Stratifying risk of disease in haematuria patients using machine learning techniques to improve diagnostics.

Background: Detailed and invasive clinical investigations are required to identify the causes of haematuria. Highly unbalanced patient population (predominantly male) and a wide range of potential causes make the ability to correctly classify patients and identify patient-specific biomarkers a major challenge. Studies have shown that it is possible to improve the diagnosis using multi-marker analysis, even in unbalanced datasets, by applying advanced analytical methods. Here, we applied several machine learning algorithms to classify patients from the haematuria patient cohort (HaBio) by analysing multiple biomarkers and to identify the most relevant ones. Materials and methods: We applied several classification and feature selection methods (k-means clustering, decision trees, random forest with LIME explainer and CACTUS algorithm) to stratify patients into two groups: healthy (with no clear cause of haematuria) or sick (with an identified cause of haematuria e.g., bladder cancer, or infection). The classification performance of the models was compared. Biomarkers identified as important by the algorithms were also analysed in relation to their involvement in the pathological processes. Results: Results showed that a high unbalance in the datasets significantly affected the classification by random forest and decision trees, leading to the overestimation of the sick class and low model performance. CACTUS algorithm was more robust to the unbalance in the dataset. CACTUS obtained a balanced accuracy of 0.747 for both genders, 0.718 for females and 0.803 for males. The analysis showed that in the classification process for the whole dataset: microalbumin, male gender, and tPSA emerged as the most informative biomarkers. For males: age, microalbumin, tPSA, cystatin C, BTA, HAD and S100A4 were the most significant biomarkers while for females microalbumin, IL-8, pERK, and CXCL16. Conclusions: CACTUS algorithm demonstrated improved performance compared with other methods such as decision trees and random forest. Additionally, we identified the most relevant biomarkers for the specific patient group, which could be considered in the future as novel biomarkers for diagnosis. Our results have the potential to inform future research and provide new personalised diagnostic approaches tailored directly to the needs of the individuals.

Biomarkers to assess the risk of bladder cancer in patients presenting with haematuria are gender-specific.

Introduction: Haematuria is a common red flag symptom of urinary tract cancer. Bladder cancer (BC) is the most common cancer to present with haematuria. Women presenting with haematuria are often underdiagnosed. Currently, no gender-specific tests are utilized in clinical practice. Considerable healthcare resources are needed to investigate causes of haematuria and this study was set up to help identify markers of BC. The aim of the study was to define biomarker algorithms in haematuria patients using an expanded panel of biomarkers to diagnose BC and investigate if the algorithms are gender-specific. Materials and Methods: A total of n=675 patients with a history of haematuria were recruited from Northern Ireland hospitals. Patients were collected on a 2:1 ratio, non-BC (control) n=474: BC n=201. A detailed clinical history, urine and blood samples were collected. Biomarkers, known to be involved in the pathobiology underlying bladder carcinogenesis were investigated. Biomarkers differentially expressed between groups were investigated using Wilcoxon rank sum and linear regression. Results: Biomarkers were gender specific. Two biomarker-algorithms were identified to triage haematuria patients; male - u_NSE, s_PAI-1/tPA, u_midkine, u_NGAL, u_MMP-9/TIMP-1 and s_prolactin (u=urine; s=serum); sensitivity 71.8%, specificity 72.8%; AUROC 0.795; and female urine biomarkers - IL-12p70, IL-13, midkine and clusterin; sensitivity 83.7%, specificity 79.7%; AUROC 0.865. Addition of the clinical variable infection to both algorithms increased both AUROC to 0.822 (DeLong p=0.014) and to 0.923 (DeLong p=0.004) for males and females, respectively. Combining clinical risk factors with biomarker algorithms would enable application of the algorithms to triage haematuria patients. Conclusion: Using gender-specific biomarker algorithms in combination with clinical risks that are associated with BC would allow clinicians to better manage haematuria patients and potentially reduce underdiagnosis in females. In this study, we demonstrate, for the first time, that blood and urine biomarkers are gender-specific when assessing risk of BC in patients who present with blood in their urine. Combining biomarker data with clinical factors could improve triage when referring patients for further investigations.

Clinical features and predictive biomarkers for bladder cancer in patients with type 2 diabetes presenting with haematuria.

AIMS: To identify clinical features and protein biomarkers associated with bladder cancer (BC) in individuals with type 2 diabetes mellitus presenting with haematuria. MATERIALS AND METHODS: Data collected from the Haematuria Biomarker (HaBio) study was used in this analysis. A matched sub-cohort of patients with type 2 diabetes and patients without diabetes was created based on age, sex, and BC diagnosis, using approximately a 1:2 fixed ratio. Randox Biochip Array Technology and ELISA were applied for measurement of 66 candidate serum and urine protein biomarkers. Hazard ratios and 95% confidence intervals were estimated by chi-squared and Wilcoxon rank sum test for clinical features and candidate protein biomarkers. Diagnostic protein biomarker models were identified using Lasso-based binominal regression analysis. RESULTS: There was no difference in BC grade, stage, and severity between individuals with type 2 diabetes and matched controls. Incidence of chronic kidney disease (CKD) was significantly higher in patients with type 2 diabetes (p = 0.008), and CKD was significantly associated with BC in patients with type 2 diabetes (p = 0.032). A biomarker model, incorporating two serum (monocyte chemoattractant protein 1 and vascular endothelial growth factor) and three urine (interleukin 6, cytokeratin 18, and cytokeratin 8) proteins, predicted incidence of BC with an Area Under the Curve (AUC) of 0.84 in individuals with type 2 diabetes. In people without diabetes, the AUC was 0.66. CONCLUSIONS: We demonstrate the potential clinical utility of a biomarker panel, which includes proteins related to BC pathogenesis and type 2 diabetes, for monitoring risk of BC in patients with type 2 diabetes. Earlier urology referral of patients with type 2 diabetes will improve outcomes for these patients. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN25823942.

Erodible thermogelling hydrogels for localized mitochondrial transplantation to the spinal cord.

We developed a thermal-gelling, erodible hydrogel system for localized delivery of viable mitochondria in vivo, as well as labeled transplanted mitochondria with specific dyes and/or genetically modified mitochondria tagged with red fluorescence protein (RFP). We also employed cell lines to optimize a hydrogel composed of methylcellulose and hyaluronic acid designed to preserve bioenergetics while facilitating mitochondrial release. We further investigated how transplantation of allogeneic or xenogeneic mitochondria into respective cell lines affects host cellular metabolism, as measured by MTS assay. We found that 70% of mitochondria are released from the hydrogel within 20 min at 37 °C, that the respiratory capacity of hydrogel-released mitochondria over 60 min was greater than those without gel, and that MTR-labeling of mitochondria is not indelible. RFP-tagged transgenic mitochondria isolated from modified SH-SY5Y human neuroblastoma cells showed effective uptake into both naïve SH-SY5Y cells and rat PC-12 cells, notably when released from hydrogel. The hydrogel both protected the mitochondria at physiological conditions in vitro while solidifying and diffusing within 60 min locally in situ. To assess metabolic effects, both cell lines were transplanted with different concentrations of SH-SY5Y or PC-12 cell line-derived mitochondria and all resulted in significant increases in metabolism at 6- and 24-hour after transplantation. Alternatively, transplanted mitochondria at highest concentration from rat brain and spinal cord tissues reduced metabolic activities after 24-hour. Along with hydrogel refinements, we are further investigating whether such metabolic changes are due to alterations in cell proliferation or the number of exogenous mitochondria incorporated into individual host cells.

Impact of health insurance status on surgical site infection incidence: A prospective cohort study.

Health insurance status may affect the risk for surgical site infection (SSI). A large prospective cohort study in a Swiss tertiary-care hospital did not find evidence of a difference in SSI risk in individuals with basic versus semiprivate or private insurance in a setting with universal health insurance coverage.

Compliance in patients with dietary hyperoxaluria: A cohort study and systematic review.

OBJECTIVE: Hyperoxaluria leads to calcium oxalate crystal formation and subsequent urolithiasis. This study aims to analyse the effect of treatment compliance in hyperoxaluria, firstly by analysis of patients with non-primary hyperoxaluria and secondly via systematic review in patients with any hyperoxaluria. METHODS: In a retrospective cohort study, adults with non-primary hyperoxaluria managed with dietary counselling in 2013 were enrolled. Twenty-four-hour (24 h) urine collections initially and at 6 months were obtained. Compliance was assessed by self-reported dietary compliance and 24 h urinary volume >2 L. Patients were followed for 24 months. Primary outcomes were urinary oxalate and calcium 24 h load at 6 months, and urolithiasis-related procedural rates at 24 months. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compatible systematic review of compliance among hyperoxaluric patients was performed. RESULTS: In the cohort study, of 19 eligible patients (4 female) with median age 52 years, 10 (53%) were considered compliant. Compared with the non-compliant group, these patients had significantly increased subsequent 24 h urinary volume (2250 mL vs. 1600 mL; p = 0.008) and lower procedural rates (10% vs. 56%; p = 0.033). Subsequent 24 h urinary oxalate load was non-significantly lower in compliant patients. Systematic review regarding compliance in hyperoxaluric patients revealed five studies. Only one utilised dietary counselling or analysed compliant vs. non-compliant patients, finding no difference. None examined the effect of compliance on procedural rates. CONCLUSION: Hyperoxaluria is an important cause of recurrent urolithiasis. Increasing fluid intake and reducing dietary oxalate reduce the risk of operative intervention and remain fundamental to the treatment of hyperoxaluria.

An early analysis of the cost-effectiveness of a diagnostic classifier for risk stratification of haematuria patients (DCRSHP) compared to flexible cystoscopy in the diagnosis of bladder cancer.

BACKGROUND: Urothelial bladder cancer (UBC) is the 5th most common cancer in Western societies. The most common symptom of UBC is haematuria. Cystoscopy the gold standard for UBC detection, allows direct observation of the bladder, but is expensive, invasive, and uncomfortable. This study examines whether an alternative new urine-based diagnostic test, the DCRSHP, is cost-effective as a triage diagnostic tool compared to flexible cystoscopy in the diagnosis of UBC in haematuria patients. METHODS: A model-based cost-utility analysis using cost per quality adjusted life year and life year gained, parameterised with secondary data sources. RESULTS: If the DCRSHP is targeted at haematuria patients at lower risk of having bladder cancer e.g. younger patients, non-smokers, then it can be priced as high as £620, and be both effective and cost-effective. Sensitivity analysis found that DCRSHP is approximately 80% likely to be cost-effective across all willingness to pay values (for a QALY) and prevalence estimates. CONCLUSION: This analysis shows the potential for a non-invasive test to be added to the diagnostic pathway for haematuria patients suspected of having UBC. If the DCRSHP is applied targeting haematuria patients at low risk of UBC, then it has the potential to be both effective and cost-effective.

Collectives of diagnostic biomarkers identify high-risk subpopulations of hematuria patients: exploiting heterogeneity in large-scale biomarker data.

BACKGROUND: Ineffective risk stratification can delay diagnosis of serious disease in patients with hematuria. We applied a systems biology approach to analyze clinical, demographic and biomarker measurements (n = 29) collected from 157 hematuric patients: 80 urothelial cancer (UC) and 77 controls with confounding pathologies. METHODS: On the basis of biomarkers, we conducted agglomerative hierarchical clustering to identify patient and biomarker clusters. We then explored the relationship between the patient clusters and clinical characteristics using Chi-square analyses. We determined classification errors and areas under the receiver operating curve of Random Forest Classifiers (RFC) for patient subpopulations using the biomarker clusters to reduce the dimensionality of the data. RESULTS: Agglomerative clustering identified five patient clusters and seven biomarker clusters. Final diagnoses categories were non-randomly distributed across the five patient clusters. In addition, two of the patient clusters were enriched with patients with 'low cancer-risk' characteristics. The biomarkers which contributed to the diagnostic classifiers for these two patient clusters were similar. In contrast, three of the patient clusters were significantly enriched with patients harboring 'high cancer-risk" characteristics including proteinuria, aggressive pathological stage and grade, and malignant cytology. Patients in these three clusters included controls, that is, patients with other serious disease and patients with cancers other than UC. Biomarkers which contributed to the diagnostic classifiers for the largest 'high cancer- risk' cluster were different than those contributing to the classifiers for the 'low cancer-risk' clusters. Biomarkers which contributed to subpopulations that were split according to smoking status, gender and medication were different. CONCLUSIONS: The systems biology approach applied in this study allowed the hematuric patients to cluster naturally on the basis of the heterogeneity within their biomarker data, into five distinct risk subpopulations. Our findings highlight an approach with the promise to unlock the potential of biomarkers. This will be especially valuable in the field of diagnostic bladder cancer where biomarkers are urgently required. Clinicians could interpret risk classification scores in the context of clinical parameters at the time of triage. This could reduce cystoscopies and enable priority diagnosis of aggressive diseases, leading to improved patient outcomes at reduced costs.

Peripheral versus central compartment starting point in hip arthroscopy for femoroacetabular impingement.

The purpose of this study was to compare the perioperative complications and traction times in femoroacetabular impingement hip arthroscopy with either a peripheral or central compartment starting point. Sixty patients with femoroacetabular impingement were treated with hip arthroscopy. Thirty patients had a peripheral compartment starting point and 30 had a central compartment starting point. Intra- and postoperative complications were documented along with traction times. The peripheral compartment starting group experienced 6 minor chondral injuries and 1 case of postoperative paresthesias. The central compartment starting group experienced 8 minor and 3 moderate chondral injuries, 2 labral penetrations, and 3 cases of postoperative paresthesias. Traction time averaged 46 minutes in the peripheral compartment starting group and 73 minutes in the central compartment starting group. Iatrogenic injury and traction times are decreased with peripheral vs central compartment starting in hip arthroscopy for femoroacetabular impingement. Consideration should be given for peripheral compartment starting in hip arthroscopy for the treatment of femoroacetabular impingement.

ERK acts in parallel to PKCδ to mediate the connexin43-dependent potentiation of Runx2 activity by FGF2 in MC3T3 osteoblasts.

The gap junction protein, connexin43 (Cx43), plays an important role in skeletal biology. Previously, we have shown that Cx43 can enhance the signaling and transcriptional response to fibroblast growth factor 2 (FGF2) in osteoblasts by increasing protein kinase C-δ (PKCδ) activation to affect Runx2 activity. In the present study, we show by luciferase reporter assays that the ERK signaling cascade acts in parallel to PKCδ to modulate Runx2 activity downstream of the Cx43-dependent amplification of FGF2 signaling. The PKCδ-independent activation of ERK by FGF2 was confirmed by Western blotting, as was the Cx43-dependent enhancement of ERK activation. Consistent with our prior observations for PKCδ, flow cytometry analyses show that Cx43 overexpression enhances the percentage of phospho-ERK-positive cells in response to FGF2, supporting the notion that shared signals among gap junction-coupled cells result in the enhanced response to FGF2. Western blots and luciferase reporter assays performed on osteoblasts cultured under low-density and high-density conditions revealed that cell-cell contacts are required for Cx43 to amplify ERK activation and gene transcription. Similarly, inhibition of gap junctional communication with the channel blocker 18ß-glycyrrhetinic acid attenuates the Cx43-dependent enhancement of Runx2-transcriptional activity. In total, these data underscore the importance of cell-cell communication and activation of the ERK and PKCδ pathways in the coordination of the osteoblast response to FGF2 among populations of osteoblasts.

The impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria.

BACKGROUND: We appraised 23 biomarkers previously associated with urothelial cancer in a case-control study. Our aim was to determine whether single biomarkers and/or multivariate algorithms significantly improved on the predictive power of an algorithm based on demographics for prediction of urothelial cancer in patients presenting with hematuria. METHODS: Twenty-two biomarkers in urine and carcinoembryonic antigen (CEA) in serum were evaluated using enzyme-linked immunosorbent assays (ELISAs) and biochip array technology in 2 patient cohorts: 80 patients with urothelial cancer, and 77 controls with confounding pathologies. We used Forward Wald binary logistic regression analyses to create algorithms based on demographic variables designated prior predicted probability (PPP) and multivariate algorithms, which included PPP as a single variable. Areas under the curve (AUC) were determined after receiver-operator characteristic (ROC) analysis for single biomarkers and algorithms. RESULTS: After univariate analysis, 9 biomarkers were differentially expressed (t test; P < .05). CEA AUC 0.74; bladder tumor antigen (BTA) AUC 0.74; and nuclear matrix protein (NMP22) 0.79. PPP included age and smoking years; AUC 0.76. An algorithm including PPP, NMP22, and epidermal growth factor (EGF) significantly improved AUC to 0.90 when compared with PPP. The algorithm including PPP, BTA, CEA, and thrombomodulin (TM) increased AUC to 0.86. Sensitivities = 91%, 91%; and specificities = 80%, 71%, respectively, for the algorithms. CONCLUSIONS: Addition of biomarkers representing diverse carcinogenic pathways can significantly impact on the ROC statistic based on demographics. Benign prostate hyperplasia was a significant confounding pathology and identification of nonmuscle invasive urothelial cancer remains a challenge.

Literature recommended as study aids for the hip reconstruction section of the orthopaedic in-training examination.

One section of the Orthopaedic In-Training Examination (OITE) assesses knowledge about hip reconstruction. In the investigation reported here, we examined OITE hip reconstruction questions and sought to identify which literature can be recommended as study aids for this section of the test. All hip reconstruction questions on the OITE from 2002 to 2006 were characterized according to diagnosis and treatment. Journals cited most often in this section were identified from the OITE key. This content domain was compared with the literature in terms of overall proportion of questions/articles related to hip reconstruction and in terms of diagnoses and treatments. Of the 1375 OITE questions asked over the 5 years, 79 were related to hip reconstruction. More than half of these hip reconstruction questions were related to primary total hip arthroplasty, with complications being the diagnosis tested most often. The results of this study suggest that residents may benefit from using general orthopedic journals when preparing for the OITE hip reconstruction section. When preparing an educational program, however, one should be aware that clinical journals may not reflect the OITE in terms of proportion of basic science and biomechanics articles.

Cost-effectiveness and efficiency of shockwave lithotripsy vs flexible ureteroscopic holmium:yttrium-aluminium-garnet laser lithotripsy in the treatment of lower pole renal calculi.

UNLABELLED: What's known on the subject? and What does the study add? Stone management economics is a complex issue. FURS and SWL are recognised treatment option for lower pole kidney stones. There are paucity of data comparing cost implication and effectiveness of both treatment options. Both treatment modalities are equally efficacious. FURS incurred greater cost burden compared to SWL in the UK setting. In the present economic circumstance, clinicians should also consider cost-impact, patient's preference and specific clinical indication when counselling patients for treatment. OBJECTIVE: • To compare the cost-effectiveness and outcome efficiency of extracorporeal shockwave lithotripsy (SWL) vs intracorporeal flexible ureteroscopic laser lithotripsy (FURS) for lower pole renal calculi ≤20 mm. PATIENTS AND METHODS: • Patients who had treatment for their radio-opaque lower pole renal calculi were categorized into SWL and FURS group. • The primary outcomes compared were: clinical success, stone-free, retreatment and additional procedure rate, and perceived and actual costs. • Clinical success was defined as stone-free status or asymptomatic insignificant residual fragments <3 mm. • Perceived cost was defined as the cost of procedure alone, and the actual cost included the cost of additional procedures as well as the overhead costs to result in clinical success. RESULTS: • The FURS (n= 37) and SWL (n= 51) group were comparable with respect to sex, age, stone size and the presence of ureteric stent. • The final treatment success rate (100% vs 100%), stone-free rate (64.9% vs 58.8%), retreatment rate (16.2% vs 21.6%) and auxillary procedure rate (21.6% vs 7.8%) did not differ significantly. • The mean perceived cost of each FURS and SWL procedure was similar (£249 vs £292, respectively); however, when all other costs were considered, the FURS group was significantly more costly (£2602 vs £426, P= 0.000; Mann-Whitney U-test). CONCLUSION: • SWL was efficacious and cost-effective for the treatment of lower pole renal calculi ≤20 mm.

Urologists versus radiologists made PCNL tracts: the U.K. experience.

We aim to explore the practice of who makes the PCNL tract in the U.K. and Northern Ireland as well as presenting our data for two different approaches to PCNL tracts in Northern Ireland. A national questionnaire survey was carried out across the National Health Services hospitals in U.K. In addition, a retrospective analysis of 134 PCNL cases was carried out. Group I included 103 (77%) cases with urologist-made tracts, while group II included 31 (23%) cases with radiologists-made tracts. The survey suggested that 45% (42) of the hospitals adopted a radiologist-made tract, 44% (41) use urologist-made tract, while the remaining 11% (11) use both. Most of the radiologists' performed tracts in our series were for complex cases. Failed access occurred in 6 (5.8%) in group I and none in Group II. The overall stone-free rate was 92 and 50% for group I and II, respectively. There is a better stone clearance rate in Group I (p = 0.0016). This however is likely to be attributed to the complexity of the cases in group II. However, urologist made percutaneous tract is safe and efficacious but a team approach with radiology is needed for more complex cases.

Young-Burgess classification of pelvic ring fractures: does it predict mortality, transfusion requirements, and non-orthopaedic injuries?

OBJECTIVES: The objectives of this study were to evaluate the ability of the Young-Burgess classification system to predict mortality, transfusion requirements, and nonorthopaedic injuries in patients with pelvic ring fractures and to determine whether mortality rates after pelvic fractures have changed over time. DESIGN: Retrospective review. SETTING: Level I trauma center. PATIENTS: One thousand two hundred forty-eight patients with pelvic fractures during a 7-year period. INTERVENTION: None. MAIN OUTCOME MEASUREMENTS: Mortality at index admission, transfusion requirement during first 24 hours, and presence of nonorthopaedic injuries as a function of Young-Burgess pelvic classification type. Mortality compared with historic controls. RESULTS: Despite a relatively large sample size, the ability of the Young-Burgess system to predict mortality only approached statistical significance (P = 0.07, Kruskal-Wallis). The Young-Burgess system differentiated transfusion requirements--lateral compression Type 3 (LC3) and anteroposterior compression Types 2 (APC2) and 3 (APC3) fractures had higher transfusion requirements than did lateral compression Type 1 (LC1), anteroposterior compression Type 1 (APC1), and vertical shear (VS) (P < 0.05)--but was not as useful at predicting head, chest, or abdomen injuries. Dividing fractures into stable and unstable types allowed the system to predict mortality rates, abdomen injury rates, and transfusion requirements. Overall mortality in the study group was 9.1%, unchanged from original Young-Burgess studies 15 years previously (P = 0.3). CONCLUSIONS: The Young-Burgess system is useful for predicting transfusion requirements. For the system to predict mortality or nonorthopaedic injuries, fractures must be divided into stable (APC1, LC1) and unstable (APC2, APC3, LC2, LC3, VS, combined mechanism of injury) types. LC1 injuries are very common and not always benign (overall mortality rate, 8.2%).

Morphological expression of KIT positive interstitial cells of Cajal in human bladder.

PURPOSE: We investigated the 3-dimensional morphological arrangement of KIT positive interstitial cells of Cajal in the human bladder and explored their structural interactions with neighboring cells. MATERIALS AND METHODS: Human bladder biopsy samples were prepared for immunohistochemistry/confocal or transmission electron microscopy. RESULTS: Whole mount, flat sheet preparations labeled with anti-KIT (Merck, Darmstadt, Germany) contained several immunopositive interstitial cell of Cajal populations. A network of stellate interstitial cells of Cajal in the lamina propria made structural connections with a cholinergic nerve plexus. Vimentin positive cells of several morphologies were present in the lamina propria, presumably including fibroblasts, interstitial cells of Cajal and other cells of mesenchymal origin. Microvessels were abundant in this region and branched, elongated KIT positive interstitial cells of Cajal were found discretely along the vessel axis with each perivascular interstitial cell of Cajal associated with at least 6 vascular smooth muscle cells. Detrusor interstitial cells of Cajal were spindle-shaped, branched cells tracking the smooth muscle bundles, closely associated with smooth muscle cells and vesicular acetylcholine transferase nerves. Rounded, nonbranched KIT positive cells were more numerous in the lamina propria than in the detrusor and were immunopositive for anti-mast cell tryptase. Transmission electron microscopy revealed cells with the ultrastructural characteristics of interstitial cells of Cajal throughout the human bladder wall. CONCLUSIONS: The human bladder contains a network of KIT positive interstitial cells of Cajal in the lamina propria, which make frequent connections with a cholinergic nerve plexus. Novel perivascular interstitial cells of Cajal were discovered close to vascular smooth muscle cells, suggesting interstitial cells of Cajal-vascular coupling in the bladder. KIT positive detrusor interstitial cells of Cajal tracked smooth muscle bundles and were associated with nerves, perhaps showing a functional tri-unit controlling bladder contractility.

Ectopic bone formation in the pelvis after combined anterior and posterior fusion of the spine with osteogenic protein-1 use: a case report.

STUDY DESIGN: Case report. OBJECTIVE: We report the first described case of ectopic bone formation with osteogenic protein-1 (OP-1) use occurring in the pelvis after combined anterior and posterior spinal fusion. SUMMARY OF BACKGROUND DATA: OP-1 is a member of the transforming growth factor-beta superfamily of extracellular proteins involved in bone growth and formation. Potential side effects of OP-1 are not yet fully understood, and clinical data have failed to show significant adverse effects of OP-1. METHODS: The patient had flat-back syndrome with symptomatic junctional degenerative disease below the level of fusion and underwent staged anterior and posterior reconstruction. OP-1 was used in conjunction with local bone graft and crushed cancellous allograft in both anterior and posterior procedures. RESULTS: Bone grew adjacent to the left superior pubic rami, extending through the left rectus sheath and into the left psoas muscle. Subsequently, complete excision of the ectopic bone was performed. No local recurrence was noted at postoperative visits up to 5 months after excision. At that time, the patient had returned to work and was pleased with the level of function. CONCLUSIONS: Caution is justified with the use of OP-1. Clinical studies must be conducted to ensure appropriate dosing to prevent ectopic bone formation and deleterious effects.

Antisense oligonucleotides in the treatment of bladder cancer.

This review examines the role that antisense oligonucleotides play in the treatment of superficial and muscle-invasive bladder cancer. The unique environment of the urinary bladder allows intravesical instillation of antisense oligonucleotides, and researchers have already demonstrated uptake of antisense oligonucleotides in models of bladder cancer. Second, proof of principle has been established by demonstrating downregulation of the antisense target mRNA and protein. Third, and most importantly from a therapeutic perspective, synergy between chemotherapy and antisense oligonucleotides has been shown in bladder cancer models in vitro and in vivo. The collective evidence points to a role for antisense oligonucleotides in the treatment of superficial and muscle-invasive bladder cancer in combination with existing treatment modalities.

Molecular markers for predicting recurrence, progression and outcomes of bladder cancer (do the poster boys need new posters?).

PURPOSE OF REVIEW: Molecular markers for bladder cancer recurrence and progression continue to drive many research programmes. Translating the laboratory findings into the clinical environment where these markers are used in clinical decision making has proved problematic. In the clinical arena, stage and grade are still the main focus for decisions about patient management. There is however an evolution in bladder cancer research from single-marker/single-pathway research to a more global assessment of the tumour cell with DNA microarrays and proteomics. RECENT FINDINGS: In the last year, DNA microarray assessment has revealed several interesting molecular markers such as p33ING1 and DEK. Parallel "conventional" single-pathway research has focused on new novel markers such as HER2/neu, survivin and matrix metalloproteinase 2 (MMP-2). Molecular markers that have a long-standing association with bladder cancer progression such as p53, E-cadherin and Ki-67 have been reviewed by both single-marker studies and by microarray studies and their status remains important. SUMMARY: It is an exciting time in the molecular biology research of bladder cancer as the focus changes to assess the global genetic and protein expression within tumour cells. From such a wealth of information it is likely that molecular markers will make the translation from benchside to bedside.

Oligoclonality in bladder cancer: the implication for molecular therapies.

PURPOSE: There is conflicting evidence in the published literature regarding the clonal or oligoclonal origin of bladder cancer. MATERIALS AND METHODS: A MEDLINE search of articles on the clonality, genetic, epigenetic and tumor microenvironment of bladder cancer cells was done. Laboratory and clinical studies were included and relevant articles were selected if tumor cell clonality was part of the study. We reviewed this published evidence. RESULTS: Current thinking proposes 2 main theories. 1) In the clonogenic theory multifocal and recurrent tumors evolve from a single transformed cell and, hence, all progeny share a number of identical genetic mutations. 2) The field change theory assumes a global change in the urothelium with multiple transformed cells evolving into mature tumors independently. The evidence for and against each theory is compelling. Of equal importance are the parallel epigenetic modifications and changes in the cellular microenvironment that permit tumor evolution. CONCLUSIONS: The presence of oligoclonality has implications for the potential efficacy of novel molecular therapeutic agents for bladder cancer. The molecular targets for such therapies must be widely sampled in a tumor population to assess expression in separate clones.