Objective documentation of hypospadias anatomy with three-dimensional scanning.

INTRODUCTION: The absence of a standardized classification of hypospadias hinders understanding of the anatomic differences among patients and the evaluation of outcomes following surgical repair. In working towards a standardized, objective method of recording patients' hypospadias anatomy, we describe our initial experience using a non-invasive three-dimensional scanner. MATERIAL AND METHODS: An Artec3D Space Spider scanner was used to obtain 3D scans in 29 patients undergoing hypospadias repair. Measurements of the urethral plate width, urethral plate length, glans width, penile shaft length, and penile shaft width were made by 2 pediatric urology attendings and 1 pediatric urology fellow. Measurements were compared and inter-rater reliability was calculated. RESULTS: A total of 435 measurements were made on 29 successfully generated 3D scans, ranging from distal to proximal hypospadias. The inter-rater reliability of measurements from the generated 3D models shown good inter-rater reliability of urethral plate width (ICC0.87 [95%CI:0.76,0.93]), penile shaft length (ICC0.87 [95%CI:0.70,0.94]) and glans width (ICC0.83 [95%CI:0.68,0.92]), excellent inter-rater reliability of urethral plate length (ICC0.96) and moderate inter-rater reliability of penile shaft width (ICC0.69 [95%CI:0.44,0.84]). DISCUSSION: There was a high degree of reliability of measurements made across multiple users. Calculation of the ratio of the urethral plate length/total penile shaft length objectively defined the initial position of the urethral meatus. When compared to the 3-dimensional volume of the glans, a more proximally positioned urethral meatus was associated with a lower glans volume. CONCLUSION: 3D scanning offers a rapid, reproducible, and non-invasive method of documenting hypospadias anatomy. The ability to evaluate three dimensional features (i.e. glans volume) offers an exciting opportunities for robust investigation of hypospadias outcomes and further understanding of the relationship between a patient's genotype and phenotype.

Improving Outcomes through Implementation of an Infant Spinal Anesthesia Program for Urologic Surgery Patients.

Introduction: Spinal anesthesia has a long history as an effective and safe technique to avoid general anesthesia in infants undergoing surgery. However, spinal anesthesia was rarely used as the primary anesthetic in this population at our institution. This healthcare improvement initiative aimed to increase the percentage of successful spinal placements as the primary anesthetic in infants undergoing circumcision, open orchidopexy, or hernia repair from 11% to 50% by December 31, 2019, and sustain that rate for 6 months. Methods: An interdisciplinary team created a key driver diagram and implemented the following interventions: education of nurses, surgeons, and patient families; focused anesthesiologist training on the infant spinal procedure; premedication; availability of supplies; and surgical schedule optimization. The team collected data retrospectively by reviewing electronic medical records (Cerner, North Kansas City, Mo.). The primary outcome was the percentage of infants undergoing circumcision, open orchidopexy, or hernia repair who received a successful spinal as the primary anesthetic. The team tracked this measure and evaluated using a statistical process control chart. Results: Between August 1, 2018, and February 29, 2020, researchers identified 470 infants (235 preintervention and 235 postintervention) who underwent circumcision, open orchidopexy, or inguinal hernia repair. Following the interventions in this project, there was a statistically significant increase in successful spinal placement from 11% to 45% (P < 0.0001). Conclusion: This quality improvement project successfully increased the percentage of patients receiving spinal anesthesia for specific surgical procedures by increasing the number of patients who underwent successful spinal anesthesia placement.

Precocious Puberty in a Boy With Bilateral Leydig Cell Tumors due to a Somatic Gain-of-Function LHCGR Variant.

Context: Autosomal dominant and rarely de novo gain-of-function variants in the LHCGR gene are associated with precocious male puberty, while somatic LHCGR variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description: We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results: Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the LHCGR gene. Digital droplet polymerase chain reaction of the LHCGR variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion: We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in LHCGR. The gain-of-function nature of the LHCGR variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys.

Upper pole pathologies in duplex kidneys: an analysis of predictive factors for surgery and urinary tract infections from the Mid-Atlantic Pediatric Academic Consortium.

BACKGROUND/OBJECTIVE: While there is significant data on the natural history and outcomes for prenatal hydronephrosis in simplex kidneys, duplex kidneys tend to be less studied. Management can be quite variable based on provider preference. We aimed to describe practice patterns from several tertiary academic institutions, identify clinical predictors for surgical intervention and urinary tract infection (UTI) for upper pole pathology, and demonstrate the natural history of lower pole vesicoureteral reflux (VUR). METHODS: We conducted a retrospective review of patients from 4 Mid-Atlantic institutions between 2015 and 2020. Inclusion criteria included patients with a duplex kidney with upper pole pathology and/or lower pole VUR. The primary outcome was predictive factors for surgical intervention and UTI. The secondary outcome was to assess the natural history of lower pole VUR including resolution rates by grade. Linear regression identified clinical predictors for UTI events. Multivariate logistic regression identified predictors of surgical intervention, UTI, and lower pole VUR resolution. Descriptive statistics and regression modeling analyses were performed using SAS. RESULTS: Two hundred forty-two patients were included with a total of 271 duplex renal units. Hydronephrosis grade (both SFU and UTD grading) and number of prior UTI events were statistically significant predictors for surgical intervention (p = 0.03/0.001 and p = 0.002 respectively). Ectopic ureter (p = 0.004), ureterocele (p = 0.02), and obstruction (p = 0.04) were the only pathologies predictive for surgery. Male gender and circumcision were significantly associated with decreased UTI risk (p = 0.03 and p = 0.01). On linear regression modeling, antibiotic prophylaxis after the first year of life was associated with decreased risk of further UTI events (p = 0.03); however, antibiotic prophylaxis within the first year of life did not decrease UTI risk (p = 0.14). For VUR outcomes, 65.0% of grades 1-3 VUR and 52.2% of grades 4-5 had resolution/improvement at mean time of 2.1 years. There were no predictive factors for resolution/improvement of VUR. CONCLUSIONS: Hydronephrosis grade and UTI events were significant predictors for surgical intervention for upper pole pathology. Pathologies that were predictive for surgery included ectopic ureter, ureterocele and obstruction. Male gender, circumcision and antibiotic prophylaxis after the first year of life were associated with a decreased UTI risk. Roughly 58% of lower pole VUR spontaneously improved/resolved. Identification of these risk factors aids in standardization of care practices to reduce long-term UTI risk and inform counseling with families about possible need for surgical intervention and expectations for long term outcomes.

Varenicline limits ischemia reperfusion injury following testicular torsion in mice.

BACKGROUND: Torsion of the spermatic cord and the resulting testicular ischemia leads to the production of inflammatory cytokines and cell death due to impaired aerobic metabolism. Following reperfusion of the testis, a robust innate inflammatory response furthers tissue injury due to the production of reactive oxygen species and disruption of normal capillary function. Blunting the innate immune response with antioxidants, anti-inflammatory medications and targeted genetic interventions reduces long term testicular injury in animal models of torsion, however these approaches have limited clinical applicability. Mediated via α7 nACh receptors, the cholinergic anti-inflammatory pathway limits NFKB signaling and prevents renal fibrosis following warm renal ischemia. We identified varenicline as an FDA approved α7 nAChR agonist and hypothesized that varenicline administration would decrease long-term testicular atrophy and fibrosis in a murine model of testicular torsion. METHODS: Using an established model, unilateral testicular torsion was induced in mature male CD1 mice by rotating the right testicle 720° for 2 h. In the treatment group, 4 doses of varenicline (1mg/grm) were administered via intraperitoneal injection every 12 h, with the first dose given 1 h after the creation of testicular torsion. The acute inflammatory response was evaluated 48 h following reperfusion of the testis. Long term outcomes were evaluated 30 days following testicular perfusion. RESULTS: 48 h following reperfusion, the testis of animals treated with varenicline demonstrated a significant reduction in the inflammatory response as measured by the acute immune cell infiltrate, myeloperoxidase activity, concentration of reduced glutathione and expression of downstream NF-KB targets. 30 days following reperfusion, animals treated with varenicline, demonstrated decreased testicular atrophy (Summary Figure), fibrosis and expression of pro-fibrotic genes. CONCLUSION: Activation of a central immunosuppressive cascade with varenicline after the onset of testicular torsion reduces ischemia reperfusion injury and prevents long term testicular atrophy and fibrosis. Further studies are needed to define the optimum dose and varenicline administration regimen. Our results suggest that varenicline offers a novel, FDA approved, adjunct to the current management of testicular torsion.

Modulation of the rat micturition reflex with transcutaneous ultrasound.

INTRODUCTION: Low intensity focused ultrasound has recently been identified as a novel method of stimulating targeted neurons. We hypothesized that ultrasound stimulation of the posterior tibial nerve would inhibit bladder contractions in an established rat model of rhythmic bladder contractions. METHODS: Cyclical detrusor contractions were initiated by placing a transurethral catheter in female rats and infusing saline into the bladder. Transcutaneous ultrasound pulses were then delivered to the lower extremity of a rat (overlying the posterior tibial nerve) using a single element spherically focused 250 kHz transducer. Sixty-three cycles were repeated at 2 kHz for 300 ms at peak negative pressure of 900 kPa pulsed at 0.5 Hz. RESULTS: We report successful suppression of bladder contractions using ultrasound stimulation in 10 animals. The average latency between the initiation of ultrasound and suppression of bladder contractions was 3 min 23 s (±51 s), the average time of contraction suppression was 13 min and 50 s (±2 min 25 s) and the average time from the end of ultrasound to return of contractions was 9 min 37 s (±2 min and 30 s). CONCLUSION: In this work, we demonstrate the ability of targeted transcutaneous ultrasound to inhibit rhythmic bladder contractions in anesthetized rats. Due to its non-invasive nature and ease of application, we believe ultrasound mediated suppression of the micturition reflex is potentially an ideal outpatient treatment of overactive bladder and dysfunctional elimination.

Interrater Reliability in Pediatric Urodynamic Tracings: A Pilot Study.

PURPOSE: Urodynamic studies are crucial to neuropathic bladder management and they often determine surgical intervention. However, current evidence indicates that interpretations show poor agreement across physicians. We sought to determine the interrater reliability of urodynamic interpretation in our practice. We hypothesized that there would be strong correlation among pediatric urologists of similar training in a single academic practice. MATERIALS AND METHODS: We retrospectively identified patients with neuropathic bladder who underwent urodynamics at our institution between 2014 and 2015. An anonymous electronic survey (phase I) was developed with 20 clinical scenarios, each containing a brief history, a single urodynamic tracing and an accompanying fluoroscopic image. Faculty members assessed each tracing by an online instrument developed using urodynamic reports and published literature. The primary outcome was statistical correlation across raters as measured by the Spearman correlation coefficient. In a followup study (phase II) we investigated the sources of variability in urodynamic interpretations. RESULTS: Six faculty members completed the study with a response rate of 100%. In comparing urodynamic interpretation across raters, the faculty demonstrated a weak to strong correlation (rs 0.39-0.61, p <0.001). A strong correlation was found for fluoroscopic and clinical decision making variables, while electromyography synergy and detrusor overactivity demonstrated weaker correlation across physicians. CONCLUSIONS: Faculty interpretations of urodynamic tracings showed only moderate agreement despite a close working relationship and similar training at a single institution. Variability in interpretation can strongly impact patient treatment. Therefore, further work is needed to standardize the reporting and interpretation of urodynamic studies to optimize patient care.

Purine Biosynthesis Metabolically Constrains Intracellular Survival of Uropathogenic Escherichia coli.

The ability to de novo synthesize purines has been associated with the intracellular survival of multiple bacterial pathogens. Uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections, undergoes a transient intracellular lifestyle during which bacteria clonally expand into multicellular bacterial communities within the cytoplasm of bladder epithelial cells. Here, we characterized the contribution of the conserved de novo purine biosynthesis-associated locus cvpA-purF to UPEC pathogenesis. Deletion of cvpA-purF, or of purF alone, abolished de novo purine biosynthesis but did not impact bacterial adherence properties in vitro or in the bladder lumen. However, upon internalization by bladder epithelial cells, UPEC deficient in de novo purine biosynthesis was unable to expand into intracytoplasmic bacterial communities over time, unless it was extrachromosomally complemented. These findings indicate that UPEC is deprived of purine nucleotides within the intracellular niche and relies on de novo purine synthesis to meet this metabolic requirement.

Blunt force trauma as a rare mechanism for chyluria.

Chyluria is an uncommon clinical entity outside of the tropics. We present a rare case of blunt force trauma leading to the formation of a lymphorenal fistula. This was successfully managed via conservative endoscopic and dietary treatment.

Prospective Evaluation of Sacral Neuromodulation in Children: Outcomes and Urodynamic Predictors of Success.

PURPOSE: Sacral neuromodulation has been demonstrated to improve refractory bowel bladder dysfunction in children. The purpose of the current study was to determine whether results are durable in children after longer followup, whether children with a lower body mass index are at risk for device failure and whether pretreatment urodynamic evaluation can predict posttreatment outcome. MATERIALS AND METHODS: Pediatric patients with refractory bowel bladder dysfunction were enrolled following informed consent and followed prospectively. All patients underwent preoperative videourodynamic evaluation and a 2-stage implantation procedure. Validated questionnaires were used to assess symptom severity and quality of life. Complications were analyzed with regard to treatment required and patient body mass index. RESULTS: During 45 months 30 patients were enrolled. Median age was 8.3 years at enrollment. Median followup was 14.8 months. Patients had significant improvement in quality of life and symptom scores, which persisted at the most recent followup. Patients who had uninhibited detrusor contractions on preoperative urodynamic assessment had significantly greater improvement in symptoms. Of the patients 23% had a complication requiring reoperation, most commonly neurostimulator lead breakage in those with a significantly lower body mass index. CONCLUSIONS: Sacral neuromodulation significantly improves quality of life and symptom severity in children with refractory bowel bladder dysfunction. Children gain greater benefit if they show uninhibited bladder contractions on preoperative urodynamic evaluation. Children have a high rate of lead breakage requiring operative revision, which was seen after minor trauma in those with a lower body mass index.

Overcoming Obesity and a Short Appendix in the Creation of Continent Catheterizable Stomas. Preliminary Outcomes of the "Casella-Ost Procedure".

OBJECTIVE: To describe a novel method of using a bladder flap to partially span the distance between the bladder and abdominal wall when creating a concealed catheterizable channel. MATERIALS AND METHODS: We retrospectively identified 3 patients in whom we performed this reconstruction and report our surgical technique and their outcomes at 23, 27, and 32 months. RESULTS: There were no immediate operative complications and all patients continue to catheterize without difficulty. Two patients reported mild stomal stress incontinence, which resolved with Ditropan in one case, and was not bothersome enough to desire additional treatment in the second. CONCLUSION: Incorporation of the bladder flap allows for a shorter proximal limb (appendix or tubularized ileum), improving ease of catheterization in addition to providing a surface where a tunneled, nonrefluxing anastomosis between the proximal limb and bladder can be easily performed. Long-term follow-up and greater patient numbers are needed, nonetheless, we have not seen this approach described in the literature and feel that it is an important reconstructive option to be considered when creating a continent catheterizable diversion.

Segmental testicular infarction due to minocycline-induced antineutrophil cytoplasmic antibody--positive vasculitis.

Segmental testicular infarction is an uncommon clinical entity marked by acute scrotal pain and swelling. Classically, these appear as wedge-shaped, avascular, hypoechoic lesions on a testicular ultrasound. We present a unique case of testicular infarct caused by an antineutrophil cytoplasmic antibody-positive vasculitis secondary to the use of the antibiotic minocycline. The patient's symptoms resolved with cessation of minocycline. We suggest that patients who present with otherwise unexplained testicular infarction undergo a careful review of medications to uncover a potential cause.

Cost analysis of pediatric robot-assisted and laparoscopic pyeloplasty.

PURPOSE: An increasing percentage of pediatric pyeloplasties are being performed with assistance of the da Vinci® Surgical System. A review of the recent literature shows decreased operative times and length of hospital stays when robotic procedures are performed, although there are few published data comparing the cost of pediatric robotic and pure laparoscopic pyeloplasty. We reviewed a representative sample of pyeloplasties performed at our institution and performed a cost analysis. MATERIALS AND METHODS: We retrospectively identified 23 robot-assisted and 23 laparoscopic pyeloplasties performed at our institution between August 2008 and April 2012. Total cost was calculated from direct and indirect costs provided by our billing department. RESULTS: Robotic procedures were shorter than pure laparoscopic procedures (200 vs 265 minutes, p <0.001) but there was no significant difference in the total cost of the 2 procedures ($15,337 vs $16,067, p <0.46). When compared to laparoscopic cases, subgroup analysis demonstrated decreased operative times (140 vs 265 minutes, p <0.00001) and total cost ($11,949 vs $16,067, p <0.0001) in robotic cases where stents were placed in an antegrade fashion. CONCLUSIONS: With widespread use the cost of robotic instrumentation may decrease, and experience may further shorten operative times. However, it currently remains to be seen whether robotic technology will become a cost-effective replacement for pure laparoscopy in the management of pediatric ureteropelvic junction obstruction.

Posterior urethral valves: renal failure and prenatal treatment.

Posterior urethral valves occur in 1 : 5000 live births. Despite the high prevalence, the few children that survive do poorly, with over 50% progressing to ESRD in 10 years. The gold standard for post-natal diagnosis is voiding cystourethrography, while pre-natal diagnosis is dependent on routine screening ultrasonography. Despite the ability to identify features of bladder outlet obstruction early in fetal development, there is no consensus on how to incorporate early detection into current screening protocols. There has yet to be a marker that allows prediction of obstruction in the absence of or prior to radiographic evidence of obstruction. With our current screening strategy, the majority of interventions are performed well after irreversible damage has occurred. Improved mortality and long term morbidity from posterior urethral valves and congenital bladder outlet obstruction will likely remain unchanged until it is possible to intervene prior to the onset of irreversible renal damage. New biologic markers and improved instrumentation will allow for more effective diagnosis and intervention at earlier stages of fetal development.

Pediatric laparoscopic and robot-assisted laparoscopic surgery: technical considerations.

Laparoscopy has become an effective modality for the treatment of many pediatric urologic conditions that need both extirpative and reconstructive techniques. Laparoscopic procedures for urologic diseases in children, such as pyeloplasty, orchiopexy, nephrectomy, and bladder augmentation, have proven to be safe and effective with outcomes comparable to those of open techniques. Given the steep learning curve and technical difficulty of laparoscopic surgery, robot-assisted laparoscopic surgery (RAS) is increasingly being adopted in pediatric patients worldwide. Anything that can be performed laparoscopically in adults can be extended into pediatric practice with minor technical refinements. We review the role of laparoscopic and RAS in pediatric urology and provide technical considerations necessary to perform minimally invasive surgery successfully.

Natural orifice transluminal endoscopic surgery (NOTES): current experience and urologic applications.

Natural orifice transluminal endoscopic surgery (NOTES) has attracted considerable recent attention for its potential to allow traditional abdominal procedures to be performed without a transabdominal incision. With considerable experience in the development and application of minimally invasive techniques, urologists have played a significant role in early experimental NOTES efforts and have contributed to early investigations in human subjects accordingly. However, adoption of these techniques has been limited due to cumbersome endoscopic equipment and concerns regarding peritonitis from failed viscerotomy closure. Experience with use of NOTES in human subjects is limited, and studies comparing NOTES to conventional minimally invasive techniques are lacking. Until adequate endoscopes are developed to facilitate a pure NOTES approach, multiple portals of entry will be necessary to facilitate both urologic and non-urologic reconstructive and extirpative procedures. Our aim is to evaluate NOTES techniques, portals of entry, early clinical experiences, and the application of NOTES to urologic surgery.

Investigational therapies for non-muscle invasive bladder cancer.

IMPORTANCE OF THE FIELD: Bacillus Calmette-Guérin (BCG) is currently the most effective adjuvant intravesical agent at preventing disease recurrence and the only therapy shown to inhibit disease progression in non-muscle invasive bladder cancer (NMIBC). However, recurrence rates as high as 30% and significant local/systemic toxicity have resulted in an increased interest in the use of alternative intravesical agents. AREAS COVERED IN THE REVIEW: Our aim is to discuss recent clinical trial evidence utilizing novel intravesical agents for treatment of NMIBC. A systematic literature review was performed via the National Center for Biotechnology Information databases to identify pertinent studies from 2000-2009. WHAT THE READER WILL GAIN: A durable response has been demonstrated with alternative agents in patients refractory to or intolerant of BCG. This review compares the merits and shortcomings of these emerging agents, focusing on clinical trial safety and efficacy results. TAKE HOME MESSAGE: Despite recent enthusiasm for novel agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy. However, evidence is accumulating that novel agents provide an efficacious alternative in patients refractory or intolerable to BCG or unfit for cystectomy. Further randomized prospective data are required to demonstrate a recurrence- and progression-free benefit compared with BCG.

Treatment of akinetic mutism with intramuscular olanzapine: a case series.

Akinetic mutism is a wakeful state of severe apathy and paucity of volitional movement. Evidence indicates a possible dopaminergic hypofunction within the anterior cingulate cortex. The authors present three cases of acute onset akinetic mutism successfully treated with intramuscular olanzapine.

Inflammation, genetic polymorphisms in proinflammatory genes TNF-A, RANTES, and CCR5, and risk of pancreatic adenocarcinoma.

Adenocarcinoma of the exocrine pancreas is the fourth leading cause of cancer-related death in men and women in the U.S. Cytokines and other proinflammatory mediators have been implicated in inflammatory pancreatic diseases including pancreatitis and cancer. We analyzed cytokine gene polymorphisms as risk factors for pancreatic cancer using questionnaire data obtained by in-person interviews and germ line DNA collected in a population-based case-control study of pancreatic cancer (532 cases and 1,701 controls) conducted in the San Francisco Bay Area. We used mass spectrometry and gel-based methods to genotype 308 cases and 964 population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression analysis and included adjustment for age, sex, and smoking. We assessed potential interactions between these polymorphisms, proinflammatory conditions (e.g., pancreatitis, ulcer, and obesity), and smoking as risk factors for pancreatic cancer. There was no overall association between pancreatic cancer risk and tumor necrosis factor-alpha (TNF-A -308G/A), regulated upon activation, normally T cell-expressed, and presumably secreted (RANTES -403G/A), and CC chemokine receptor 5 (CCR5-Delta32) polymorphisms. There was a nearly 7-fold increased relative risk estimate for pancreatic cancer in individuals with a history of pancreatitis (adjusted OR, 6.9; 95% CI, 3.4-14.1). Among patients with pancreatic cancer, pancreatitis was significantly associated with TNF-A -308 GA + AA (OR, 3.1; 95% CI, 1.3-7.4) and with RANTES -403 GA + AA (OR, 2.3; 95% CI, 1.0-5.4). There was evidence for a possible interaction between current active smoking and CCR5-32del. Our results lend support for the hypothesis that proinflammatory gene polymorphisms, in combination with proinflammatory conditions, may influence the development of pancreatic cancer.

Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility.

Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene-gene and gene-environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers [adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0-6.2]. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers [adjusted OR 0.4, 95% CI 0.2-0.9)]. The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D' = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer [e.g. adjusted OR 2.5, 95% CI 1.7-3.6] and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene-gene and gene-environment interactions.