Impact of radiation on the incidence and management of ureteroenteric strictures: a contemporary single center analysis.

BACKGROUND: Ureteroenteric stricture incidence has been reported as high as 20% after urinary diversion. Many patients have undergone prior radiotherapy for prostate, urothelial, colorectal, or gynecologic malignancy. We sought to evaluate the differences between ureteroenteric stricture occurrence between patients who had radiation prior to urinary diversion and those who did not. METHODS: An IRB-approved cystectomy database was utilized to identify ureteroenteric strictures among 215 patients who underwent urinary diversion at a single academic center between 2016 and 2020. Chart abstraction was conducted to determine the presence of confirmed stricture in these patients, defined as endoscopic diagnosis or definitive imaging findings. Strictures due to malignant ureteral recurrence were excluded (3 patients). Statistical analysis was performed using chi squared test, t-test, and Wilcoxon Rank-Sum Test, logistic regression, and Kaplan-Meier analysis of stricture by cancer type. RESULTS: 65 patients had radiation prior to urinary diversion; 150 patients did not have a history of radiation therapy. Benign ureteroenteric stricture rate was 5.3% (8/150) in the non-radiated cohort and 23% (15/65) in the radiated cohort (p = < 0.001). Initial management of stricture was percutaneous nephrostomy (PCN) in 78% (18/23) and the remaining 22% (5/23) were managed with primary retrograde ureteral stent placement. Long term management included ureteral reimplantation in 30.4% (7/23). CONCLUSIONS: Our study demonstrates a significant increase in rate of ureteroenteric strictures in radiated patients as compared to non-radiated patients. The insult of radiation on the ureteral microvascular supply is likely implicated in the cause of these strictures. Further study is needed to optimize surgical approach such as utilization of fluorescence angiography for open and robotic approaches.

Defining Thermally Safe Laser Lithotripsy Power and Irrigation Parameters: In Vitro Model.

Introduction: High-power laser settings are commonly employed for stone dusting techniques. Previous in vitro and in vivo studies have demonstrated that a toxic thermal dose can result from treatment within a renal calix without adequate irrigation. Hence, both laser power and irrigation rate must be considered together to determine safe laser lithotripsy parameters. The objective of this in vitro study was to map parameter safety boundaries and create guidelines for selection of safe laser and irrigation settings. Methods: The experimental system consisted of in vitro models simulating ureter, renal calix, and renal pelvis placed in a water bath maintained at 37°C. Temperature was recorded during ureteroscopy with laser activation for 60 seconds. Trials were conducted at strategically selected power levels and irrigation rates. Thermal dose for each trial was calculated based on Sapareto and Dewey t43 methodology with thermal dose >120 equivalent minutes considered to result in thermal tissue injury. A parameter safety boundary was established by plotting the maximal safe power level for each irrigation rate. Results: The parameter safety boundary was found to be linear for each scenario with the renal pelvis able to tolerate the highest laser power and the renal calix the least power without injury. Conclusion: This study describes the methodology to determine parameter safety boundaries that can be used to guide proper selection of thermally safe laser settings and irrigation rates during ureteroscopy with laser lithotripsy. This work provides a framework to assess the effectiveness of various strategies to control and mitigate thermal dose.

Risk Factors for Ureteral Stricture After Radiochemotherapy Including Image Guided Adaptive Brachytherapy in Cervical Cancer: Results From the EMBRACE Studies.

PURPOSE: Ureteral stricture is a rare but severe side effect of radiation therapy for locally advanced cervical cancer. This report describes the incidence and risk factors for ureteral stricture in a large patient cohort treated with 3-dimensional image guided adaptive brachytherapy and radiochemotherapy within the EMBRACE studies. METHODS AND MATERIALS: A total of 1860 patients were included. Treatment consisted of external beam radiation therapy (45-50 Gy in 25-30 fractions), concomitant cisplatin, and image guided adaptive brachytherapy. Grade 3 to 4 ureteral strictures were assessed with Common Terminology Criteria for Adverse Events v. 3.0. Risk factors for grade 3 to 4 ureteral stricture were analyzed. These factors included age, hydronephrosis on imaging at time of diagnosis, TNM stage, high-risk clinical target volume, laparoscopic staging, chemotherapy, radiation therapy doses to targets and organs at risk, applicator type, intracavitary versus intracavitary/interstitial technique, and dose rate. RESULTS: At a median follow-up of 34 months (range, 2-163), 31 patients received diagnoses of grade 3 to 4 ureteral stricture. Actuarial 3- and 5-year risk for ureteral stricture grade 3 to 4 was 1.7% and 2.1%, respectively, for all patients. Advanced tumor stage T3-4 with hydronephrosis at diagnosis was the only independent risk factors for ureteral stricture (P = .01). Patients with TNM stage T1 (n = 359) had a low risk of 0.4% and 1.0% at 3 and 5 years, and those with T2 (n = 1085) had a low risk of 1.0% and 1.0% at 3 and 5 years, respectively. Patients (n = 274) with T3-T4 without hydronephrosis at diagnosis had a 3- and 5-year risk of 2.2% and 4.8%, respectively, compared with 11.5% and 11.5%, respectively, in those with baseline hydronephrosis (n = 142). CONCLUSIONS: Severe to life-threatening ureteral stricture occurs rarely in patients with locally advanced cervical cancer with T1-2 tumors. The risk for ureteral stricture is significantly increased in patients with T3-T4 tumors with hydronephrosis at diagnosis.

Urologic Complications Following Pelvic Radiotherapy.

Radiotherapy is widely used as a curative treatment for pelvic malignancies. The location of these organs leads to unavoidable exposure of the bladder, urethra, and distal ureters to radiation and may cause subsequent development of radiation cystitis, fistulae, strictures, and secondary malignancy. As cancer survival improves, an ever-increasing number of patients is living with the long-term complications of radiotherapy. Symptoms are not only debilitating for the patient but also pose a treatment challenge to the urologist. This review provides a comprehensive overview of the pathophysiology, clinical presentation, and current management strategies for the urologic complications following pelvic radiotherapy.

Long term outcomes in the use of ileal ureter for radiation-induced ureteral strictures.

PURPOSE: Radiation-induced ureteral stricture disease poses significant surgical challenges. Ureteral substitution with ileum has long been a versatile option for reconstruction. We evaluated outcomes in patients undergoing ileal ureter replacement for ureteral reconstruction due to radiation-induced ureteral stricture versus other causes. METHODS: Between July 1989 and June 2013, 155 patients underwent consecutive ileal ureter creation. The study cohort included 104 patients with complete data sets and at least 7 months of follow up. Records were retrospectively reviewed with regard to demographics, indications, complications, and renal deterioration. RESULTS: Surgical indications included radiation-induced stricture in 23 (22%) and non-radiation-induced stricture in 81 (78%). Comparing ileal ureter substitution due to radiation versus other stricture etiologies, no statistical significance was observed in regard to age (45.6 vs. 51.2, p = 0.141), hospital length of stay in days (8.8 vs. 7.7, p = 0.216), percent GFR loss (MDRD-4 vs. -5%, p = 0.670 and CKD-EPI-7 vs. -6%, p = 0.914), 30-day surgical complications (26.1 vs. 30.1%, p = 0.658), metabolic acidosis (8.7 vs. 1.2%, p = 0.059), and renal failure requiring dialysis (4.3 vs. 1.2%, p = 0.337). Fistula formation (13.0 vs. 3.7%, p = 0.095), partial small bowel obstructions (21.7 vs. 7.4%, p = 0.063), and small bowel obstructions requiring reoperation (13.0 vs. 1.2%, p = 0.033) approached or reached statistical significance. Using Kaplan-Meier methodology, there was no difference in time to worsening renal outcome between the radiation and non-radiation groups (p > 0.05). CONCLUSION: Ureteral substitution with ileum is an effective reconstructive option for radiation-induced ureteral strictures in carefully selected patients.

Systematic review and meta-analysis of the diagnostic accuracy of low-dose computed tomography of the kidneys, ureters and bladder for urolithiasis.

Renal colic is a common clinical condition which is often investigated with a CT of the kidneys, ureters and bladder (CTKUB). Recent technological improvements have allowed a reduction in dose with the emergence of low-dose CTKUB (LD-CTKUB) techniques. The present meta-analysis aims to determine the diagnostic accuracy of LD-CTKUB in the diagnosis of clinically significant uroliths. A systematic review was performed using nine electronic databases from their dates of inception to May 2016. Inclusion criteria included studies reporting comparative outcomes using LD-CTKUB with a dose less than 3 millisieverts compared to an imaging gold standard or clinical and surgical evaluation. The primary endpoint was detection of a urolith ≥3 mm where specified and any urolith when size was unspecified. Twelve studies were identified according to selection criteria, involving 1250 patients. LD-CTKUB demonstrated a pooled sensitivity of 93.1% (95%CI 91.5-94.4), specificity of 96.6% (95%CI 95.1-97.7%), positive likelihood ratio of 19.9 (95%CI 12.7-31.2), negative likelihood ratio of 0.05 (95%CI 0.02-0.10) and AUC of 0.9877 in the detection of clinically significant uroliths. Although 86 alternative diagnoses were noted across seven studies, none assessed the accuracy of LD-CTKUB in their detection. The majority of newer studies report an average radiation dose from 1 to 1.5 millisieverts. This study demonstrates a high sensitivity, specificity and positive predictive value in the detection of uroliths, however, its accuracy in the detection of alternative diagnoses is unknown. Therefore, we recommend using LD-CTKUB when the pre-test probability of stone disease is significantly higher than the pre-test probability of alternative diagnoses, such as follow-up of known calculi. We suggest caution when the pre-test probability of alternative diagnoses is high, such as the initial presentation of renal colic.

Comparison of escalating, constant, and reduction energy output in ESWL for renal stones: multi-arm prospective randomized study.

This study was designed to find out the optimized energy delivery strategy in Shock Wave Lithotripsy (SWL) that yield to the best stone-free rate (SFR). In this clinical trial, 150 consecutive patients were randomized into three groups: (a) Dose escalation, 1500 SW at 18 kV, followed by 1500 SW at 20 kV then 1500 SW at 22 kV. (b) Constant dose, 4500 SW at 20 kV. All patients undergo plain X-ray film of the urinary tract at day 1, 14, and 90 to assess stone-free rate (SFR) which was defined as no stones or painless fragments less than 4 mm. (c) Dose reduction, 1500 SW at 22 kV, followed by 1500 SW at 20 kV and then 1500 SW at 18 kV. The three treatment groups were comparable in terms of age, sex, stone size and distribution of the kidneys, and the need for Double J stent use. On day 90, the SFR achieved was 82, 90, and 84 % in the escalating, constant, and reduction energy groups, respectively. However, this rate was not statistically significant (x 2 = 1.38, p level = 0.28). At a slow rate of 60 shocks, there was no difference in stone-free rate between different voltages at 1, 14, and 90 days. Our randomized clinical trial showed no statistically significant difference in SFR between the three groups while using the slow SWL rate. Our trial is the first randomized trial comparing the three strategies. As such, a dose adjustment strategy while delivering SWL in slow rate was not recommended.

The effect of extracorporeal shock wave lithotripsy on distribution of interstitial cells of Cajal in rabbit renal pelvis and proximal ureter.

BACKGROUND/AIM: An experimental study was performed to evaluate the effect of extracorporeal shock wave lithotripsy (ESWL) on the distribution of interstitial cells of Cajal (ICC) in rabbit renal pelvis and proximal ureter. MATERIALS AND METHODS: Six New Zealand rabbits were included. Right kidneys were exposed to a total of 3000 shock waves (14 kV) by using an electrohydraulic-type ESWL device. Right sides were allocated as the ESWL group (EG, n = 6) and left sides as the control group (CG, n = 6). Tissues were harvested on day 7. Tissues were examined histopathologically for the presence of edema, inflammation, congestion, hemorrhage, fibrosis, and vascularization. Mast cell tryptase and CD 117 (c-kit) staining was performed for ICC distribution. RESULTS: Although increased tissue edema in renal pelvises and increased inflammation in ureters were observed in EG, no statistical difference was detected between groups (P > 0.05). In CG, positive CD117 staining was detected in 2 renal pelvises and ureters. None of the EG samples showed CD117 staining and no statistical difference was detected between groups (P > 0.05). CONCLUSION: Rabbit does not appear to be a good model for investigating ICCs. ESWL may cause histopathological alterations in the renal pelvis and ureter. Since it has not been statistically proven, reduced contractility of the ureter after ESWL may not be attributed to altered distribution of ICCs in the renal pelvis and ureter.

Validating a claims-based method for assessing severe rectal and urinary adverse effects of radiotherapy.

OBJECTIVE: To validate a claims-based algorithm for detecting severe rectal and urinary adverse effects (AEs) of radiotherapy (RT) to inform the design and interpretation of outcomes studies, using administrative datasets to detect such RT AEs. METHODS: An institutional billing analysis was performed to identify patients managed with RT for prostate or cervical cancer at the University of Minnesota, between 2000 and 2006. A priori, we identified Current Procedural Terminology procedural codes consistent with treatment for severe RT AEs. A retrospective chart review and a billing (ie "claims") analysis were performed to detect the procedures used to treat RT AEs. The accuracy of the claims-based algorithm was compared with chart review (the reference standard). RESULTS: On chart review, 31 patients (7.6%) with severe rectal and urinary RT AEs were detected among 406 patients with nonmetastatic cancer at diagnosis. The most common AE was ureteral stenosis (25% of all AEs). The sensitivity and specificity of the claims-based analysis were 75% and 100% respectively for urethral stricture, 100% and 99% respectively for ureteral stricture, 60% and 100% respectively for radiation cystitis, 88% and 100% respectively for rectal or urinary fistula, and 88% and 100% respectively for radiation proctitis. CONCLUSION: We demonstrated an excellent specificity and yet fairly good sensitivity of our claims-based algorithm for detecting treatment of urethral stricture, rectal or urinary fistulas, radiation proctitis, and ureteral stricture. These data might inform the design and interpretation of studies using claims-based methods for the detection of severe urinary AEs of pelvic RT.

Determination of patient radiation dose during ureteroscopic treatment of urolithiasis using a validated model.

PURPOSE: We measured organ specific radiation dose rates and determined effective dose rates during simulated ureteroscopy using a validated model. To calculate the effective dose, patients were exposed to ureteroscopic management of stones at our institution. MATERIALS AND METHODS: A validated anthropomorphic male phantom was placed on a fluoroscopy table and underwent simulated ureteroscopy. High sensitivity metal oxide semiconductor field effect transistor dosimeters were placed at 20 organ sites in the phantom and used to measure organ specific radiation doses. These dose rates were multiplied by the appropriate tissue weighting factor and summed to calculate effective dose rates. Also, we retrospectively reviewed the charts of patients who underwent ureteroscopy at our institution. A total of 30 nonobese males with data on fluoroscopy time were included in analysis. The median effective dose was determined by multiplying median fluoroscopy time by the effective dose rate. RESULTS: The skin entrance was exposed to the highest absorbed dose rate, followed by the small intestine (mean ± SD 0.3286 ± 0.0054 and 0.1882 ± 0.0194 mGy per second, respectively). The mean effective dose rate was 0.024 ± 0.0019 mSv per second. Median fluoroscopy time was 46.95 seconds (range 12.9 to 298.8). The median effective dose was 1.13 mSv (range 0.31 to 7.17). CONCLUSIONS: The fluoroscopy used during ureteroscopy contributes to overall radiation exposure in patients with nephrolithiasis. Nonobese males are exposed to a median of 1.13 mSv during ureteroscopy, similar to that of abdominopelvic x-ray. More data are needed to determine clinical implications but urologists must be aware and decrease patient radiation during ureteroscopy.

Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse.

BACKGROUND: Since transitional cell carcinoma (TCC) of the upper urinary tract is a relatively uncommon malignancy, the role of adjuvant radiotherapy is unknown. METHODS: We treated 133 patients with TCC of the renal pelvis or ureter at our institution between 1998 and 2008. The 67 patients who received external beam radiotherapy (EBRT) following surgery were assigned to the radiation group (RT). The clinical target volume included the renal fossa, the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph nodes, which were at risk of harbouring metastatic disease in 53 patients. The tumour bed or residual tumour was targeted in 14 patients. The median radiation dose administered was 50 Gy. The 66 patients who received intravesical chemotherapy were assigned to the non-radiation group (non-RT). RESULTS: The overall survival rates for the RT and non-RT groups were not significantly different (p = 0.198). However, there was a significant difference between the survival rates for these groups based on patients with T3/T4 stage cancer. A significant difference was observed in the bladder tumour relapse rate between the irradiated and non-irradiated bladder groups (p = 0.004). Multivariate analysis indicated that improved overall survival was associated with age < 60 years, T1 or T2 stage, absence of synchronous LN metastases, and EBRT. Acute gastrointestinal and bladder reactions were the most common symptoms, but mild non-severe (> grade 3) hematologic symptoms also occurred. CONCLUSION: EBRT may improve overall survival for patients with T3/T4 cancer of the renal pelvis or ureter and delay bladder tumour recurrence in all patients.

Urethral toxicity vs. cancer control--lessons to be learned from high-dose rate brachytherapy combined with intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer.

PURPOSE: To describe biochemical relapse-free survival (BRFS) and late toxicity after combined high-dose rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT) in intermediate- and high-risk prostate cancer patients. METHODS AND MATERIALS: From March 2003 to September 2005, 64 men were treated by 3×7Gy HDR-B using one implant followed by 50Gy IMRT. Median age was 66.1 years; risk of recurrence was intermediate in 30 (47%) or high in 34 (53%) patients. Forty-four (69%) patients received hormonal therapy. Patients were treated with a median of 13 HDR-B applicators (range, 8-17). Biochemical relapse was defined according to Phoenix criteria. Toxicity was scored according to the Common Toxicity Criteria scale version 3.0. RESULTS: Median followup was 5.1 years. The 3-year BRFS was 100% and 91% for intermediate- and high-risk patients. Late Grade 2 gastrointestinal (GI) toxicity occurred in 3 (4.7%) patients, late Grade 3 GI toxicity was absent. Late Grade 3 and 4 genitourinary (GU) toxicity was observed in 7 (10.9%) and 2 (3.1%) patients. The 5-year Grade 3 or higher late GU toxicity-free survival was associated with a higher number of HDR-B applicators (p=0.049). CONCLUSIONS: The 3-year BRFS was excellent and late GI toxicity was negligible. However, the late Grade 3 and 4 GU toxicity was unacceptably high.

[Ureteric reconstruction with reconfigured ileal segments according to Yang-Monti. A 4-year prospective report]. / Harnleiterrekonstruktion mit rekonfigurierten Ileumsegmenten nach Yang-Monti. Prospektiver 4-Jahres-Bericht.

BACKGROUND: We report on 4 years experience with ileal ureteric replacement using the Yang-Monti procedure. PATIENTS AND METHODS: From April 2001 to January 2009 reconfigured ileal segments were used for total (in 16) or partial (in 2) substitution of the ureter in 18 patients (mean age 47.4 years) with functional ureteric loss secondary to radiogenic or iatrogenic conditions. An antireflux implantation into the native bladder was done in 16 patients. All patients were followed prospectively according to a standardized protocol. RESULTS: The mean follow-up was 4.2 years (0.5-8 years). There were no perioperative deaths. Ultrasound controls showed an improvement of the upper tract dilatation in 11, a constant finding in 5 and a worsening in 2 cases. All of the treated renal units had evidence of improved renal function in ten and stabilization in eight patients. Neither a metabolic complication nor mucous obstruction was observed. Minor short-term complications, mainly febrile urinary tract infection and paralytic ileus, occurred in 50% and long-term complications, infections and hernia in 22%. CONCLUSIONS: The ileal ureteral substitute with reconfigured segments offers distinct advantages. A short bowel segment is used with the consequent absence of metabolic complications and excessive mucous production. It allows construction of an ileal ureter with a suitable cross-sectional diameter without any need for tailoring and makes it possible to use an antireflux technique. The intermediate results are encouraging.

[Palliative therapy of locally-advanced prostate cancer following radical treatment].

Both radical and combined radiotherapy for locally-advanced prostate cancer may be followed by complications involving the upper and lower urinary tracts. Such conditions are generally reversible but still they may turn chronic and even call for surgery. Our study used the data gathered in the course of examination and treatment of 107 patients with prostate cancer T3-4N0-1M0, some of them suffering from post-radical treatment complications.

[Prospective study of the treatment of localised ureteric strictures by wire mesh stent]. / Etude prospective de traitement des sténoses urétérales localisées par endoprothèse grillagée métallique.

AIMS: To assess efficacy of Mémotherm BARD ureteral metallic stent in the treatment of non-operable ureteral stenoses. MATERIAL AND METHOD: Prospective evaluation of ureteral stenoses consecutively treated using Mémotherm BARD ureteral metallic stent. Assessment criteria (recurrence frequency, permeability, tolerance, complications) were measured by clinical examination, Intra Veinous Pyelography, renal sonography, urine culture at 1, and every 3 months. RESULTS: Thirteen stents were inserted in 12 patients (mean age: 68 yrs) presenting with subsequent ureteral stenosis (9 neoplastic, 3 following radiotherapy) over a 3 year period. No technical difficulty was observed. Mean follow-up was 19 months. Stenosis recurrence was observed in 5 patients, due to tumoural progression, but with no tumour in-growth. There was non incrustation or migration, pain, hematuria, infection due to the stent. All stent remained permeable and functional in surviving patients. CONCLUSIONS: In our experience, Mémotherm BARD ureteral metallic stent could be considered a useful cost-effective alternative to double J stent or traditional surgery in non-operable or end-of-life patients. The high ureteral stenosis recurrence rate was linked to the patient initial pathology. Considering these encouraging results, this study could represent the first stage of a multicenter tracker-study, which would permit to take into account further technological development of this type of material.

Intraoperative electron-beam radiotherapy and ureteral obstruction.

PURPOSE: To quantify the risk of ureteral obstruction (UO) after intraoperative electron-beam radiotherapy (IOERT). METHODS AND MATERIALS: One hundred forty-six patients received IOERT of 7.5 to 30 Gy to 168 ureters; 132 patients received external radiotherapy. RESULTS: Follow-up ranged from 0.01 to 19.1 years (median, 2.1 years). The rates of clinically apparent type 1 UO (UO from any cause) after IOERT at 2, 5, and 10 years were 47%, 63%, and 79%, respectively. The rates of clinically apparent type 2 UO (UO occurring at least 1 month after IOERT, excluding UO caused by tumor or abscess and patients with stents) at 2, 5, and 10 years were 27%, 47%, and 70%, respectively. Multivariate analysis revealed that the presence of UO before IOERT (p < 0.001) was associated with an increased risk of clinically apparent type 1 UO. Increasing IOERT dose (p < 0.04) was associated with an increased risk of clinically apparent type 2 UO. UO rates in ureters not receiving IOERT at 2, 5, and 10 years were 19%, 19%, and 51%, respectively. CONCLUSIONS: Risk of UO after IOERT increases with dose. However, UO risk for ureters not receiving IOERT was also high, which suggests an underlying risk of ureteral injury from other causes.

Influence of irradiated volume on ureteral injury after intraoperative radiation therapy: experimental study in dogs.

PURPOSE: To investigate the role of irradiated volumes at intraoperative radiation therapy in the development of ureteral injury in dogs. MATERIALS AND METHODS: Sixteen beagle dogs were randomized to receive 30 Gy of intraoperative radiation therapy in the right ureter. Lead shielding ensured that different volumes were irradiated. Six dogs received a 4 x 12-cm field, five dogs a 4 x 8-cm field, and five dogs a 4 x 4-cm field. Follow-up included magnetic resonance (MR) imaging, clinical examination, and resting sequential renography. Twelve months after irradiation, the animals were killed, and autopsy was performed. Functional outcome was defined as MR imaging and renography findings and was evaluated statistically by using the Cochran-Armitage test at a.05 significance level. RESULTS: Twelve months after therapy, ureteral obstruction with consecutive hydronephrosis of the right kidney was observed in four of six animals that received the largest volume of irradiation. Two dogs that received the medium volume developed ureteral obstruction. None of the five dogs that received the smallest volume showed abnormal findings (P <.05). The irradiated parts of the ureters in all dogs showed abnormal histopathologic findings, such as fibrosis. CONCLUSION: The probability of ureteral obstruction following intraoperative radiation therapy increases with the irradiated partial volume of the ureter.

A proliferation-dependent bystander effect in primary porcine and human urothelial explants in response to targeted irradiation.

The aim of this study was to test whether radiation-induced bystander effects are involved in the response of multicellular systems to targeted irradiation. A primary explant technique was used that reconstructed the in vivo microarchitecture of normal urothelium with proliferating and differentiated cells present. Sections of human and porcine ureter were cultured as explants and irradiated on day 7 when the urothelial outgrowth formed a halo around the tissue fragment. The Gray Cancer Institute charge particle microbeam facility allowed the irradiation of individual cells within the explant outgrowth with a predetermined exact number of (3)He(2+) ions (which have very similar biological effectiveness to alpha-particles). A total of 10 individual cell nuclei were irradiated with 10 (3)He(2+) ions either on the periphery, where proliferating cells are located, or at the centre of the explant outgrowth, which consisted of terminally differentiated cells. Samples were fixed 3 days after irradiation, stained and scored. The fraction of apoptotic and micronucleated cells was measured and a significant bystander-induced damage was observed. Approximately 2000-6000 cells could be damaged by the irradiation of a few cells initially, suggesting a cascade mechanism of cell damage induction. However, the fraction of micronucleated and apoptotic cells did not exceed 1-2% of the total number of the cells within the explant outgrowth. It is concluded that the bystander-induced damage depends on the proliferation status of the cells and can be observed in an in vitro explant model.