) and still much greater than the estimates of 0.75 that were reported from urology practice- and media-based settings. CONCLUSIONS: In a community-based setting, serum PSA levels provide better discrimination between men with and without clinically localized prostate cancer than has been observed in studies that were conducted in urologic practices. These results suggest that previous decision analyses may have underestimated the predictive value of PSA for the detection of prostate cancer in a primary care or community-wide screening program.
Assuntos
Antígeno Prostático Específico/sangue , Neoplasias da Próstata/imunologia , Fatores Etários , Idoso , Estudos de Casos e Controles , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Vigilância da População , Valor Preditivo dos Testes , Neoplasias da Próstata/diagnóstico , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Epidemiologic survey response rates were studied in relation to maneuvers introduced to improve acceptance: (a) variation in invitation letters, (b) the use of a brochure with the recruitment mailing, and (c) options for interview location. The baseline population-based survey of a prospective cohort investigation of the natural history of benign prostatic hyperplasia was used. Invitations to participate were mailed to eligible, randomly selected men aged 40 to 79 years from the Olmsted County, Minnesota, population during 1989 to 1991. Of the 3874 men identified, 2119 (55%) participated. Overall, there was no difference in response rate according to invitation characteristics (chi 2(5) = 8.02, P = 0.16). Nevertheless, response rates varied with age (chi 2(7) = 30.9, P < 0.001) and home location (rural versus Rochester city; chi 2(1) = 76.9, P < 0.001). This suggests the innovations used to bolster acceptance did not materially improve response rates. Further, since response rates were highest for men aged 60 to 74 years, men with more symptoms and free time may have joined the cohort more often than others.
Assuntos
Inquéritos Epidemiológicos , Seleção de Pacientes , Estudos Prospectivos , Adulto , Fatores Etários , Idoso , Métodos Epidemiológicos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Doenças Urológicas/epidemiologiaRESUMO
Although the general approach to management of a sufficient degree of benign prostatic hyperplasia in the past was surgical intervention (transurethral resection of the prostate), the current availability of effective pharmacologic therapy has changed the initial management strategy. At present, two types of drugs are available for treatment of prostatism: (1) selective alpha-adrenergic blocking agents (terazosin, doxazosin, and tamsulosin) and (2) an inhibitor of the 5 alpha-reductase enzyme (finasteride). Pharmacologic blockade of the alpha(1)-adrenoceptors is thought to result in relaxation of the smooth muscle in the prostate and bladder neck, which reduces urethral resistance, improves voiding function, and minimizes the symptoms of prostatism. These effects may be noted by the patient within several weeks after initiation of treatment. The mechanism of action of finasteride is a blocking of the conversion of testosterone to dihydrotestosterone and an associated volume shrinkage of the prostate. On the average, a 25% reduction in prostate volume can be achieved, but a period of 12 months or longer of finasteride therapy is needed for maximal shrinkage and maximal decrease in symptoms of prostatism. The expanding population of middle-aged and elderly men with prostatism of moderate severity will undoubtedly prompt the development of additional pharmacologic options for treatment of prostatism and benign prostatic hyperplasia.
Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Finasterida/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Ensaios Clínicos como Assunto , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Flow cytometry was used to determine the DNA ploidy pattern of paraffin-embedded archival tissue specimens from 90 surgically resected uterine smooth muscle tumors (49 leiomyosarcomas and 41 leiomyomas). The technique of Hedley was used for preparation of paraffin-embedded tissue into single dissociated nuclei, and the method of Vindeløv was used for staining with propidium iodide. Among the 41 leiomyomas, most tumors (88%) had a DNA diploid pattern; the exceptions were two DNA tetraploid/polyploid and three DNA aneuploid samples. The DNA histograms of the 49 leiomyosarcomas (including 6 epithelioid leiomyosarcomas) were classified as follows: 9 cases (18%) exhibited a DNA diploid pattern, 29 cases (59%) had a DNA tetraploid/polyploid pattern, and 11 cases (23%) had DNA aneuploid peaks. Although DNA ploidy pattern cannot be used diagnostically to distinguish malignant from benign uterine smooth muscle tumors, the nuclear DNA ploidy pattern is an easily measured, objective determination that may have important prognostic significance for patients with uterine leiomyosarcomas.
Assuntos
DNA de Neoplasias/análise , Leiomioma/ultraestrutura , Leiomiossarcoma/ultraestrutura , Neoplasias Uterinas/ultraestrutura , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/análise , Feminino , Citometria de Fluxo , Humanos , Leiomioma/genética , Leiomioma/mortalidade , Leiomiossarcoma/genética , Leiomiossarcoma/mortalidade , Pessoa de Meia-Idade , Índice Mitótico , Ploidias , Neoplasias Uterinas/genética , Neoplasias Uterinas/mortalidadeRESUMO
Paraffin-embedded archival tissue samples were used for determination of DNA ploidy by flow cytometry on 117 surgically resected gastric smooth muscle tumors (44 leiomyosarcomas, 53 leiomyomas, and 20 benign leiomyoblastomas). The technique of Hedley was used for preparation of paraffin-embedded tissue into single dissociated nuclei, and the method of Vindeløv was used for staining with propidium iodide. Among the 53 leiomyomas, the DNA ploidy pattern was diploid in most tumors (87%), except for 2 DNA tetraploid/polyploid and 5 DNA aneuploid samples. In comparison, the 20 benign leiomyoblastomas had more frequent abnormal DNA histograms: DNA tetraploidy/polyploidy in 5 (25%) and DNA aneuploidy in 2 (10%). The DNA histograms of the 44 leiomyosarcomas (including 4 epithelioid leiomyosarcomas) were classified as follows: 20 cases (45%) exhibited a DNA diploid pattern, 14 cases (32%) had a DNA tetraploid/polyploid pattern, and 10 cases (23%) had DNA aneuploid peaks. For the patients with leiomyosarcomas, the DNA ploidy pattern was significantly correlated with survival (P less than 0.001), as were tumor grade (P less than 0.001) and tumor size (P less than 0.05). Furthermore, both benign and malignant gastric smooth muscle tumors with DNA tetraploid/polyploid patterns were significantly larger than those with a DNA diploid histogram (P less than 0.05). DNA ploidy pattern cannot be used for diagnosis--that is, to distinguish malignant from benign gastric smooth muscle tumors. For gastric leiomyosarcomas, however, nuclear DNA ploidy pattern is an easily measured objective determination with important prognostic significance.