A phase-1 study of sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in recurrent superficial bladder carcinoma

OBJECTIVE: To report a phase-1 study of patients with recurrent superficial bladder cancer treated with photodynamic therapy (PDT) using sequential mitomycin C and 5-aminolaevulinic acid (ALA). PATIENTS AND METHODS: Twenty-four patients were treated, the primary endpoint being the safety and tolerability of combined therapy at increasing doses of ALA and light. RESULTS: Mitomycin C instillation was followed by ALA concentrations of 6%, 8% or 10%; there was no effect on toxicity. The light dose, at a wavelength of 635 nm, was increased from zero to 25 J/cm(2), with the upper fluences producing transient symptoms. There were no episodes of skin photosensitivity or systemic toxicity. A total fluence of 25 J/cm(2) represented the upper light dose for the tolerability of this procedure by patients. There were no persistently high urinary symptom scores or reduction in functional bladder capacity up to > or =24 months of follow-up. In this group, cumulative tumour recurrences were none at 4, two at 8, six at 12, nine at 18 and 11 at 24 months after PDT, respectively. CONCLUSION: Sequential mitomycin C and ALA-PDT is a safe and well tolerated treatment, with potential for managing difficult-to-control superficial transitional cell carcinoma and carcinoma in situ of the bladder.     

The morphological changes in rat bladder after photodynamic therapy with 5-aminolaevulinic acid-induced protoporphyrin IX

OBJECTIVE: To assess the optimum light energy needed to induce only superficial bladder wall damage during photodynamic therapy (PDT) as a treatment for bladder cancer. Materials and methods The urinary bladder (with normal epithelium) of 64 female rats was treated with PDT using a continuous-wave argon-ion laser as an energy source and aminolaevulinic acid (ALA)-induced protoporphyrin IX photosensitizer. Four hours after the intravenous administration of ALA (300 mg/kg) the bladders were intravesically exposed to light fluences of 20-80 J/cm2. The control rats received no ALA and were exposed to 20 J/cm2 light. After 1, 3, 7 and 21 days the animals were killed and the morphological changes in bladder wall analysed both macroscopically and using light and scanning electron microscopy. RESULTS: At the dose of ALA given, a fluence of 20-40 J/cm2 caused mainly superficial damage, whereas 80 J/cm2 produced full-thickness injuries to the bladder wall. The maximum effect of PDT occurred after 1 and 3 days of irradiation. After 3 weeks of PDT the histology showed few full-thickness injuries and only in those treated with 80 J/cm2 light. CONCLUSION: These results indicate that PDT can be used to safely induce a selective superficial removal of bladder mucosa with no fibrotic effects on detrusor musculature, when optimum photosensitizing drug and fluences are used. These findings support the use of PDT in the therapy of superficial bladder cancer.     

The effect of photodynamic therapy on rat urinary bladder with orthotopic urothelial carcinoma

OBJECTIVE: To assess the effect of whole-bladder photodynamic therapy (PDT) on a rat model with orthotopic superficial bladder cancer, as PDT is an alternative intravesical therapy for treating superficial bladder cancer, based on an interaction between a photosensitizer and light energy to induce oxygen radicals that destroy tissue by lipid peroxidation. MATERIALS AND METHODS: In all, 76 female Fischer F344 rats were inoculated intravesically with AY-27 tumour cells. After establishing superficial tumour, 24 rats were treated with PDT using aminolaevulinic acid (ALA)-induced protoporphyrin IX as a photosensitizer, and a continuous-wave argon pumped-dye laser (638 nm). At 4 h after intravenous (300 mg/kg) or intravesical (100 mg/mL) administration of ALA the bladders were intravesically exposed to a 40 J/cm(2) light dose; 12 rats received no ALA but were exposed to the same light dose. Before administering ALA, urine cytology samples were taken for analysis. At 3 or 21 days the treated rats were killed and morphological changes in the bladder walls analysed by light microscopy. Forty rats served as controls to examine the presence of tumour. RESULTS: The tumour established in 33 of 40 rats (83%) in the controls, but after PDT with intravesical ALA there was carcinoma in only in one of 12 (P < 0.001, Pearson's chi(2) test). After PDT with intravenous ALA there was carcinoma in five of 11 rats (P = 0.063, Pearson's chi2 test). In the control group of 12 rats receiving only light energy there was carcinoma in three (P = 0.001, Pearson's chi(2) test). Histologically, at 3 days after PDT there was only mild superficial damage in all six rats treated intravesically. Bladder wall destruction reached the muscular layer, with an abscess in one of six rats treated intravenously. After 3 weeks of PDT there was muscular necrosis with perforation and abscess from catheterization two of six rats treated intravesically and in three the bladder wall totally recovered. In the intravenous group the bladder walls were normal or had only mild superficial damage. Cytology of the urine sediment failed to detect half the tumours in the treatment groups. CONCLUSION: These results support the use of PDT with intravesical ALA-induced protoporphyrin X for treating superficial bladder carcinoma. Intravesical was better than intravenous ALA in eradicating bladder carcinoma with PDT.     

Electromotive drug administration of lidocaine to anesthetize the bladder before botulinum-A toxin injections into the detrusor

STUDY DESIGN: Prospective, open label, cross-over-designed clinical study. OBJECTIVE: To evaluate the effectiveness of an instillation of lidocaine into the bladder with versus without electromotive drug administration (EMDA) to anesthetize the bladder before botulinum-A toxin injections. SETTING: Neurourology, Swiss Paraplegic Center, Balgrist University Hospital, Zurich, Switzerland. METHODS: In all, 28 patients with severe neurogenic detrusor overactivity but preserved bladder sensibility were treated with botulinum-A toxin injections into the detrusor muscle. A measure of 300 u of botulinum-A toxin (Botox) was injected at 30 sites sparing the trigone. Prior to the injection, the bladder was anesthesized with conventional lidocaine instillation in a group of 10 patients and with lidocaine instillation enhanced by EMDA in 28 patients. The patients scored the injection pain on a 10-point rating scale. Pain rating scores with versus without EMDA enhancement of the lidocaine instillation were analyzed and the costs of the EMDA procedure were compared to general/spinal anesthesia. RESULTS: The mean pain score of the 10 patients who underwent the injections of Botox after conventional lidocaine instillation was 4.0 (SD 1.6). Following EMDA enhanced lidocaine instillation slight even or no pain occurred during the injections of Botox, and the mean pain score was 0.5 (SD 0.2). Compared to spinal or general anesthesia, the local anesthesia saved around 15% of the costs. CONCLUSIONS: EMDA enhanced instillation of lidocaine enables a sufficient anesthesia of the bladder wall that ensures a painless application of the botulinum-A toxin injections into the detrusor muscle. This method may avoid general or spinal anesthesia in patients with preserved bladder sensibility. It ensures considerable cost reduction, avoids anesthesia-related risks and complications and enables the procedure on an outpatient basis.     

Photodynamic therapy for refractory superficial bladder cancer: long-term clinical outcomes of single treatment using intravesical diffusion medium

BACKGROUND: Diffuse superficial transitional-cell carcinoma (TCC) refractory to standard therapies poses a clinical dilemma. Photodynamic therapy (PDT), which uses an interaction between absorbed light and a retained photosensitizing agent to destroy tissue, has been used to treat diffuse superficial bladder TCC, although there are few reports of long-term outcomes. PATIENTS AND METHODS: A series of 34 patients, 29 with TCC carcinoma in situ (CIS) and 5 with multiple small papillary stage T(a) or T(1) lesions, received porfimer sodium (P) 48 hours before whole-bladder PDT with 630-nm laser light. A 0.02% soybean emulsion diffusion medium was instilled into the bladder, and the laser optical fiber was positioned under triplanar sonography prior to PDT. The mean follow-up was 52 months. RESULTS: At 3 months, a complete response (CR) in 14 (44%) of the 32 evaluable patients, a partial response (PR) in 4 (12%), and no response (NR) in 14 (44%). Four of the five patients with extensive papillary lesions did not respond. The NR rate for patients with CIS with or without resected papillary lesions was 37%. The mean time to recurrence in the CR group was 9.8 months, and five members of this group (36%) underwent cystectomy (mean time 20 months) for persistent/progressive disease (N = 3) or bladder contracture (N = 2). In the NR group, 6 (43%) underwent cystectomy (mean time 14 months) for persistent/progressive disease. Metastatic bladder cancer was the cause of death in only 4 of the 12 patients who have died. Of the remaining 22 patients, 15 are still alive and have an intact bladder, nine with no disease and six with only superficial disease. CONCLUSION: This is the first report of long-term results following whole-bladder PDT using diffusion medium for isotropic light distribution. More than half of the patients with TCC refractory to traditional intravesical therapy received benefit from a single PDT session. Patients with extensive flat papillary lesions do not appear to respond well. Patients who achieve a CR have less likelihood of and longer time interval before needing cystectomy for progressive disease than NR patients. Our PDT protocol is associated with minimal morbidity in these high-risk patients.     

Pilot study of the feasibility of in-office bladder distention using electromotive drug adminstration (EMDA)

PURPOSE: Cystoscopic bladder distention is an important tool in the diagnosis and treatment of interstitial cystitis (IC). We investigated the feasibility of performing bladder distention in the office using two different anesthetic strategies: simple instillation of alkalized lidocaine and electromotive drug administration (EMDA) of lidocaine. MATERIALS AND METHODS: Patients presenting with urinary frequency, urgency, and bladder pain were recruited for an office evaluation protocol which included bladder distention under local anesthesia. An initial group of 10 patients underwent bladder distention after instillation of 5 mg/kg alkalized lidocaine. A second group of 11 patients had lidocaine EMDA anesthesia prior to distention. RESULTS: In the alkaxlized lidocaine group, 6 of the 10 distentions were aborted after less than 5 minutes at only 40 cm H(2)O. In the EMDA group, 7 of 11 of the distentions were completed using 60 cm H(2)O for 7 minutes. EMDA afforded a more effective distention as manifest by a greater percent increase in distention capacity over cystometric capacity compared to alkalized lidocaine (135% vs. 70%). Despite the lower pressure used in the alkalized lidocaine group, the median distention time was only 3 minutes compared to 7 minutes using EMDA. CONCLUSIONS: These results represent the first study of the efficacy of EMDA as local anesthesia for bladder distention compared to another method of anesthesia. Lidocaine EMDA is superior to alkalized lidocaine in that it allows for a greater distention of the bladder for a longer period of time but does not eliminate the pain of bladder distention.     

Aminolevulinic acid for photodynamic therapy of bladder carcinoma cells

A new concept in photosensitizing tumor cells is photosensitizer synthesis in situ. Aminolevulinic acid (ALA) is a precursor of protoporphyrin IX (PP IX), a potent photosensitizer. The goal of our study was to examine dark toxicity, phototoxic potential, metabolism of ALA and morphological alterations in Waf bladder cancer cells. Dark toxicity of Waf cells was observed after incubation with ALA, beginning at a concentration of 15 mM. Photodynamic treatment with ALA at concentrations of 1,5 and 10 mM showed a drug- and light-dose-dependent cell survival rate in comparison to a control group. Two incubation times of 3.5 and 5.5 h were compared for cell survival. After a longer incubation time of 5.5 h, cell survival was decreased in all experiments; this is consistent with our extraction data where higher fluorescence was found after 5.5 than after 3.5 h. The results show that ALA-induced photosensitization has a high potential for photodynamic therapy (PDT) of superficial bladder carcinoma.     

Updates in intravesical electromotive drug administration<Superscript>®</Superscript> of mitomycin-C for non-muscle invasive bladder cancer

Electromotive drug administration^® (EMDA) increases the local drug efficacy by controlling and enhancing transmembranous transport into tissue. EMDA of intravesical mitomycin-C (MMC) has been used for treatment of non-muscle invasive bladder cancer (NMIBC) for about a decade on the basis of laboratory studies that demonstrated an enhanced administration rate of MMC into all bladder wall layers after EMDA compared to standard instillation/passive diffusion (PD). Higher MMC concentrations might have a clinical impact since EMDA was associated with lower recurrence rates than PD in randomized studies. Further data suggest that EMDA/MMC is at least equivalent to BCG in treatment of high-risk bladder tumours. In addition, BCG combined with EMDA/MMC as well as preoperative EMDA/MMC are new therapeutic strategies with promising preliminary results in terms of higher remission rates and longer remission times. In summary, these findings suggest that EMDA for MMC delivery in the bladder could be a major therapeutic breakthrough in the treatment of NMIBC.     

INTRAVESICAL ELECTROMOTIVE DRUG ADMINISTRATION TECHNIQUE: PRELIMINARY RESULTS AND SIDE EFFECTS

Purpose

We performed intravesical electromotive drug administration (EMDA) for various bladder disorders during a 3-year period and assessed the technique, possible applications, complications and outcomes of this procedure.

Materials and Methods

Intravesical EMDA was performed with local anesthetics for transurethral surgery and in combination with dexamethasone for the treatment of noninfectious chronic cystitis (interstitial/radiation cystitis), with mitomycin C for recurrence prophylaxis of high risk superficial bladder cancer and with oxybutynin/bethanechol for the hyperreflexive/acontractile detrusor. A standardized power source and electrode catheter were used for 215 treatments in 84 patients.

Results

Transurethral bladder tumor resections were pain-free in 10 of 12 patients. Of the 25 patients with chronic noninfectious cystitis 15 were free of symptoms for a mean of 6.6 months, and there was a 73% increase in mean bladder capacity from 244 before to 421 cc after EMDA. Of the 16 patients with superficial bladder cancer 9 were free of recurrence for a mean of 14.1 months. In 10 of 14 patients with acontractile detrusors urodynamic examination showed detrusor contraction during EMDA of bethanechol. There were no contractions without electric current. EMDA of oxybutynin reduced detrusor hyperreflexia. A bladder ulcer was the single severe local complication and 4.6% of patients, mainly those with chronic cystitis, reported significant post-EMDA bladder/urethral pain. Minor side effects accounted for 23% of all treatments. No systemic side effects occurred.

Conclusions

Intravesical EMDA is effective and innocuous. The therapeutic concept combines the advantages of increased drug administration without systemic side effects.     

Phase II study of intravesical therapy with AD32 in patients with papillary urothelial carcinoma or carcinoma in situ (CIS) refractory to prior therapy with bacillus Calmette-Guerin (E3897): a trial of the Eastern Cooperative Oncology Group

ObjectiveTo assess the safety and effectiveness of AD32, a doxorubicin analogue with little systemic exposure when administered intravesically, in patients with recurrent or refractory superficial urothelial carcinoma (formerly called transitional cell carcinoma [TCC]), or carcinoma in situ (CIS), who have failed prior BCG-based immunotherapy.MethodsEligible patients received six weekly doses (800 mg) of intravesical AD32 and were evaluated at 12-week intervals for 24 months or until date of worsening disease. Primary analysis was the proportion of all patients recurrence-free at 12 months. Treatment-related and GU-specific toxicities were also examined. All participating institutions submitted the protocol for Institutional Review Board (IRB) approval.ResultsThe study was halted due to unavailability of study drug after accrual of 48 of a planned 64 patients; 42 were included in the analysis. Of these, 28 (67%) were still alive after median follow-up of 61.1 months. Of 21 TCC patients, 18 (85.7%) experienced disease recurrence (median time to recurrence, 5.3 months). Of the 5 CIS patients with complete response (CR), 3 (60%) experienced disease recurrence; (median time to recurrence, 37.3 months). Recurrence-free rates at 12 and 24 months were 20% (90% CI, 7.8%, 36.1%) and 15% (90 CI, 4.9%, 30.2%), respectively, for patients with TCC and 80% (90% CI, 31.4%, 95.8%) at both intervals for CIS patients with CR. Infection was the most common treatment-related toxicity; no grade 4 or higher toxicity was observed. The most common GU-specific toxicity was increased frequency/urgency.ConclusionsAD32 is safe and active for treatment of recurrent or refractory superficial bladder carcinoma. The agent awaits more complete characterization when drug production problems can be solved.     

Effect of photodynamic therapy on urinary bladder function: an experimental study with rats

Photodynamic therapy (PDT) produces localized necrosis with light after prior administration of a photosensitizing drug. The problems with laser light dosimetry and complications relating to bladder function appear to be important limiting factors of PDT in urology. Photodynamic therapy on urinary bladder with normal epithelium of rats was performed using an argon ion laser as an energy source, with aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photosensitizer. Four hours after ALA intravenous administration, the bladders were intravesically radiated with light doses 20, 40, or 80 J/cm². Animals in the control group did not receive ALA and were radiated with 20 J/cm² light dose. Three weeks prior to PDT, the bladder capacity and pressure changes during filling cystometry were assessed. Cystometrics were repeated 1, 3, 7, or 21 days after laser therapy. The light dose 20 J/cm² and 40 J/cm² together with the used ALA dose caused no reduction in bladder capacity, whereas 80 J/cm² light dose produced up to 50% reduction in the capacity at 3 weeks postoperatively. In control group without ALA, the animals did not regain more than 34% of the capacity of their control values at 3 weeks. The light dose of 20 J/cm² and 40 J/cm² with ALA induced functional changes that subsided after day 1. Our results indicate that with proper dosing of photosensitizing drug and light energy, the functional impairment of urinary bladder may be reduced as transient. These findings support the use of PDT as safe therapy of superficial bladder cancer. Received: 10 April 2000 / Accepted: 16 November 2000     

Spinal anaesthesia with glucose–free 2% lignocaine. Effect of different volumes

Spinal anaesthesia with 2, 3 or 4 ml of glucose-free 2% lignocaine was studied in 64 patients undergoing transurethral surgery of the bladder. Cephalad spread of analgesia, onset time, duration of analgesia, duration of motor block, quality of analgesia, and the cardiovascular effects were assessed. Two ml of 2% lignocaine was insufficient to produce reliable analgesia. Three ml provided sufficient analgesia in most of the patients, but 4 ml was needed to guarantee sufficient analgesia in all patients. Onset times for analgesia and motor block were 10-20 min. After 4 ml the median and interquartile values were: maximum cephalad spread: T8, (T10-T5); time from injection to regression of analgesia to T11: 84 min, (60-103 min); duration of complete motor block: 90 min, (60-120 min). All patients in the 3-ml and 4-ml groups developed complete motor block. There was a positive correlation between the dose and the duration of analgesia and motor block. A positive correlation, although weaker, was also seen between the dose and the maximum cephalad spread of analgesia. There was an inverse relationship between the cephalad spread of analgesia and the duration of motor block. Falls in systolic blood pressure greater than 30% were noted in seven patients in whom the cephalad spread of analgesia was higher than in the rest of the patients. Spinal anaesthesia with glucose-free 2% lignocaine in doses of 3-4 ml provides reliable analgesia for transurethral surgery of the bladder.     

Contemporary results of radical radiotherapy for bladder transitional cell carcinoma in a district general hospital with cancer-centre status

OBJECTIVE: To assess the current efficacy and safety of definitive external beam radiotherapy (EBRT) in the treatment of invasive bladder transitional cell carcinoma (TCC) in a district general hospital with cancer-centre status. PATIENTS AND METHODS: The case notes of all patients with bladder TCC undergoing EBRT with curative intent over an 8-year period (1988-95) were reviewed. Additional missing outcome data were collected. RESULTS: In all, 120 patients (109 men; median age 70 years, range 34-90) underwent radical EBRT (40-65 Gy; fraction median=20) over the 8-year period. Staging, as assessed by examination under anaesthesia and computed tomography, was T1 in 16%, T2 in 43%, T3 in 38% and T4 in 3%. In 96 patients (80%) the tumour was poorly differentiated (G3). The overall morbidity at 12 months was 12%; proctitis occurred in nine patients (8%) and cystitis in five (4%). Sixty-seven patients (59%) developed a local recurrence and in 36 (30%) this was invasive. The overall median survival was 60 months. Thirty-three patients underwent salvage cystectomy with a subsequent median survival of 12.5 months. CONCLUSION: Modern radical multifraction EBRT in invasive bladder TCC has a low morbidity, with an overall median survival of 5 years.     

Upper tract transitional cell carcinoma following cystectomy for bladder cancer.

PURPOSE: We assessed the incidence of upper urinary tract tumors (UUTTs) after cystectomy for invasive or superficial transitional cell carcinoma (TCC) of the bladder. The risk factors, patients' characteristics and evolution of those who developed UUTTs are analyzed. MATERIALS AND METHODS: From August 1980 to February 1994, 568 radical cystectomies were performed for TCC of the bladder: in 469 instances (82.5%) due to invasive tumor (T2-T4), and in 99 cases (17.5%) for superficial tumor (Ta, T1, Tis). All patients were followed for at least 5 years or until death. A retrospective study of patients who developed UUTTs has been performed. A revision of bladder tumor and UUTT characteristics, and the intervals between both is also evaluated. RESULTS: 26 patients (4.5%) developed UUTTs: 11 of the 99 patients cystectomized for superficial TCCs (11.1%); 6 of the 392 patients with primary invasive TCC (1.5%), and 9 of the 77 (11.6%) patients with invasive tumors and a prior history of superficial TCC. The interval to the development of UUTT was higher after cystectomy for superficial tumor. TCCs of the bladder that subsequently developed UUTTs were high grade in 84%, multifocal in 80%, or had carcinoma in situ in 65%, tumor in the prostatic urethra in 52%, and involvement of the distal ureter in 57%. Twenty-two UUTTs (84%) were located in the calyces or the renal pelvis, 3 were bilateral (11.5%), 14 multiple (58%) and 4 superficial (16%). With a median follow-up time of 18 (range 3-103) months, 14 patients (53.8%) died of tumor, 2 were alive with disease, 2 were lost for follow-up, and 8 (30%) were alive and free of disease. CONCLUSIONS: We found that patients cystectomized for superficial or invasive TCC with a prior history of superficial TCC have a higher incidence of UUTTs. These cases require follow-up with annual urography or loopography.     

Electromotive Administration of Oxybutynin into the Human Bladder Wall

Purpose

To compare concentrations of oxybutynin in the human bladder wall after either passive delivery (PD) or electromotive administration (EMDA).

Materials and Methods

Tissue sections of human bladder were inserted into a diffusion cell with urothelium exposed to the donor compartment containing oxybutynin (4.5 mg. in 100 ml. NaCl 0.45%) and an anode. Twelve paired experiments, "current 5 mA/no current", were conducted over 15 minutes. Oxybutynin tissue contents were measured and tissue viability, morphology and oxybutynin stability were assessed.

Results

Mean oxybutynin tissue concentrations were 3.84 micro g./gm. in samples exposed to EMDA and 0.87 micro g./gm. in samples exposed to PD (p = 0.0006). The mean coefficients of variation were 57.85% in EMDA experiments and 89.78% in PD experiments. Tissues were viable and undamaged histologically and no oxybutynin structural modification was observed.

Conclusions

EMDA enhances oxybutynin administration into viable bladder wall and reduces the variability in drug delivery rate.     

The management of T1G3 bladder cancer

INTRODUCTION: The treatment of T1G3 bladder cancer is still a controversial issue. Nowadays, intravesical bacillus Calmette-Guérin (BCG) instillation is considered to be the treatment of choice for patients with high-grade superficial bladder tumour after transurethral resection of all visible tumour. The aim of this retrospective study was to determine the effects and results of this approach, recurrence and progression rates in patients with T1G3 superficial bladder tumours. MATERIALS AND METHODS: 43 patients (28 male, 15 female; mean age 65.5 years, range 21-82) with T1G3 TCC (transitional cell carcinoma) bladder tumour underwent transurethral resection and subsequent intravesical BCG according to Morales protocol, in the period 1993-1998 at our institution. The mean follow-up period was 52.5 (range 30-96) months. RESULTS: After one or more initial courses of therapy, 33 patients were disease-free. Twelve patients (27.90%) had recurrent tumour after a median of 7 (range 3-46) months. After a second course of BCG treatment, 6 patients had no evidence of disease, 3 patients had progression and 3 had recurrence. Progression occurred in 7 (16.27%) patients after a median of 19 (range 3-43) months. Five patients underwent radical cystectomy and the remaining 2 underwent bladder-preserving therapies. Two patients died of TCC and 3 due to disease-unrelated conditions. CONCLUSION: Intravesical BCG instillation can be recommended as treatment modality for responders with T1G3 TCC bladder tumour. The benefit of the second course of intravesical BCG therapy has to be confirmed in further investigations.     

Photodynamic therapy of high-grade cervical intraepithelial neoplasia with 5-aminolevulinic acid

BACKGROUND AND OBJECTIVES: To determine the safety and efficacy of 5-aminolevulinic acid (ALA) as a topically applied photosensitizer for photodynamic therapy (PDT) of cervical intraepithelial neoplasia (CIN). STUDY DESIGNS/MATERIALS AND METHODS: Forty women, who were at least 18 years old with persistent biopsy-proven CIN 2 and CIN 3 within the previous 3 months of enrollment, underwent PDT in a phase I and II design. Five escalating radiant energies (increments of 25 J/cm(2), beginning at 50-150 J/cm(2)) using a Coherent Dye Model 920 argon pumped dye laser providing light at 630 nm (maximum output 0.8 W) were used to perform PDT with a fixed dose of ALA (200 mg/ml). ALA was placed in a cervical cap fitted to the cervix. After 90 minutes, the cap was removed and the ectocervix was illuminated for 5-16 minutes, depending on the irradiance. Success was defined as the absence of CIN on Pap smear or colposcopic examination at 12-months. Patients were monitored for toxicity. RESULTS: Thirty-two women (80%) completed the study with 1 year of follow-up. Sixty percent had CIN 3 and 40% CIN 2. Success rates at 4, 8, and 12 months were 51, 46, and 31%, respectively, and were not light-dose dependent. Three patients progressed from CIN 2 to CIN 3. Toxicity was tolerable and only consisted of spotting, vaginal discharge, mild cramping, and vaginal warmth. There was no apparent dose relationship to toxicity. CONCLUSIONS: PDT at this light and ALA dose is well tolerated but has minimal activity in the treatment of CIN 2 and CIN 3. Other doses and schedules of light and ALA or novel photosensitizers may improve efficacy.     

Ultrasound guided surgery under Dilutional Local Anaesthesia and no sedation in breast cancer patients

BackgroundBreast cancer surgery under local anaesthesia (LA) can be challenging due to limitation of dose and quantity of anaesthetic agent that can be used safely. Elderly patients with breast cancer and with multiple co-morbidities are often prevented from having a standard treatment as they are considered unfit for general anaesthesia. We describe a technique of surgery under local anaesthesia without sedation that employs dilution to generate large volumes of LA and infiltration under ultrasound guidance.MethodsWe present a case series by a single surgeon of breast cancer patients who underwent surgery under LA. 40 mls of 1% lignocaine with 1:200,000 adrenaline was diluted with 160 mls of normal saline to make a total of 200 mls, resulting in dilution to a concentration of 0.2% lignocaine. Radioactive isotope having been injected before patient's arrival in theatre, 1 ml of diluted anaesthetic solution is used with 2 mls of 2.5% patent blue to inject in the sub-areolar space. Local anaesthetic is infiltrated at operative site under ultrasound guidance using a long echogenic needle.ResultsA total of 71 patients with breast cancer underwent surgery under the LA between September 2015 and October 2018. 64 (90%) patients had wide local excisions and 7 (10%) had mastectomies. All had axillary surgery, 65 (91.5%) had dual technique sentinel lymph node biopsy as a day case and 6 (8.5%) patients had axillary clearance. 8 patients had re excision (12.5%). All patients had ‘0′ pain score and no postoperative analgesia was required in recovery. Local anaesthetic used did not exceed the maximum safe dose in any of the cases. One patient returned to theatre for postoperative wound bleeding. No other postoperative complication was observed.ConclusionUltrasound guided infiltration allows accurate placement of large volume of diluted local anaesthetic solution safely and provides effective anaesthesia.     

Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder

Objective:Prostatic transitional cell carcinoma (TCC) may involve urethral mucosa, ducts, acini and stroma of the gland. In this study, we evaluated the risk factors for mucosal prostatic urethral (PU) involvement in superficial TCC of the bladder.Methods:The data of 340 consecutive male patients with the diagnosis of primary superficial TCC of the bladder who were treated at our institution were reviewed. Median age of the patients was 64 years and median follow-up was 66 months. The impact of pathological stage, grade, tumour multiplicity and presence of carcinoma in situ (CIS) on mucosal PU involvement were evaluated.Results:Twenty one patients (6.2%) had mucosal involvement of the PU and concomitant multifocal TCC of the bladder. Of those, 12 patients (3.5%) had macroscopic mucosal involvement of the PU while the other 9 patients (2.7%) had microscopic tumour. Increased pathological stage, grade and tumour multiplicity were found to be risk factors for mucosal PU involvement in patients with superficial bladder cancer. Multivariate analysis showed that only the tumour multiplicity was found to be an independent risk factor for mucosal PU involvement by TCC (p = 0.001).Conclusions:The incidence of mucosal PU involvement increases as the stage, grade and number of tumours increase in patients with superficial TCC of the bladder. We recommend PU sampling particularly in patients with multiple bladder tumours which may have an impact on further management of these patients.     

Prognostic significance of estrogen receptor expression in superficial transitional cell carcinoma of the urinary bladder

OBJECTIVES: The role of estrogens in human bladder cancer still remains to be resolved. This study was undertaken to determine the estrogen receptor (ER) expression status and to elucidate the prognostic significance of ER in superficial transitional cell carcinoma (TCC) of the human bladder. METHODS: Tumor tissue blocks which were obtained by transurethral resection (TUR) from 121 patients with superficial TCC and 30 control subjects were investigated. Median follow-up was 40 months. The expression of nuclear ER was evaluated by immunohistochemistry using avidin-biotin-peroxidase method and a monoclonal ER antibody. ER staining intensity in samples was assessed semi-quantitatively. Staining characteristics were compared with the clinico-pathological results. RESULTS: ERs were detected in 12.4% of the superficial TCC patients and in 10% of the controls (P = 0.73). No association was found between ER immuno-reactive score and patients' age, sex, tumor multiplicity or tumor size. An association between the ER staining intensity and higher tumor grade was observed (P = 0.01). Grades I, II and III tumors showed 10.6, 8.7 and 44.4% staining, respectively. Survival was not affected by ER expression. In multivariate analysis ER expression was not an independent prognostic factor. CONCLUSION: Superficial TCC of the bladder shows low ER expression and it appears that ERs do not have any direct role on the prognosis of patients with superficial TCC.