ORGOTEIN: a new antiinflammatory metalloprotein drug evaluation of clinical efficacy and safety in inflammatory conditions of the urinary tract

Results are presented for 148 patients to assess the clinical efficacy and safety of a new antiinflammatory metalloprotein drug, generic name Orgotein. The drug was not only well tolerated upon systemic administration, but also was found to be completely safe without any side effects as administrated by special routes of administration, such as instillation into the tunica vaginalis, intramurally by needle catheter into the bladder wall, and locally into the plaques of induratio penis plastica. Based on our experience to date, we can report excellent therapeutic success in the treatment of radiation cystitis in the female, and also in all other forms of chronic interstitial cystitis. The results of orgotein therapy in radiation cystitis are extraordinarily good and surpass those of all other methods of treatment. The rate therapeutic success in chronic prostatitis with systemic orgotein administration is equal to that with other methods of treatment. The treatment of induratio penis plastica appears promising. Orgotein efficacy in hydrocele was demonstrated in a double-blind placebo-controlled study.     

Therapy of acute radiation cystitis. A case report

We report a patient with prostate cancer who suffered from severe radiation cystitis after combined interstitial radiation with 125-Iodine-Seeds and external radiation (2000 rad). This patient was treated very successfully with intramural injection of Orgotein (Peroxinorm) into the bladder wall. Besides discussion of the aetiology of radiation cystitis we report our first favourable results with local and systemic treatment with Orgotein (Peroxinorm).     

Evaluation of intravesical alum irrigation for massive bladder hemorrhage

The efficacy of intravesical alum irrigation was analyzed after application to 9 patients with continuous and severe bladder hemorrhage. Causes of bleeding were radiation cystitis in 4 patients, vesical invasion by cervical cancer in 3, bladder cancer in 1 and cyclophosphamide-induced cystitis in 1. Though alum treatment was initially effective for control of massive bladder hemorrhage in all patients, it eventually failed to suppress a subsequent hemorrhage in 2 patients (78% success rate). No significant side effects directly related to this therapy were observed. In conclusion, alum irrigation is effective for controlling massive bladder hemorrhage for a rather short time. Therefore, additional treatment modalities should also be considered for primary diseases.     

Urologic complications of radiotherapy

Radiation therapy is commonly used to treat pelvic or retroperitoneal cancers but has some impact on genito-urinary system: short-term side effects are frequent with usually a completed regression. However, the incidence of major complications is about 12% and is probably underestimated due to a long delay between radiation therapy and diagnosis of some adverse events such as ureteral strictures or fistula. Clinical follow-up must absolutely include an early diagnosis and treatment of radiation therapy complications such as renal dysfunction, ureteral stricture, ureteral fistula, chronic bladder injury, bladder fistula, urethral stricture, infertility or erectile dysfunction.     

Sensitizers as an adjunct in the treatment of bladder cancer

Summary For the past 25 years, there have been repeated efforts at improving the effectiveness of radiation therapy by combining it with various sensitizing agents. The problem has not been that these agents did not work, but rather that to be effective, they were associated with unacceptable side effects. Since certain chemotherapeutic agents are radiomimetic, and are administered over a more prolonged time period than radiation therapy, there is reason to believe that their effectiveness could be improved without undue toxicity by the addition of sensitizers. In this paper, we will review the mechanism of action of sensitizers and show that, against the MBT-2 mouse bladder tumor, a number of sensitizing agents increased the antitumor activity of cyclophosphamide.     

New hemostatic therapy of bleeding of bladder by technique of drip-irrigation using a thrombin solution

To control the bleeding from the bladder caused by radiation cystitis or transurethral surgery, drip-irrigation of bladder by indwelling a three-way Foley catheter using a thrombin solution, as a clotting agent, was done in 10 patients. Five hundreds ml of solution containing 25,000 units of thrombin was dripped out within 3 hours and repeated 2 times a day for 2 to 7 days. The results were excellent in 2 cases, good in 6 cases and poor in 2 cases. No remarkable side effects were observed.     

Complications of intravesical therapy for urothelial cancer of the bladder

PURPOSE: Intravesical therapy is an integral part of treatment in patients with superficial urothelial carcinoma of the bladder. The American Urological Association and European Association of Urology guidelines on bladder cancer incorporate it for the treatment of superficial bladder cancer. Given the extensive use of intravesical immunotherapy and chemotherapy, it is essential for the practicing urologist to be aware of the local and systemic side effects of these therapies. MATERIALS AND METHODS: We reviewed the literature on intravesical immunotherapy and chemotherapy with particular emphasis on side effects, complications and their management. A Medline search of the English language literature for the last 25 years was done on Entrez PubMed and all relevant articles were studied in full. All side effects and complications were studied and their management was reviewed. RESULTS: Intravesical therapy for transitional cell carcinoma of the bladder is generally safe. There is a high incidence of local, usually self-limiting, relatively minor side effects and infrequent, potentially severe local and systemic side effects. Most side effects are avoidable. CONCLUSIONS: Although intravesical therapy is generally safe, local and systemic side effects occur and it is important to be aware of them. Identifying complications early, preventing them when possible and managing them efficiently are critical. Most complications are preventable. Knowing the risks and benefits of chemotherapeutic and immunotherapeutic agents may decrease the short-term and long-term toxicity of these agents. Adherence to guidelines may prevent inappropriate use, which can lead to unnecessary complications, resulting in bladder dysfunction and even cystectomy.     

The value of bladder-conserving strategies in muscle-invasive bladder carcinoma compared with radical surgery

PURPOSE OF REVIEW: Patients with muscle-invasive bladder cancer will practically all develop progression, often associated with severe side effects including pain, dysuria or macrohematuria. Recent reports demonstrate multimodality bladder-sparing approaches as primary treatment for muscle-invasive bladder cancer. RECENT FINDINGS: Bladder-conserving strategies include thorough transurethral resection of the bladder tumor, external beam radiation therapy and chemotherapy. It has been shown that survival rates are similar to those of radical cystectomy series; additionally, a substantial number of patients survive with an intact bladder. The high costs, close cooperation between clinical specialists and a highly compliant patient need to be taken into consideration, however. SUMMARY: Nowadays, the good long-term results after radical cystectomy with the creation of an orthotopic neobladder make the substantial advantage of a bladder-preserving strategy questionable when the patient's quality of life is addressed. Multimodality bladder-conserving strategies are a therapeutic option for selected patients; however, radical cystectomy remains the gold standard of treatment.     

Phenolization of bladder in treatment of massive intractable hematuria

Intractable hemorrhagic cystitis secondary to radiation or cyclophosphamide (Cytoxan) therapy could lead to serious complications; however, intravesical instillation of phenol has reduced the dilemma of this life-threatening problem. We present a case of intractable hemorrhagic cystitis secondary to cyclophosphamide therapy treated with 100 per cent phenol with no untoward side effects. Since formalin instillation into the bladder has been associated with severe complications, phenol appears to be safer and more effective in the treatment of intractable hematuria, and, therefore, its clinical trial is recommended.     

Intravesical atropine compared to oral oxybutynin for neurogenic detrusor overactivity: a double-blind, randomized crossover trial

PURPOSE: We tested the efficacy and side effect profiles of intravesical atropine compared to oxybutynin immediate release when used by individuals with multiple sclerosis. MATERIALS AND METHODS: We performed a study to determine the most effective dose of atropine. Eight participants used increasing doses of intravesical atropine during a 12-day period. Bladder diary data showed that the instillation of 6 mg atropine 4 times daily was most effective for increasing bladder capacity (voided/catheter volumes). We then did a randomized, double-blind crossover trial. Participants received 14 days of treatment with oral oxybutynin or with intravesical atropine, followed by 14 days of alternative treatment. Participants recorded a bladder diary and rated side effects and quality of life. The primary outcome variable was bladder capacity. RESULTS: A total of 57 participants with multiple sclerosis completed the study. Average change in bladder capacity was higher in the atropine arm. The mean +/- SD oxybutynin change was 55.5 +/- 67.2 ml, the mean atropine change was 79.6 +/- 89.6 ml and the mean difference between arms was 24.1 ml (95% CI -0.4, 49.7; p = 0.053). Changes in incontinence events and voiding frequency were not statistically different between the arms. Changes in total side effect and dry mouth scores were significantly better in the atropine treatment arm. CONCLUSIONS: Intravesical atropine was as effective as oxybutynin immediate release for increasing bladder capacity and it was probably better with less antimuscarinic side effects. We recommend that intravesical atropine should be made available to patients with neurogenic detrusor overactivity and voiding problems requiring intermittent catheterization as an alternative to oral therapy, which often has troublesome side effects.     

Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer?

Single modality bladder sparing therapy for muscle-invasive bladder cancer, including transurethral resection, systemic chemotherapy or radiotherapy have been demonstrated to result in insufficient local control of the primary tumor as well as decreased long-term survival of the patients when compared to radical cystectomy. Therefore, multimodality treatment protocols that aim at bladder preservation and involve all of the aforementioned approaches have been established. Arguments for combining systemic chemotherapy with radiation are to sensitize tumor tissue to radiotherapy and to eradicate occult metastases that have already developed in as many as 50% of patients at the time of first diagnosis. It has been shown that the clinical outcome observed with this approach approximates that after radical cystectomy. Additionally, a substantial number of patients survive with an intact bladder. However, bladder preserving approaches are costly, and require close co-operation between different clinical specialists as well as very close follow-up. The good long-term results obtained after cystectomy and creation of an orthotopic neobladder make the possible advantage of a bladder preservation strategy questionable in consideration of quality of life issues. Additionally, side effects related to bladder sparing therapy may result in an increased morbidity and mortality in those patients who in fact need to undergo surgery due to recurrent or progressive disease. Multimodality bladder sparing treatment is a therapeutic option that can be offered to the patient at centres that have a dedicated multidisciplinary team at their disposal. However, radical cystectomy remains the standard of care for muscle-invasive bladder tumors.     

22例晚期膀胱癌患者术中放疗随访报告

目的：对晚期膀胱癌术中放疗患者进行临床效果观察，并与传统的全膀胱切除术进行比较，以探索一种更合理、有效的治疗晚期膀胱癌的途径。方法：术中将肿瘤处理完毕后，根据肿瘤情况，用直线加速器给予一次性剂量照射，作长期随访报告。结果：术中放疗后，膀胱内肿瘤局部复发低，本组仅有4例膀胱内小肿瘤复发，经TURBT治疗后未再复发。22例具有全膀胱切除指征的患者均保留了膀胱正常排尿功能，患者生活质量提高，生存期明显延长。结论：对位于膀胱三角区周围浸润型多发性膀胱癌，尤其是膀胱腺癌、鳞癌，可采用电子直线加速器进行术中放疗，是一种理想的治疗方法。     

Radiation induced inflammatory changes in the mouse bladder: the role of cyclooxygenase-2

PURPOSE: We assessed the effect of irradiation on COX-2 expression in blood vessels of the mouse bladder wall during the early and late radiation response phases. Vasodilatation was quantified as an additional marker of inflammation related to COX-2 activity. MATERIALS AND METHODS: Female C3H/Neu mice were irradiated with a single dose of 20 Gy. The intensity of the COX-2 immunohistochemical staining signal was assessed using an arbitrary semiquantitative score of 0 to 3. To evaluate vasodilatation the percent of the bladder wall covered by the lumen of the blood vessels, depicted as vascular area, was determined. RESULTS: Constitutive COX-2 expression was found in the tunica intima and media of bladder blood vessels. During the early response significant biphasic changes were detected in the COX-2 staining signal as well as in the vascular area with peak values on days 4 and 16 after irradiation. A significant association was found between vascular area and COX-2 expression in blood vessels during the early radiation response (p <0.0001). No changes in COX-2 expression were observed during the late phase, that is between days 90 and 360 after irradiation. Minor vasodilatation seen during the late phase did not correlate with COX-2 activity. CONCLUSIONS: Irradiation resulted in pronounced COX-2 dependent inflammatory changes in the bladder wall during the early but not during the late radiation reaction. Therefore, a potential effect of COX-2 inhibition on early radiation side effects in the bladder can be proposed.     

羟基喜树碱预防膀胱肿瘤术后复发的系统评价

目的：评价膀胱灌沣羟基喜树碱预防国人膀胱肿瘤术后复发的疗效和副作用。方法：按设定的纳入杯准，检索国内已公开发表的关于羟基喜树碱膀胱灌注治疗国人膀胱肿瘤术后复发的研究资料，并应用Revman1．2软件进行数据处理和分析。结果：共有16个研究符合标准被纳入，涉及总病例数1671例．其中进行羟基喜树碱灌注治疗779例（193/779），对照组治疗892例（267/892）。Meta分析结果提示羟基喜树碱膀胱灌注可降低膀胱肿瘤复发风险（OR=0.76．95%CI[0.61．0.96]，P=0.02）；与13个研究主要副作用膀胱刺激痱化学性膀胱炎的文献比较，Meta分析结果提示羟基喜树碱膀胱灌注所致膀胱刺激症化学性膀胱炎发生率极低（OR=0.08.95%CI[0.03，0.19]P＜0.00001）。结论：羟基喜树碱膀胱灌注可以有效降低膀胱肿瘤术后复发率，虽然也可以引起一些副作用，但可以耐受，不影响患者继续治疗。     

Neoadjuvant chemoradiotherapy in locally invasive transitional cell carcinoma of the urinary bladder: early results of PVB and CAP therapy

A total of 22 patients with locally invasive transitional cell carcinoma of the urinary bladder were treated with neoadjuvant cis-diamminedichloroplatinum (CDDP), vincristine, peplomycin (PVB) or cyclophosphamide, doxorubicin, CDDP (CAP) combined with radiation therapy in our institutes between June, 1982 and May, 1988. Twelve patients were entered into the PVB regimen and the remaining 10 patients into the CAP regimen. In the PVB treated group, clinical response was obtained in 2 complete response (CR) and 6 partial response (PR), 8 out of 12 patients (66.7%). Downstaging was noted in 8 out of 12 patients (66.7%). In the CAP treated group, a clinical response was obtained in 1 of CR and in 2 of PR out of the 9 patients with evaluable lesions (33.3%). Downstaging was noted in 6 out of 9 patients (66.7%). There were no significant side effects in either the PVB or CAP treated groups, and these neoadjuvant therapies were well-tolerated. These results indicated that neoadjuvant PVB or CAP combined with radiation therapy would be useful in the management of invasive bladder cancer.     

Surgical bladder preserving strategies in the treatment of muscle-invasive bladder cancer

Single modality bladder-sparing therapy for muscle-invasive bladder cancer, including transurethral resection (TUR), partial cystectomy, systemic chemotherapy or radiotherapy, have been demonstrated to result in insufficient local control of the primary tumour, as well as decreased long-term survival in the patients when compared to radical cystectomy. Therefore, multimodality treatment protocols that aim at bladder preservation and involve all of the aforementioned approaches have been established. Arguments for combining systemic chemotherapy with radiation are to sensitise tumour tissue to radiotherapy and to eradicate occult metastases that have already developed in as many as 50% of patients at the time of first diagnosis. It has been shown that the clinical outcome observed with this approach approximates that after radical cystectomy. Additionally, a substantial number of patients survive with an intact bladder. However, bladder-sparing approaches are costly, and require close co-operation between different clinical specialists as well as careful follow-up. The good long-term results that are observed after cystectomy and the creation of an orthotopic neobladder make the substantial advantage of a bladder preservation strategy questionable when the patient's quality of life is addressed. Additionally, bladder-sparing therapy-related side effects might result in an increased morbidity and mortality in those patients who need to undergo surgery due to recurrent or progressive disease. Multimodality bladder-sparing treatment is a therapeutic option that can be offered to the patient at centres that have a dedicated multidisciplinary team at their disposal. However, radical cystectomy remains the standard of care for muscle-invasive bladder cancer.     

Bladder botulinum toxin A injection can benefit patients with radiation and chemical cystitis

OBJECTIVE

To investigate the potential utility of botulinum toxin A (BoNT‐A) bladder injections in patients with radiation cystitis and bacillus Calmette‐Guérin (BCG)‐induced chemical cystitis.

PATIENTS AND METHODS

In all, six patients with refractory radiation cystitis were treated with 200 U bladder BoNT‐A injections and two patients with refractory cystitis after intravesical BCG therapy were treated with 100 U bladder BoNT‐A injections. All the patients were refractory to anticholinergic agents. Under sedation or local anaesthesia, BoNT‐A was injected through a cystoscope into 20 sites submucosally in the trigone and floor of the bladder.

RESULTS

There were no side‐effects or retention after BoNT‐A injection. In five of the six patients with radiation cystitis there was a moderate to significant improvement; the mean (sd ) bladder capacity increased from 105 (25) mL to 250 (35) mL and the urinary frequency decreased from 14 (2) to 11 (1) episodes per day. In the two patients with BCG cystitis both reported significant symptomatic improvement; the mean (sd ) bladder capacity increased from 110 (23) to 230 (23) mL, the urinary frequency decreased from 16 (1) to 12 (1) episodes per day, and using a 10‐point visual analogue pain scoring system, the perceived pain score decreased from 8 to 2. Microscopically, the bladder tissue at 1 month after BCG injection showed marked acute and chronic inflammation with eosinophilic infiltration and focal granulomatous formation. At 2 months after BoNT‐A injection, there was only a mild degree of chronic inflammation with few eosinophils.

CONCLUSION

These preliminary results suggest that BoNT‐A injected into the bladder is a promising treatment for patients with refractory radiation and BCG cystitis.     

Clinical study of proton radiotherapy in urological cancers

Therapy with proton beam is superior to that with photon beam in concentrating the dose within a lesion. Fifteen patients with urinary malignant tumors were treated by proton irradiation during the period from June, 1985 to March, 1989 at Particle Radiation Medical Center, University of Tsukuba. Four patients were with renal cell carcinoma, five with prostatic cancer and six with bladder cancer. Treatment results were assessed by change in tumor size either three or six months after the irradiation. In all the four cases with renal cell carcinoma, the tumor sizes were found to be unchanged without any enlargement. Of the five cases with prostatic cancer, two showed that the treatment was effective and the tumor sizes in the other three cases were found to be unchanged. In three of the six cases with bladder cancer the tumors disappeared while the treatment was found effective in two other and it did not cause any enlargement of the tumor in the remaining one. Although local control of the tumor was successful in all the cases, one patient with prostatic cancer and three with bladder cancer died of cancer. Various side effects, such as radiation cystitis, were observed. This prospective therapy is expected to replace the conventional photon therapy. However, some improvement is needed to make full use of the advantageous properties in dose distribution. Combination therapy with other general therapy is required for some cases.     

Inhibiting the hyperreflexic bladder with electrical stimulation in a spinal animal model

Uninhibited bladder contractions are a problem in spinal cord injured patients. Accordingly, methods using electrical stimulation to inhibit the bladder were investigated in chronic spinal cord injured (C6-T1) male cats. In unanesthetized, restrained animals, spontaneous bladder contractions were observed after the bladder was filled above the micturition threshold. In 3 of the 5 cats studied, this bladder activity could be inhibited with stimulation of either sacral nerves or pudendal nerves. Pudendal nerve stimulation, however, was more selective than sacral nerve stimulation for inhibition with fewer side effects such as leg spasms. Tibial nerve stimulation was ineffective and caused leg spasms and increased bladder activity. Finally, high-frequency stimulation (1,000 Hz) of the sacral nerves was shown to block bladder contractions in 2 of 3 cats investigated. However, this method had adverse side effects such as leg flexion and secondary bladder contractions. We conclude that pudendal nerve/pelvic floor stimulation at low frequency is a relatively effective method in this model.     

Radiation-induced bladder carcinoma

Two cases are presented of radiation-induced bladder carcinoma which followed prior irradiation for cervical carcinoma of the uterus. One was a sixty-eight-year-old woman with bladder carcinoma fourteen years after irradiation (total dose of 4,500 rad) for cervical carcinoma of the uterus. The other was a sixty-four-year-old woman with bladder carcinoma twenty-five years after irradiation with 150-K volt apparatus for cervical carcinoma of the uterus. From the late radiation change of the skin, it was estimated that the total dose of prior radiation might be 4,000 rad or more. Both had high-grade, high-stage transitional cell bladder carcinoma, and the former was with marked mucus-forming adenomatous metaplasia.