Sex and the clinical value of body mass index in patients with clear cell renal cell carcinoma.

BACKGROUND: An increased body mass index (BMI) is significantly associated with favourable prognosis in renal cell carcinoma (RCC). This study investigated the associations among sex, BMI, and prognosis in clear cell RCC patients. METHODS: We retrospectively analysed 435 patients with clear cell RCC who underwent a nephrectomy. The associations among sex, BMI, clinicopathologic factors, and cancer-specific survival (CSS) were analysed. RESULTS: As a continuous variable, increased BMI was associated with higher CSS rate by univariate analysis in the whole population (hazard ratio, 0.888 per kg m(-2); 95% confidence interval, 0.803-0.982; P=0.021). A sub-population analysis by sex demonstrated that BMI was significantly associated with CSS in men (P=0.004) but not in women (P=0.725). Multivariate analysis revealed BMI to be an independent predictor of CSS in only men. CONCLUSION: Body mass index was significantly associated with clear cell RCC prognosis. However, the clinical value of BMI may be different between men and women.

Delivery of replication-competent retrovirus expressing Escherichia coli purine nucleoside phosphorylase increases the metabolism of the prodrug, fludarabine phosphate and suppresses the growth of bladder tumor xenografts.

We have developed unique replication-competent retroviral (RCR) vectors based on murine leukemia virus that provide improved efficiency of viral delivery, allow for long-term transgene expression and demonstrate an intrinsic selectivity for transduction of rapidly dividing tumor cells. The purpose of this study was to evaluate the in vivo transduction efficiency and the therapeutic efficacy of the RCR vector mediated delivery of Escherichia coli purine nucleoside phosphorylase (PNP) in combination with fludarabine phosphate for bladder cancer. We constructed vectors containing green fluorescent protein (GFP) gene (ACE)-GFP) or PNP gene (ACE-PNP). KU-19-19 bladder tumors exhibited 28.3+/-16.1, 46.6+/-5.8 and 93.7+/-7.8% of GFP expression on 14, 18 and 26 days after intratumoral injection of ACE-GFP, respectively. GFP expression could not be observed in normal tissues surrounding the injected tumors. No detectable polymerase chain reaction products of GFP gene could be observed in any distant organs. Intratumoral injection of ACE-PNP, followed by systemically administered fludarabine phosphate, significantly inhibited the growth of pre-established KU-19-19 tumors. Our results indicate that RCR vectors are a potentially efficient gene delivery method and that the RCR vector mediated PNP gene transfer and fludarabine phosphate treatment might be a novel and potentially therapeutic modality for bladder cancer.

Incidence, location, and significance of periprostatic and periseminal vesicle lymph nodes in prostate cancer.

Pelvic lymph node metastases in prostate cancer (PCa) carry an ominous prognosis. Periprostatic/periseminal vesicle (PP/PSV) lymph nodes are present in some individuals, but their incidence and involvement by metastases are unknown. A total of 832 of 1233 (67.5%) patients who underwent radical retropubic prostatectomy for clinically localized PCa at the Methodist Hospital from 1983 to 1998 by one surgeon (P.T.S.) had whole-mount slides available for review. Of these, 92 (11.1%) had received preoperative therapy (radiation in 48 [5.8%], hormonal in 44 [5.3%]). Slides were examined with the naked eye by placing them on a white illuminated background, and any area suggestive of a lymph node in PP/PSV fat was confirmed microscopically and assessed for the presence of metastases. Thirty-seven of 832 patients (4.4%) had 39 PP/PSV lymph nodes-one bilateral, one with two ipsilateral lymph nodes, and the rest solitary. Sizes ranged from 0.7 to 4.5 mm (mean 1.8 mm). Distribution was 2 of 39 (5.1%) apical, 3 of 39 (7.7%) mid, 17 of 39 (43.6%) base, and 17 of 39 (43.6%) seminal vesicle. Five patients (0.6%) had metastatic PCa to the PP/PSV lymph nodes. All five patients were of advanced pathologic T stage [one pT3a (extraprostatic extension) and four pT3b (seminal vesicle invasion)]. Only two of those five (40%) had metastases (all ipsilateral) to pelvic lymph nodes. In three of five (60%) the metastases were isolated to the PP/PSV lymph nodes. Metastases were to the lymph nodes in the periseminal vesicle fat in four of five (80%) of the cases and in the fat surrounding the base of the prostate in one of five (20%). Four of five (80%) patients recurred. Histologic grade (Gleason score), tumor volume, and failure (recurrence) rates were significantly different between the five patients with metastases and the 32 patients without metastases to the PP/PSV lymph nodes (p <0.0001, p <0.0001, and p = 0.005, respectively). However, there was no evidence that an individual patient's probability of having a PP/PSV lymph node increased with resection of the neurovascular bundle (p = 0.7698). PP/PSV lymph nodes are uncommon, but based upon these limited data, it appears that patients with metastases limited to PP/PSV lymph nodes have a poor prognosis (similar to pelvic lymph node metastases) and should be included in the American Joint Committee on Cancer (AJCC) Staging Manual to indicate "N1" if positive for metastases.

[Minimally invasive therapy for bladder and prostate cancer].

Recently, minimally invasive therapy has been a key word in the medical field. Many new therapies have been developed in the field of urology. In this area, bacillus Calmette-Guerin (BCG) instillation therapy, transurethral resection of the bladder tumor and intra-arterial infusion with irradiation therapy are noted as minimally invasive therapies for bladder cancer. Laparoscopic prostatectomy, brachytherapy, three-dimensional conformal radiotherapy (3D-CRT) and high-intensity focused ultrasound (HIFU) have also been developed as minimally invasive therapies for prostate cancer. Though the establishment of the validity of each treatment will still take time, the best treatment for each patient should be chosen case by case, including considerations of postoperative quality of life and economic efficiency.

Prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens.

We assessed whether the quantification of cancer invasion into the perineural space influences the prognosis of patients treated with radical prostatectomy. We conducted a retrospective study of clinical and pathologic features in 640 consecutive patients with clinical stage Tla-T3bNXM0 prostate cancer who were treated with radical retropubic prostatectomy by the same surgeon between 1989 and 1995. None had received preoperative hormonal therapy or radiotherapy. Detailed pathologic analysis, including the presence and maximum diameter of perineural invasion (PNI), was performed by 2 pathologists. Treatment failure was defined as either a serum prostate-specific antigen (PSA) level > 0.4 ng/mL and rising or initiation of adjuvant therapy. The median follow-up time was 48 months (range, 1 to 111 months). Overall, PNI was detected in 477 patients (75%). The progression-free 5-year probability rate after prostatectomy for patients with PNI was 70% +/- 3% compared with 94% +/- 2% for patients without PNI (P <.001). The mere presence of PNI was not an independent predictor of progression in a Cox proportional hazards analysis when the other established prognostic factors (serum PSA level, pathologic stage, surgical margin, and tumor volume) were considered. However, the increasing diameter of the largest focus of PNI was strongly associated with other established prognostic factors and the probability of progression after radical prostatectomy. Although little adverse effect in patients with PNI < 0.25 mm was seen 5 years after surgery, those with a PNI diameter of 0.25 to 0.5 mm were significantly (P <.001) less likely to remain free of progression; only 36% of those with PNI of 0.5 to 0.75 mm (P <.001) and 14% of those with PNI > or =0.75 mm (P =.002) were free of progression. In a Cox proportional hazard analysis, the PNI diameter was an independent predictor of prognosis. These results support that the measurement of the PNI diameter, easily recorded from prostatectomy specimens, could add important information to the prognosis of prostate cancer patients. Controversy regarding the significance of PNI may result from the lack of quantitative assessment of PNI in previous studies.

Primary Gleason pattern as a predictor of disease progression in gleason score 7 prostate cancer: a multivariate analysis of 823 men treated with radical prostatectomy.

Gleason score (GS) is a powerful predictor of disease progression in men with prostate cancer (PCa). The majority of clinically localized prostate cancers, however, are moderately (GS5/6) or moderate to poorly (GS7) differentiated tumors with indeterminate prognosis. Differences in disease progression between patients with GS5/6 and GS7 tumors suggest the presence of any component of high-grade tumor (Gleason pattern [GP] 4/5) worsens prognosis markedly. Indeed, McNeal et al. have shown that quantification of GP4/5 provides prognostic information beyond the standard GS. Few investigators have analyzed whether primary and secondary GPs are important prognostically within GS7 PCa. All 823 whole-mount radical prostatectomy specimens with GS7 from a single surgeon (P.T.S.) were analyzed. Tumors were either 3+4 or 4+3, and primary GP was assigned by the same pathologist (T.M.W.). A total of 643 patients with 3+4 tumors and 180 patients with 4+3 tumors were studied. Statistical analysis using the log-rank test showed a significant difference in recurrence-free survival between patients with primary GP4 and those with GP3 (p <0.0001). However, in multivariate analysis with preoperative prostate-specific antigen, total tumor volume, surgical margin status, and the presence or absence of seminal vesicle involvement, extraprostatic extension, and lymph node metastasis, the primary GP did not retain independent significance (p = 0.0557). GS7 PCa is a heterogeneous group of tumors. In this cohort of men with GS7 tumors treated by radical retropubic prostatectomy, primary GP showed a significant correlation with other histologic and clinical predictors of disease progression; however, it was not independently predictive of disease progression in multivariate analysis (p = 0.76).

[Extragonadal seminoma with testicular microlithiasis: a case report].

A 43-year-old men presented with left supraclavicular growing mass. Ultrasonography revealed a 31 x 21 mm solid mass with a homogeneous echoic pattern. Lymph node metastasis of some malignant neoplasms was highly suspected. However, whole body evaluation with computed tomographic scan revealed no findings in the primary region. In addition, tumor markers including alpha fetoprotein, human chorionic gonadotropin and carcinoembryonic antigen were within normal limits. Then, extirpation of supraclavicular mass was performed and pathological diagnosis was made as pure seminoma. Evaluation of testicle by ultrasonography revealed a diffuse calcification. However, histological examination of biopsy specimen of testicle revealed no malignancy. The mass was finally diagnosed as extragonadal or "burned-out" pure seminoma. The patient received two courses of Peplomycin, vinblastine and cisplatin (PVP) therapy, and there has been no evidence of recurrence for 34 months.

Efficacy and limitations of delayed/salvage radiation therapy after radical prostatectomy.

OBJECTIVE: To assess the kinetics of prostate specific antigen (PSA) and the degree of PSA suppression, to better understand the efficacy and limitations of delayed/salvage radiation therapy after radical prostatectomy. PATIENTS AND METHODS: The PSA doubling time was calculated in patients with biochemical failure after radical prostatectomy and in those who underwent delayed/salvage radiation therapy. Patients in whom PSA was undetectable by conventional assay after irradiation were followed using a hypersensitive PSA assay. RESULTS: Of 125 patients who underwent radical prostatectomy for clinically resectable prostate cancer, 47 developed biochemical failure at a mean of 11.8 months after surgery; 38 of these patients underwent radiotherapy (36 for isolated biochemical failure and two for local progression with elevated PSA levels). The mean (sd) PSA doubling time after surgery was 14.6 (16.2) months (n=44) and after radiation therapy it was 13.3 (23.9) months (n=32). Eleven of 30 evaluable patients (37%) had a sustained PSA suppression lasting at least 12 months after radiotherapy. Only the time to biochemical failure after surgery approached statistical significance for predicting a durable response to radiotherapy (P=0.08). The mean nadir value of PSA in the 11 patients with at least 12 months of sustained PSA suppression was 0.032 ng/mL at 26.9 months. CONCLUSIONS: The rapidity with which PSA levels double after surgery may provide a clinically significant indication of the nature of these recurrent tumours, which deserve the best possible attempt at cure. Slow-growing tumours with longer PSA doubling times may be better candidates for delayed/salvage radiation therapy. Larger studies involving more patients are needed to determine whether the PSA doubling time can define subgroups for which specific treatment strategies should be developed.

Parathyroid hormone-related protein is an independent prognostic factor for renal cell carcinoma.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) has been shown to be the principal cause of humoral hypercalcemia associated with renal cell carcinoma (RCC). Recent studies have demonstrated that the amino-terminal region of PTHrP has growth factor-like activities, suggesting it may play a role in the development of RCC. In this study, expression of the carboxy-terminal region of PTHrP was assessed immunohistochemically and its significance in predicting the prognosis of RCC was studied. METHODS: Forty radical nephrectomy specimens were immunostained with a murine monoclonal antibody (9H7) against the carboxy-terminal region (amino acids 109-141) of PTHrP using the streptavidin-peroxidase enzyme conjugate method. Staining intensity was evaluated semiquantitatively and compared with clinicopathologic features of the corresponding RCC. RESULTS: Immunoreactivity to 9H7 was observed to be localized to the cytosol of tumor cells at various staining intensities. There were 30 cases (75.0%) with strong staining and 10 cases (25.0%) in which staining was weak or nonexistent. Staining intensity showed no significant correlation with gender, tumor greatest dimension, stage, or grade. Tumors of the clear cell type expressed PTHrP to a significantly greater extent than tumors of the granular cell type. Tumor recurrence was significantly greater in the weakly stained or unstained group compared with the strongly stained group (P = 0.035). Multivariate analysis indicated that PTHrP expression and tumor stage were equally significant prognostic indicators in RCCs measuring <10 cm in greatest dimension. CONCLUSIONS: Evident PTHrP(109-141) expression is present in the majority of RCCs. The results of the current study indicate PTHrP(109-141) may be a possible marker of cellular differentiation and may be useful for predicting recurrence free survival in RCC patients after radical nephrectomy.

[Histological characteristics and clinical significance of Japanese prostate cancer with low levels of prostate specific antigen of 4.0 ng/ml or lower].

PURPOSE: They set a normal limit of prostate specific antigen (PSA) to 4.0 ng/ml in Tandem R assay at most institutions. We investigated clinical and histological characteristics of prostate cancer based on whole mount step-section histology of radical prostatectomy specimens, and taking notice of Japanese prostate cancer whose levels of PSA are less than 4.0 ng/ml in normal levels. MATERIALS AND METHODS: One hundred and twenty-two patients underwent radical prostatectomy for clinically resectable prostate cancer at University Hospital from February 1992 to April 1997. Clinicopathological findings were stratified according to the preoperative PSA levels in 111 patients without preoperative endocrine therapy. Immunohistochemical study for PSA was conducted in 7 randomly selected patients. RESULTS: Of the patients 22 (19.8%) had normal (4.0 ng/ml or lower) preoperative serum PSA. Mean tumor volume in this PSA range was 1.5 cm3 with one pT 0 case included. Pathologically organ confined, potentially curable disease (< pT 3) was found in 17 (77.3%) patients and extracapsular extension and seminal vesicle invasion in 5 (23.8%), respectively. No patients had positive pelvic lymph nodes. Well differentiated tumors of Gleason scores 2-4 were found in 9 (40.9%) of the patients, moderately differentiated tumors (Gleason scores 5, 6) in 5 (22.7%) and poorly differentiated histology (Gleason scores 7-10) in 7 (31.8%). Sixteen (72.7%) patients had clinically significant tumors (> 0.5 cm3, Gleason score > or = 7). All 7 patients had positive staining for PSA, but its intensity did not correlate with serum PSA levels. CONCLUSIONS: Many prostate cancers found in surgical specimens were clinically significant despite the low levels of PSA and potentially curable by definitive treatment. Age, co-morbidity and other clinicopathological variables as well as PSA levels should all be taken into account when treatment options are discussed.

BRCA1 gene mutation and loss of heterozygosity on chromosome 17q21 in primary prostate cancer.

The tumor suppressor gene BRCA1 on chromosome 17q21 has been characterized and shown to be mutated in patients with familial breast and ovarian cancer. Several studies examined the relatives of women with breast cancer and noted an association with ovarian and prostate cancer. This study investigated 24 human prostate cancer specimens for BRCA1 gene mutations and loss of heterozygosity (LOH) on chromosome 17q21 assessed by the polymerase chain reaction. LOH was identified using 7 highly polymorphic tandem repeat markers on chromosome 17q21, in addition to an analysis of the whole coding region of the BRCA1 gene. Four of the 24 prostate cancer specimens showed LOH at one or more loci, all of which were histologically poorly differentiated (4 of 11) and stage D (4 of 15). One of the 24 cases showed a germ-line mutation of the BRCA1 gene, and a sister of this patient died of ovarian cancer. It appears that the BRCA1 gene is not frequently involved in the development of primary prostate cancer.

Pathological features and prognostic significance of prostate cancer in the apical section determined by whole mount histology.

PURPOSE: We test the hypothesis that cancer in the apical section of the prostate is an important independent factor in predicting the progression of clinically localized prostate cancer. MATERIALS AND METHODS: We analyzed clinical data and whole mount histological step sections for 500 patients who had undergone radical retropubic prostatectomy for clinically localized prostate cancer. RESULTS: Cancer was in the apex of the prostate in 175 patients (35%). These patients had a larger cancer and higher incidence of positive surgical margins, and were more likely to have a poorly differentiated cancer than the 325 patients without cancer in the apex. However, the presence of apical cancer was not a significant predictor of clinical or prostate specific antigen progression in either univariate or multivariate Cox proportional hazards models when analyzed for the entire group or only in patients with tumor confined to the prostate. CONCLUSIONS: Apical cancer in a radical prostatectomy specimen is simply a sign of a larger volume cancer and is not independently associated with an increased risk of clinical or prostate specific antigen progression.

Factors influencing morbidity in patients undergoing transurethral resection of the prostate.

OBJECTIVES: Transurethral resection of the prostate (TURP) has become the primary method to relieve bladder outlet obstruction for patients with benign prostatic hyperplasia (BPH). Data from 3861 consecutive patients with BPH who underwent TURP from 1971 to 1996 at our hospital were retrospectively analyzed. METHODS: The patients were classified into two groups comprising 1930 patients who underwent TURP from 1971 to 1985 (early group) and 1931 patients who underwent TURP from 1985 to 1996 (late group). Risk factors associated with blood transfusions and perioperative complications were analyzed in these patients. RESULTS: Mortality, morbidity, and blood transfusions were noted in 5 (0.1 %), 516 (13.4%), and 507 (13.1%) patients, respectively. The blood transfusion and morbidity rates decreased over the 25-year period (P <0.001, chi-square test for trends), which was reflected in a decrease in these rates in the late group (6.1% and 9.5%, respectively) compared with those of the early group (20.2% and 17.2%, respectively). Postoperative bleeding and morbidity were closely related to prostatic gland size and operating time. The most significant differences for the risk of a blood transfusion were related to resection time, the amount of tissue resected, age, and the decade (1970s, 1980s, or 1990s) in which the surgery was performed (P <0.0005), whereas resection time was significantly correlated with morbidity (P <0.0005). As risk factors for each complication, the time of surgical resection, the decade of surgery, and the amount of tissue resected directly correlated with the incidence of extravasation and hemostatic procedures (P < or =0.003), whereas the incidence of postoperative epididymitis positively correlated with a preoperative vasectomy and a closed drainage system (P <0.0005). CONCLUSIONS: Since the 1970s, the rates of blood transfusions and morbidity have decreased for patients undergoing TURP. Advances in techniques, instrumentation, and surgical and perioperative management, including anesthesia, have made TURP a relatively safe procedure, and it remains an effective means for treating patients with BPH.

[Mutation of p53 gene and genomic instability in testicular tumors].

BACKGROUND: During the past decade, studies of human cancer have begun to yield molecular information on the identify of the multiple genetic changes in the development and progression of tumorigenesis. We investigated alterations of p53 and genomic instability in testicular tumors. MATERIALS AND METHODS: Polymerase chain reaction (PCR) single-strand conformation polymorphism was performed for analysis from exons 5 to 8 of p53 gene in 22 cases and PCR-microsatellite instability analysis using 8 microsatellite markers were conducted in 19 cases of testicular tumor. RESULTS: No mutations were noted for exons 5 to 8 of the p53 gene. Differences in unrelated microsatellites for tumor and corresponding normal DNA were detected in 5 of 19 (26.3%) cases examined. Alterations noted in more than 2 microsatellites were observed in 3 of 19 (15.8%) and categorized as replication error (RER) phenotype. Two of 7 (28.6%) seminomatous and 1 of 12 (8.3%) non-seminomatous testicular tumors patients showed RER. Two of 16 (12.5%) stage T1-3N0M0 and 1 of 3 (33.3%) stage T1-3N1-3M0-1 showed RER. CONCLUSIONS: Alterations in microsatellite instability may be involved in the development of testicular tumor.

[The definition and frequency of clinically unimportant prostate cancer in the patients treated with radical prostatectomy].

In autopsy studies more than 20% of men > 50 years old have prostate cancer, yet the lifetime risk of developing clinical cancer of the prostate is much less. Thus, early detection should not aim to all cancers, but only those that are potentially morbid or lethal. In the detailed morphometric examination of radical prostatectomy specimens, we found only 10% of the 610 patients had clinically unimportant cancer. Of the 207 patients with non-palpable tumor, 11% had clinically unimportant cancer compared to 10% of the 403 patients with palpable tumor (p = 0.52). And these non-palpable tumor were more likely to be curable disease compared to palpable tumor (66% versus 57%, p = 0.007). All recent studies indicated that most of prostate cancers which were detected with current diagnostic tests were clinically important and, therefore, should be treated aggressively.

Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer.

This study was performed to assess the relationship between the level and extent of prostatic capsular invasion (PCI) by cancer and the clinical and pathological features and prognosis of early-stage prostate cancer. We conducted a retrospective analysis of the clinical (age, stage, grade, prostate specific antigen [PSA] level) and pathological (tumor volume, stage, grade, surgical margins) features of 688 patients treated with radical prostatectomy to determine the pathological features and probability of recurrence associated with various levels of PCI. Radical prostatectomy specimens were serially sectioned and examined by whole-mount technique. Progression-free probabilities (PFP) after radical prostatectomy were determined by Kaplan-Meier and Cox proportional hazards regression analysis. Progression was defined as a rising serum PSA < or = 0.4 ng/mL or clinical evidence of recurrent cancer. Increasing clinical stage, Gleason grade in the biopsy specimen, and pretreatment serum PSA levels were each associated with increasing levels of PCI (P < .001). In the radical prostatectomy specimen, increasing levels of PCI were significantly associated with increasing tumor volume (P < .001), Gleason grade (P < .0001), seminal vesicle involvement (SVI, P < .001) and lymph node metastases (+LN, P < .001). None of 138 patients without capsular invasion had SVI or lymph node metastases (+LN), and all remained free of progression, even though some had large volume (up to 6.26 cm3) or poorly differentiated (Gleason sum up to 8) cancers. Invasion into the capsule (n = 271) was occasionally associated with SVI (6%) or +LN (3%) and a significantly (log-rank test) lower PFP of 87% at 5 years. Focal and extensive extraprostatic extension (EPE) were associated with progressively increased risk of SVI and +LN and lower PFP (73% and 42%, respectively). In a multivariate analysis, the level of PCI was an independent prognostic factor (P < .001). There is a strong association between the level of invasion of cancer into or through the prostatic capsule and the volume, grade, pathological stage, and rate of recurrence after radical prostatectomy. Prostate cancer does not appear to metastasize in the absence of invasion into the capsule regardless of the volume or grade of the intracapsular tumor. Subclassification of patients according to the levels of PCI provides valuable prognostic information.

Use of systematic biopsy results to predict pathologic stage in patients with clinically localized prostate cancer: a preliminary report.

BACKGROUND: The purpose of this study was to determine the ability of clinical tests to predict advanced pathologic stage (seminal vesicle invasion, pT3c, or pelvic lymph node metastases, pN+). METHODS: T stage, PSA, PSA density, and pathologic features in systematic biopsy specimens were correlated with pathologic stage in 190 consecutive patients with clinically localized (T1-3) prostate cancer detected by systematic needle biopsies and treated with radical prostatectomies. RESULTS: Thirty-three patients (17%) had an advanced pathologic stage cancer (pT3c or pN+). In logistic regression analysis, the total length of cancer in all biopsy cores (P < 0.0005), the percent of poorly-differentiated cancer in each specimen (P< 0.021), and serum PSA (P< 0.028) were the only significant predictors of advanced stage. A model was constructed to predict advanced stage: if the PSA was > or = 6 ng/mL and 4 or more biopsy cores were positive and the total length of cancer in all cores was > or = 20 mm and at least 10% of the cancer was poorly-differentiated, then 14 (93%) of 15 patients had an advanced pathologic stage cancer compared to 11% of the remaining 175 patients (P < 0.0005). CONCLUSION: The pathologic features of cancer in systematic needle biopsy specimens more accurately predicts which patients have advanced stage cancer than standard clinical tests alone.