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.

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.

Reduced Insulin Receptor Expression Enhances Proximal Tubule Gluconeogenesis.

Reduced insulin receptor protein levels have been reported in the kidney cortex from diabetic humans and animals. We recently reported that, targeted deletion of insulin receptor (IR) from proximal tubules (PT) resulted in hyperglycemia in non-obese mice. To elucidate the mechanism, we examined human proximal tubule cells (hPTC) and C57BL/6 mice fed with high-fat diet (HFD, 60% fat for 20 weeks). Immunoblotting revealed a significantly lower protein level of IR in HFD compare to normal chow diet (NCD). Furthermore, a blunted rise in p-AKT308 levels in the kidney cortex of HFD mice was observed in response to acute insulin (0.75 IU/kg body weight, i.p) relative to NCD n = 8/group, P < 0.05). Moreover, we found significantly higher transcript levels of phosphoenolpyruvate carboxykinase (PEPCK, a key gluconeogenic enzyme) in the kidney cortex from HFD, relative to mice on NCD. The higher level of PEPCK in HFD was confirmed by immunoblotting. However, no significant differences were observed in cortical glucose-6-phosphatase (G6Pase) or fructose-1,6, bisphosphosphatase (FBPase) enzyme transcript levels. Furthermore, we demonstrated insulin inhibited glucose production in hPTC treated with cyclic AMP and dexamethasone (cAMP/DEXA) to stimulate gluconeogenesis. Transcript levels of the gluconeogenic enzyme PEPCK were significantly increased in cAMP/DEXA-stimulated hPTC cells (n = 3, P < 0.05), and insulin attenuated this upregulation Furthermore, the effect of insulin on cAMP/DEXA-induced gluconeogenesis and PEPCK induction was significantly attenuated in IR (siRNA) silenced hPTC (n = 3, P < 0.05). Overall the above data indicate a direct role for IR expression as a determinant of PT-gluconeogenesis. Thus reduced insulin signaling of the proximal tubule may contribute to hyperglycemia in the metabolic syndrome via elevated gluconeogenesis. J. Cell. Biochem. 118: 276-285, 2017. © 2016 Wiley Periodicals, Inc.

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.

Bladder cancer: Micro RNAs as biomolecules for prognostication and surveillance.

INTRODUCTION: Bladder cancer (BC) has varied clinical behavior in terms of recurrence and progression. Current pathological characteristics are insufficient to prognosticate the outcome of a given treatment. Cellular metabolic regulatory molecules, such as micro RNA (miRNA), could be a potential biomarker to prognosticate the treatment outcomes. MATERIALS AND METHODS: PubMed and Google Scholar databases were searched for publications from 1990 to 2016, related to miRNA biogenesis, its function, and role in the pathogenesis of bladder as well as other cancers. Articles were searched using MeSH terms micrornas, micrornas AND neoplasm, and micrornas AND urinary bladder neoplasm. Out of the 108 publications reviewed 75 references were selected based on the clinical relevance. Articles were reviewed to assess the role of miRNA in various cancers and those in BC as a diagnostic or therapeutic tool. RESULTS: More than 35 miRNAs were found to be associated with different pathways of cellular dedifferentiation, proliferation, and progression of BC as well as other cancers. A normal looking mucosa may show molecular changes preceding phenotypic changes in the form of varied expression of miR-129, miR-200a, and miR-205. miR-214, miR-99a, and miR-125b have been shown to be potential urinary biomarkers of BC. miRNAs could act as a repressor for protein molecule functioning or activator of different pathways to be used as a therapeutic target too. CONCLUSIONS: Despite certain limitations, such as instability, rapid plasma clearance, and targeting antagonist proteins of cellular metabolic pathways, miRNAs have potential to be studied as a biomarker or a therapeutic target for BC.

NMR spectroscopy of filtered serum of prostate cancer: A new frontier in metabolomics.

BACKGROUND: To address the shortcomings of digital rectal examinations (DRE), serum prostate-specific antigen (PSA), and trans-rectal ultrasound (TRUS) for precise determination of prostate cancer (PC) and differentiation from benign prostatic hyperplasia (BPH), we applied (1) H-nuclear magnetic resonance (NMR) spectroscopy as a surrogate tactic for probing and prediction of PC and BPH. METHODS: The study comprises 210 filtered sera from suspected PC, BPH, and a healthy subjects' cohort (HC). The filtered serum approach delineates to identify and quantify 52 metabolites using (1) H NMR spectroscopy. All subjects had undergone clinical evaluations (DRE, PSA, and TRUS) followed by biopsy for Gleason score, if needed. NMR-measured metabolites and clinical evaluation data were examined separately using linear multivariate discriminant function analysis (DFA) to probe the signature descriptors for each cohort. RESULTS: DFA indicated that glycine, sarcosine, alanine, creatine, xanthine, and hypoxanthine were able to determine abnormal prostate (BPH + PC). DFA-based classification presented high precision (86.2% by NMR and 68.1% by clinical laboratory method) in discriminating HC from BPH + PC. DFA reveals that alanine, sarcosine, creatinine, glycine, and citrate were able to discriminate PC from BPH. DFA-based categorization exhibited high accuracy (88.3% by NMR and 75.2% by clinical laboratory method) to differentiate PC from BPH. CONCLUSIONS: (1) H NMR-based metabolic profiling of filtered-serum sample appears to be assuring, swift, and least-invasive for probing and prediction of PC and BPH with its signature metabolic profile. This novel technique is not only on a par with histopathological evaluation of PC determination but is also comparable to liquid chromatography-based mass spectrometry to identify the metabolites. Prostate 76:1106-1119, 2016. © 2016 Wiley Periodicals, Inc.

Predictors for progression of metastatic prostate cancer to castration-resistant prostate cancer in Indians.

BACKGROUND & OBJECTIVES: There is lack of data on natural history and progression of prostate cancer (PC) which have implications in the management of the disease. We undertook this retrospective study to analyze factors predicting progression of metastatic PC to castration-resistant prostate cancer (CRPC) in Indian men. METHODS: Complete records of 223 of the 489 patients with metastatic PC were obtained from computerized data based system in a tertiary care hospital in north India between January 2000 to June 2012. Patients with follow up of < 6 months were excluded. Age (≤ and > 65 yr), baseline PSA (< and ≥ 50 ng/ml), bone scan and Gleason score (≤7 and >7) were recorded. Extent of bone disease (EOD) was stratified according to the number of bone lesions i.e., < 5, 5-10, > 10. CRPC was defined as two consecutive PSA rise of > 50 per cent from nadir or an absolute value of > 5 ng/ml. RESULTS: Mean age of patients was 61.5 ± 12.45 yr and their PSA level was 325.6 ± 631.35 ng/dl. Of the 223 patients, 193 (86%) progressed to CRPC at median time of 10.7 (4-124) months. Median follow up was 24 (6-137) months. On univariate and multivariate analyses EOD on bone scan was found to be a significant predictor ( P=0.006) for time to CRPC. Median time to CRPC was 10 months (CI 95%, 7.5-12.48) with >10 lesions or super scan versus 16 months (CI 95%, 10.3-21.6) with <10 bone lesion (P=0.01). Ninety (46.6 %) patients of CRPC died with median time to death from time of CRPC 21 (10-120) months. INTERPRETATION & CONCLUSIONS: Median time for progression of metastatic PC to CRPC ranged from 10-16 months depending on the extent of the bone involvement. In Indians, the aggressive course of advanced prostate cancer warrants further clinical trials to explore the need for additional treatment along with initial castration.

Molecular cystoscopy: Micro-RNAs could be a marker for identifying genotypic changes for transitional cell carcinoma of the urinary bladder.

INTRODUCTION: Normal-looking mucosa may harbor genetic changes preceding a visible tumor. This study was aimed at exploring the role of the quantitative expression of micro-RNAs (miRNAs) in bladder cancer tissue in comparison with normal mucosa and healthy controls (HCs) as a molecular marker. MATERIALS AND METHODS: Between October 2011 to December 2012, tissue from the bladder tumor of 21 patients (cases tumor, CT), normal mucosa (case control, CC) of the same patients (n-21) and normal bladder mucosa from 10 HCs were obtained. miRNAs of angiogenesis, endothelial mesenchymal transition and apoptosis were quantified using stem-loop RT Taq Man polymerase chain reaction. Statistical analysis was performed using the Chi square and independent sample T tests by using SPSS version 16. RESULTS: The mean age of the patients and controls were 55.41 ± 11.03 and 52.14 ± 13.04 years. miR-21, miR-205, miR-126, miR-10b and miR-200a were highly expressed in CT (P < 0.027, <0.048, <0.025, <0.029 and < 0.005) as compared with HC. Expression of miR-21 and miR-129 were both correlated with grade and stage (P = 0.001 and < 0.009, respectively) and the level of expression was different in the same grade of non-muscle invasive tumors. The fold change of miR129, miR205 and miR200a was significantly higher in the normal-looking mucosa of bladder tumor patients than the HC (P < 0.005). CONCLUSION: Expression of miR129, miR205 and miR200a in the normal-looking mucosa of bladder cancer patients was significantly higher than the normal mucosa of a HC. This may help in predicting recurrence and formulating the follow-up strategy.

An audit of early complications of radical cystectomy using Clavien-Dindo classification.

INTRODUCTION: Despite the major improvements in surgical technique and perioperative care, radical cystectomy (RC) remains a major operative procedure with a significant morbidity and mortality. The present study analyzes the early complications of RC and urinary diversion using a standardized reporting system. MATERIALS AND METHODS: Modified Clavien-Dindo classification was used to retrospectively assess the peri-operative course of 212 patients who had RC with urinary diversion between October 2003 and October 2014 at a single institution. The indications for surgery were muscle invasive urothelial carcinoma, high-grade nonmuscle invasive bladder cancer (BC), and Bacillus Calmette-Guerin-resistant nonmuscle invasive BCs. Data on age, sex, comorbidities, smoking history, American Society of Anaesthesiologists score, and peri-operative complications (up to 90 days) were captured. Statistical analysis was performed using SPSS 20.0 software (Chicago, USA). RESULTS: The mean age was 56.15 ± 10.82. Orthotopic neobladder was created in 113 patients, ileal conduit in 88 patients, and cutaneous ureterostomy in 11 patients. A total of 292 complications were recorded in 136/212 patients. 242 complications (81.16%) occurred in the first 30 days, with the remaining 50 complications (18.83%) occurring thereafter. The rates for overall complication were 64.1%. The most common complications were hematologic (21.6%). Most of the complications were of Grade I and II (22.9% and 48.9%, respectively). Grade IIIa, IIIb, IVa, IVb, and V complications were observed in 10.2%, 8.9%, 3.4%, 2.7%, and 2.7% of the patients, respectively. CONCLUSIONS: RC and urinary diversion are associated with significant morbidity. This audit would help in setting a benchmark for further improvement in the outcome.

Impact of changing trends in technique and learning curve on outcome of hypospadias repair: An experience from tertiary care center.

INTRODUCTION: Apart from numerous clinical factors, surgical experience and technique are important determinants of hypospadias repair outcome. This study was aimed to evaluate the learning curve of hypospadias repair and the impact of changing trends in surgical techniques on the success of primary hypospadias repair. MATERIALS AND METHODS: We retrospectively analyzed of data of 324 patients who underwent primary repair of hypospadias between January 1997 and December 2013 at our center. During the initial 8 years, repairs were performed by multiple 5 different urologists. From 2005 onwards, all procedures were performed by a single urologist. The study cohorts was categorized into three groups; Group I, surgeries performed between 1997-2004 by multiple surgeons, Group II, between 2005-2006 during the initial learning curve of a single surgeon, and Group III, from 2007 onwards after completion of the learning curve of the single surgeon. The groups were compared in respect to surgical techniques, overall success and complications. RESULTS: Overall 296 patients fulfilled the inclusion criterion, 93 (31.4%), 50 (16.9%), and 153 (51.7%) in Group I, II, and III, respectively. Overall success was achieved in 60 (64.5%), 32 (64%), and 128 (83.7%) patients among the three groups respectively (P < 0.01). Nineteen (20.4%), 20 (40%), and 96 (62.7%) patients underwent tubularized incised plate repair in Group I, II, and III, with successful outcome in 12 (63.2%), 15 (75%), and 91 (94.8%) patients, respectively (P < 0.01). The most common complication among all groups was urethrocutaneous fistula, 20 (21.5%) in Group I, 11 (22%) in Group II, and 17 (11.1%) in Group III. CONCLUSION: There is a learning curve for attaining surgical skills in hypospadias surgery. Surgeons dedicated for this surgery provide better results. Tubularized incised plate urethroplasty appear promising in both distal and proximal type hypospadias.

Metabolomics-derived prostate cancer biomarkers: fact or fiction?

Despite continuing research for precise probing and grading of prostate cancer (PC) biomarkers, the indexes lack sensitivity and specificity. To search for PC biomarkers, we used proton nuclear magnetic resonance ((1)H NMR)-derived serum metabolomics. The study comprises 102 serum samples obtained from low-grade (LG, n = 40) and high-grade (HG, n = 30) PC cases and healthy controls (HC, n = 32). (1)H NMR-derived serum data were examined using principal component analysis and orthogonal partial least-squares discriminant analysis. The strength of the model was verified by internal cross-validation using the same samples divided into 70% as training and 30% as test data sets. Receiver operating characteristic (ROC) curve examination was also achieved. Serum metabolomics reveals that four biomarkers (alanine, pyruvate, glycine, and sarcosine) were able to accurately (ROC 0.966) differentiate 90.2% of PC cases with 84.4% sensitivity and 92.9% specificity compared with HC. Similarly, three biomarkers, alanine, pyruvate, and glycine, were able to precisely (ROC 0.978) discriminate 92.9% of LG from HG PC with 92.5% sensitivity and 93.3% specificity. The robustness of these biomarkers was confirmed by prediction of the test data set with >99% diagnostic precision for PC determination. These findings demonstrate that (1)H NMR-based serum metabolomics is a promising approach for probing and grading PC.

Functional genetic variability at promoters of pro-(IL-18) and anti-(IL-10) inflammatory affects their mRNA expression and survival in prostate carcinoma patients: Five year follow-up study.

BACKGROUND: Inflammation is an important hallmark of all cancers. The net inflammatory response is determined by a delicate balance between pro- and anti-inflammatory cytokines, which, in turn, is determined by the genetic make-up. The present study investigates the role of variations in the promoter regions of IL-18 and IL-10 (anti-inflammatory) cytokines on mRNA expressions and survival in prostate cancer (PCa) patients. METHODS: The study was conducted on 584 volunteer males (291 patients of PCa, between 40-80 years of age. Genetic variants were studied by using RFLP and confirmed by probe based method. Expressions of mRNA were evaluated by real-time PCR (Roche light cycler 480). Relative mRNA and fold change gene expressions were analyzed by ([1/2] (ΔCt) ) and (2(-ΔΔCt) ) methods, respectively, and 5 year follow-ups were evaluated by Log-rank (Mantel-Cox) test with Log-rank test for trends. RESULTS: IL-18 mRNA expression was significantly elevated in GG genotypes (at -137) of PCa with relative mRNA expression of 13.95, that is, 8.48 folds higher (P < 0.05) than controls; and showed a significant median survival of 1243 days. The CC genotypes of IL-10 at both loci (-819 T/C and -592C/A) showed 3.63 and 3.52 higher relative mRNA expressions than controls, but poor survival of 984 and 1052 days than TT of 1359 days and AA of 1371 days. CONCLUSIONS: Genetic variants of pro-inflammatory IL-18 which showed higher relative mRNA expressions have better survival. Genetic variants of anti-inflammatory IL-10 with higher relative mRNA expression showed decreased chances of survival.

Genetic variability at promoters of IL-18 (pro-) and IL-10 (anti-) inflammatory gene affects susceptibility and their circulating serum levels: An explorative study of prostate cancer patients in North Indian populations.

Inflammation is an important hallmark of all types of cancers with a well-established role in carcinogenesis. The net inflammatory response is determined by the balance between pro- and anti-inflammatory cytokines, the levels of which may be affected by the genetic make-up. Interleukin (IL)-18, a pro-inflammatory cytokine expressed by various cells including those of the prostate, is a key mediator of anti-cancer immune response. IL-10, an anti-inflammatory cytokine associated with tumour malignancy, causes escape from immune surveillance. This study hypothesizes that genetic variants of IL-18 (-607 C/A and -137 G/T) and IL-10 (-819 C/T and -592 C/A) may influence the circulating levels of these interleukins, thereby generating susceptibility risk to prostate cancer. The study was conducted on 676 subjects (controls and patients of prostate cancer (PCa): 291 each; and 94 patients with benign prostate hypertrophy (BPH)). Genotyping was performed by PCR-RFLP and Real-Time PCR probe-based method. Circulating interleukin levels were obtained by ELISA. Circulating IL-18 levels were significantly elevated in cancer and BPH patients carrying GG genotypes for -137 of IL-18. The trend of circulating IL-18 levels was GG>GC>CC, observed in all groups. The -137 genetic variants of IL-18 significantly associated with PCa risk were GC, CC, and GC+CC, compared to GG (OR: 1.71, 95% CI: 1.20-2.46; OR: 3.35, 95% CI: 2.03-5.53; and OR: 2.05, 95% CI: 1.46-2.87, respectively). A significant association of AA and CA+AA against CC genotype was observed at -607 locus of IL-18 (OR: 0.46, 95%CI: 0.29-0.72; OR: 0.61, 95% CI: 0.41-0.90, respectively). Significantly elevated levels of IL-10 were observed with TT (wild) genotype at -819 of IL-10, compared to the CC (homozygous mutant) genotype in all three groups of subjects. However, no significant association was found between IL-10 promoter genotypes and PCa risk. We conclude that genetic variants of IL-18 and IL-10 promoters influence the circulating levels of these interleukins. Variations at -137 and -607 loci of IL-18 are associated with susceptibility to PCa.

A new classification of inferior vena cava thrombus in renal cell carcinoma could define the need for cardiopulmonary or venovenous bypass.

INTRODUCTION: Although the level of inferior vena cava (IVC) thrombus governs the type of surgical approach, there is no consistency in reporting the levels of IVC thrombus in the literature. This prospective study illustrates a simple three-level classification based on the need for clamping hepatoduodenal ligament and venovenous or cardiopulmonary bypass. MATERIALS AND METHODS: Between January 2010 and June 2014, 30 patients of renal mass with renal vein and/or IVC thrombus were treated after classifying the IVC thrombus into three levels on the basis of need for clamping the hepatoduodenal ligament. After excluding renal vein thrombi, level I was described as thrombus located caudal to the hepatic vein. Level II included all retrohepatic, suprahepatic infradiaphragmatic or supradiaphragmatic thrombi reaching till the right atrium. Atrial thrombi were categorized as level III. Level I and II thrombi were managed without venovenous or cardiopulmonary bypass. Level III thrombus required cardiopulmonary bypass. RESULTS: Of 26 patients with thrombus, 13 had level I thrombus. Of eight cases with level II thrombus, three were retrohepatic, three were suprahepatic infradiaphragmatic and two were supradiaphragmatic. All were removed successfully. Of five patients with level III thrombus, three were operated with cardiopulmonary bypass while the remaining two patients were too sick to be taken up for surgery. The median hepatoduodenal ligament clamp time was 10 min. One patient with level II thrombus had transient liver enzyme elevation. CONCLUSION: Renal vein thrombus should not be categorized as level I thrombus. Level II thrombus, irrespective of its relation to the diaphragm, could be managed without venovenous or cardiopulmonary bypass.