Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting.

Tumor growth is dependent on angiogenesis, which is thought to be controlled by angiogenic factors. Therefore, the immunoreactivity of the angiogenic cytokine vascular endothelial growth factor (VEGF) was semiquantitatively scored in archival prostate tumors obtained at diagnosis in 221 patients followed expectantly. At diagnosis, 125 patients suffered from clinically localized disease. Median length of follow-up was 15 years, and 57% of the patients eventually died of prostate cancer. All of the tumors exhibited cytoplasmic staining for VEGF. The staining intensity was weak in 47 tumors and moderate and strong in 107 and 67, respectively. VEGF expression was significantly correlated with microvessel density (MVD; median, 43; range, 16-151; P = 0.014), increasing T-classification (P = 0.001), dedifferentiation (P < 0.001), and disease-specific survival (P = 0.013). Strongly VEGF-immunoreactive, neuroendocrine-differentiated (NE) tumor cells were observed in 125 tumors. NE expression was significantly correlated with increasing MVD, increasing T-classification, dedifferentiation, and survival (all, P < 0.001). MVD and NE tumor cell expressions were significant variables in a multivariate analysis that included patients with clinically localized prostate cancer only. VEGF and NE expression were significantly correlated with MVD, clinical characteristics, and disease-specific survival. NE expression was a significant prognostic marker in localized prostate cancer patients, whereas the applied semiquantitatively scoring of VEGF expression was inadequate to make this growth factor provide any additional prognostic information. Moreover, the significant VEGF expression of NE tumor cells suggests an additional important character of these cells in the involvement in disease progression.

[Angiogenesis: prognostic marker in prostatic cancer]. / Angiogenese: prognostisk markør ved cancer prostatae.

Angiogenesis, the formation of new blood vessels, has been suggested to provide important prognostic information in prostate cancer. The aim of this study was to investigate, whether microvessel density (MVD) at diagnosis was correlated with disease-specific survival in a non-curative treated population of prostate cancer patients. MVD was immunohistochemically (factor VIII-related antigen) quantified in archival tumours obtained at diagnosis in 221 prostate cancer patients. The maximal MVD was quantified inside a 0.25 mm2 area of the tumour and the median MVD was 43 (range 16-151). MVD was statistically significantly correlated with clinicopathological characteristics and disease-specific survival. A multivariate analysis demonstrated that MVD was a significant predictor of disease-specific survival in the entire cancer population, as well as in the clinically localized cancer population. These findings suggest that quantitation of angiogenesis reflects the spontaneous clinical outcome of prostate cancer.

Surgical repair of vesicovaginal fistulae--a ten-year retrospective study.

OBJECTIVE: Vesicovaginal fistulae in the western world generally occur as complications to pelvic surgery or radiation therapy of pelvic cancers. We have reviewed our results of vesicovaginal fistula closure procedures over a 10-year period. PATIENTS AND METHODS: From 1985 to 1996, 55 patients were referred to our department due to vesicovaginal fistulae. Five patients had fistulae due to malignant recurrence and one patient was considered inoperable. Thus, 49 patients were operated on. Thirty patients had fistulae resulting from pelvic surgery. Nineteen of the 25 patients admitted with fistulae secondary to radiation therapy of pelvic cancers were operated on. RESULTS: Of the 30 patients with postoperative fistulae, 23 had an abdominal repair and 7 a vaginal repair. A success rate of 90% was achieved after a first closure procedure, as 3 patients within a month experienced a recurrence. These three recurrences were all successfully closed in a second operation, augmenting the success rate to 100% in this group of patients. In the group of patients with fistulae caused by irradiation, a urinary diversion was performed in 12 patients, and in 7 patients a primary attempt to close the fistula was made, either by an abdominal approach (2 patients) or by a vaginal approach (5 patients). The fistula recurred in 6 of these 7 patients. Despite several additional attempts to close the recurrent fistulae, only one patient was successfully operated on. CONCLUSION: It seems that vesicovaginal fistulae resulting from pelvic surgery, in our hands, can be managed successfully either by an abdominal or vaginal approach. For patients with vesicovaginal fistulae resulting from radiation therapy, a urinary diversion appears to be the method of choice.

Microvessel density predicts survival in prostate cancer patients subjected to watchful waiting.

The biological potential of prostate cancer is highly variable and cannot be satisfactorily predicted by histopathological criteria alone. Angiogenesis, the formation of new blood vessels, has been suggested to provide important prognostic information in prostate cancer. The aim of this study was to investigate whether microvessel density (MVD) at diagnosis was correlated with disease-specific survival in a non-curative treated population of prostate cancer patients. MVD was immunohistochemically (factor VIII-related antigen) quantified in archival tumours obtained at diagnosis in 221 prostate cancer patients. Median length of follow-up was 15 years. The maximal MVD was quantified inside a 0.25 mm2 area of the tumour and the median MVD was 43 (range 16-151) mm2. MVD was statistically significantly correlated with clinical stage (P < 0.0001) and histopathological grade (P < 0.0001). When dichotomized by the median counts, MVD was shown to be significantly associated (P = 0.0001) with disease-specific survival in the entire population as well as in the theoretically curable clinically localized subpopulation. A multivariate analysis demonstrated that MVD was a significant predictor of disease-specific survival in the entire cancer population (P = 0.0004), as well as in the clinically localized cancer population (P < 0.0001). These findings suggest that quantitation of angiogenesis reflects the spontaneous clinical outcome of prostate cancer.

DNA ploidy and survival of patients with clinically localized prostate cancer treated without intent to cure.

BACKGROUND: The optimal approach to diagnosis and treatment of localized prostate cancer remains controversial. Deoxyribonucleic acid (DNA) ploidy has been suggested as an important predictor for outcome in prostate cancer. The purpose of this study was to correlate DNA ploidy with disease-specific survival in patients with clinically localized prostate cancer treated with no intent to cure. METHODS: DNA ploidy was determined by flow cytometry in archival formalin fixed, paraffin embedded tumor tissue obtained at diagnosis in 120 patients with clinically localized prostate cancer with a nearly complete follow-up. RESULTS: Ninety (75%) of the tumors were diploid, while only 11 (9%) tumors were categorized as tetraploid. Tumor DNA ploidy (diploid versus nondiploid) significantly associated with histopathological grade (P=0.002) and disease-specific survival (P=0.011), while there was no association with tumor stage (P=0.054). In a multivariate Cox analysis, histopathological grade (P=0.005) was the only significant predictor of disease-specific death, while analyzing the 96 low-grade tumors separately, DNA ploidy became significant (P= 0.024). CONCLUSIONS: Flow cytometric determined nondiploidy was associated with disease-specific death in patients with clinically localized prostate cancer, but DNA ploidy provided additional prognostic information in patients with low-grade tumors only.

Tumor cell proliferation and survival in patients with prostate cancer followed expectantly.

PURPOSE: Prostate cancers have different biological potentials, and aggressive tumors are difficult to identify when still localized. Tumor cell proliferation determined by MIB-1 expression has been suggested as an important predictor for outcome in several human cancers including the prostate. We test the possible prognostic value of tumor cellular proliferation in prostate cancer patients treated with no intent to cure. MATERIALS AND METHODS: Formalin fixed, paraffin embedded tumor tissue obtained at the time of diagnosis from 221 patients originating from a well known complete Danish prostate cancer population was immunohistochemically investigated. The tumor cell proliferation rate was determined using the MIB-1 antibody. Tumors were clinically localized in 57% of the patients. RESULTS: Tumor cell proliferation rate expressed by the MIB-1 score significantly correlated with tumor stage (p <0.001) and malignancy grade (p <0.001). The MIB-1 score, divided into low and high by the median value, showed significant association with disease specific survival in the entire study population (p <0.0001), as well as in the 125 patients suffering from clinically localized disease (p=0.018). Multivariate analyses showed that MIB-1 was a significant (p=0.0003) prognostic factor in the entire population, including advanced disease stages. However, in the theoretically curable clinically localized subpopulation MIB-1 was not significant (p=0.08) contrary to histopathological grade (p=0.02), erythrocyte sedimentation rate (p=0.02) and T classification (p=0.035). CONCLUSIONS: Prostate tumor cell proliferation, expressed by MIB-1 immunoreactivity, demonstrated significant association with disease specific survival. However, MIB-1 is a close alternative to histopathological grade in describing the natural history of clinically localized prostate cancer. The additional prognostic value and the practical consequence of tumor cell proliferation remain to be clarified.

Association between in vivo iododeoxyuridine labeling, MIB-1 expression, malignancy grade and clinical stage in human prostate cancer.

Large variability in the biological behavior of prostate cancer makes prognostic markers important. The extent of tumor cell proliferation has been suggested as an important predictor of clinical outcome. Fifty-five patients suspected of having or with previously diagnosed prostate cancer were labeled in vivo with IdUrd (a thymidine analogue incorporated into DNA in S-phase cells) by intravenous infusion before transurethral resection. IdUrd-labeled cells and MIB-1-positive cells were detected by immunohistochemistry. We found statistically significant associations between the tumor cell proliferation rates measured by in vivo IdUrd labeling and MIB-1 expression in formalin-fixed paraffin-embedded tumors. Good correlations were also found between S-phase fraction, MIB-1 expression, clinical stage and malignancy grade. These results make larger retrospective studies on archival tissue meaningful.

Immunohistochemical BCL-2 and Ki-67 expression predict survival in prostate cancer patients followed expectantly.

The prognostic value of BCL-2 expression, solely and combined with Ki-67 expression, was determined in prostate cancer patients followed expectantly. Furthermore, associations with well established prognostic markers were tested. Formalin fixed, paraffin-embedded tumour tissue obtained at diagnosis was immunohistochemically investigated in 221 patients with a 15 y median follow-up time. BCL-2 protein was expressed in 114 (52%) tumours and was significantly associated with tumour stage (P=0.01). The prognostic value of BCL-2 expression was significant, using both disease-specific (P=0.0015) and overall survival (P=0.005) as endpoint. Patients with a combined BCL-2 negative/Ki-67 'low' tumour had the most favourable prognosis. This combined BCL-2/Ki-67 variable was of independently prognostic value in both the entire population (P=0.0001) and in the clinically localized subpopulation (P=0.035).

The natural history of prostate carcinoma based on a Danish population treated with no intent to cure.

BACKGROUND: Prostate carcinoma is one of the most commonly diagnosed cancers among Western males. In Denmark, the traditional therapeutic approach to prostate carcinoma regardless of tumor stage has been limited to palliative procedures. This conservative approach combined with a complete cancer and personal registration in Denmark provides an opportunity to describe the still debatable natural history of prostate carcinoma. METHODS: The data, originating from hospital records and death certificates, included a complete prostate carcinoma population residing in Aarhus County diagnosed between January 1, 1979 and December 31, 1983. The patients were retrospectively followed from diagnosis until death (median length of follow-up, 15.0 years). RESULTS: The total number of 719 new cases of prostate cancer were diagnosed without any screening programs. Forty-five percent of patients were diagnosed incidentally, and 31% of all patients had organ-confined disease (T1a-T2, Nx, M0). The disease specific survival rates at 1, 5, and 10 years were 80%, 38%, and 17%, respectively, and 62% of the patients died primarily of prostate carcinoma. A multivariate analysis demonstrated a statistically significant relationship between disease specific death and T classification, tumor differentiation, and erythrocyte sedimentation rate at diagnosis. CONCLUSIONS: Prostate carcinoma patients have a poor survival and the majority of the patients diagnosed suffer and die from their disease rather than with it. Nevertheless, approximately one-third of patients neither suffer nor die from their disease. Therefore, the development of prognostic markers to improve the identification of patients who will benefit from early aggressive treatment is important. [See editorial on pages 827-33, this issue.]

[Prostatic cancer: an expensive dilemma]. / Cancer prostatae: et kostbart dilemma.

The aim of this retrospective study is to describe the increasing human suffering as well as the Health-Service costs in Denmark due to palliative treatment of prostate cancer, at a time characterized by a still more aggressive therapeutic approach to prostate cancer but without effective prognostic factors. All 719 prostate cancer patients with residence in Aarhus County diagnosed over a five year period (01.01.79-31.12.83) identified by the Danish Cancer Registry were registered. The data originates from hospital case records and Death Certificates. The national incidence of prostate cancer has increased dramatically even without screening programs. These patients have a considerable need for hospital care and palliative treatment of their cancer disease from the time of diagnosis until death. Based on these data the Danish hospital expenses in 1995 due to palliative treatment of prostate cancer were calculated to amount 0.72% of the total National Health Budget.

The dilemma of prostate cancer--a growing human and economic burden irrespective of treatment strategies.

All prostate cancer patients (719 patients) within a specified population were studied in order to assess both the overall economic burden of this disease to the health-care economy and its burden to the individual patient. The economic burden was estimated as the total lifetime expense (1995 prices) of all palliative hospital treatment. The expenses associated with prostate cancer therapy averaged US$ 19755 per person. By extrapolation, palliative therapy for this disease currently consumes almost 1% of the entire Danish health-care budget. A total of 62% of the patients died from the disease. During hospitalization these patients on average required three times as much hospital care as other patients and about one-third needed regular treatment with opiates or equivalent drugs. Under the present circumstances we cannot recommend an aggressive strategy towards localized prostate cancer even though the incidence of this disease is increasing at an alarming speed and its economic and human costs are excessive.

Erythrocyte sedimentation rate--a predictor of malignant potential in early prostate cancer.

The prognostic value of the erythrocyte sedimentation rate (ESR) was investigated in a population-based prostate cancer study, comparing 556 patients treated with no intent to cure. The data originated from hospital charts and death certificates. A statistically significant relationship between ESR at diagnosis and overall as well as disease-specific survival was demonstrated by univariate and multivariate analyses. A similar result was demonstrated in the 179 patients suffering from clinically organ-confined (T1-2,Nx,M0) disease. In a subpopulation consisting entirely of clinically organ-confined, small (T1), well-differentiated tumors, the dichotomized ESR (< or =20 mm/h vs. >20 mm/h) at the time of diagnosis distinguished between aggressive and non-aggressive tumors. In a small, second prostate cancer population it was demonstrated that ESR was not a surrogate marker for prostate- specific antigen (PSA). Our results indicate that ESR is a significant predictor of survival in early localized prostate cancer.

Treatment of advanced bladder cancer category T2 T3 and T4a. A randomized multicenter study of preoperative irradiation and cystectomy versus radical irradiation and early salvage cystectomy for residual tumor. DAVECA protocol 8201. Danish Vesical Cancer Group.

From 1983 to 1986 183 patients with transitiocellular carcinoma of the urinary bladder, category T2-T4a, entered a randomized study. The patients were allocated to receive either preoperative irradiation (40 Gy) followed by cystectomy or radical irradiation (60 Gy) followed by salvage cystectomy in cases of residual tumor. The two randomization groups were comparable in regard to sex, age, T-categories, tumor size, histological grade and concomitant dysplasia. The two randomization groups included 88 and 95 patients respectively. The treatment plan was followed by 66 patients (75%) in the planned cystectomy group and by 88 (92%) in the radical radiotherapy group of which 27 (28%) were treated with salvage cystectomy. The results showed a trend to a higher survival rate following the combined treatment with preoperative irradiation and cystectomy compared to radical irradiation followed by salvage cystectomy in case of residual tumor, but a statistical significant difference could not be demonstrated. The lack of difference also applied according to the actually given treatment. There was no difference in surgical complications between planned and salvage cystectomy and there were no postoperative deaths among the cystectomized patients. The type of late complications was different in the two treatment groups, but there were no major differences in the number of complications except for the fact that all male patients experienced erective impotence after cystectomy. The T-category, response to radiotherapy and frequency of lymph node metastases were found to be of prognostic importance.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative symptomatology and diagnostic findings in relation to outcome of pyeloplasty in patients with primary hydronephrosis.

Sixty-seven patients, aged 3-71 years, with primary hydronephrosis were operated at our department during a 5-year period. All patients had Anderson-Hynes pyeloplasty. The primary clinical result of surgery was excellent in 63 patients (94%). Of the patients with reduced renographic uptake fraction preoperatively, 38% had a significant gain 6 months after reconstruction, while only 1 patient had a reduction. There was no correlation between the outcome of reconstruction and preoperative history, degree of hydronephrosis on IVP, preoperative functional share on renography or the peroperative finding of aberrant vessels compressing the ureter. It was concluded that surgery should be undertaken on rather wide indications as reconstruction leads to stable or improved renal function regardless of preoperative symptoms or diagnostic findings.

Painful bladder disease: clinical and pathoanatomical differences in 115 patients.

The diagnostic criteria for interstitial cystitis considered as a subgroup of painful bladder disease (that is sensory bladder disease and chronic abacterial cystitis) are not well established. Some urologists rely on symptoms, while others rely on cystoscopic appearance or pathological findings. Among 115 patients with painful bladder disease we compared symptoms, and cystoscopic and urodynamic findings in those with and without detrusor mastocytosis (28 or more mast cells per mm.2) and attempted to elucidate possible differences between the groups. We chose the pathological anatomical criterion of detrusor mastocytosis to be diagnostic for interstitial cystitis. A total of 43 patients had detrusor mastocytosis and other pathological anatomical signs of interstitial cystitis, and 72 had no mastocytosis but the pathological diagnoses of chronic unspecific cystitis, fibrosis of the bladder, detrusor myopathy, intestinal metaplasia and normal findings. When the 2 groups of patients were compared we found no differences in regard to symptoms (pain, dysuria, frequency, nocturia and urgency), frequency of allergy and hysterectomy, duration of symptoms, petechial bleeding during cystoscopy with bladder distension and cystometric findings. The patients with mastocytosis differed from those without mastocytosis in that they were older, and had a higher frequency of hematuria, a higher frequency of a red, scarred and richly vascularized bladder at cystoscopy before distension, and a smaller cystoscopic bladder capacity. We conclude that by dividing patients with painful bladder into 2 groups according to the mast cell counts in the detrusor, certain differences in the clinical findings in the groups can be ruled out. However, in individual patients one cannot note with certainty to which pathological anatomical group the patient belongs, since great overlapping between the groups exists. Whether only patients with detrusor mastocytosis have interstitial cystitis depends on definitions and still remains an open question.

A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease.

Painful bladder disease, sensory bladder disease, chronic abacterial cystitis and interstitial cystitis are ill-defined conditions of unknown etiology and pathogenesis, and, therefore, they are without any rational therapy. Pathogenetic theories concerning defects in the epithelium and/or mucous surface coat (including glycosaminoglycans) of the bladder, and theories concerning immunological disturbances predominate. Sodium pentosanpolysulfate (Elmiron) acts by substituting a defective glycosaminoglycan layer and inhibits complement reactions in inflammatory processes. We compared sodium pentosanpolysulfate versus placebo in a prospective double-blind, clinically controlled multicenter trial of 115 patients with painful bladder disease. Two protocols were used. Protocol A included 43 patients with clinically and pathologically anatomically verified interstitial cystitis (28 or more mast cells per mm.2), and protocol B included 72 patients with a painful bladder and unspecific histological findings. The patients were randomized to receive either sodium pentosanpolysulfate (200 mg. twice daily) or placebo capsules for 4 months. Before and after the trial the patients were evaluated with symptom grading, urodynamics and cystoscopy with distension and deep bladder biopsies. The results showed no difference between the pre-trial and post-trial values in the sodium pentosanpolysulfate and placebo groups in both protocols in regard to symptoms, urodynamic parameters, cystoscopic appearance and mast cell counts. A significant increase in the cystoscopically determined bladder capacity in the sodium pentosanpolysulfate group in protocol A was found. We conclude that no statistically or clinically significant effect of sodium pentosanpolysulfate was found compared to placebo in patients with painful bladder disease.

Constant perfusion provocation in idiopathic hydronephrosis.

Twenty-two hydronephrotic units in 20 patients underwent preoperative pressure flow study in combination with electromyographic study of pelvic and ureteric peristalsis. Ten units had a continuous pressure rise during perfusion, whereas the rest had a stabilization of the intrapelvic pressure below 20 cm. of water. The high pressure group was identical with the low pressure group concerning degree of hydronephrosis judged by intravenous urography and function judged by the two-minute uptake of isotope on the renogram. The major difference was the presence of aberrant vessels which were present in 7 of 10 high pressure units and absent in 8 of 12 low pressure units. Long-term records prior to surgery were obtainable in only 1 patient who had spontaneous progression of hydronephrosis during a ten-year period. This unit had a low pressure response to perfusion. The investigation seems to indicate that pressure flow studies might reveal external obstruction, an obstruction which might not be fundamental to the course of the disease. More studies are needed before consequence are to be taken from urodynamic studies of the upper urinary tract.

Electrophysiological investigation of hydronephrosis in children.

The hydrostatics and dynamics of the upper urinary tract were studied in 12 children with congenital hydronephrosis by means of intrapelvic pressure and bipolar electromyography leads from the pelvis and ureter. Studies were performed intraoperatively with the child under general anesthesia. Measurements were obtained during a baseline period of normal diuresis and during diuresis induced by furosemide. The baseline pressure in the hydronephrotic pelvis was within normal limits in most cases but a tendency toward an increased mean baseline pressure was observed in severe hydronephrosis when the cases were grouped according to the excretory urogram. During diuresis the average pressure increase in severe hydronephrosis was parallel to that in moderate hydronephrosis. The peristaltic pattern showed discoordination in pelvis conus transmission but usually preserved anterograde transmission from the conus down the ureter. The results seem to indicate a slight functional obstruction at the pelvioureteral junction. This obstruction leads to the observed alterations in peristalsis and to a slight elevation of the intrapelvic pressure in more severe cases.