The role of pelvic lymph node dissection as a predictive and prognostic factor in bladder cancer.

The aim of this study was to evaluate the value of pelvic lymph node dissection (PLND) performed as a separate procedure in a consecutive Danish bladder cancer cohort and also to analyse if the number of lymph nodes excised had an impact on outcome. From 1992 to 1998, 339 cystectomy candidates were retrospectively reviewed. Based on a preoperative PLND, 248 patients (10% N+) underwent radical cystectomy and 91 (87% N+) underwent radio- or chemotherapy. The median follow-up was 6.3 years. PLND was able to separate N+ from N0 patients with a false-negative rate of 3% compared with the following cystectomy. Lymph node-positive patients treated with cystectomy (n=24) all died from their bladder cancer. Therefore, accurate pathological N classification before the treatment decision seems worthwhile. The median number of lymph nodes excised was six and the number of lymph nodes had an independent prognostic impact on survival. This underlines the need for guidelines for surgical lymphadenectomy and the pathological assessment of lymph nodes in bladder cancer.

Acute and late radiation damage in mouse bladder: a comparison of urination frequency and cystometry.

Functional damage in the mouse bladder was measured sequentially from 1 to 53 weeks after irradiation with a range of X ray doses (10 to 30 Gy). Damage was assessed from the independent assays of urination frequency and cystometric measurement of bladder volume at a constant intravesical pressure. There was an early, transient wave of damage from 1 to 3 weeks after bladder irradiation. During this period the urination frequency was increased to greater than or equal to 2 times control levels in 20 to 70% of the mice (depending on dose) after 15 to 30 Gy. Bladder volume was reduced to less than or equal to 50% of control values in 20 to 40% of the mice after doses of 20 to 30 Gy. This early damage usually lasted for less than 1 week and occurred at times ranging from 5 to 21 days, independent of dose. There was no significant correlation between response as measured by the two assays on an individual animal basis during the early period. The incidence of reduced bladder volume, measured cystometrically in anesthetized mice, tended to be less than the incidence of increased urination frequency, measured in non-anesthetized animals. Late bladder damage developed from 16 to 40 weeks after doses of greater than or equal to 20 Gy, and the time of onset was inversely related to dose. Less than 20% of mice treated with 10 to 15 Gy developed late bladder damage as assessed by increased urination frequency or reduced bladder volume. Late bladder damage was irreversible and there was a good correlation between response of individual animals as measured by the two assays. We conclude that changes in both urination frequency and bladder volume can be used as quantitative measures of early and late functional damage after bladder irradiation. The early, transient damage was not associated with changes in the urothelium or muscle layers of the bladder, whereas the late, persistent damage was accompanied by epithelial denudation and focal hyperplasia, with fibrosis and ulceration after higher doses.

Cystometric evaluation of early and late irradiation damage to the mouse urinary bladder.

The present study reports a simple, non-invasive, in vivo method for detecting early and late radiation damage to the mouse urinary bladder using transurethral bladder filling. The study also describes a useful experimental model for irradiation of mouse urinary bladder without any concomitant irradiation of the rectum and bony structures and maximal shielding of the small intestine. Within 30 days after single fraction bladder irradiation at 5-30 Gy, repeated cystometric investigations reveal a change in the reservoir function of the bladder illustrated by a considerable dose-dependent decrease in the compliance of the bladder wall. The changes in the reservoir function is reversible hence the bladder function is restored after another month. At various time intervals after the irradiation, however, the late radiation damage appears, the time of manifestation being dose-dependent. This final change is irreversible and consistent with the clinically known contracted bladder.

Fractionation sensitivity and latency of late radiation injury to the mouse urinary bladder.

Transurethral bladder filling is a functional, non-invasive, in vivo assay of early and late radiation injury to the mouse bladder. Fractionated irradiations using single doses or 2, 3, 5, or 10 dose fractions in an overall time of 4 or 4.5 days, with a range of total doses, were given to the bladder of 12-14 week-old C3D2F1/Bom mice. In 372 mice, bladder volume at an intravesical pressure of 20 mmHg was measured before irradiation and at regular intervals thereafter. The endpoint for late bladder injury was a volume of less than 50% of the median pretreatment volume in all animals, occurring more than 30 days after irradiation. This endpoint was reached after a latent period ranging between 35 and 401 days. Fractionation and latency parameters were estimated using a mixture model. There was a highly statistically significant dose-dependency of the latent period (p < 10(-8)). The alpha/beta ratio was estimated at 5.8 Gy [95% confidence limits (3.6; 8.8) Gy] for 250 kVp X-rays. Thus late radiation injury in the mouse urinary bladder is one of the least sensitive late endpoints with respect to change in dose per fraction. Introducing early bladder injury as a variable in the model improved the fit significantly (p = 0.03), but the alpha/beta ratio remained unchanged. Thus the hypothesis that late bladder injury may be, at least in part, consequent upon early injury did not explain the relatively high alpha/beta ratio for this late endpoint.

Late changes in the normal mouse bladder after irradiation alone or in combination with cis-DDP or cyclophosphamide, assessed by stereological analysis.

Stereological analysis has been performed to investigate the late changes in the normal mouse bladder one year after radiation alone (10-25 Gy) or radiation (10-15 Gy) combined with cyclophosphamide (CTX), 100 mg/kg, or cis-diamminedichloroplatinum (II) (cis-DDP), 6 mg/kg. A significant increase in total volume of urothelium was found in the group treated with CTX combined with radiation compared with the control. The total volume of connective tissue in the muscular layer in the groups which received X-rays only showed a significant increase compared to the control. There also seemed to be an increase in the amount of connective tissue in muscular tissue, although this was not statistically significant, in the groups treated with CTX and irradiation compared with CTX alone. This indicates the importance of radiation in the development of late damage. Results from bladders treated with cis-DDP alone or combined with radiation were statistically inconclusive due to the small number of animals in each group. The group treated with CTX and radiation (15 Gy) showed a significant decrease in the total volume of lamina propria, but no difference was found in the other treatment groups when comparing connective tissue, the muscular layer or the amount of vessels and capillaries with their corresponding control groups. Stereological analysis seems a feasible method to demonstrate late bladder tissue changes encountered after irradiation alone or combined with chemotherapy.

Absorption of doxorubicin hydrochloride during bladder washings in treatment of noninvasive bladder tumors.

The absorption of doxorubicin hydrochloride (Adriamycin) in or through the urothelium has been determined as the difference between the instilled amount and the amount recovered after complete drainage of the bladder in 9 patients suffering from superficial urinary bladder tumors (grade I-II). A total of 22 absorption experiments were done. The relative deficit was found to be between 0 and 16 per cent (median 4 per cent). One of the reasons for the variations in the relative deficit was probably intravesical bleedings. One hundred seventy-two mumol. (100 mg.) doxorubicin was dissolved in 100 ml. isotonic saline, and the instilled liquid was retained in the bladder for one hour. No patient showed any sign of systemic side effects caused by doxorubicin. The results seem to indicate that it is possible to use a dose for intravesical instillation which is five times as high as the maximum dose for intravenous administration.

Metabolic acidosis: an emerging problem in patients with intestinal segments as part of urinary diversion. A report of two cases.

Two cases of severe metabolic acidosis are reported, one of which led to severe disablement of the patient due to osteomalacia. Both patients had a urinary diversion performed years beforehand, one consisting of a continent ileal Kock reservoir and the other of a urethral Kock pouch. The mechanisms of these complications and their treatment are discussed.

Acute changes in the bladder reservoir function after irradiation alone or in combination with chemotherapy: a matter of mouse strain.

The acute change in bladder reservoir function was investigated in two different strains of mice [C3H/HaA and C3D2F1 (C3H/Tif x DBA/2)] to elucidate strain dependent differences in response. Both groups were investigated by repeated bladder fillings over a period of 30 days after various treatments. The end point was a 50% reduction in bladder volume at an intravesical pressure of 20 mmHg. Treatment consisted of irradiation alone, chemotherapy alone [Cyclophosphamide (CTX) or Cis-diamminedichloroplatinum (II) (Cis-DDP)] or irradiation in combination with either drug. A significant difference in response between the two strains of mice was noted in the groups treated with CTX alone, irradiation alone and a combination of Cis-DDP plus irradiation. The importance of a strain-dependent response in experimental assays is emphasized.

Transurethral treatment of invasive tumours of the urinary bladder (T1, T2): recurrence and progression.

Forty-six newly diagnosed patients with T1 and T2 bladder tumours were treated with radical transurethral resection. During a six-month period more than 50% of the tumours recurred. Subsequently progression of tumours was seen within 24 months in 30 and 50% of the patients with T1 and T2 tumours, respectively. Prognosis with regard to the progression was significantly better in patients with Ta recurrence at first TUR control than in patients with invasive recurrent tumours.

Transabdominal ultrasonography plus urine cytology in control of benign bladder tumours.

Transabdominal ultrasonography can detect bladder tumours down to 5 mm in diameter, and in combination with urine cytology it is a potential alternative to cystoscopy for control of bladder tumour patients. This modality was compared with cystoscopy in 260 investigations on patients with previous non-invasive tumours. Of 153 negative ultrasonographies 55 (21%) were false negative, overlooking 15 tumours above 5 mm (including 5 flat papillomatous areas), 30 tumours 5 mm or less and 10 flat dysplastic lesions (diagnostic sensitivity 64%). In 14 of the false negative ultrasonographies urine cytology was abnormal, increasing the combined diagnostic sensitivity to 73%. Most overlooked tumours above 5 mm were in bladder neck, anterior wall and dome. Of 89 positive ultrasonographies 15 were false positive (diagnostic specificity 83%). Two patients developed invasive tumours in the study period. One was detected by ultrasound and urine cytology, the other - a flat muscle invasive tumour - was not. Ultrasonography plus urine cytology is only acceptable for control of patients with very little risk of invasive and few non-invasive recurrences, i.e. patients with previous Ta, grade I or II transitional cell tumours and no recurrences after 1 or 2 control cystoscopies.

Early and late changes in the normal mouse bladder reservoir function due to irradiation and cis-DDP.

Early and late changes in the reservoir function of the mouse bladder were investigated after radiation alone or a combination of radiation and cisplatinum (cis-DDP). Bladder function was investigated by repeated cystometries. Treatments consisted of either single fraction radiation (5-10-15-25-30 Gy) or 20 Gy in combination with cis-DDP (6 mg kg-1; i.p.) administered at various time intervals from 14 days before until 14 days after radiation. At two selected time intervals (15 min and 4 h before) radiation was given at different dose levels (5-10-15-20 Gy). Within 30 days after irradiation a dose-dependent early response was noticed both in the radiation alone group and the group where cis-DDP was administered 15 min before radiation. The dose-response curve showed a slight but non-significant shift to the left in the combined treatment group (dose effect factor (DEF) = 1.18). Investigation of the early change in bladder reservoir function in the animals treated with 20 Gy alone or a combination of 20 Gy plus cis-DDP at various intervals in relation to irradiation demonstrated a significant increase in response when cis-DDP was administered 24 h and 15 min before and 4 h, 72 h and 336 h after 20 Gy (P less than 0.05). The reversible nature of the early damage was demonstrated. Late response was irreversible and significantly increased in most groups were cis-DDP was administered from 168 h before until 72 h after compared to radiation alone. Comparing groups treated with radiation alone with groups where cis-DDP was administered 15 min and 4 h before radiation revealed DEF values up to 1.45 (P less than 0.05), reflecting the significantly larger response in combined treatment groups. Survival was significantly decreased in all combined treatment groups compared to groups treated with radiation only and likewise survival was decreased in the group treated by cis-DDP alone compared to control (no treatment at all).

A pharmacological in vitro study of the mouse urinary bladder at the time of acute change in bladder reservoir function after irradiation.

Mouse urinary bladder strips were investigated as to whether the acute change in bladder reservoir function seen after irradiation might be due to major changes in basic nerve and smooth muscle functions. The release mechanism of acetylcholine, cholinergic and non-cholinergic nerve activation explored by indomethacin and potassium channel activation were investigated. It was concluded that the normal mouse bladder is partly cholinergically and partly non-cholinergically innervated. The role of acetylcholine is of the same importance as in other rodents. However, it was not possible to distinguish any difference between normal and irradiated mouse bladders in respect to nerve and smooth muscle function.

Intravesical therapy of noninvasive bladder tumors (stage Ta) with doxorubicin and urokinase.

A double-blind investigation was done on 44 patients with noninvasive bladder tumors (stage Ta) given randomized intravesical treatment with doxorubicin with or without urokinase. The bladder tumors were not removed before treatment in any patient. No significant difference in response was detected between the 2 types of treatment. Of the patients 86 per cent responded to treatment, including 52 per cent who achieved complete remission. At 12 and 42 months after termination of treatment 42 and 35 per cent of the patients, respectively, remained free of recurrent tumor.

Phase II study of adriamycin, 5-fluorouracil, levamisole, and irradiation in carcinoma of the bladder.

Since July 1976, 19 patients with carcinoma of the bladder have been treated with adriamycin, 5-fluorouracil, and levamisole combined with radiotherapy (60 Gy [6000 radsA1/24 fractions/6 weeks). Chemotherapy and radiotherapy were initiated simultaneously, with the entire treatment lasting 7--8 months. Three months after the completion of radiotherapy, 14 of the 18 patients in whom cystoscopy was performed were found to be in complete remission. Overall, 17 of the 19 patients have responded to the treatment and 15 patients have at some time shown complete remission. The toxic effects seen were myelosuppression, nausea, vomiting, diarrhea, loss of weight, and alopecia. Thirteen patients received the entire treatment as outpatients while six patients had to be hospitalized for a period of 8--14 days because of severe side effects, especially in Weeks 3--8. Serious complications such as bowel perforation were not seen, but one patient died with septicemia as a result of agranulocytosis, which was attributed to the treatment with levamisole.

Impact of the category of early tumor recurrence on tumor progression in bladder tumors treated by transurethral resection.

Forty-six newly diagnosed patients with T1 and T2 bladder tumors were treated with transurethral resection. During a 6-months period more than 50% of the tumors recurred. Subsequent progression of tumors was seen within 24 months in 35 and 28% of the patients with T1 and T2 tumors, respectively. Prognosis with regard to progression was significantly better in patients with Ta recurrence at first control than in patients with invasive recurrent tumors, irrespective of category of tumor at a later recurrence. It is concluded that the continued transurethral treatment of patients with early recurrent invasive tumors may have to be reconsidered.