Inhibition of two-step urinary bladder carcinogenesis by the somatostatin analogue RC-160

Summary Fisher 344 female rats were exposed for 4 weeks to the initiator carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) 0.05% in the drinking water and thereafter to the promoter carcinogen mitomycin C (0.08 mg per animal per week) intravesically for 12 weeks. High incidence of urinary bladder transitional cell cancers was observed (17 in situ and 17 invasive carcinomas among 40 rats). When the somatostatin analogue RC-160 (d-Phe-Cys-Tyr-d-Trp-Lys-Val-Cys-Trp-NH₂) was administered s.c. at the dose of 50 g per animal per day during 6-week period of promotion with mitomycin C, the incidence of urinary bladder cancer was dramatically reduced. Only 1 in situ carcinoma was observed among 20 rats and only preblastomatous lesions (dysplasias and papillomas) occurred. This effect could indicate that RC-160 interferes with the process of promotion by induction of enhanced apoptosis (programmed cell death) of the dysplastic urothelial cells. RC-160 could be tried therapeutically for the hormonal prevention of malignant transformation of preneoplastic lesions in the urinary bladder.     

Chemopreventive property of dietary ginger in rat urinary bladder chemical carcinogenesis

The modifying potential of ginger on the development of preneoplasia and tumors in the male Wistar rat urinary bladder was investigated in a 36-week-long initiation-promotion assay for chemical carcinogenesis. Groups G1 to G3 were given 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in drinking water for 5 weeks and a 3% uracil meal for the subsequent 3 weeks. Groups G4 and G5 were treated with 3% uracil only for the same period. After these steps, groups G2, and G3 and G4 were fed for 26 weeks a ginger extract mixed at 0.5 and 1.0% in a basal diet, respectively. Thirty six weeks after the beginning of the experiment all rats were killed. The multiplicity of urothelial lesions (hyperplasia and neoplasia) was significantly lower (P = 0.013) in group G3 than in groups G1 and G2. The results suggest that 1.0% ginger meal exerts a protective effect on the post-initiation stage of rat chemically-induced urothelial carcinogenesis.Elizabeth Teràn: deceased.     

Promoting effect of sodium chloride in 2-stage urinary bladder carcinogenesis in rats initiated by N-Butyl-N-(4-hydroxybutyl)-nitrosamine

Summary The promoting effect of sodium chloride (NaCl) in 2-stage urinary bladder carcinogenesis in F344 rats initiated by 2 doses of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was investigated. The incidences of PN hyperplasia were significantly higher in rats initiated with 0.01 or 0.05% BBN when they were given diet containing 10% NaCl for 32 weeks than when they were given control diet. The incidence of papilloma in rats given 0.05% BBN followed by diet containing 10% or 5% NaCl tended to be higher than that in control rats. The urine of rats given diet containing NaCl was larger in volume and had lower osmolality than that of controls. The total urinary sodium and chloride contents were also increased, whereas those of potassium and phosphorus were decreased. No calculus formation or crystalluria was observed. These data suggest that excess intake of sodium as NaCl has a weak promoting effect in 2-stage urinary bladder carcinogenesis.     

Prosthetic urinary bladder implantation to facilitate bladder regeneration

A temporary artificial bladder was implanted in 15 female dogs undergoing total or subtotal cystectomy. One or two months after implantation, the prosthesis was removed. In three dogs sacrificed 6 months after prosthesis implantation, a new urinary reservoir was identified. Two dogs failed to develop a urinary reservoir, and both ureters anastomosed directly to the top of a dilated urethra. Seven dogs died from complications (infection, urine leakage, etc). Three additional dogs are alive and well 2.5 months after implantation, and in these animals a new urinary reservoir has been demonstrated by cystography. Histologic examination of the new urinary reservoir revealed a thin lining of transitional cell-like epithelium and an underlying attenuated muscle layer. The ability of the canine species to generate a functioning urinary reservoir after total or subtotal cystectomy may hold promise for eventual clinical application in humans.     

Effect of acute distension on cholinergic innervation of the rat urinary bladder

Summary The effect of short-term urinary bladder distension on its cholinergic innervation was studied in Sprague-Dawley rats. Distension was induced for 3 h by forced diuresis and balloon outlet obstruction, and whole thick biopsy specimens were taken from the dome and lateral side of the anterior body 2, 7 and 21 days afterwards. The acetylcholinesterase (AChE) method was used to demonstrate the cholinergic nerves in the distended bladder wall. Cholinergic hypoinnervation was observed 7 days after the distension, persisting up to 21 days, although AChE-reactive nerves were then observed to be more numerous. The distribution of hypoinnervation was uneven, being more marked in the lateral side of the anterior body than in the dome. The distribution of AChE-reactive nerves varied even in the same biopsies, with areas of total hypoinnervation occurring next to areas of slightly diminished innervation. This was especially true 21 days after cholinergic innervation, which may in turn explain the prolonged voiding difficulties often seen after catheterization of an overdistended bladder in a patient with urinary retention. The short-lasting effect of bladder dilatation therapy used to treat detrusor instability or interstitial cystitis may be due to the fairly rapid regeneration of cholinergic innervation.     

Chemopreventive effects of cyclooxygenase-2 inhibitor and epidermal growth factor-receptor kinase inhibitor on rat urinary bladder carcinogenesis

OBJECTIVE: To examine the chemopreventive effects of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, and a selective epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor, gefitinib (as a single agent) on a carcinogen-induced rodent bladder carcinogenesis model. MATERIALS AND METHODS: The study comprised 103 male Fisher-344 rats (8 weeks old); after initial carcinogen treatment for 8 weeks with 0.05%N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, the rats were divided into five groups, i.e. group 1, control (vehicle only); group 2, gefitinib high-dose (15 mg/kg by gavage once daily); group 3, gefitinib low-dose (5 mg/kg); group 4, meloxicam high-dose (1.8 mg/kg by gavage once daily); and group 5, meloxicam low-dose (0.6 mg/kg). Twelve weeks later the rats were killed; after fixing the bladder in 10% formalin, the number and size of hyperplasia and carcinoma foci were recorded microscopically in sections stained with haematoxylin and eosin, submitted entirely as multiple strips. RESULTS: The incidence of carcinoma, confirmed microscopically, was: control 14/20 (70%); high-dose gefitinib, 7/20 (35%); low-dose gefitinib, 7/20 (35%); high-dose meloxicam 7/21 (33%); and low-dose meloxicam, 12/20 (60%). The mean numbers of carcinomas per bladder in groups 1-5 were 1.2, 0.5, 0.4, 0.5 and 1.1, respectively. The incidence and the mean number of carcinomas per bladder were significantly lower in the treatment groups (P < 0.05) than in the control group, except in the low-dose meloxicam group. There were no significant adverse effects. CONCLUSION: Both meloxicam and gefitinib have inhibitory effects on rat bladder carcinogenesis with no significant adverse effects. A combination of these drugs would be worth studying for their synergistic effects.     

Effect of distension on adrenergic innervation of the rat urinary bladder

Summary The effect of distension on adrenergic innervation was investigated in the rat urinary bladder. Bladders were distended for 3 h by forced diuresis and ballon obstruction, and specimens were taken from the bladder dome, body and neck for the demonstration of glyoxylic acid-induced fluorescence of catecholamines. Depletion of catecholamines started after 10 h and was almost complete after 2 days. The fluorescence had recovered part way after 5–7 days and was practically normal after 21 days. Small, intensely fluorescent (SIF) cells in the ganglia continued to leak catecholamines throughout the 21-day study period. The primary clinical success of distension therapy for the treatment of unstable bladder may be at least partly due to a reversible disturbance in the function of the adrenergic nerves, which have an excitatory alpha-adrenergic dominance in such cases, but the persistent leakage from SIF cells raises the question of whether distension causes prolonged disturbances in bladder function.     

膀胱镜下膀胱肿瘤激光切除术与电切术的临床疗效对比研究

目的:探讨膀胱镜下膀胱肿瘤激光切除术与电切术的临床疗效及安全性。方法:选择2012年11月至2014年8月行膀胱肿瘤激光切除或电切术的163例患者,其中85例行激光切除术(激光组),电切组78例,对比分析两组手术时间、术中出血量、并发症发生率、术后导尿管留置时间、术后住院时间及随访情况。结果:163例均顺利完成手术,激光组与电切组手术时间[(24.2±2.4)min vs.(29.7±2.4)min]、术后留置导尿管时间[(2.83±0.96)d vs.(3.19±0.91)d]差异有统计学意义(P<0.001),激光组闭孔神经反射发生率低于电切组,术中出血量[(19.5±3.7)mL vs.(26.5±2.3)mL]低于电切组。两组患者术后均随访36个月,Kaplan-Meier生存曲线显示两组无瘤生存率差异无统计学意义(P=0.406),术后3年总体复发率差异无统计学意义。结论:与传统膀胱肿瘤电切术相比,激光切除的手术时间短,并发症发生率低,可作为膀胱镜下膀胱肿瘤切除术安全、可靠的替代术式,并且激光切除术可获取完整的术后病理组织,对于判断预后及后续治疗方案的制定具有重要作用。     

Bladder outlet obstruction accelerates bladder carcinogenesis

OBJECTIVE

To examine the correlation between partial bladder outlet obstruction (PBOO) and bladder carcinogenesis.

MATERIALS AND METHODS

Female Wistar rats (6 weeks old) were divided into three groups of 10 each: group 1 was exposed to n‐butyl‐n‐butanol nitrosamine (BBN, a carcinogen) in drinking water for 8 weeks; group 2 had PBOO induced surgically after exposure to BBN for 8 weeks; group 3 had a sham operation and the rats drank normal water (control group). After 20 weeks, all of the rats were killed humanely and their bladders analysed.

RESULTS

There were no significant differences in body weight among the groups. The bladder weight of group 2 was significantly greater than either group 1 or group 3. Histopathologically, bladder smooth muscle hypertrophy was the major cause of the increased bladder weight for group 2. In group 2 there were increases in bladder wall thickness and many nipple‐shaped urothelial tumours. Basic fibroblast growth factor and hypoxia‐inducible factor‐1α expression were significantly greater in group 2 than in groups 1 and 3.

CONCLUSIONS

Exposure of the bladder to carcinogens during bladder hyperplasia and hypertrophy induced by PBOO results in a greater incidence of superficial bladder carcinoma.     

T1G3期膀胱肿瘤经尿道二次电切的临床疗效分析

目的探讨二次经尿道膀胱肿瘤电切术（TURBT）治疗T1G3期膀胱肿瘤患者的临床疗效。方法回顾分析2005年1月至2011年12月在我院初次行TURBT治疗病理诊断为T1G3期膀胱肿瘤、并规律进行丝裂霉素膀胱灌注的49例患者资料。其中行二次TURBT治疗的患者19例（观察组）,未行二次电切的患者30例（对照组）。观察两组间肿瘤复发率差异、残余肿瘤存在与否,以及肿瘤病理分期、分级的变化。结果二次电切后发现5例（26．3％）有残余肿瘤,3例（15．9％）有肿瘤分期的升高,其中1例改行根治性膀胱切除术。随访8～18个月（平均15个月）,观察组有3例（15．9％）肿瘤复发,对照组13例（43．3％）肿瘤复发。结论二次TURBT可切除残存肿瘤,更准确了解肿瘤分期情况,是确定患者是否应行根治性膀胱切除的重要依据,并可明显降低肿瘤的复发与进展。     

Ureterosigmoidostomy in rats: A model for the study of bladder tumour carcinogenesis and cocarcinogenesis

Summary A modified Coffey I ureterosigmoidostomy has been developed in rats as a model of urinary diversion for studying bladder carcinogenesis and co-carcinogenesis. Diverted and sham-operated animals were killed at 1, 3 and 6 months. Excretory urograms revealed minimal hydroureteronephrosis in most diverted animals. Upper tract bacterial colonisation was 9 times more frequent in diverted animals. Approximately one-third of the diverted animals had focal cortical scarring; however, renal function was normal in all groups as assessed by serum creatinine and electrolytes. These studies indicate that ureterosigmoidostomy in rats is a satisfactory model of urinary diversion for studying carcinogenesis.     

Central cholinergic mechanisms in L-DOPA induced hyperactive urinary bladder of the rat

Summary The involvement of central and peripheral cholinergic structures in the mediation of a centrally induced hyperactive urinary bladder response to L-2,3-dihydroxyphenylalanine (L-DOPA), after peripheral decarboxylase inhibition, registered by a cystometric procedure, has been analysed pharmacologically in anaesthetised rats. The urinary bladder response to L-DOPA was unchanged after blockade of cholinergic receptors with methylscopolamine, diminished after atropine and totally inhibited after hexamethonium. In addition, activation of muscarinic receptors in the pontine-mesencephalic brain region with oxotremorine after methylsopolamine pretreatment generates a hyperactive urinary bladder response, mediation of which seems to be independent of endogenous catecholamine stores. It is suggested that cholinergic receptors in the pontine-mesencephalic brain region are of importance for regulation of urinary bladder function in the rat. Furthermore, the bladder hyperactivity induced by L-DOPA might be propagated via muscarinic receptors in this brain area, and mediated peripherally via cholinergic receptors in the autonomic ganglia, but in the bladder detrusor via non-cholinergic receptors.     

Hemangiopericytoma arising from the wall of the urinary bladder

Hemangiopericytoma (HPC) arising from within the urinary bladder is exceptionally rare. A 45-year-old man having the symptoms of left groin pain, vague suprapubic discomfort and frequency was admitted to our clinic. Pelvic tomography revealed a tumor in the bladder wall measuring 4 × 3 cm and was not clearly distinct from the lower abdominal wall. Partial cystectomy was performed and the histopathological examination confirmed the hemangiopericytoma. Three thousand rad exterior beam irradiation was performed after operation. Partial cystectomy and adjuvant radiotherapy may be a simple and effective alternative operation for the patient with HPC.     

Cystometrical evaluation of acute and chronic overdistension in the rat urinary bladder

The urodynamic effects of an experimental, partial infravesical outlet obstruction in rats were studied and compared with the effects in sham-operated controls, and in animals that had undergone 24 h of total outlet obstruction. The animals were studied up to 42 days after surgery. Bladder weight increased with time in the partially obstructed group to reach a final value of 6 times that of the control. In water loading experiments micturition volume was unaffected by sham operation. In the partially obstructed bladders it decreased initially but normalized with time. In the group that had undergone 24 h of total obstruction micturition volume also decreased initially but then became significantly higher than in the controls. In cystometry experiments the partially obstructed bladders developed a considerable residual urine and increased threshold and micturition pressures. Detrusor instability was present already after 10 days. Also in the cystometry experiments the bladders that had been totally obstructed for 24 h had increased micturition volumes. Residual volume was only slightly affected by atropine in the control and partially obstructed bladders but increased 7-fold in rats in which the bladder had been totally obstructed for 24 h 42 days previously. We conclude that there is a close relationship between bladder weight, residual volume and micturition pressure in the partially obstructed bladder, and that 24 h of total obstruction results in disturbances of bladder function that might be related to denervation phenomena previously reported by others. Received: 19 February 1997 / Accepted: 18 September 1997     

大鼠膀胱ICC样细胞与逼尿肌神经调控关系的形态学研究

目的 从形态学上探讨膀胱ICC样细胞在逼尿肌神经调控中的作用.方法 采用透射电镜观察大鼠膀胱内ICC样细胞、神经和逼尿肌细胞之间的超微结构关系.通过c-kit免疫荧光染色对大鼠膀胱ICC样细胞进行鉴定,并通过c-kit与PGP9.5免疫荧光双标观察ICC样细胞与神经的结构关系.结果 透射电镜显示,ICC样细胞与逼尿肌细胞紧密相邻处可见典型缝隙连接.在局部区域可见ICC样细胞的突起与神经末梢联系紧密.c-kit免疫荧光染色显示,大鼠膀胱内ICC样细胞主要位于黏膜下层、肌束边缘以及肌细胞间.c-kit与PGP9.5免疫荧光双标显示ICC样细胞与神经末梢在结构上关系紧密.结论 从形态学上看,膀胱内ICC样细胞具备参与逼尿肌神经调控的结构基础,进一步从功能学上予以证实将有助于全面阐明逼尿肌神经调控理论.     

Malignant paraganglioma of the urinary bladder. A case report

Paraganglioma (pheochromocytoma) is probably the most fascinating of alltumors as it can present with a wide range of clinical manifestations.Paraganglioma of the urinary bladder is one of the rare tumors andconstitute less than 10% of all bladder tumors. The common presentationof paraganglioma of the urinary bladder is painless haematura, headache,palpitation and anxiety. Malignancy is uncommon and no histological featureis characteristic of malignancy. Invasion of adjacent organs or metastasisto the lymph nodes is the only criteria to suggest malignancy. In thepresence of proven metastasis radical cystectomy with pelviclymphadenectomy is recommended. In the present case the tumor wasarising from anterior wall of the bladder away from the bladder neck andthat in a large capacity bladder it was possible to get a wide margin forpartial cystectomy along with bilateral pelvic lymphadenectomy withoutviolating the oncological principles. At a follow up of two years there is noevidence of recurrence of tumor.     

再次经尿道电切术治疗非肌层浸润性膀胱癌

目的 总结再次经尿道电切术(Re-TUR)治疗非肌层浸润性膀胱癌的疗效.方法 2004年3月至2008年8月共收治462例非肌层浸润性膀胱癌,男性350例,女性112例,年龄35～83岁.在初次经尿道电切术后根据肿瘤分期和分级,以及标本有无肌层组织进行评估,有125例患者在术后4～6周行Re-TUR,其中Ta期49例,T1期76例;低级别癌58例,高级别癌67例;T1期肿瘤标本内未见肌层组织30例.结果 125例非肌层浸润性膀胱癌患者行Re-TUR,34.4%(43/125)发现有肿瘤残留,其中35例肿瘤未侵犯肌层,Ta期15例,T1期20例;8例肿瘤侵犯肌层.高级别癌的肿瘤残留率较低级别癌高(P<0.05);初次电切标本中无肌层的肿瘤残留率较有肌层的高(P<0.05).12例(9.6%)患者在初次电切术时肿瘤分期被低估.Re-TUR术中发生膀胱穿孔6例,膀胱出血7例.随访3～56个月;Re-TUR发现肿瘤残留的患者,37.2%(16/43)复发,高于Re-TUR未发现肿瘤残留的患者(12.2%,P<0.05).结论 T1期、高级别或初次电切标本无肌层的非肌层浸润性膀胱癌患者术后4～6周应行Re-TUR.Re-TUR能提高分期的准确性.     

Doxazosin modifies serotonin-mediated rabbit urinary bladder contraction

5-Hydroxytryptamine (5-HT) induces rabbit detrusor contractions via 5-HT₃ receptors. Similarly, 5-HT₄ receptors are known to be present in the human bladder. Doxazosin, a non-selective α₁ antagonist, is used for the symptomatic relief of bladder outflow obstruction. Previous work has shown that doxazosin inhibits 5-HT₂-mediated platelet shape change. Hence, the aim of this study was to assess, using organ baths and autoradiography, whether doxazosin has any 5-HT-inhibiting activity in the rabbit detrusor. Detrusor strips from adult New Zealand White rabbits were placed in organ baths; phenoxybenzamine (10⁻⁵ M) was added to block alpha-receptors. After KCl responses were assessed, the tissues were exposed to 10⁻³ M 5-HT. Subsequently, the strips were incubated with doxazosin or ondansetron (10⁻⁵ M; 5-HT₃ antagonist) followed by a further exposure to 5-HT. In some experiments, after the initial 5-HT-induced contractions, the tissues were washed and then re-exposed to 5-HT. These latter experiments acted as controls. Low-resolution autoradiography was performed on detrusor sections to assess the effect of doxazosin on 5-HT binding. These sections were analyzed densitometrically. Doxazosin and ondansetron produced a significant reduction in 5-HT-mediated contractions. Inhibition by doxazosin was in a concentration-dependent manner. Autoradiography demonstrated a significant reduction in [³H]-5-HT binding by doxazosin. Doxazosin significantly inhibits 5-HT-mediated contractions in the rabbit detrusor. This effect appears to be mainly mediated via 5-HT₃ receptor inhibition. Autoradiographic evidence suggests that doxazosin reduces 5-HT binding in the rabbit detrusor. The beneficial effects of doxazosin in bladder outflow obstruction may be due, at least in part, to 5-HT antagonism. Received: 13 June 1999 / Accepted: 28 October 1999     

The distribution of intramural nerves in urinary bladder after partial denervation in the female rat

We evaluated the degree of neuronal plasticity following a partial denervation of the rat urinary bladder. Using acetylcholinesterase staining we found that the postganglionic nerves from the pelvic ganglion reach the intact bladder as 1–4 nerve trunks on each side, slightly ventral and caudal to the ureteral orifices. Normally a few thinner nerves also reach the bladder posterolateral to the ureterovesical junction. The nerves ventral to the ureters run in the ventral longitudinal muscle layer as well-defined trunks with a pattern that does not differ much from one animal to another. The nerves reaching the bladder dorsolaterally innervate the dorsolateral aspects in a more irregular fashion. Some anastomoses are found across the midline between nerves from either side. This nerve pattern is already in place in newborn rats. After removal of the pelvic ganglion on one side in the adult rat the ipsilateral ventral nerves rapidly degenerate, whereas some dorsolateral␣nerves usually survive. Axons from the intact ventral␣nerves can be seen crossing over to the denervated side in the anastomoses. After 13 weeks the surviving ventral nerves, which normally run at some distance from the ventral midline, now run in the midline with equal amounts of ventral longitudinal muscle on either side, and with their branches evenly distributed to both sides. The same pattern is seen after 27 weeks. Unilateral ganglionectomy in 3-week-old rats leads to the same changes in nerve distribution as in the adult rat. We conclude that there is a high degree of plasticity in the bladder innervation following a partial denervation, and that this plasticity includes the distribution of its main intramural nerve trunks. Received: 2 October 1997 / Accepted: 2 January 1998     

The effects of cold-restraint stress on urinary bladder wall compared with interstitial cystitis morphology

Stress is associated with many diseases of unknown aetiology. This study demonstrates the effects of cold-restraint stress on the morphology of the urinary bladder. Additionally, it compares the results obtained with the morphology of the interstitial cystitis. The animals were subjected to three hours of cold-restraint stress and then starved for 48 h. The morphology and histochemistry of the urinary bladder was investigated with light and electron microscopy. The proliferative activity was analysed via flow cytometry. Increased and degranulated mast cells in the mucosa, leucocyte infiltration in the lamina propria, vacuole formation in the urothelial cells, loose tight junction, dilated intercellular spaces and altered proliferative activity were observed in the stress group when compared with the control. The increase in the number of mast cells and especially degranulated mast cells and vacuole formation and the loose tight junction of the urothelium correlated with the histopathological findings of interstitial cystitis. Received: 12 December 1998 / Accepted: 25 June 1999