Fluorescence in situ hybridization analysis of matched primary tumour and lymph-node metastasis of D1 (pT2-3pN1M0) prostate cancer

OBJECTIVE: To describe the chromosomal numerical changes present in primary prostate tumours and their matched lymph-node metastases, to identify a clonal cell migration process which could account for the metastatic behaviour. MATERIALS AND METHODS: Twenty-eight cases of unsuspected stage D1 (pT2-3pN1M0) prostate cancer were detected among patients who had a radical prostatectomy for clinically localized prostate cancer. Fluorescence in situ hybridization (FISH), using centromeric probes to enumerate chromosomes 7, 8, 10 and 12, was used to assess numerical chromosomal changes. FISH analysis was used on isolated nuclei obtained from matched primary tumours and their lymph node metastases. RESULTS: Of the 28 suitable cases it was possible to complete the study in 18 pairs of matched tissues; the remainder were excluded because of insufficient tissue or poor preservation of at least one of the tissues. There was cytogenetic change (aneuploidy) in 16 of the 18 primary tumours, the most common being monosomy 8, detected in 14, followed by trisomy 7, in 13 aneuploid tumours. All lymph node metastases were aneuploid by FISH. As in the primary tumours, monosomy 8 and trisomy 7 were the most common cytogenetic alterations, in 13 and 15 of the lymph node tissues. FISH analysis showed a high correlation (83%) in the cytogenetic pattern of changes between the primary tumours and their lymph node metastases. Moreover, a similar number of cells had the most common aneusomies when comparing prostate and the lymph node tissues. CONCLUSIONS: These results show a similar pattern of cytogenetic alteration in the primary tumour and its lymph node metastasis, characterized by the frequent presence of trisomy 7 and monosomy 8, suggesting that clonal cell selection is not involved in the metastatic process.     

Neuroendocrine differentiation in stage D2 prostate cancers

Objectives: Chromogranin A (CgA) and neuro‐specific enolase (NSE) are gaining acceptance as markers of several types of neuroendocrine tumors and the concentration of CgA and NSE have been reported to be elevated in relation to neuroendocrine differentiation of prostate cancer. The aim of the present study was to examine the correlation between the immunohistochemical (IHC) findings and serum value for CgA and NSE in untreated stage D₂ prostate cancer patients. Methods: Immunohistochemistry was carried out using antibodies against CgA and NSE in 58 patients and, pretreatment serum CgA and NSE levels were measured by monoclonal immunoradiometric assay in 18 patients with stage D₂ prostate cancer treated by androgen ablation. We examined the relationship of the pretreatment serum level to IHC findings for CgA and NSE in prostate cancer patients to clinicopathological parameters, and prognosis. Also, we evaluated the correlation of IHC findings to serum levels for CgA and NSE. Results: There was a statistically significant correlation between CgA positivity and serum CgA level (P = 0.0421). However, there was no statistically significant correlation between NSE positivity and serum NSE level (P > 0.05). We divided stage D₂ patients into three groups according to IHC positivity of CgA and NSE. The cause‐specific survival was significantly poorer in patients with strongly positive (++) patients for independent CgA and combined CgA with NSE (P = 0.0379). Multivariate analysis of cause‐specific survivals in patients with stage D₂ prostate cancer demonstrated that strong IHC stain was considered as independent variable associated with greater risk of death (P = 0.0142). Conclusion: Neuroendocrine differentiation in stage D₂ prostate cancer has attracted considerable attention as a potentially findings prognosis. Thus, CgA had a stronger relationship between serum levels and IHC positivity in contrast to NSE, suggesting clinical usefulness as a tumor marker in predicting the extent of neuroendocrine differentiation in prostate cancer.     

Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients

BACKGROUND: Oncogene amplification and chromosomal anomalies are found in many solid tumors and are often associated with aggressiveness of cancer. We evaluated the frequency and the association of c-myc and androgen receptor (AR) gene amplification and gain of chromosome 8 or X in prostate cancer in Japanese patients. METHODS: We examined a total of 42 prostate cancer specimens, using fluorescence in situ hybridization (FISH). Dual-labeling hybridization with a directly labeled centromere probe for chromosome 8 or X together with a probe for the c-myc or AR locus was performed. RESULTS: Gain of chromosome 8 was identified in 54.8% of specimens and was associated with Gleason sum and nuclear anaplasia in untreated prostate cancers. c-myc gene amplification was found in 14.3% of specimens. Gain of chromosome X was identified in 42.9% of specimens. AR gene amplification was detected in 0 of 37 untreated prostate cancers, but in 1 of 5 hormone-refractory prostate cancers. CONCLUSIONS: Our results suggest that c-myc and AR gene amplification and gain of chromosome 8 or X may be associated with the development and progression of prostate cancers. These results obtained in Japanese cases are consistent with the results observed in prostate cancer in Western countries.     

Detection of C-erb B2 gene amplification in bilharzial associated bladder cancer using fluorescence in situ hybridization

BACKGROUND: Gene amplifications are common events in different tumor types and may confer diagnostic, prognostic, or therapeutic information for patient management. Fluorescence in situ hybridization (FISH) represents a standard methodologic approach for testing for this genetic alteration, as it is rapid, reproducible and extremely reliable in detecting presence of C-erb-B2 gene amplification for clinical utility. PATIENTS AND METHODS: In this study, FISH is used in a series of archival human bilharzial bladder cancer specimens to evaluate for the presence of cerbB-2 gene alterations in the most common malignant tumor in bilharzial endemic areas, e.g., Egypt and some other countries. The study included 40 cases, 30 males and 10 females. Their ages ranged between 30 years and 76 years (median: 51 years). Twenty-one cases had squamous cell carcinoma, 16 had transitional cell carcinoma, two had adenocarcinoma, and one case had undifferentiated carcinoma. RESULTS: Thirteen out of 40 tumor samples (32.5%) show evidence of true C-erb-B2 gene amplification. Of the remaining samples, 24 (60%) show no gene amplification and three (7.5%) fall into the borderline category with a ratio between one and two C-erb-B2 genes/cell relative to chromosome 17 centromeres. No evidence of chromosome 17 polysomy was found in any cases scored as single copy with the C-erb-B2 probe. CONCLUSION: No significant association was found between gene amplification and any of the tested clinicopathologic parameters or tumor recurrence except for tumor grade where higher tumor grades tended to be associated with more C-erb-B2 gene amplification (P = 0.01) thus reflecting more tumor aggressiveness. So, the amplification of C-erb-B2 in bilharzial associated bladder cancer is probably not independently related to clinical outcome of patients.     

应用荧光原位杂交技术检测骨肉瘤患者人表皮生长因子2受体基因扩增状态

目的 应用荧光原位杂交技术检测骨肉瘤人表皮生长因子2受体(HER-2/neu)基因是否存在扩增.方法 以HER-2/neu及17号染色体为探针,应用荧光原位杂交技术分析23例骨肉瘤病例HER-2/neu基因扩增情况,以HER-2/neu基因扩增阳性的乳腺癌病例作为阳性对照.结果 FISH检测23例骨肉瘤标本,无一例出现HER-2/neu基因扩增.结论 骨肉瘤中出现HER-2/neu基因扩增的频率极低,骨肉瘤患者可能不适合应用以HER-2/neu基因为靶点的靶向性药物.     

荧光原位杂交技术在膀胱移行细胞癌诊断中的应用

目的 应用荧光原位杂交技术对膀胱癌患者尿液中脱落细胞染色体基因异常做出判断,从而探究其在诊断膀胱癌中的应用价值,为膀胱癌患者寻求一种无创的诊断膀胱癌的新方法.方法 应用荧光标记的3、7、17号染色体着丝粒探针及定位于p16基因的探针检测膀胱癌患者尿液中脱落细胞的染色体基因变化,从而对膀胱癌作出诊断,同时将FISH诊断膀胱移行细胞癌敏感性与尿细胞学结果进行比较.结果 FISH和尿细胞学诊断膀胱癌的总敏感性分别为85.5%和34.2%.FISH诊断膀胱癌的总敏感性高于尿细胞学(P<0.05).在肿瘤的各种分期分级中,FISH诊断膀胱癌的敏感性也高于尿细胞学.且FISH敏感性随肿瘤病理级别的增高而增高(P<0.05),但不随肿瘤临床分期的增高而增高(P＞0.05).结论 FISH对于膀胱移行细胞癌的诊断有较高的敏感性,有可能成为在中国人群中检测膀胱移行上皮癌的有效手段.     

Loss of heterozygosity on chromosome 2 in Japanese patients with prostate cancer

BACKGROUND: Loss of heterozygosity (LOH) on chromosome 2 is thought to occur only occasionally in prostate cancer (PCa), but allelic losses in this region are frequent in other types of human cancer, such as lung, thyroid, head and neck, and cervix. Here, we show a high-resolution deletion map of markers on chromosome 2 in Japanese patients with PCa. METHODS: Tissue samples were obtained from 66 patients with PCa. DNA from normal, tumor, or metastatic tissue was used as the template for polymerase chain reaction amplification for LOH using 24 microsatellite markers on human chromosome 2. RESULTS: Nineteen of the 66 cases (29%) showed LOH for at least one locus on chromosome 2. LOH on 2p was observed more frequently in cancer death cases than in organ confined and regional diseases (P < 0.001). Paired DNAs were available from both primary and metastatic tumors in the eight cases of cancer death; among those pairs, we detected LOH on 2p in four primary tumors, and in all metastatic foci (P < 0.05). Detailed deletion mapping in these tumors identified four distinct commonly deleted regions on 2p 16.3, 2p 12-cent, 2q 21.3, and 2q 23.1-2q 32.1. CONCLUSIONS: These results suggest that inactivation of putative tumor suppressor genes on chromosome 2 that may play an important role in the progression of Japanese patients with PCa.     

Health-related quality of life in Japanese men with localized prostate cancer: Assessment with the SF-8

Objectives:   To evaluate health related quality of life (HRQOL) using the Medical Outcomes Study 8-items Short Form Health Survey (SF-8) questionnaire in Japanese patients with early prostate cancer.
Methods:   A cross-sectional analysis was done in 457 patients with prostate cancer treated with radical prostatectomy, external beam radiotherapy, brachytherapy, androgen deprivation therapy, and watchful waiting or a combination these therapies. General HRQOL was measured using the Japanese version of the SF-8 questionnaire and disease-specific HRQOL was assessed using the Japanese version of the Extended Prostate Cancer Index Composite.
Results:   The external beam radiotherapy group reported significantly lower values for the physical health component summary score (PCS) in comparison to the radical prostatectomy and brachytherapy groups ( P  < 0.05). In the analysis of both the PCS and the mental health component summary score (MCS) over time after treatment, higher scores with time were found in the radical prostatectomy group. No significant change over time after androgen deprivation therapy in the PCS was found. In contrast, the MCS was found to deteriorate in the early period, showing a significant increase over time.
Conclusions:   SF-8 in combination with the Extended Prostate Cancer Index Composite has shown to be a helpful tool in the HRQOL assessment of Japanese patients treated for localized prostate cancer.     

Proteomic analysis of normal and malignant prostate tissue to identify novel proteins lost in cancer.

BACKGROUND: Alterations of important protein pathways, including loss of prostate secretory granules, and disruption of the prostatic secretory pathway have been identified as early events in malignancy. In this study, proteomics was used to map the differences in protein expression between normal and malignant prostate tissues and to identify and analyze differentially expressed proteins in human prostate tissue with particular regard to the proteins lost in malignancy. METHODS: Small quantities of normal and malignant prostate tissue were taken fresh from 34 radical prostatectomy cases. After histological examination, proteins were solubilized from selected tissues and separated using two-dimensional electrophoresis. Using image analysis, the proteome of normal and malignant tissues were mapped and differentially expressed proteins (present in normal and absent in malignant tissue) were identified and subsequently analyzed using peptide mass finger printing and N-terminal sequencing. Western blotting and immunohistochemistry were performed to examine expression profiles and tissue localization of candidate proteins. RESULTS: Comparison of protein maps of normal and malignant prostate were used to identify 20 proteins which were lost in malignant transformation, including prostate specific antigen (PSA), alpha-1 antichymotrypsin (ACT), haptoglobin, and lactoylglutathione lyase. Three of the 20 had not previously been reported in human prostate tissue (Ubiquitin-like NEDD8, calponin, and a follistatin-related protein). Western blotting confirmed differences in the expression profiles of NEDD8 and calponin, and immunohistochemistry demonstrated differences in the cellular localization of these two proteins in normal and malignant prostate glands. CONCLUSIONS: The expression of NEDD8, calponin, and the follistatin-related protein in normal prostate tissues is a novel finding and the role of these important functional proteins in normal prostate and their loss or reduced expression in prostate malignancy warrants further investigations.     

Treatment of androgen-independent prostate cancer with dexamethasone: A prospective study in stage D2 patients

PURPOSE: In order to evaluate the efficacy of dexamethasone in the treatment of Japanese men with androgen-independent prostate cancer, a prospective study was conducted using prostate-specific antigen (PSA) as a primary end-point. METHODS: Nineteen Japanese men with stage D2 androgen-independent prostate cancer were registered and treatment was started. After ruling out anti-androgen withdrawal syndrome, they were treated with dexamethasone (1.5 mg daily). Patients were monitored for PSA, symptoms, radiologic response, survival rate, time to disease progression, time to treatment failure and complications. RESULTS: Prostate-specific antigen levels decreased in nine patients (50.0%); five (27.8%) showed a 50% or greater decrease and two (11.1%) showed an 80% or greater decrease. For the nine patients, the mean duration of PSA response was 7.3 months and the median duration was 2.1 months (range, 1.2-27.5+). Bone pain, which was noted in 13 patients at study entry, improved in seven patients (53.8%). Of nine patients who had serial radiographic examinations with bone scan, three (33%) showed partial response, two (22%) were stable and four (44%) showed disease progression. Treatment was well tolerated, except for one patient who suffered a severe pulmonary infection. CONCLUSION: Dexamethasone decreased PSA levels and produced subjective symptomatic improvement in the patients with stage D2 androgen-independent prostate cancer.     

Effectiveness of mass screening for the prognosis of prostate cancer patients in Japanese communities

BACKGROUND: A study was conducted to investigate the effectiveness of mass screening (MS) for prostate cancer in Japanese communities using the long-term follow-up results. METHODS: Subjects were 279 patients with prostate cancer detected by MS in Gunma prefecture (MS group) and 624 patients with prostate cancer who did not undergo screening (non-MS group). From the follow-up data, the prognoses were compared between the groups. RESULTS: The ratio of patients with Stage II cancer was higher for the MS group (59.1%) when compared to non-MS group (25.3%). As a whole, the prognosis of the MS group was more favorable than that of the non-MS group for relative survival rate. Prognosis was especially favorable for patients with Stage III prostate cancer in mass screening group considering the effect of lead-time bias. CONCLUSIONS: Early detection and longer survival of the patients with prostate cancer detected by mass screening suggested the effectiveness of prostate cancer screening.     

Value of prostate specific antigen α1-antichymotrypsin complex for the detection of prostate cancer in patients with a PSA level of 4.1–10.0ng/mL: Comparison with PSA-related parameters

BACKGROUND: The aim of the present study was to evaluate the usefulness of prostate specific antigen alpha1-antichymotrypsin complex (PSA-ACT) in the differential diagnosis of prostate cancer in patients with a PSA level of 4.1-10.0 ng/mL compared to several PSA- and PSA-ACT-related parameters. METHODS: Serum samples were obtained from 103 patients with no evidence of malignancy on biopsy and 29 with histologically confirmed prostate cancer. All patients had pretreatment serum PSA levels between 4.0 and 10.0 ng/mL. The different forms of serum PSA, including total PSA (tPSA), free PSA (fPSA) and PSA-ACT were measured using immunofluorometric techniques with different monoclonal antibodies against PSA and ACT. Furthermore, tPSA and PSA-ACT densities of the whole prostate (PSAD and ACTD, respectively) and the f-to-tPSA and the f-to-PSA-ACT ratios (F/T ratio and F/ACT ratio, respectively) were calculated. RESULTS: The differences between patients with prostate cancer and benign prostatic disease were significant with respect to all six parameters examined in this study. Analysis of receiver operating characteristics revealed that the areas under the curve for PSA-ACT, ACTD and the F/ACT ratio were larger than those for tPSA, PSAD and the F/T ratio, respectively. However, there were no significant differences in discrimination between benign and malignant diseases among these six parameters. CONCLUSIONS: In patients who have an intermediate serum PSA level, PSA-ACT and its associated parameters may not be significantly superior in the differential diagnosis between prostate cancer and benign prostatic diseases compared to tPSA and its traditional relatives.     

Determinants of quality of life in prostate cancer patients: A single institute analysis

ObjectiveTo determine factors that influence quality of life in prostate cancer patients.Patients and methodsPatients with pathologically verified prostate cancer and treated at the National Cheng Kung University Hospital were invited to fill out the World Health Organization Quality of Life-BREF questionnaires at the outpatient clinic. We explored the determinants of quality of life including age, education, income, marital status, disease stage, and treatment modality using a mixed-effects model.ResultsFrom January 2013 to July 2014, a total of 248 patients were investigated and 404 measurements were performed. Among them, there were 110 patients, 48 patients, and 90 patients with localized, locally advanced, and metastatic disease, respectively. After adjustment for comorbidities and other confounders, patients who were married showed a significantly higher score in the domains of physical health, social relationships including sexual satisfaction, and opportunities to obtain information and leisure activities. A higher income was associated with a higher score in physical, psychological, and environment domains. Patients with metastatic disease showed lower scores in the physical domain.ConclusionOur data demonstrated that marital status is an important determinant of quality of life in prostate cancer patients besides other sociodemographic factors. Clinicians are advised to provide more social support recourses for patients who do not have a partner.     

Lymphovascular invasion is an independent predictor of prostate‐specific antigen failure after radical prostatectomy in patients with pT3aN0 prostate cancer

Objectives: To investigate the association of lymphovascular invasion (LVI) in radical prostatectomy (RP) specimens with prostate‐specific antigen (PSA) failure in patients with pT3aN0 prostate cancer (PCA). Methods: We retrospectively reviewed the clinical records of 94 patients with pT3aN0 PCA treated with RP alone. All of the 94 patients were prospectively observed without any treatment until PSA failure was confirmed. We investigated the association of LVI with the adverse pathological findings in RP specimens and the PSA failure‐free survival rate. The Cox proportional hazard model was used to elucidate predictors of PSA failure. Results: Median follow up was 47.4 months (quartile range 9.1 to 146.8). LVI was found in 26 (27.7%) of the 94 patients. In a multivariate analysis, PSA (P = 0.0054) and LVI (P = 0.015) were significant and independent predictors of PSA failure. Stratifying patients into four risk groups by LVI status and PSA level, the PSA failure‐free survival rate in patients with negative LVI and PSA ≤10 ng/mL was significantly better than any other groups (positive LVI and/or PSA >10 ng/mL). Conclusions: Adjuvant therapy would not be indicated to patients with pT3aN0 PCA with negative LVI and PSA ≤10 ng/mL.