Evaluation of efficacy and toxicity in two different hypofractionated 3D-conformal external beam radiotherapy schedules in localised muscle invasive bladder cancer.

PURPOSE: To evaluate the efficacy as well as acute and late toxicity of two different accelerated hypofractionated 3D-conformal radiotherapy (Hypo-3DCRT) schedules in patients with bladder cancer. METHODS: Between February 2006 and June 2011, 50 elderly patients with cT1-2N0 bladder carcinoma were treated with Hypo-3DCRT. Mean age was 75 years. All patients were medically inoperable, with poor performance status, who couldn't tolerate either cystectomy or radical external beam irradiation on a daily basis. A dose of 36 Gy in 6 weekly fractions (arm A, N=39) or 39.96 Gy of 3.33 Gy twice daily, once a week, for 6 weeks (arm B, N=11) were prescribed. The primary study endpoints were the evaluation of acute/late gastrointestinal (GI) toxicity according to the EORTC/RTOG scale together with the visual analogue bladder-related pain score (VAS). RESULTS: The GI acute toxicities were: grade 1: arm A 24/39 (61.5%), arm B 9/11 (81.8%); grade 2: arm A 14/39 (35.9%), arm B 1/11 (9.1%); grade 3: arm A 1/39 (9.1%) (x(2), p=0.29). Only grade 1 late GI toxicity was seen and was significantly higher in arm A: arm A 17/39 (43.6%) and arm B 1/11 (9.1%) (x(2), p=0.037). The reduction of VAS score was similar in both arms (p=0.065). The median relapse free survival (RFS) was 15 and 16 months for arm A and B, respectively (log rank, p=0.71). CONCLUSIONS: Beyond the non-randomized design of the trial, the Hypo-3DCRT schedules used appear to be an acceptable alternative to the traditional longer radiotherapy (RT) schedules for elderly patients unfit for daily irradiation.

Development and validation of a prognostic model in patients with metastatic renal cell carcinoma treated with sunitinib: a European collaboration.

BACKGROUND: Accurate prediction of outcome for metastatic renal cell carcinoma (mRCC) patients receiving targeted therapy is essential. Most of the available models have been developed in patients treated with cytokines, while most of them are fairly complex, including at least five factors. We developed and externally validated a simple model for overall survival (OS) in mRCC. We also studied the recently validated International Database Consortium (IDC) model in our data sets. METHODS: The development cohort included 170 mRCC patients treated with sunitinib. The final prognostic model was selected by uni- and multivariate Cox regression analyses. Risk groups were defined by the number of risk factors and by the 25th and 75th percentiles of the model's prognostic index distribution. The model was validated using an independent data set of 266 mRCC patients (validation cohort) treated with the same agent. RESULTS: Eastern Co-operative Oncology Group (ECOG) performance status (PS), time from diagnosis of RCC and number of metastatic sites were included in the final model. Median OS of patients with 1, 2 and 3 risk factors were: 24.7, 12.8 and 5.9 months, respectively, whereas median OS was not reached for patients with 0 risk factors. Concordance (C) index for internal validation was 0.712, whereas C-index for external validation was 0.634, due to differences in survival especially in poor-risk populations between the two cohorts. Predictive performance of the model was improved after recalibration. Application of the mRCC International Database Consortium (IDC) model resulted in a C-index of 0.574 in the development and 0.576 in the validation cohorts (lower than those recently reported for this model). Predictive ability was also improved after recalibration in this analysis. Risk stratification according to IDC model showed more similar outcomes across the development and validation cohorts compared with our model. CONCLUSION: Our model provides a simple prognostic tool in mRCC patients treated with a targeted agent. It had similar performance with the IDC model, which, however, produced more consistent survival results across the development and validation cohorts. The predictive ability of both models was lower than that suggested by internal validation (our model) or recent published data (IDC model), due to differences between observed and predicted survival among intermediate and poor-risk patients. Our results highlight the importance of external validation and the need for further refinement of existing prognostic models.

Update on intracorporeal laser lithotripsy.

Nowadays, rigid and flexible ureteroscopy is a precise, minimal invasive surgery that can assess the entire collecting system in order to treat a stone with intracorporeal lithotripsy. The implication of laser technology has revolutionized the intracorporeal lithotripsy. Currently, laser lithotripsy is advancing in two different directions: improvements of the existing Ho:YAG laser platform and the development of novel laser systems. Herein, we review the current literature upon intracorporeal lithotripsy.

Procalcitonin as an early indicator of outcome in sepsis: a prospective observational study.

This study explores the role of procalcitonin (PCT) in predicting the outcome of sepsis. In a prospective multicentre observational investigation, blood was sampled within 24 h of onset of sepsis in 1156 hospitalised patients; 234 were in the intensive care unit (ICU) at the point of presentation of sepsis while 922 were not. PCT was estimated in serum by the ultrasensitive Kryptor assay in a double-blinded fashion. Among patients outside the ICU, mortality was 8% in those with PCT ≤0.12 ng/mL but 19.9% in those with PCT >0.12 ng/mL [P<0.0001, odds ratio (OR) for death: 2.606; 95% confidence interval (CI): 1.553-4.371]. Among patients whose sepsis presented in ICU, mortality was 25.6% in those with PCT ≤0.85 ng/mL but 45.3% in those with PCT >0.85 ng/mL (P=0.002; OR for death: 2.404; 95% CI: 1.385-4.171). It is concluded that PCT cut-off concentrations can contribute to predicting the outcome of sepsis and might be of particular value in identifying patients who would benefit from ICU admission.

Immunomodulatory effect of three-day continuous administration of clarithromycin for experimental sepsis due to multidrug-resistant Pseudomonas aeruginosa.

Based on former animal studies showing the effect of clarithromycin in experimental sepsis by multidrug-resistant Pseudomonas aeruginosa following administration of single doses, the significance of its administration for three consecutive days was evaluated. Acute pyelonephritis was induced in 20 rabbits after inoculation of the test isolate in the renal pelvis. Therapy was administered upon signs of sepsis in group B; A served as control. Survival was recorded; monocytes were isolated for determination of ex vivo TNFalpha secretion. Quantitative cultures of organs were performed after death. Mean survival of groups A and B was 2.65 and 7.95 days respectively. At 24 hours, serum malondialdehyde of group B, which is an index of the oxidant status in serum, was lower than A. Ex vivo release of TNFalpha by the isolated monocytes of group B was lower than A at 3.5 and 48 hours. Tissue bacterial load was similar in two groups after animal death. It is concluded that clarithromycin possessed considerable immunomodulatory effects restraining release of TNFalpha from blood monocytes.

Precursor lesions of prostate cancer.

Several morphological lesions have been proposed that may act as potential precursor lesions of prostate cancer. These are the morphologically distinct entities of focal atrophy or post-atrophic hyperplasia (PAH), atypical adenomatous hyperplasia (AAH) or adenosis, and prostatic intraepithelial neoplasia (PIN). The diagnostic criteria of low-and high-grade PIN (LGPIN and HGPIN, respectively) and of lesions suspicious for cancer (LSC) have been established. In the present review, we present the current knowledge about the precursor lesions of prostate cancer. We focus on the epidemiology, pathogenesis, clinical markers, and differential diagnosis of PIN. The similarities between HGPIN and prostate cancer are also discussed. Furthermore, potential markers and management strategies (that is, repeat biopsy, chemoprevention, radical prostatectomy, radiotherapy) are outlined along with updated recommendations.

Can prostate biopsies affect erectile function?

The impact of transrectal ultrasound (TRUS)-guided prostate biopsies on erectile function was prospectively studied. Forty-six men (median age: 67.51 years) who underwent TRUS-guided prostate biopsies completed the International Index of Erectile Function (IIEF)-5 questionnaire at the day of the biopsy, 1 and 3 months later. Erectile dysfunction (ED) severity was classified into five categories. Concomitant ED-related systemic diseases and/or medications that could affect erectile function were also recorded. The paired t-test was used for statistical analysis. The median IIEF-5 score was 15.91 prior to biopsies, while 1 and 3 months after, the median IIEF-5 score was 14.33 and 14.81 respectively (P > 0.05). Prior to prostate biopsies, ED was reported by 38 patients (82.60%): mild ED in 39.13%, mild to moderate in 19.56%, moderate in 15.21% and severe ED in 8.69%. Concomitant ED-related systemic diseases and/or medications were recorded in 28 patients (60.86%). One month after, ED was revealed in 42 patients (91.30%): mild ED in 26.08%, mild to moderate in 30.43%, moderate in 19.56%, and severe ED in 15.21%. Three months post-biopsy, ED was reported by 41 patients (89.13): mild ED in 21.73%, mild to moderate in 28.26%, moderate in 21.73%, and severe ED in 17.39%. Overall, three and two patients (6.52% and 4.34%) had prostate biopsy attributed ED (i.e. without concomitant ED-related disease or medication) 1 and 3 months after prostate biopsies. TRUS-guided prostate biopsies did not induce ED in a statistically significant manner. Evaluating potency at referral for TRUS-guided prostate biopsies is advisable.

Urinary diversion in high-risk elderly patients: modified cutaneous ureterostomy or ileal conduit?

OBJECTIVES: To evaluate the efficacy and safety of the type of urinary diversion during radical cystectomy in high-risk elderly patients by comparing a modified cutaneous ureterostomy with the ileal conduit urinary diversion. METHODS: Of 481 patients who underwent radical cystectomy between 1993 and 2002, 54 individuals older than 75 years with an American Society of Anesthesiologists score of 3e, 4, or 4e were characterized as high risk. These patients were grouped according to those who underwent a modified cutaneous ureterostomy (group 1, 29 patients) and those who underwent ileal conduit urinary diversion (group 2, 25 patients). Student's t and Fisher's exact tests were used for statistical analysis. RESULTS: The patients in group 2 had a longer operative time (P < 0.001), an increased need for blood transfusion (P = 0.025), an increased need for intensive care monitoring (P = 0.032), and a longer mean hospitalization time (P < 0.001) than the patients in group 1. In group 2, we recorded statistically greater rates of intraoperative complications (P = 0.035), early medical and surgical complications (P = 0.031 and P = 0.012, respectively), and late surgical complications (P = 0.004). The intraoperative, early, and late surgical complication rate was 13.7%, 24.1%, and 17.2% in group 1 and 40%, 60%, and 56% in group 2, respectively. One patient in group 2 died in the early postoperative period. CONCLUSIONS: Cutaneous ureterostomy represents a simplified alternative for urinary diversion in high-risk elderly patients. It can be performed quickly, with few early and late postoperative complications compared with the ileal conduit operation.

HPV 16/18-associated condyloma acuminatum of the urinary bladder: first international report and review of literature.

Condyloma acuminatum is an anogenital lesion caused by human papillomavirus (HPV) infection, a common sexually transmitted disease. It usually affects the external genitalia while urethral and/or bladder involvement is rare. HPV types are classified into three categories depending on their oncogenic potential: low risk (type 6, 11, 42, 43, 44, 59, 66, 68, 70), intermediate risk (type 30, 31, 33, 34, 35, 39, 40, 49, 51, 52, 53, 57, 58, 63, 64) and high risk (type 16, 18, 45, 56). High-risk and intermediate-risk HPV-DNA types, together with other co-factors still to be defined, are responsible for over 90% of the cases of anogenital pre-malignant and malignant tumours. We report a unique case of a urinary bladder condyloma acuminatum positive for HPV 16/18 DNA, presented as the primary and only site of the disease in an immunocompetent patient. We review the treatment and follow-up strategies of this rare lesion.

Management and follow-up of impacted ureteral stones.

INTRODUCTION: Impacted stones are those that remain unchanged in the same location for at least 2 months. MATERIALS AND METHODS: We evaluated 42 patients with impacted ureteral stones, and followed them for two and a half years to check for long-term results. The calculi location included all three segments of the ureter (proximal, mid and distal). Patients' age ranged from 22 to 83 years (mean 52.5 years). Primarily, patients were manipulated with extracorporeal shock wave lithotripsy (ESWL) in situ, or following stenting. If the result was not satisfactory, then we proceeded to retrograde ureteroscopy and ureterolithotripsy. Open ureterolithotomy was our final choice. RESULTS: Thirty-six of the 42 patients (85.7%) were stone-free without the need of an open procedure. Follow-up period ranged from 10 up to 40 months, with a median period of 30 months and was achieved in 30 patients (71.4%). Stone recurrence was noted in 4 cases, while hydronephrosis without evidence of stone presence in 2. CONCLUSIONS: The initial approach for the treatment of impacted lithiasis should be attempted by ESWL. If this fails, alternative therapeutic solutions such as endoscopy can result in removal of the stone.

Spontaneous rupture of the ureter after cystectomy and creation of orthotopic ileal neobladder: treatment with percutaneous nephrostomy and drainage.

A case of rupture of the upper ureter following creation of a continent orthotopic neobladder, treated conservatively with percutaneous nephrostomy and drainage of a paranephric collection, is reported.

Shockwave lithotripsy in unrecognized pregnancy: interruption or continuation?

A 32-year-old woman underwent SWL of a 4 x 6-mm calculus in the distal third of the right ureter, receiving 2100 shocks at a maximum intensity of 18 kV. Approximately 1 month later, it was discovered that she had been 10 weeks pregnant at the time of SWL. She chose to continue the pregnancy and delivered a normal infant at term. We do not advocate SWL in pregnancy, but further research is mandatory to determine if this procedure can ever be performed safely during pregnancy.

Orthotopic bladder substitution after radical cystectomy: 5 years of experience with a novel personal modification of the ileal s pouch.

PURPOSE: We report a 5-year experience with 52 patients who underwent radical cystoprostatectomy for bladder cancer and orthotopic bladder substitution using a novel personal modification of the S pouch. MATERIALS AND METHODS: From September 1995 to December 1999, 52 men 36 to 72 years old (mean age 63) underwent bladder substitution with an S pouch. They were followed until September 2000. The pouch was constructed with a 36 cm. segment of ileum with the whole length used for the reservoir. The ureters were directly anastomosed with one above the other in the mid segment of the pouch without any antireflux procedure. Complications were documented and classified as early or up to 3 months postoperatively and late, and further subdivided by the relationship to neobladder construction. Continence and voiding pattern were evaluated by personal interview and neobladder function was urodynamically assessed. Mean followup in our patients was 30 months. RESULTS: The most common of the 5 early and 9 late neobladder related complications were persistent urine leakage and reflux, respectively. There was no reflux greater than grade III in the 4 patients with reflux (5 refluxing ureters) and no functional disorders. We observed 12 early and 5 late complications unrelated to the neobladder. Open reoperation was required in 5 cases. Good or satisfactory daytime and nighttime continence was reported by 95% and 88% of our patients, respectively. By year 1 postoperatively 91% of our patients voided at an interval of 3 to 5 hours during the day. Mean maximum neobladder capacity was 672 ml. and mean post-void residual was 30 ml. by year 3 postoperatively. Two patients required self-catheterization once daily and mild hyperchloremia without acidosis developed in 2. CONCLUSIONS: The advantages of our modified S pouch are technical simplicity, substantially shorter operative time and decreased bowel length required. It is associated with an acceptable complication rate and functional parameters with subsequent patient satisfaction and good quality of life.

Pharmacokinetics of intravenously administered pefloxacin in the prostate; perspectives for its application in surgical prophylaxis.

In an attempt to define whether intravenously administered pefloxacin might be appropriate for surgical prophylaxis in prostatectomy, 50 patients undergoing transvesical prostatectomy for benign prostate hyperplasia were given a single intravenous dose of 800 mg; surgery was then performed after 2, 4, 6, 8 or 10 h. Concentrations of pefloxacin were determined in serum and in both the centre and periphery of the prostate adenoma using a microbiological plate assay. Elevated concentrations of pefloxacin were found in the adenoma from 2 h onwards. The central and peripheral concentrations were similar and had a mean value of 4.39 microg/g of tissue. These concentrations were similar to those achieved in serum. Although concentrations of pefloxacin were not determined separately in the intercellular, interstitial or excreted fluid, the tissue levels found were well above the MICs of pefloxacin for the bacteria commonly causing acute and chronic prostatitis. These data suggest the intravenous administration of pefloxacin to be a satisfactory alternative for the surgical prophylaxis before prostatectomy as well as in the therapy of acute prostatitis.

The long-term outcome after laparoscopic nephroureterectomy: a comparison with open nephroureterectomy.

OBJECTIVES: To assess the long-term outcome of the endourological management of upper tract transitional cell carcinoma (TCC) by laparoscopic nephroureterectomy (LNU) or open nephroureterectomy (ONU). PATIENTS AND METHODS: The records and pathology reports were reviewed retrospectively for 67 nephroureterectomy specimens (42 obtained by ONU and 25 by LNU). The grade, stage, lymph node status and site of the tumour were recorded for each patient. The primary end-point of the follow-up was disease-related death. RESULTS: Overall there was a high proportion of G2 (44%) and G3 (39%) disease, with a significant correlation between increasing grade and stage of TCC (r = 0.74, P < 0.001). Of the 25 patients who underwent LNU, 22 had pelvicalyceal or upper ureteric TCC and conversion to open surgery was required in three (12%). Of the TCCs in this group half were G3 and half were invasive (pT1-3). In the ONU group there were more ureteric tumours because of selection criteria and overall 16 (39%) were G3 and half were invasive. Information on nodal status was available in one LNU and two of the ONU reports. Within a mean follow-up of 32.9 months for LNU and 42.3 months for ONU, nine (21%) of the ONU group and four (16%) of the LNU group had died, with a mean survival of 15.1 and 17 months, respectively, after surgery (not significant). All of these deaths were associated with G3 pT1-3 disease. CONCLUSIONS: In this series the case mix and outcomes were similar for those undergoing LNU and ONU. As laparoscopic renal surgery is associated with less postoperative morbidity it would seem reasonable to offer LNU to all patients with upper tract TCC, where appropriate and when there is no evidence of local invasion or metastasis. Because of the strong correlation between grade and stage, preliminary ureteroscopic assessment and biopsy may influence the surgical approach adopted.

Laparoscopic ureterolithotomy: the Edinburgh experience.

OBJECTIVE: To review our experience with laparoscopic ureterolithotomy. PATIENTS AND METHODS: Since 1993, we have performed laparoscopic ureterolithotomy in 14 patients with ureteric stones. Laparoscopy was carried out in nine patients as a salvage procedure after failed ureteroscopy (six), shock wave lithotripsy (two), or both (one), and in five patients as a primary procedure for large stones (mean 27.2 mm, range 18-40). Patients in the former group had already undergone a mean of 1.88 procedures (range 1-4). Laparoscopic ureterolithotomy was carried out via a transperitoneal approach. Associated ureteric strictures were incised at the time of ureterotomy. RESULTS: All procedures were completed laparoscopically and all patients were rendered stone-free after a single procedure. The mean operative duration was 105 min. Ureteric strictures were incised in three patients, in two of whom dilatation was subsequently required; all three had a successful result. There were three minor complications. CONCLUSIONS: Laparoscopic ureterolithotomy can be a safe and effective procedure; it should be considered as a primary procedure for large mid- and upper ureteric stones.

Electrokinetic lithotripsy: safety, efficacy and limitations of a new form of ballistic lithotripsy.

OBJECTIVE: To investigate the safety and efficacy of electrokinetic lithotripsy (EKL), a ballistic lithotripter which uses high-energy magnetic fields to propel an impactor to fragment calculi. PATIENTS AND METHODS: The records and radiographs of 121 patients who underwent ureteroscopy using the EKL for stones in the upper (26), mid (28) or lower (67) ureter were reviewed retrospectively. Ureteroscopy was performed with an 8.5 F semi-rigid ureteroscope, through which a 3 F EKL probe was passed. RESULTS: A total of 148 stones (mean stone size 11.5 mm, range 6-40) in 121 patients were treated using the EKL. One patient was lost to follow-up. Of 148 stones, 147 (99.3%) were fragmented, including five that had resisted fragmentation with either pulsed-dye laser or electrohydraulic lithotripsy. Despite this, only 45 of 56 patients (80%) with a single stone in the lower ureter were rendered stone-free after a single ureteroscopic procedure. Seven patients in this group (12%) required shock-wave lithotripsy for fragments that had been propelled into the kidney, while four patients (7%) required repeat ureteroscopy for retained ureteric fragments. Complications were limited to minor ureteric perforations in two patients, both of which were treated with a stent. CONCLUSION: EKL is an inexpensive and reliable endoscopic method which fragments nearly all urinary calculi. Its limitations include the propulsion of fragments and the need to use an offset, semi-rigid ureteroscope. We recommend the use of a basket or graspers to remove fragments of >/=4 mm after EKL.

Determination of interferon-alpha receptors in urothelial cancer and in normal urothelium.

PURPOSE: We determined and compared the presence and frequency of interferon-alpha 2b receptors in urothelial neoplasms and normal urothelium, since the biological activity of interferons becomes apparent only after they bind to specific receptors. MATERIALS AND METHODS: With our method detection of interferon-alpha 2b receptors required a large number of cells, that is more than 1 x 10(6) cells per ml. We studied 14 patients with relatively large tumors of all stages and grades. Three patients had grade I, 4 grade II and 7 grade III disease. As controls we used biopsies of normal urothelium from 14 patients who underwent transvesical prostatectomy. Interferon-alpha 2b receptors were detected quantitatively through the binding of radiolabeled 125iodine human recombinant interferon-alpha 2b in normal and malignant urothelial tissue samples. The interferon-alpha 2b receptors are expressed as receptor sites per cell, and the results were evaluated with Scatchard analysis. RESULTS: The number of interferon-alpha 2b receptor sites per cell ranged from 43 to 100 (mean plus or minus standard deviation 62 +/- 18) in normal urothelium and from 110 to 210 (mean 174 +/- 25) in malignant epithelium. This difference was statistically significant (p < 0.001), Student's t test 13.75). The difference in the number of interferon-alpha 2b receptors in grades I plus II and grade III tumors is suggestive but not statistically significant (p < 0.10, Student's t test 2.075). High grade tumors expressed greater numbers of interferon-alpha 2b receptors than low grade tumors. CONCLUSIONS: The method used needs refining so that it will require fewer cells to determine interferon-alpha 2b receptors. Interferon-alpha 2b receptors are detected in bladder urothelium and are abundant in malignant tissue with increasing frequency as tumor grade increases. If we can establish, in the future, a correlation of the number of interferon-alpha 2b receptors with the potential response of patients to intravesical instillation therapy with interferon, we might have an important prognostic method for selecting subgroups of patients with transitional cell carcinomas who will benefit from interferon-alpha 2b instillation.