Radical prostatectomy as primary monotherapy in capsular-penetrating prostate cancer. Results over 15 years

Summary Twenty-five patients with locally advanced prostate cancer (stage pT3pN0) underwent pelvic lymphadenectomy and radical prostatectomy and were followed up thereafter for at least 15 years. No hormonal treatment was given prior to tumor progression. Overall and disease-free 15-year survival rates were observed to be 44 and 24 %, respectively. These data suggest that a cure from prostate cancer by radical prostatectomy can be expected in a quarter of patients with capsular penetration. From our results, no justification can be derived to exclude radical prostatectomy from the spectrum of treatment options for patients with capsular penetration of prostate cancer. More detailed analysis of the results depending on the local extent of the tumor and histological grade revealed distinct differences with respect to the risk of progression. Histological grade was the single most predictive parameter of progression. Out of all subgroups of patients with capsular penetration of prostate cancer, those with a poorly differentiated tumor showed the shortest progression-free interval after surgery, the highest level of overall progression and the largest proportion of tumor-related deaths. By contrast, the prognosis was only slightly influenced by the presence or absence of seminal vesicle involvement. The role of adjuvant treatment after radical prostatectomy for patients with stage pT3pN0 prostate cancer or for subgroups of them remains to be determined within the scope of prospective randomized trials.      

Transforming growth factor-β1 (TGF-β1) levels in plasma of patients with prostate cancer and benign prostatic hyperplasia (BPH)

Summary Transforming growth factor-β1 (TGF-β1) is a pleiotrophic growth factor in carcinogenesis and regulars multiple cell functions. We wanted to evaluate the diagnostic meaning of TGF-β1 plasma levels in patients with a biopsy proven prostate cancer. The TGF-β1 blood level was analysed in 394 patients. In 242 patients (group I) the blood was taken before any prostate manipulation and biopsy. The TGF-β1 plasma concentrations were almost similar in the group of patients with a prostate cancer (n = 157) and patients with a benign prostate hyperplasia (n = 85; 14 258 pg/ml versus 14 658 pg/ml, SD 10 516 pg/ml). In 152 patients the blood was taken 6–12 months after radical prostatectomy (group II). There was no significant difference between the patients with a PSA-progress and without PSA-progress after. Our results suggest that TGF-β1 plasma levels can not be used to distinguish between patients with prostate cancer and benign prostate hyperplasia.      

Radical perineal prostatectomy without lymphadenectomy in patients with cT1 + 2, G1 + 2PSA ≤ 10 ng/ml prostate cancer

Summary Pelvic lymphadenectomy in patients with organ confined prostate cancer (PCa) is of no therapeutic value and is questionable in many patients because of the low incidence of metastases. 49 patients with ≤ cT2 b, G1 + 2, PSA ≤ 10 ng/ml underwent laparocopic pelvine lymphadenectomy and radical perineal prostatectomy. Only 1 patient (2 %) had microscopic metastases which were missed on frozen section. Because of these own results and those reported in the literature we then performed in patients with this constellation the radical perineal prostatectomy without lymphadenectomy (n = 32). The differences present in both groups concerning complication rate and morbidity are due to laparoscopic lymphadenectomy and the learning curve in perineal prostatectomy.      

Serum insulin-like growth factor binding protein-3/prostate-specific antigen ratio is a useful predictive marker in patients with advanced prostate cancer

BACKGROUND: Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) play an important role in regulation of prostate cancer cell growth. We studied the prognostic significance of serum IGF-1 and IGFBP-3 levels, and IGF-1/prostate-specific antigen (PSA) and IGFBP-3/PSA ratios in patients with prostate cancer. METHODS: Serum levels of IGF-1, IGFBP-3, and PSA were determined in 112 patients diagnosed with prostate cancer. Serum samples from 32 patients with histologically confined benign prostatatic hyperplasia (BPH) served as control. RESULTS: Serum IGF-1 levels were significantly higher in advanced prostate cancer (n = 84) than in BPH patients (P < 0.01). IGFBP-3 levels were significantly lower in patients with advanced prostate cancer than in localized tumor (n = 28) or BPH (P < 0.05, each). Univariate analysis showed that serum PSA, IGF-1/PSA ratio, IGFBP-3/PSA ratio, T, N and M classifications correlated significantly with relapse-free survival of advanced prostate cancer patients treated with hormonal therapy. Multivariate analysis identified IGFBP-3/PSA ratio as the only significant variable for relapse-free survival (odds ratio 5.81, 95% CI 1.57-21.51). IGFBP-3/PSA ratio was also an independent predictor of cause-specific survival (stepwise analysis, odds ratio 4.86, P < 0.01). CONCLUSIONS: Our results suggested that IGFBP-3/PSA ratio might be a useful prognostic marker of advanced prostate cancer.     

壶腹癌MMP-9、TIMP-1的表达及其与淋巴结转移的相关性研究

目的：探讨基质金属蛋白酶9（MMP－9）、组织金属蛋白酶抑制因子－1在壶腹癌中表达的意义。方法：采用免疫组化S－P法对32例壶腹癌组织进行MMP－9、TIMP－1的检测。结果：MMP－9、TIMP－1在壶腹癌组织中阳性表达率分别为65．6％（21／32），46．9％（15／32），MMP－9的表达与壶腹癌患者淋巴结转移呈正相关（P＜0．05），而TIMP－1的表达则相反，MMP－9和TIMP－1的表达呈负相关（P＜0．01）。结论：MMP－9可作为判断壶腹癌恶性生物学行为的标记物。人工诱导TIMP－1的表达可能抑制肿瘤的浸润和转移，为肿瘤治疗提供了新的方向。     

Urinary levels of matrix metalloproteinases and their tissue inhibitors in nephrotic children

The aim of this study was to determine the effects of cyclosporine A (CyA) on urinary levels of matrix metalloproteinase 2 and 9 (MMP2, MMP9) and their tissue inhibitors 1 and 2 (TIMP1, TIMP2) in steroid-dependent nephrotic syndrome (SDNS). The study group (1) consisted of 18 children SDNS aged 3.5-17.0 years treated with CyA. All NS children were examined three times: (A) at proteinuria relapse, before CyA treatment, (B) after 6 months, and (C) after 12 months of CyA administration. The control group (2) consisted of 18 healthy children. Serum CyA level was assessed by immunofluorescence. Enzyme-linked immunosorbent assay kits for total human MMP2 and 9 and TIMP1 and 2 were obtained from R&D Systems. Compared with healthy controls, urinary MMP9/Cr in NS children before CyA was on the same level and increased during CyA treatment, and urinary TIMP1/Cr was twice as high and increased significantly during CyA treatment. MMP9/TIMP1 in NS children treated with CyA increased, but the difference was not statistically significant. Urinary MMP2/Cr was similar, and urinary TIMP2/Cr was significantly higher in children treated with CyA (p < 0.01). The MMP2/TIMP2 ratio in NS children treated with CyA was significantly lower in comparison with healthy controls (p < 0.01). A negative correlation was noted between urinary MMP2/TIMP2 ratio and serum CyA in NS children (r = -0.541, p < 0.01). An imbalance within the MMP2 and TIMP2 and MMP9 and TIMP1 system may play a role in the pathogenesis CyA nephropathy.     

What is to be done if the margin of resection is positive after radical prostatectomy?

Summary In the last years radical retropubic prostatectomy has become the treatment of choice for locally confined prostate cancer (PCa). However, in the literature local recurrence is described in 4–23 % of patients with clinical stage T1–2 prostate cancer and in 43 % of patients with clinical stage T3 respectively. The problem is further aggravated that postoperatively raised PSA values are detected in 6–8 % of patients with locally confined prostate cancer indicating either local residual tumor or systemic disease. Current datas show that wait-and-watch appears to be the best option for patients with locally confined prostate cancer and positive margins. In case of persistent or raising PSA-values following prostatectomy without detectable local recurrence or metastasis mere local therapy cannot be recommended. Primary radiotherapy should be considered in cases with confirmed clinical local recurrence without distant metastasis. Further prospective and randomized trials have to be initiated to identify the patients with positive margins who will benefit from adjuvant treatment.      

Prostate-specific antigen and prostate acid phosphatase in the detection of early prostate cancer and the prediction of regional lymph node metastases.

Serum values of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) were determined in 180 patients prior to pelvic lymphadenectomy and radical prostatectomy and in 40 patients prior to pelvic lymphadenectomy alone. In all tumor stages, PSA was superior to PAP in detecting cancer of the prostate. By PSA determination using a cutoff level of 4 ng/ml (Tandem assay), 28.8% of the patients with prostate cancer, stage pT2pN0M0, and 17.8% of the cases with a stage pT3pN0M0 tumor could not be detected. All these tumors had been noticed, however, by digital rectal examination. This indicates that PSA determination cannot replace digital rectal examination as a screening method for prostate cancer. In this study, it was possible neither by PSA nor by PAP to define a practicable cutoff level for patients with and without lymph node metastases. A clear differentiation between the stages pT2pN0M0 and pT3pN0M0 was not possible by either PSA or PAP alone.     

Prostate-specific antigen and prostatic acid phosphatase in the detection of early prostate cancer and in the prediction of regional lymph node metastases.

Serum values of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) were determined in 180 patients prior to pelvic lymphadenectomy and radical prostatectomy and in 40 patients prior to pelvic lymphadenectomy alone. In all tumor stages, PSA was superior to PAP in detecting cancer of the prostate. By PSA determination using a cutoff level of 4 ng/ml (Tandem assay), 28.8% of the patients with prostate cancer, stage pT2pN0M0, and 17.8% of the cases with a stage pT3pN0M0 tumor could not be detected. All these tumors had been noticed, however, by digital rectal examination. This indicates that PSA determination cannot replace digital rectal examination as a screening method for prostate cancer. In this study, it was possible neither by PSA nor by PAP to define a practicable cutoff level for patients with and without lymph node metastases. A clear differentiation between the stages pT2pN0M0 and pT3pN0M0 was not possible by either PSA or PAP alone.     

Video-assisted thoracic surgery lobectomy for lung cancer is associated with less immunochemokine disturbances than thoracotomy.

OBJECTIVE: Major surgery is immunosuppressive and could have an impact on postoperative tumor immunosurveillance and recurrence in cancer patients. Low circulating levels of insulin growth factor binding protein (IGFBP)-3 have been linked to advance prostate and the development of colonic cancers. This prospective study examined the early postoperative circulating levels of IGFBP-3, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 in early stage non-small cell lung cancer (NSCLC) patients undergoing major lung resection by VATS versus thoracotomy. METHODS: Forty-two consecutive patients with resectable primary NSCLC were assigned to VATS or thoracotomy approach over a 7-month-period. Blood samples were collected preoperatively and postoperatively on days (POD) 1 and 3 for enzyme linked immunosorbent assay determination of IGFBP-3, MMP-9 and TIMP-1 levels in the serum. RESULTS: There were no demographic differences between the two groups. VATS lung resection was associated with lower levels of MMP-9 and TIMP-1 on POD1 (median 628 vs 1311ng/ml, p=0.009; and 131 vs 211ng/ml, p=0.004, respectively) but higher levels of IGFBP-3 on POD3 (1366 vs 1144ng/ml, p=0.02), when compared with the thoracotomy approach. There was no perioperative mortality. CONCLUSIONS: VATS major lung resection for NSCLC is associated with higher circulating levels of IGFBP-3, and lower levels of MMP-9 and TIMP-1, compared to the thoracotomy approach. The clinical relevance of these postoperative changes on tumor biology following lung resection for cancer warrants further investigation.     

Transurethral holmium laser resection of the prostate – progress in the treatment of BPH?

Summary After the initial enthusiasm subsided lasercoagulation of the prostate has been criticized because the extent of tissue destruction cannot be controlled and many patients may be expected to have significant postoperative obstructive as well as irritative voiding symptoms which may last for weeks. Thanks to new laservaporization techniques these disadvantages have been largely eliminated. With the Holmium laser a real resection of prostatic tissue is possible allowing the surgeon to see the prostatectomy defect immediately and to assess tissue destruction during the operation (“what you see is what you get”). The postoperative voiding disturbances are diminished and comparable to those after TUR-P. At the Departement of Urology of the University of Berne 116 patients were treated with the Holmium laser for benign prostatic hyperplasia (BPH). During the initial learning period 12 patients required a secondary TUR-P due to persistent obstruction and in 12 patients a combined laser/conventional resection was performed due to underestimated prostate size. 5 patients were lost to follow-up. In the remaining 87 patients the median duration of catheterization was 2 days. 10/87 patients required postoperative treatment for urinary tract infection. There were no significant perioperative decreases in hemoglobin and no cases of TUR syndrome. 66 patients have been followed for 6 months and 30 patients have been followed for 12 months. The maximum urinary flow improved from 7 ml/s preoperatively to 15 ml/s at 6 months and 14 ml/s at 12 months. The volume of residual urine decreased from a median of 120 ml preoperatively to 24 ml at 6 and 12 months. The IPSS decreased from a median of 20 preoperatively to 3 at 6 and 12 months. In 50 patients followed with pressure-flow study pre- and 6 months postoperatively detrusor pressure at maximum flow decreased from 90 cm H₂O to 55 cm H₂O and linear PURR sank from 2,06 to 0,6. Taking into account the initial learning curve, transurethral Holmium laser resection of the prostate is a promising method of treatment for BPH as shown by the increase in urinary flow and decrease in detrusor pressure. Although it does not yet rank equally with TUR-P, it is a less invasive alternative providing efficient, safe and almost bloodless treatment of BPH.      

Palliative treatment of painful osseous metastases in prostate carcinoma with the osteotropic β-emitter rhenium-186-HEDP

Summary Systemic administration of strontium-89 is an important option for pain relief in advanced prostate carcinoma with multiple osseous metastases. Recently, rhenium-186-HEDP was introduced as a new substance which has important advantages (shorter physical half-life, scintigraphic imaging, dose distribution). The myelosuppressive effect can be estimated more accurately in advance, so that adverse effects can be reduced and the treatment can be repeated after a shorter period of time and more often. Our study comprises 15 treatments with rhenium-186-HEDP in advanced prostate cancer patients using the 1.4- to 2-fold standard dose. The response rate, estimated as reduction in pain and increase in patient mobility, was 87 % with no major myelosuppressive effects. The mean duration of pain relief was 4–6 weeks. All four patients with repeated therapy were also responding to the second treatment. Radionuclide therapy for painful osseous metastases with rhenium-186-HEDP appears to be an effective and, even at higher doses, safe procedure.      

Positron-emission tomography with 18F-2-fluoro-2-deoxy-D-glucose (18FDG-PET) in the diagnosis of retroperitoneal lymph-node metastases from testicular tumors

Summary In 1991, this prospectively designed study was started to assess the potentials of positron emission tomography with ¹⁸FDG in the diagnostic workup for the detection of lymph node metastases in testicular cancer, since there were no data available concerning this subject at this time. In 54 patients (27 patients with pure seminoma, 27 patients with non-seminomatous tumors) ¹⁸FDG-PET results were compared with the findings obtained with abdominal computed tomography, serum level of tumor markers (AFP, β -HCG), and the histopathological findings after primary or post-chemotherapy retroperitoneal lymph node dissection. In 21 patients with pure seminoma (clinical stage I according to the Lugano classification) ¹⁸FDG-PET results were identical with those of the abdominal computed tomography, so PET does not add relevant informations in this group of patients. In 7 patients presenting with non-seminomatous testicular cancer (stage I), PET was not able to detect the existing micrometastases in 4 patients. In 1/7 case PET examination showed a suspicious focal lesion, this lymph node had 2 micrometastases within inflammatory changes. In 1/7 patient ¹⁸FDG-PET definitely revealed metastatic lesions, while the CT scans where judged to be unobtrusive and tumor marker levels were within the normal range. In the 4 patients with pure seminomas stage II B and II C (N = 6), that have undergone retroperitoneal lymph node dissection following chemotherapy, ¹⁸FDG-PET correctly predicted absence of tumor in 3 out of these 4, and in 1/4 patient the benign nature of a persistent large tumor after two cycles of polychemotherapy was correctly identified wich eventually turned out to be a ganglioneuroma. This lesion falsely was classified as malignant tumor with abdominal computed tomography, and in 2/4 patients post-chemotherapy residual retroperitoneal lesions in the CT scans could not be assessed exactly whether or not malignant tumor was present. In 20 patients presenting with non-seminomatous testicular cancer (stage II and III) ¹⁸FDG-PET was able to demonstrate therapeutic effects of chemotherapy by showing decreasing tracer activity in those regions, that had hypermetabolic foci prior to chemotherapy. It became evident in testicular cancer that there is a single entity which is not characterized by increased glucose metabolism, the mature teratoma. In lesions detected by abdominal computed tomography which do not present increased ¹⁸FDG uptake, mature teratoma as well as scar/necrosis or rare other tumors with normal glucose metabolism can be supposed, but additional characteristics based on different ¹⁸FDG uptake were not observed. In 1/20 case post-chemotherapy PET scan detected a hypermetabolic lesion, which was suspicious for metastatic spread, but in the histopathological examination this lesion was identified as inflammatory tissue reaction. Based on the data reported here in ¹⁸FDG-PET cannot be considered a standard diagnostic tool in the staging examinations in testicular cancer. It is of clinical relevance in patients who present residual tumor after chemotherapy. In this situation ¹⁸FDG-PET is helpful in deciding whether or not a residual mass post-chemotherapy contains active tumor. ¹⁸FDG-PET can not replace retroperitoneal lymph node dissection for staging purposes.      

基质金属蛋白酶(MMP)9、MMP2 mRNA及基质金属蛋白酶抑制剂2 mRNA在人膀胱移行细胞癌中的表达及意义

目的探讨膀胱移行细胞癌中基质金属蛋白酶（MMP）9、MMP2及基质金属蛋白酶抑制剂2（TIMP2）mRNA表达与膀胱肿瘤恶性程度和侵袭性之间的关系及其临床意义。方法采用逆转录-聚合酶链反应（RT-PCR）方法检测36例膀胱移行细胞癌及5例正常膀胱组织MMP9、MMP2、TIMP2mRNA的表达。结果MMP9、MMP2mRNA随着肿瘤分级分期的增高，表达明显增强[x^-值（MMP9）G1：1．218，G2：1．681，G3：1．811；T2～T4：1．840，Tis～T1：1．399；P〈0．01；（MMP2）G1：1．323，G2：1．694，G3：2．060；T2～T4：1．950，Tis-T1：1．505；P〈0．01]，且明显高于正常膀胱组织中的表达[互值（MMP9）0．455，（MMP2）0．461；P〈0．01]。TIMP2mRNA随肿瘤分级的增高而明显减少（x^-值：G1：1．489，G2：1．391，G3；0．580；P〈0．01）。结论（1）MMP9、MMP2mRNA的高表达与BTCC的恶性程度呈正相关；（2）TIMP2mRNA的表达与BTCC的恶性程度呈负相关。     

MMP2、TIMP2在人肾透明细胞癌中的表达及意义

目的　研究基质金属蛋白酶 -2(MMP2)、基质金属蛋白酶组织抑制剂- 2(TIMP2)在肾透明细胞癌(RCCC)中的表达及意义。　方法　采用免疫组织化学SAB法测定 44例RCCC及20例正常肾组织中MMP2与TIMP2蛋白的表达。44例RCCC中病理分级G1 14例,G2 28例,G3 2例,病理分期pT1 24例,pT2 8例,pT3 12例。　结果　MMP2在RCCC中的阳性表达率为 79. 6% (35 /44),高于正常肾组织的 15% ( 3 /20 ),MMP2表达与RCCC病理分级、分期呈正相关 (r=0. 6316,P<0. 01;r=0.5096,P<0. 01);TIMP2在RCCC中的阳性表达率为 100% (44 /44),高于正常肾组织的 35% (7 /20),但TIMP2表达与RCCC病理分期、分级无相关性(r=0.2404,P>0. 05;r=-0.1236,P>0. 05)。在RCCC中MMP2与TIMP2阳性表达率无相关性 (r=0.2015,P>0. 05 )。　结论　RCCC中MMP2表达与RCCC病理分期、分级呈正相关,提示MMP2免疫活动增高不良预后有关系,而TIMP2的反常表达以及作用值得进一步深入研究。MMP2可以作为判断RCCC预后的分子指标。     

PDX-1和MMP-9在结直肠癌中的表达及意义

目的 检测胰腺-十二指肠同源盒-1（pancreatic duodenal homeobox-1,PDX-1）和基质金属蛋白酶-9（MMP-9）在结直肠癌中的表达,探讨其临床价值、相关性及对预后判断的意义.方法 162例结直肠癌标本作为观察组,80例正常结肠黏膜组织作为对照组,应用免疫组织化学技术检测两组中PDX-1和MMP-9的表达,分析其不同临床病理特征中的意义及对预后的判断价值,同时对患者进行5年生存率的随访.结果 PDX-1和MMP-9在结直肠癌中高表达,PDX-1和MMP-9的表达与肿瘤的Dukes分期、淋巴结转移、浸润深度及肿瘤体积密切相关.结直肠癌中PDX-1和MMP-9的表达呈正相关.生存分析显示结直肠癌中PDX-1和MMP-9的表达与预后明显相关.结论 结直肠癌中PDX-1和MMP-9异常表达,二者在肿瘤的发生发展中具有重要作用,术后联合检测PDX-1和MMP-9的表达对判断结直肠癌的预后有重要价值.     

Surgical treatment of metastases in patients with renal cell carcinoma

Summary The aim of the present study was to investigate the efficacy of surgical excision of metastases in patients with renal cell carcinoma (RCC). Eighteen patients with metastatic RCC underwent resection of metastases between 1988 and 1994 (pulmonary: n = 6; skeletal: n = 6; cerebral: n = 3; local relapse: n = 3). Two patients suffered from synchronous appearance of metastases, whereas in 16 cases a metachronous occurrence was observed. In 12 out of a total of 18 patients metastases were completely resected. These patients survived longer than patients in whom metastases were incompletely resected (30 vs. 12 months). Six out of these 12 patients with a complete resection of metastases are presently free of disease for a mean duration of 24 months (10–34 months). The resection of lung metastases seems to be associated with longer survival times. In conclusion, surgical resection of metastases – solitary or single organ site – especially in the lung appears to be justified in patients with RCC. The surgical excision of skeletal metastases at least improves quality of life.      

Meta‐Analyses Qualify Metzincins and Related Genes as Acute Rejection Markers in Renal Transplant Patients

Definition of acute renal allograft rejection (AR) markers remains clinically relevant. Features of T‐cell–mediated AR are tubulointerstitial and vascular inflammation associated with excessive extracellular matrix (ECM) remodeling, regulated by metzincins, including matrix metalloproteases (MMP). Our study focused on expression of metzincins (METS), and metzincins and related genes (MARGS) in renal allograft biopsies using four independent microarray data sets. Our own cases included normal histology (N, n = 20), borderline changes (BL, n = 4), AR (n = 10) and AR + IF/TA (n = 7). MARGS enriched in all data sets were further examined on mRNA and/or protein level in additional patients. METS and MARGS differentiated AR from BL, AR + IF/TA and N in a principal component analysis. Their expression changes correlated to Banff t‐ and i‐scores. Two AR classifiers, based on METS (including MMP7, TIMP1), or on MARGS were established in our own and validated in the three additional data sets. Thirteen MARGS were significantly enriched in AR patients of all data sets comprising MMP7, ‐9, TIMP1, ‐2, thrombospondin2 (THBS2) and fibrillin1. RT‐PCR using microdissected glomeruli/tubuli confirmed MMP7, ‐9 and THBS2 microarray results; immunohistochemistry showed augmentation of MMP2, ‐9 and TIMP1 in AR. TIMP1 and THBS2 were enriched in AR patient serum. Therefore, differentially expressed METS and MARGS especially TIMP1, MMP7/‐9 represent potential molecular AR markers.     

Significance of vitamin D receptor gene polymorphism for risk and disease severity of prostate cancer and benign prostatic hyperplasia in Japanese

OBJECTIVE: Recent studies have demonstrated an association between vitamin D receptor (VDR) genotype and prostate cancer. Currently, there is a scarcity of data regarding the association of VDR genotype with benign prostatic hyperplasia (BPH). The purpose of this study was to investigate the TaqI VDR polymorphism in Japanese prostate cancer patients, Japanese BPH patients and Japanese controls in order to determine if an association exists between VDR genotype and the risk of developing prostate cancer and BPH as well as disease severity. METHODS: 110 prostate cancer patients, 83 BPH patients and 90 male age-matched controls were genotyped for a previously described TaqI restriction fragment length polymorphism at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of a TaqI restriction site with individuals being classified as TT, Tt or tt. RESULTS: The frequency of the genotype tt was higher in the control group (6.7%) compared to patients with prostate cancer (1.8%) and BPH (3.6%) but this was not statistically significant. However, the frequency of the genotype TT was significantly higher among prostate cancer patients with locally advanced or metastatic disease (T3/ T4/N1/M1) compared to controls (p = 0.001). In addition, the genotype TT was significantly higher among prostate cancer patients with a high Gleason grade of tumor (grade 5) compared to controls (p = 0.0001). In addition, the genotype TT was statistically higher in BPH patients with high prostate volume (volume >50 cm(3)) compared to controls (p = 0.001). CONCLUSION: These data demonstrate that VDR genotype plays an important role in determining the risk of more advanced and aggressive prostate cancer as well as prostatic enlargement in Japanese men.