Long-term oncological outcomes of a phase II trial of neoadjuvant chemohormonal therapy followed by radical prostatectomy for patients with clinically localised, high-risk prostate cancer.

OBJECTIVE: To determine long-term oncological outcomes of radical prostatectomy (RP) after neoadjuvant chemohormonal therapy (CHT) for clinically localised, high-risk prostate cancer. PATIENTS AND METHODS: In this phase II multicentre trial of patients with high-risk prostate cancer (PSA level >20 ng/mL, Gleason ≥8, or clinical stage ≥T3), androgen-deprivation therapy (goserelin acetate depot) and paclitaxel, carboplatin and estramustine were administered before RP. We report the long-term oncological outcomes of these patients and compared them to a contemporary cohort who met oncological inclusion criteria but received RP only. RESULTS: In all, 34 patients were enrolled and followed for a median of 13.1 years. Within 10 years most patients had biochemical recurrence (BCR-free probability 22%; 95% confidence interval [CI] 10-37%). However, the probability of disease-specific survival at 10 years was 84% (95% CI 66-93%) and overall survival was 78% (95% CI 60-89%). The CHT group had higher-risk features than the comparison group (123 patients), with an almost doubled risk of calculated preoperative 5-year BCR (69% vs 36%, P < 0.01). After adjusting for these imbalances the CHT group had trends toward improvement in BCR (hazard ratio [HR] 0.76, 95% CI 0.43-1.34; P = 0.3) and metastasis-free survival (HR 0.55, 95% CI 0.24-1.29; P = 0.2) although these were not statistically significant. CONCLUSIONS: Neoadjuvant CHT followed by RP was associated with lower rates of BCR and metastasis compared with the RP-only group; however, these results were not statistically significant. Because this treatment strategy has known harms and unproven benefit, this strategy should only be instituted in the setting of a clinical trial.

Contemporary management of penile cancer: greater than 15 year MSKCC experience.

INTRODUCTION: Penile cancer is a rare malignancy, and few guidelines are available to define treatment paradigms. For greater understanding of the natural history of surgically treated penile cancer, we analyzed the experience at our institution. MATERIALS AND METHODS: Using an institutional database, we identified 127 patients treated for squamous cell carcinoma of the penis from 1995-2011. Cancer-specific survival (CSS) was calculated using the Kaplan-Meier method. Survival data were compared using the log-rank test. The difference in risk of cancer-specific death by lymph node status and histological grade was determined by univariate Cox regression analysis. RESULTS: Five year CSS for pTis, pT1, pT2, and pT3/4 was 100%, 84% (95% CI 58%-95%), 54% (95% CI 33%-71%), and 54% (95% CI 25%-76%), respectively (p ≤ .005). Three year CSS for patients with N0, N+, and Nx disease was 90% (95% CI 47%-99%), 65% (95% CI 47%-79%), and 86% (95% CI 73%-93%), respectively (p = .03). The receipt of neoadjuvant chemotherapy did not change per 5 year period over the 16 years of our study. Median follow up was 2.8 years. CONCLUSIONS: Penile cancer patients with advanced disease had poor survival. Tumor stage and nodal status were significant predictors of CSS. Penis-sparing approaches may be considered for most patients; however, pathological stage and grade dictate the management and ultimate outcome. Further studies are necessary to clarify the benefits of chemotherapy in this disease.

Trends in partial and radical nephrectomy: an analysis of case logs from certifying urologists.

PURPOSE: Surgical treatment options for renal masses include radical vs partial nephrectomy and the open vs laparoscopic approach. Using American Board of Urology (ABU) case log data, we investigated contemporary trends in these treatment options, and how surgeon and practice characteristics may influence these trends. MATERIALS AND METHODS: Annualized case log data for nephrectomy were obtained from the ABU for all urologists certifying or recertifying from 2002 to 2010. We evaluated trends in nephrectomy use. Logistic regression was used to evaluate surgeon and practice characteristics as predictors of partial and laparoscopic procedures. RESULTS: From the 3,852 case logs submitted by nonpediatric urologists we analyzed a total of 48,384 nephrectomies. From 2002 to 2010 the proportion of annual nephrectomies performed as open radical nephrectomy gradually decreased from 54% to 29%. During the same period, there was a moderate gradual increase in laparoscopic radical nephrectomies (from 30% to 39%). The proportion of open partial nephrectomies remained stable at 15%, while laparoscopic partial nephrectomy increased from 2% to 17%. On multivariable analysis the use of partial nephrectomy and laparoscopy was predicted by urologist annual nephrectomy volume, initial or recertification status, subspecialty, practice area size and geographic region. CONCLUSIONS: Since 2002, the use of laparoscopic nephrectomy and partial nephrectomy has increased. However, the diffusion of these techniques is not uniform. Initial certification, higher surgical volume, and practicing in areas with more than 1,000,000 population and in the Northeast region were associated with greater use of laparoscopy and partial nephrectomy. Factors that affect the adoption of these techniques require further research.

Urinary diversion practice patterns among certifying American urologists.

PURPOSE: We investigated trends in urinary diversion use and surgeon characteristics in the performance of incontinent and continent urinary diversion using American Board of Urology data. MATERIALS AND METHODS: Annualized case log data for urinary diversion were obtained from the American Board of Urology for urologists who certified or recertified from 2002 to 2010. We evaluated the association between surgeon characteristics and the performance of any urinary diversion or the type of urinary diversion. RESULTS: Of the 5,096 certifying or recertifying urologist case logs examined 1,868 (37%) urologists performed any urinary diversion. The median number of urinary diversions was 4 per year (IQR 2, 6) and 222 urologists (4%) performed 10 or more per year. On multivariate analysis younger urologists, those self-identified as oncologists or female urologists, those who certified in more recent years and those in larger practice areas or outside the Northeast region of the United States were more likely to perform any urinary diversion. Only 9% of the total cohort (471 urologists) performed any continent urinary diversion. The likelihood of performing any continent urinary diversion increased with the number of urinary diversions (p <0.0001). As urinary diversion volume increased, the proportion representing continent urinary diversion also increased (p <0.0005). Surgeons in private practice settings and those in the Northeast were less likely to perform continent urinary diversion. CONCLUSIONS: Few urologists perform any urinary diversion. Continent urinary diversion is most frequently done by high volume surgeons. The type of urinary diversion that a patient receives may depend in part on surgeon characteristics.

Surgical practice patterns for male urinary incontinence: analysis of case logs from certifying American urologists.

PURPOSE: Several options exist for the surgical correction of male stress urinary incontinence including periurethral bulking agents, artificial urinary sphincters and the recently introduced male urethral slings. We investigated contemporary trends in the use of these treatments. MATERIALS AND METHODS: Annualized case log data for incontinence surgeries from certifying and recertifying urologists were obtained from the ABU (American Board of Urology), ranging from 2004 to 2010. Chi-square tests and logistic regression models were used to evaluate the association between surgeon characteristics (type of certification, annual volume, practice type and practice location) and the use of incontinence procedures. RESULTS: Among the 2,036 nonpediatric case logs examined the number of incontinence treatments reported for certification has steadily increased over time from 1,936 to 3,366 treatments per year from 2004 to 2010 (p = 0.008). Nearly a fifth of urologists reported placing at least 1 sling. The proportion of endoscopic procedures decreased from 80% of all incontinence procedures in 2004 to 60% in 2010, but they remained the exclusive incontinence procedure performed by 49% of urologists. A urologist's increased use of endoscopic treatments was associated with a decreased likelihood of performing a sling procedure (OR 0.5, p <0.0005). Artificial urinary sphincter use remained stable, accounting for 12% of procedures. CONCLUSIONS: Incontinence procedures are on the rise. Urethral slings have been widely adopted and account for the largest increase among treatment modalities. Endoscopic treatments continue to be commonly performed and may represent overuse in the face of improved techniques. Further research is required to validate these trends.

Comparative outcomes of pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation in patients treated with radical cystectomy.

PURPOSE: We compared clinical outcomes, and identified predictors of cancer specific and overall survival after radical cystectomy in patients with urothelial carcinoma with squamous differentiation and those with pure squamous cell carcinoma. MATERIALS AND METHODS: We reviewed data on 2,031 patients treated with radical cystectomy and pelvic lymph node dissection at a single high volume referral center. Of these patients 78 had squamous cell carcinoma and 67 had squamous differentiation. Survival estimates by histological subtype were described using Kaplan-Meier methods. Within histological subtypes pathological stage, nodal invasion, soft tissue margins, age and gender were evaluated as predictors of cancer specific survival and overall survival using univariate Cox regression. RESULTS: Median followup was 44 months. Of 104 patient deaths 60 died of their disease. We did not find a statistically significant difference between survival curves of patients with squamous cell carcinoma and squamous differentiation (log rank overall survival p = 0.6, cancer specific survival p = 0.17). Positive soft tissue margins were associated with worse cancer specific survival (HR 6.92, 95% CI 2.98-16.10, p ≤0.0005) and overall survival (HR 3.68, 95% CI 1.84-7.35, p ≤0.0005) in patients with pure squamous cell carcinoma. Among patients with squamous differentiation, pelvic lymphadenopathy was associated with decreased overall survival (HR 2.52, 95% CI 1.33-4.77, p = 0.004) and cancer specific survival (HR 3.23, 95% CI 1.57-6.67, p = 0.002). CONCLUSIONS: There appears to be no evidence of a difference in cancer specific survival or overall survival between patients with squamous cell carcinoma and those with squamous differentiation treated with radical cystectomy and pelvic lymph node dissection. Patients with squamous differentiation and tumor metastases to pelvic lymph nodes should be followed more closely, and adjuvant treatment should be considered to improve survival. Wide surgical resection is critical to achieve local tumor control and improve survival in patients with squamous cell carcinoma.

Is adolescent varicocelectomy safe after previous inguinal surgery?

PURPOSE: Varicocelectomy after previous inguinal surgery poses a potential risk of testicular volume loss. To assess the extent to which varicocelectomy can be done without the complication of ipsilateral testis atrophy we present outcomes in adolescent patients with a history of inguinal surgery who underwent ipsilateral varicocelectomy. MATERIALS AND METHODS: We retrospectively reviewed patient data from a single urologist practice. Testicular volume was recorded preferentially by ultrasound or, when unavailable, by ring orchidometry. Testicular asymmetry was calculated using the formula, [(right testis volume - left testis volume)/right testis volume] × 100. Symmetry was defined as less than 10% asymmetry. Catch-up growth was defined as resolution of asymmetry. RESULTS: We identified 22 adolescent patients who fit study criteria. The patients underwent a total of 25 varicocelectomies since 3 underwent bilateral repair after previous bilateral inguinal surgery. Initial inguinal surgery included inguinal herniorrhaphy, hydrocelectomy and orchiopexy. Varicocelectomy was done laparoscopically in 17 cases and via open technique in 8 with variations in preservation/sacrifice of the lymphatics and artery. Median ± SD followup was 24.2 ± 18.2 months. After varicocelectomy mean testicular asymmetry decreased from 27.6% to 10.5%. There was no incidence of testicular atrophy postoperatively. The incidence of catch-up growth was 43% with no difference between the artery sparing and the nonartery sparing technique. CONCLUSIONS: Varicocelectomy with a history of previous inguinal surgery is safe and provides a significant incidence of testicular catch-up growth. Artery sparing vs sacrificing technique did not make a difference in terms of catch-up growth.

Testicular asymmetry and adolescent varicoceles managed expectantly.

PURPOSE: Adolescent varicocele is often associated with testicular asymmetry. Depending on the degree of asymmetry, some physicians will recommend surgery. However, given the possibility that asynchronous growth may be transient, others advocate for a period of observation. We reviewed our outcomes in such patients who were initially treated expectantly. MATERIALS AND METHODS: We retrospectively reviewed our pediatric varicocele database. We analyzed the outcomes of patients presenting for evaluation of varicocele who were followed with serial testicular volume measurements using scrotal ultrasound or ring orchidometry and who had at least a 6-month interval between measurements. Fisher's exact test was used to compare groups based on initial and final testicular asymmetry. RESULTS: We identified 181 patients (median age 13.8 years) who were followed expectantly. Serial volume measurements had been obtained at a median interval of 12 months (interquartile range 8 to 21) between first and most recent visits. Mean percent asymmetry for the group did not change with time. Among patients who initially had less than 20% asymmetry 35% had 20% or greater asymmetry on followup, and among those with 20% or greater asymmetry initially 53% remained in that range (p = 0.007). CONCLUSIONS: Asymmetry can be a transient phenomenon. Patients with initial asymmetry can end up with significant asymmetry, and many with significant asymmetry can have catch-up growth. However, when patients have a peak retrograde flow of 38 cm per second or greater on duplex Doppler ultrasound in association with 20% or greater asymmetry spontaneous catch-up growth is unlikely to occur.

Adolescent varicocele: influence of Tanner stage at presentation on the presence, development, worsening and/or improvement of testicular hypotrophy without surgical intervention.

PURPOSE: Testicular asymmetry in adolescents with varicocele can worsen, remain unchanged or decrease on followup. We determined the incidence of testicular asymmetry at presentation by Tanner stage and the correlation between Tanner stage at presentation and subsequent changes in percent asymmetry (ability for catch-up growth or progressive asymmetry) without surgical intervention. MATERIALS AND METHODS: We retrospectively studied the records of 115 boys with a mean age of 14.1 years (range 9.2 to 20.0) with grade 2 or 3 left varicocele who underwent testicular volume measurement at 2 visits at least that were a minimum of 6 months apart. Of the patients 92% and 8% underwent Doppler duplex ultrasound and orchidometry, respectively. Patients were divided into 2 groups, including those with less than 15% and those with 15% or greater asymmetry. Catch-up growth was defined as less than 15% asymmetry at any subsequent visit. RESULTS: At presentation 58%, 64%, 67%, 35% and 39% of Tanner 1 to 5 cases showed 15% or greater testicular asymmetry, respectively. When Tanner 1 to 3 cases were combined and compared with Tanner 4 and 5 cases, the difference in initial asymmetry was significant (64% vs 38%, p = 0.007). Although it was not statistically significant, there was a trend toward more catch-up growth for the later Tanner stages, including 27% for Tanner 1 to 3 vs 53% for Tanner 4 and 5 (p = 0.06). CONCLUSIONS: Slightly more than 50% of children and adolescents referred with varicocele have 15% or greater testicular asymmetry at presentation. Initial asymmetry is statistically more common in cases of earlier Tanner stages (1 to 3). Adolescents with 15% or greater testicular asymmetry who present at higher Tanner stages (4 and 5) show a trend toward a higher incidence of catch-up growth, although it is not significant.

Adolescent varicocelectomy--is the potential for catch-up growth related to age and/or Tanner stage?

PURPOSE: Adolescent varicocelectomy is associated with a 70% incidence of postoperative catch-up growth in boys with ipsilateral testicular hypotrophy. We determined whether preoperative patient age and Tanner stage were related to subsequent catch-up growth. In other words if patients are followed with a period of observation, will a window of opportunity be lost for achieving catch-up growth? MATERIALS AND METHODS: We studied a total of 163 boys (mean age 15.1 years, range 10 to 24) with left or bilateral varicoceles who demonstrated 10% asymmetry or greater preoperatively, and had preoperative and postoperative testicular volume measurements available (using either ring orchidometer or ultrasound). Of these patients 59 also had preoperative Tanner stage recorded. RESULTS: Of the patients with preoperative left hypotrophy 69% had achieved catch-up growth at last followup (mean followup 28 months). When treated as a continuous variable, or when divided into general prepubertal vs postpubertal groupings, age at surgery was not significantly associated with catch-up growth. Similarly, there was no significant difference in catch-up growth associated with grade of varicocele, duration of postoperative followup or presence of unilateral left vs bilateral varicocele. No association with Tanner stage was found, although the patient numbers were too small to draw any statistically significant conclusions. CONCLUSIONS: The prevalence of testicular catch-up growth after varicocelectomy is high, even for patients in their early 20s. Among males 10 to 24 years old there is no specific age or Tanner stage that offers the best opportunity for catch-up growth.

Peak retrograde flow: a novel predictor of persistent, progressive and new onset asymmetry in adolescent varicocele.

PURPOSE: The major indication for adolescent left varicocelectomy is testicular asymmetry. However, a period of observation is often recommended preoperatively to determine if the asymmetry resolves, persists or progresses. We investigated whether varicocele grade or the duplex Doppler ultrasound measurements of peak retrograde flow and mean vein diameter could be used as predictors of persistent, progressive or new onset asymmetry. MATERIALS AND METHODS: Only patients with left varicoceles who had undergone at least 2 duplex Doppler ultrasounds without intervening surgery were included in the study. Grade of varicocele, peak retrograde flow and mean vein diameter were analyzed as possible determinants of catch-up growth, or persistent or new onset asymmetry. RESULTS: A total of 77 patients (mean age 14.3 years, range 9 to 20) were identified with a mean observation period of 13.2 months. Of the patients 50 (65%) had 10% or greater asymmetry at the first measurement. Of patients with initial 20% or greater asymmetry 71% had persistent or worsening asymmetry on followup evaluation. All 14 patients with the combination of an initial peak retrograde flow 38 cm per second or greater and 20% or greater asymmetry had progressive asymmetry on followup examination. Peak retrograde flow was the only significant parameter of predictive value for persistent or worsening asymmetry (p = 0.032). CONCLUSIONS: Peak retrograde flow can serve as a valuable tool in predicting persistent, progressive and new onset asymmetry. Varicoceles associated with a peak retrograde flow of 38 cm per second or greater and 20% or greater asymmetry should be considered for varicocelectomy at initial presentation. Patients with peak retrograde flow greater than 30 cm per second need to be monitored carefully. Those with peak retrograde flow less than 30 cm per second are less likely to require surgery.

Invasion of renal sinus fat is not an independent predictor of survival in pT3a renal cell carcinoma.

OBJECTIVE: To clarify the significance of the location of extrarenal tumour extension of renal cell carcinoma (RCC) as in the 2002 Tumour-Nodes-Metastasis classification. Renal cortical tumours with perirenal fat invasion (PFI) or sinus fat invasion (SFI) are consolidated within the pT3a grouping; tumours with SFI are close to the renal veins, lymphatics and the collecting system. This might carry a worse prognosis for disease-specific survival (DSS), but reports are limited and contradictory. PATIENTS AND METHODS: We retrospectively reviewed 1244 patients treated with nephrectomy from 1988 to 2007, to identify patients with pT3a renal tumours. They were classified as having PFI or SFI. Kaplan-Meier analysis and Cox proportional hazards regression models were used to assess predictors of survival. RESULTS: The 230 patients who met the inclusion criteria had a median follow-up of 24 months. SFI was found in 63 (27.4%) patients and was associated with a worse 5-year DSS than the 167 (72.6%) with PFI (62.5% vs 75.0%; log rank P = 0.022). On univariate analysis, diameter (hazard ratio, HR 1.1), nuclear grade (HR 4.5), margin status (HR 5.8), lymph node metastases (HR 6.4), and systemic metastases (HR 15.4) were significant for DSS. In a multivariate model, only nuclear grade (HR 3.1), margin status (HR 8.9) and systemic metastases (HR 9.8) were independent predictors. CONCLUSION: Patients with renal tumours with SFI are more likely to die from RCC than those with PFI. However, in the present patients the presence of SFI was not an independent predictor of DSS.

The extracellular chaperone clusterin potently inhibits human lysozyme amyloid formation by interacting with prefibrillar species.

We have studied the effects of the extracellular molecular chaperone, clusterin, on the in vitro aggregation of mutational variants of human lysozyme, including one associated with familial amyloid disease. The aggregation of the amyloidogenic variant I56T is inhibited significantly at clusterin to lysozyme ratios as low as 1:80 (i.e. one clusterin molecule per 80 lysozyme molecules). Experiments indicate that under the conditions where inhibition of aggregation occurs, clusterin does not bind detectably to the native or fibrillar states of lysozyme, or to the monomeric transient intermediate known to be a key species in the aggregation reaction. Rather, it seems to interact with oligomeric species that are present at low concentrations during the lag (nucleation) phase of the aggregation reaction. This behavior suggests that clusterin, and perhaps other extracellular chaperones, could have a key role in curtailing the potentially pathogenic effects of the misfolding and aggregation of proteins that, like lysozyme, are secreted into the extracellular environment.

Laparoscopic lymphatic sparing varicocelectomy in adolescents.

PURPOSE: Laparoscopic varicocelectomy is similar to an open Palomo repair. Both procedures involve en masse ligation of the internal spermatic cord, and both are associated with a 1% to 3% incidence of recurrence and up to a 30% incidence of hydroceles. We sought to determine the impact of lymphatic preservation on hydrocele formation and the success of varicocelectomy. MATERIALS AND METHODS: We retrospectively evaluated 191 patients with a mean age of 15.2 years who underwent laparoscopic varicocelectomy and at least 6 months of followup. Patients were divided into 2 groups-those who had undergone a lymphatic sparing procedure and those who had undergone a nonlymphatic sparing technique. The incidence of recurrence/persistence, postoperative hydrocele formation and postoperative hydrocele requiring surgery or aspiration was analyzed. RESULTS: A total of 174 laparoscopic lymphatic sparing procedures (132 patients, 42 bilateral) and 88 nonlymphatic sparing repairs (59 patients, 29 bilateral) were performed, with a mean followup of 26.1 months. Lymphatic sparing surgery was associated with a decreased incidence of postoperative hydrocele (3.4% vs 11.4%, p = 0.025). There was no significant difference in incidence of persistent or recurrent varicocele requiring reoperation following lymphatic sparing (5 sides, 2.9%) vs nonlymphatic sparing (4 sides, 4.5%) varicocelectomy (p = 0.736). CONCLUSIONS: Laparoscopic lymphatic sparing varicocelectomy is preferable to an open or laparoscopic Palomo repair that does not preserve the lymphatics. It has a significantly lower incidence of postoperative hydroceles, especially those requiring surgical intervention, and still maintains a low incidence of persistence/recurrence. The procedure is especially advantageous for bilateral varicocelectomy.

The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures.

Clusterin is an extracellular chaperone present in all disease-associated extracellular amyloid deposits, but its roles in amyloid formation and protein deposition in vivo are poorly understood. The current study initially aimed to characterize the effects of clusterin on amyloid formation in vitro by a panel of eight protein substrates. Two of the substrates (Alzheimer's beta peptide and a PI3-SH3 domain) were then used in further experiments to examine the effects of clusterin on amyloid cytotoxicity and to probe the mechanism of clusterin action. We show that clusterin exerts potent effects on amyloid formation, the nature and extent of which vary greatly with the clusterin:substrate ratio, and provide evidence that these effects are exerted via interactions with prefibrillar species that share common structural features. Proamyloidogenic effects of clusterin appear to be restricted to conditions in which the substrate protein is present at a very large molar excess; under these same conditions, clusterin coincorporates with substrate protein into insoluble aggregates. However, when clusterin is present at much higher but still substoichiometric levels (e.g., a molar ratio of clusterin:substrate=1:10), it potently inhibits amyloid formation and provides substantial cytoprotection. These findings suggest that clusterin is an important element in the control of extracellular protein misfolding.

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity.

The in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerbate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

Clusterin is an extracellular chaperone that specifically interacts with slowly aggregating proteins on their off-folding pathway.

Clusterin is an extracellular mammalian chaperone protein which inhibits stress-induced precipitation of many different proteins. The conformational state(s) of proteins that interact with clusterin and the stage(s) along the folding and off-folding (precipitation-bound) pathways where this interaction occurs were previously unknown. We investigated this by examining the interactions of clusterin with different structural forms of alpha-lactalbumin, gamma-crystallin and lysozyme. When assessed by ELISA and native gel electrophoresis, clusterin did not bind to various stable, intermediately folded states of alpha-lactalbumin nor to the native form of this protein, but did bind to and inhibit the slow precipitation of reduced alpha-lactalbumin. Reduction-induced changes in the conformation of alpha-lactalbumin, in the absence and presence of clusterin, were monitored by real-time (1)H NMR spectroscopy. In the absence of clusterin, an intermediately folded form of alpha-lactalbumin, with some secondary structure but lacking tertiary structure, aggregated and precipitated. In the presence of clusterin, this form of alpha-lactalbumin was stabilised in a non-aggregated state, possibly via transient interactions with clusterin prior to complexation. Additional experiments demonstrated that clusterin potently inhibited the slow precipitation, but did not inhibit the rapid precipitation, of lysozyme and gamma-crystallin induced by different stresses. These results suggest that clusterin interacts with and stabilises slowly aggregating proteins but is unable to stabilise rapidly aggregating proteins. Collectively, our results suggest that during its chaperone action, clusterin preferentially recognises partly folded protein intermediates that are slowly aggregating whilst venturing along their irreversible off-folding pathway towards a precipitated protein.

Polyelectrolyte complex materials consisting of antibacterial and cell-supporting layers.

The characterization of a polyelectrolyte complex material comprised of two biopolymers, a chitosan upper layer and a gellan gum under layer, is reported. It is shown that the upper layer of chitosan with incorporated levofloxacin displays an antibacterial activity, while the under layer of a gellan gum/TiO(2) composite supports the growth of fibroblastic cells.

Evaluation and management of the persistent/recurrent varicocele.

OBJECTIVE: To review outcomes in adolescent patients following redo varicocelectomy surgery. METHODS: The composite varicocele registry of a single surgeon was queried to identify patients who had undergone redo varicocelectomy. Variables of testicular asymmetry, testicular volume, presence and degree of retrograde venous flow, and incidence of postoperative hydrocele were evaluated. RESULTS: Nineteen boys were identified as having had a redo varicocelectomy (16 open, 1 laparoscopic, 2 radiographic embolization) with a minimum postoperative follow-up of 6 months (mean: 23.4; range: 6-53 months). No varicocele was palpable postoperatively among the 17 surgical redoes; one patient's testicle was significantly smaller after surgery, and 3 developed a hydrocele requiring repair. One of two boys who underwent radiographic embolization had a persistent varicocele. Eight of the nine boys who had asymmetry of 10% or greater before redo demonstrated catch-up growth after repair. The consistent intraoperative finding in all redo patients was the presence of large veins within the cord, just proximal to the junction with the vas and in continuity with the dilated veins distal to the internal ring. Post-redo retrograde venous flow was not identifiable in 16 and minimal in three. CONCLUSIONS: Redo varicocelectomy can be accomplished successfully and has a similar chance of achieving catch-up growth as does an initial repair. Postoperatively, there exists a small risk of testicular volume compromise and a significant risk of hydrocele development. Distal collateral veins may have a smaller role in varicocele formation and recurrence than previously thought.

Cutaneous vesicostomy for palliative management of hemorrhagic cystitis and urinary clot retention.

We present the case of a 9 year old boy with hemorrhagic cystitis and urinary clot retention in the setting of chemotherapy refractory pre-B cell acute lymphocytic leukemia. The patient was undergoing palliative care which was complicated by severe discomfort from urinary clot retention. The decision was made to perform a cutaneous vesicostomy for clot removal and urinary drainage given the goals of care. The patient tolerated the procedure well and was comfortable with no further urinary tract symptoms until he expired. Cutaneous vesicostomy should be considered as an effective surgical option for severe clot retention in children.