Contact-Active Layer-by-Layer Grafted TPU/PDMS Blends as an Antiencrustation and Antibacterial Platform for Next-Generation Urological Biomaterials: Validation in Artificial and Human Urine.

Urinary tract infections and urinary encrustation impede the long-term clinical performance of urological implants and medical devices. Together, biofilm formation and encrustation constitute serious complications, driving the development of next-generation urological biomaterials. The currently available bioengineered solutions have limited success during long-term usage in the urinary environment. In addressing this unmet clinical challenge, contact-active, antiencrustation surface grafting were conceived onto a dynamically cross-linked polydimethylsiloxane (PDMS) modified thermoplastic polyurethane (TPU) blend using the layer-by-layer (LbL) assembly route. To the best of the authors' knowledge, the present study is the first to investigate the LbL grafting in developing an antiencrustation platform. These multilayered assemblies strategically employed covalent cross-linking and electrostatic interaction-assisted progressive depositions of branched polyethyleneimine and poly(2-ethyl-2-oxazoline). While polyethyleneimine conferred the contact-killing bactericidal activity, the much-coveted antiencrustation properties were rendered by incorporating a partially hydrolyzed derivative of poly(2-ethyl-2-oxazoline). The performance of the resultant surface-modified TPU/PDMS blends was benchmarked against the conventional urological alloplasts, in a customized lab-scale bioreactor-based dynamic encrustation study and in human urine. After 6 weeks of exposure to an artificial urine medium, simulating urease-positive bacterial infection, the surface-modified blends exhibited a remarkable ability to suppress Ca and Mg encrustation. In addition, these blends also displayed superior grafting stability and antibacterial efficacy against common uropathogens. As high as 4-fold log reduction in the planktonic growth of Gram-negative P. mirabilis and Gram-positive MRSA was recorded with the LbL platform vis-à-vis medical-grade TPU. In conjunction, the in vitro cellular assessment with human keratinocytes (HaCaT) and human embryonic kidney cells (HEK) established the uncompromised cytocompatibility of the multilayered grafted blends. Finally, the physiologically relevant functionality of the LbL grafting has been validated using clinical samples of human urine collected from 129 patients with a broad spectrum of disease conditions. The phase-I pre-clinical study, entailing 6 week-long incubation in human urine, demonstrated significantly improved encrustation resistance of the blends. The collective findings of the present work clearly establish the success of LbL strategies in the development of stable, multifunctional new-generation urological biomaterials.

Experience with management of renal cell carcinoma with inferior vena cava/right atrial tumor thrombus.

INTRODUCTION: We aimed to present our experience in managing renal cell carcinoma (RCC) with inferior vena cava (IVC) thrombus. METHODS: Records of all patients aged 18 years and older, with a diagnosis of primary renal masses with IVC thrombus, presenting to our institute from January 2012 to August 2020 were retrospectively reviewed. Patients with tumor thrombus limited only to renal vein were excluded from the analysis. Their hospital course and outcomes were recorded and evaluated for predictors of survival. RESULTS: During the study period, we treated 61 patients with a renal mass and concurrent IVC thrombus and 56 of these underwent surgery. 7 of them had level III and 6 had level IV thrombus. A total of six patients received neoadjuvant tyrosine kinase inhibitor (TKI) therapy and all of them showed a decrease in size and level of tumor thrombus and cardiopulmonary bypass was safely avoided. Fourteen patients had distant metastasis and underwent cytoreductive surgery and of these 12 patients received TKI therapy after surgery with a mean survival of 26.8 months. The overall survival at 2 and 5 years of nonmetastatic group was 81.1% and 47.5% respectively and in metastatic group was 35.1% and 0%, respectively. Poor performance status, distant metastasis, higher T stage, higher thrombus levels, and positive surgical margins were all predictors of decreased survival. CONCLUSIONS: Complete surgical resection in both nonmetastatic and metastatic RCC with IVC thrombus has long-term survival benefits. Neoadjuvant TKI therapy, with adequate preoperative planning, helps in decreasing the size of the thrombus and in safely avoiding bypass in level III and IV IVC thrombi.

Metabolomics of prostate cancer: Knock-in versus knock-out prostate.

Several metabolomics-derived biomarkers of prostate cancer (PC) have been reported with pre-radical prostatectomy (RP) (knock-in PC) conditions; however, uncontested PC biomarkers panel appraisal and investigation of correlative evidence of these measures is lacking through post-RP (knock-out PC). We sought to explore patients' filtered serum-based metabolomics derived signature measures in knock-in PC (n = 90) using nuclear magnetic resonance spectroscopy and multiple rigorous statistical analyses, and to develop the correlative evidence of these measures through knock-out PC (n = 90) follow-up on the 15th and 30th days. The glutamate, citrate and glycine were observed as hallmarks of PC. Observed trends revealed; augmented glutamate level in knock-in PC following a sudden drop and subsequently upside of glutamate at 15th and 30th days of knock-out PC, reduction of citrate in knock-in PC subsequently gradual increase of citrate in knock-out PC, and glycine lessening in knock-in PC following augmentation on 30th day of knock-out PC. This study-based evidence clears the doubts regarding the discovery of metabolomics-derived PC biomarkers.

Prostate-specific antigen screening of men with lower urinary tract symptoms (opportunistic screening) and of asymptomatic men undergoing executive health check: an audit from two institutions.

INTRODUCTION: We evaluated incidence ofprostate-specific antigen (PSA) positivity (>4ng/mL) and cancer detection rate on prostate biopsy in two populations of men, one undergoing opportunistic testing for lower urinary tract symptoms and another during routine health checks. METHODS: Data regarding PSA screening, rectal examination (RE), transrectal ultrasound-guided biopsy, clinical stage, and risk assessment grouping according to NCCN guidelines were studied. Group A included patients with lower urinary tract symptoms (LUTS) (opportunistic screening) at SGPGIMS, Lucknow and Group B included healthy men who had executive health check-up with PSA testing at Medanta the Medicity, Gurugram. RESULTS: PSA positivity rate in 9906 symptomatic men for LUTS (Group A) and 24919 healthy men (Group B) was 28.4% and 3% respectively. In group A, PSA positivity rate was 28.4% but only around half of all men with an indication underwent a biopsy. Among men with PSA of 4-10 ng/mL, cancer was detected in 93 of 241 who underwent a biopsy (38.5%). In Group B, only 69 men (9.3% of those with an elevated PSA) underwent a prostate biopsy, of which 38/57 (with PSA of 4-10 had cancer. In Group A, the cancers was metastatic in 61.5% men, while none in-Group B had metastatic disease. CONCLUSION: Opportunistic screening and executive health check with PSA identifies a significant number of men with PSA positivity and may help decrease the proportion of men diagnosed in metastatic prostate cancer.

Dynamically crosslinked polydimethylsiloxane-based polyurethanes with contact-killing antimicrobial properties as implantable alloplasts for urological reconstruction.

A large population of patients is reported to suffer from urinary bladder-associated irreversible physiological disorders, rationalizing a continuous surge for structural and functional substitutes of urinary tissues, including ureters, bladder-wall, and urethra. The current gold standard for bladder reconstruction, an autologous gastrointestinal graft, is proven not to be an ideal substitute in the clinic. While addressing this unmet clinical need, a unique platform of antimicrobial polydimethyl siloxane-modified polyurethanes (TPU/PDMS) is designed and developed for its potential application as a urological implant. To the best of our knowledge, this study reports for the first time the successful integration of varying contents of PDMS within the molten polyurethane matrix using in situ crosslinking methodology. Thus, compatibilized binary blends possess clinically relevant viscoelastic properties to sustain high pressure, large distensions, and surgical manipulation. Furthermore, different chemical strategies are explored to covalently incorporate quaternized moieties, including 4-vinyl pyridine (4-VP), branched-polyethyleneimine (bPEI) as well as bPEI-grafted-(acrylic acid-co-vinylbenzyltriphenyl phosphonium chloride) (PAP), and counter urinary tract infections. The modified compositions, endowed with contact killing surfaces, reveal nearly three log reduction in bacterial growth in pathogenically infected artificial urine. Importantly, the antimicrobial TPU/PDMS blends support the uninhibited growth of mitochondrially viable murine fibroblasts, in a manner comparable to the medical-grade polyurethane. Collectively, the obtained results affirmed the newly developed polymers as promising biomaterials in reconstructive urology. STATEMENT OF SIGNIFICANCE: The clinical procedure for end-stage bladder disease remains replacement or augmentation of the bladder wall with a section of the patient's gastrointestinal tract. However, the absorptive and mucus-producing epithelium of intestinal segment is liable to short- and long-term complications. The dynamically crosslinked polydimethyl siloxane-based polyurethanes proposed herein, and the associated synthesis strategies to induce polycation grafted non-exhaustive contact-killing surfaces against uropathogents, have a significant clinical prospect in reconstructive urology. As an 'off-the-shelf' available alloplastic substitute, these blends offer the potential to circumvent the challenges associated with non-urinary autografts or scaffold based regenerative engineering and, thereby, shorten as well as simplify the surgical treatment. The targeted application has been conceived for a bladder patch to assist in various urinary diseases including, bladder carcinoma, refractory overactive bladder, interstitial cystitis, etc. However, given the ease of fabrication, moldability and the wide spectrum of mechanical properties that could be encompassed, these blends also present the possibility to be manifested into artificial ureteral or urethral conduits.

NMR-derived targeted serum metabolic biomarkers appraisal of bladder cancer: A pre- and post-operative evaluation.

With high morbidity and mortality, urinary bladder cancer (BC) ranks fifth among common cancers globally. The inherent limitations of urine cytology and cystoscopy, and marginal enhancements in the rate of survival promt us to develop surrogate serum based metabolic biomarkers of screening, identification, and follow-up protocols of management for BC patients. Earlier, we exhibited that abnormal expression levels of dimethylamine (DMA), malonate, lactate, glutamine, histidine, and valine in serum may be used as signature metabolites to differentiate BC from healthy controls (HC) (J. Proteome Res. 2013; 12(12):5839-50). Here we further gauge and validate these observations by comparing pre-operative to post-operative follow-up BC patients. This study was conducted on 160 sera samples involving HC (n = 52), pre-operative (n = 55) and post-operative (n = 53) BC cases. 1H nuclear magnetic resonance (NMR) spectroscopy was used to generate serum metabolic profiles and to gauge aberrantly expressed metabolites. The targeted metabolomic approach revealed that the expression levels of these signature metabolites were progressively and significantly decreased in post-operative follow-up at the interval of 30, 60, and 90 days compared to pre-operative BC sera samples and were maintained at HC levels. Serum metabolic biomarkers appear to be an inspiring and least-invasive tactic for detection and prognosticating BC patient follow-up.

A modified cutaneous ureterostomy provides satisfactory short and midterm outcomes in select cases.

OBJECTIVE: We present the outcomes of modification of cutaneous ureterostomy by extreme lateralization of the stoma and use of skin flap for formation of ureterostomy. MATERIAL AND METHODS: Between June 2012 and June 2016, 36 patients had modified cutaneous ureterostomy for ureteral obstruction due to pelvic malignancy or genitourinary tuberculosis. Transureteroureterostomy was made with cutaneous stoma at anterior axillary line between iliac crest and lower rib cage, instead of spinoumbilical line. To prevent stenosis a 'V' shaped skin was fed into the stoma. Double J stents were used in all patients for 6 weeks. Perioperative morbidity and mortality were evaluated. All patients were followed up at 3 month intervals. RESULTS: Of 36 patients, 22 had radical cystoprostatectomy (including nephroureterectomy in 2 patients) and 7 had palliative cystectomy. Others had locally advanced prostate cancer (n=1), locally advanced cervical cancer (n=3), ovarian cancer (n=1) and genitourinary tuberculosis with small capacity bladder along with a large vesicovaginal fistula (n=1). One patient developed ureteral necrosis requiring conversion to ileal conduit. Three patients developed stomal stenosis: two were managed by self-dilatation while one required revision of stoma. Thirteen patients died of the disease at a median follow up of 6 months with functioning stoma. Remaining 19 patients survived without any complications at a median follow-up of 20.5 months (5.5-43.5 months). None of the patients had any problem related to ureterostomy bag application. CONCLUSION: Modified lateral cutaneous ureterostomy provides relatively straighter and shorter retroperitoneal course of ureter with acceptable morbidity and avoids use of bowel in selected patients.

Relevance of MIC-1 in the Era of PSA as a Serum Based Predictor of Prostate Cancer: A Critical Evaluation.

To reduce the ambiguity of contradictory observations in different studies regarding the expression level of Macrophage Inhibitory Cytokine-1 (MIC-1) in serum in prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy controls (HC), we designed this double-blind study. The study comprises 240 sera from PC, BPH and HC subjects. The expression level of MIC-1 in PC, BPH and HC were appraised using Western blot (WB) and ELISA based approach. WB and ELISA appraisal reveals that the expression level of MIC-1 is significantly higher in PC than in HC or BPH subjects. Regression analysis revealed a significant correlation between MIC-1 vs. PSA (r = 0.09; p < 0.001) and MIC-1 vs. GS (r = 0.7; p < 0.001). ROC analysis using discriminant predicted probability revealed that the MIC-1 was better than PSA. Moreover, the combination of MIC-1 and PSA was allowing 99.1% AUC for the differentiation of BPH + PC from HC, 97.9% AUC for differentiation of BPH from HC, 98.6% AUC for differentiation of PC from HC, and 96.7% AUC for the differentiation of PC from BPH. The augmented expression of MIC-1 in PC compared to BPH and HC subjects is in concurrent of the over-expression of MIC-1 in PC reports and confiscates the contradictory findings of other studies.

Importance of lower pole nephrectomy during ureterocalicostomy.

Ureterocalicostomy is usually a salvage procedure for recurrent pelvi-ureteric junction (PUJ) stricture or upper ureteric injury. It requires meticulous dissection of the upper ureter, and lower pole nephrectomy is considered an essential step to achieve a wide funneled and dependent ureterocaliceal anastomosis. We, hereby, highlight the importance of guillotine lower pole nephrectomy through a case report of recurrent PUJ stricture managed with ureterocalicostomy that failed due to the omission of lower pole nephrectomy.

MicroRNA-21 could be a molecular marker to predict the recurrence of nonmuscle invasive bladder cancer.

INTRODUCTION: High relapse rate of nonmuscle invasive bladder cancer (NMIBC) is a major challenge. Overexpression of microRNA-21 (miR-21) which targets phosphatase and tensin homolog (PTEN), a gene associated with malignancy, has been reported in the bladder tumor tissue compared to normal mucosa by us and others. We have tested whether miR-21 levels in bladder mucosa could predict tumor recurrence. METHODS: In a prospective cohort setting, tumor tissues and normal bladder mucosa (NBM) were taken from BC patients during transurethral resection of bladder tumor. Age- and ethnicity-matched NBM from benign prostate hyperplasia patients was taken as controls. The expression of miR-21 was analyzed using quantitative reverse transcription polymerase chain reaction. Patients were followed for 4 years for tumor reoccurrence. Postoperative recurrence were recorded and calculated by Kaplan-Meier curve. RESULTS: In 31 patients, miR-21 was up-regulated (>4-fold, P = 0.003), and PTEN levels were significantly lower (<7-folds, P = 0.001) in tumor tissue relative to NBM. Moreover, the fold change in miR-21 levels was significantly higher (>3-folds, P = 0.03) in patients showing recurrence compared to those in which tumor did not recur. Further, Kaplan-Meier analysis shows overexpression of miR-21 corresponds to less time to recurrence with higher cumulative hazard. CONCLUSION: We found overexpression of miR-21 in tumor tissue and its association with recurrence, time to recurrence and invasiveness in BC. Quantification of miR-21 along with other pathological parameters could be more objective molecular approach to predict recurrence in NMIBC.

Utility of anteroposterior diameter ratio of tumor and abdomen for laparoscopic approach for radical nephrectomy in large renal masses.

INTRODUCTION: Laparoscopic radical nephrectomy (LRN) is now increasingly done for tumors larger than 10 cm. Despite selection of favorable cases, LRN may not be successful due to lack of adequate working space with large tumors. We describe a new feature on Contrast Enhanced Computed Tomography (CECT) abdomen to predict feasibility of LRN for large renal masses between 10 and 15 cm. METHODS: From January 2005 to December 2015, renal tumors between 10 and 15 cm were selected retrospectively for LRN. Patients with retroperitoneal lymphadenopathy, Inferior vena cava (IVC) thrombus and involvement of adjacent organs were excluded. Anteroposterior (AP) diameter ratio of renal tumor and abdomen (APROTA) was calculated by dividing the maximum AP diameter of tumor along with normal renal parenchyma, by the AP diameter of abdomen on CECT. The patients were stratified into two groups: Group A (successful LRN) and Group B (conversion to open surgery) and outcomes were compared. The reasons for conversion were also noted. RESULTS: Of 29 patients, 16 (55.2%) had successful LRN (Group A), while 13 (44.8%) had conversion to open surgery (group B). The median tumor size in Group A was 11.3 ± 1.8 cm and in Group B was 13.6 ± 1.26 cm. Eleven of 13 patients had conversion due to large tumor size causing failure to progress. Two conversions were due to bleeding and injury to the colon each. There was a significant difference in the APROTA in group A and B [0.43 ± 0.09 in group A and 0.64 ± 0.14 in group B (p = 0.0001)]. CONCLUSIONS: Patients with APROTA of more than 0.65 are unlikely to have successful outcome with LRN.