Cyclin D1 as a therapeutic target of renal cell carcinoma- a combined transcriptomics, tissue microarray and molecular docking study from the Kingdom of Saudi Arabia.

BACKGROUND: Renal cell carcinoma (RCC) is a seventh ranked malignancy with poor prognosis. RCC is lethal at metastatic stage as it does not respond to conventional systemic treatments, and there is an urgent need to find out promising novel biomarkers for effective treatment. The goal of this study was to evaluate the biomarkers that can be potential therapeutic target and predict effective inhibitors to treat the metastatic stage of RCC. METHODS: We conducted transcriptomic profiling to identify differentially expressed genes associated with RCC. Molecular pathway analysis was done to identify the canonical pathways and their role in RCC. Tissue microarrays (TMA) based immunohistochemical stains were used to validate the protein expression of cyclinD1 (CCND1) and were scored semi-quantitatively from 0 to 3+ on the basis of absence or presence of staining intensity in the tumor cell. Statistical analysis determined the association of CCND1 expression with RCC. Molecular docking analyses were performed to check the potential of two natural inhibitors, rutin and curcumin to bind CCND1. RESULTS: We detected 1490 significantly expressed genes (1034, upregulated and 456, downregulated) in RCC using cutoff fold change 2 and p value < 0.05. Hes-related family bHLH transcription factor with YRPW motif 1 (HEY1), neuropilin 2 (NRP2), lymphoid enhancer-binding factor 1 (LEF1), and histone cluster 1 H3h (HIST1H3H) were most upregulated while aldolase B, fructose-bisphosphate (ALDOB), solute carrier family 12 (SLC12A1), calbindin 1 (CALB1) were the most down regulated genes in our dataset. Functional analysis revealed Wnt/ß-catenin signaling as the significantly activated canonical pathway (z score = 2.53) involving cyclin D1 (CCND1). CCND1 was overexpressed in transcriptomic studies (FC = 2.26, p value = 0.0047) and TMA results also showed the positive expression of CCND1 in 53 % (73/139) of RCC cases. The ligands - rutin and curcumin bounded with CCND1 with good affinity. CONCLUSION: CCND1 was one of the important upregulated gene identified in microarray and validated by TMA. Docking study showed that CCND1 may act as a potential therapeutic target and its inhibition could focus on the migratory, invasive, and metastatic potential of RCC. Further in vivo and in vitro molecular studies are needed to investigate the therapeutic target potential of CCND1 for RCC treatment.

Effects of varicocele on serum testosterone and changes of testosterone after varicocelectomy: a prospective controlled study.

OBJECTIVE: To examine the hypotheses that clinical varicoceles affect baseline serum total testosterone levels (T) and varicocelectomy improves T. MATERIALS AND METHODS: This prospective, nonrandomized, controlled study involved 4 groups of adult men. Varicocele-infertile treatment group (VIT) included 66 men who underwent varicocelectomy. Thirty-three varicocele-infertile control men (VIC) and 33 varicocele-fertile control men (VFC) were only observed. Normal-control (NC) group included 33 fertile men without varicocele. Varicocele groups were stratified into baseline hypogonadal (T <300 ng/dL) or eugonadal (T ≥300 ng/dL) subgroups. Main outcome measurements were between-group baseline T differences; and within-group T changes at 6- and 12-month follow-ups of men with varicocele. P <.05 was considered significant. RESULTS: Means (standard deviations) of baseline T in VIT, VIC, VFC, and NC were 347.4 (132.1), 339.7 (125.8), 396.6 (164.9), and 504.8 (149.7) ng/dL, respectively. The baseline T levels of varicocele groups were comparable, whereas they were significantly low compared with NC group. At 6-month follow-up, VIT demonstrated significant T improvements (mean change = 44.7 ng/dL; 12.9%; P <.0001). T changes were more remarkable among baseline hypogonadals (mean change = 93.7 ng/dL; 40.1%; P <.0001) compared with eugonadals (mean change = 8.6 ng/dL; 2.01%; P = .1223). These improvements were persistent at 12-month follow-up. Contrariwise, VIC and VFC exhibited nonsignificant T changes. Postvaricocelectomy T changes correlated significantly and inversely with baseline T (r = -0.689; P <.0001). This correlation was stronger and more significant among hypogonadals (r = -0.528; P = .004) than eugonadals (r = -0.400; P = .013). T improvements also exhibited significant positive correlations with preoperative and postoperative sperm concentrations. CONCLUSION: Baseline T was significantly low in men with varicocele compared with normal men. Varicocelectomy yielded significant T improvements among hypogonadal men but insignificant changes in eugonadals. T changes correlated strongly and significantly with baseline T and sperm concentrations.

Gleason grading of prostate cancer in needle core biopsies: a comparison of general and urologic pathologists.

BACKGROUND AND OBJECTIVES: The Gleason grading of prostate carcinoma (PCa) in needle core biopsies is a major determinant used in management planning. The objective of this study was to evaluate the concordance between general pathologists Gleason grading and that of a urologic pathologist in our community. DESIGN AND SETTING: Retrospective review conducted at three tertiary care hospitals in Jeddah and Riyadh for all prostatic biopsies with carcinoma from January 2002 to January 2011. METHODS: Gleason scores assigned by the original pathologist were compared with that of the reviewing urologic pathologists. Biopsies were originally obtained and diagnosed at different referring hospitals and independent laboratories. The kappa test was used to evaluate agreement between the original and review scores. RESULTS: For 212 biopsies the exact concordance of the Gleason score assigned by the original pathologist and the reviewer was 38.7% (82/212). However, when grouped into the main four-score categories of 2-4, 5-6, 7, and 8 or greater, disagreement was noted in 88 (41.5%) biopsies; 87 were upgraded and 1 was downgraded on review. When grouped into two-score categories of low grade (≤6) and high grade (≥7), disagreement was noted in 32 (15%) of the biopsies. CONCLUSION: Gleason grade score shows that there was only slight to fair agreement between outside and review scoring (kappa=0.43). When using only low versus high grade categorization, there was good agreement (kappa=0.69). Almost all of the cases with score disagreement were upgraded on review.

Photoselective vaporization of the prostate using GreenLight 120-W lithium triborate laser to treat symptomatic benign prostatic hyperplasia: A single-centre prospective study.

OBJECTIVE: We evaluated the safety and efficacy of photoselective vaporization of the prostate (PVP) using GreenLight 120-W lithium triborate (LBO) laser to treat symptomatic small-to-medium sized benign prostatic hyperplasia (BPH). METHODS: This prospective non-controlled observational study included symptomatic BPH men ≥50 years with international prostate symptom score (IPSS) ≥14, prostate volume (PV) ≤80 cc and maximum flow rate (Q-max) ≤15 mL/s. PVP was performed using the GreenLight 120-W LBO laser machine. Patients were assessed at baseline and postoperatively at discharge, 2 weeks, and 3, 6 and 12 months. We measured changes in IPSS, PV, PSA, Q-max, post-void residual (PVR), hemoglobin (Hb), serum sodium (Na+) and reported complications. Statistical significance was p < 0.05. RESULTS: The study included 103 men with mean age of 67 (±standard deviation)±9.7 years. Thirty patients were on indwelling urethral catheters for refractory urinary retention and 12 on ongoing anticoagulants. The mean baseline IPSS, PV, PSA, Q-max and PVR parameters significantly improved at follow-up (p < 0.001; each). Mean measurements at baseline versus at six months were: IPSS 25.6 ± 4.2 vs. 7.4±2.3; PV 44.6 ± 9.2 vs. 21.6 ± 6.3 cc (51.6% reduction); Q-max 5.8 ± 3.4 vs. 20.4 ± 4.8 mL/s; PVR 110 ± 40 vs. 35 ± 9 cc. Mean baseline Hb and serum Na+ declined non-significantly (p > 0.05) at discharge and at 2 weeks. No patient needed a blood transfusion. Secondary procedures were needed in 2 patients for urethral and bladder neck strictures. The re-treatment rate for residual adenoma was 0.97%. CONCLUSION: PVP using the GreenLight 120-W LBO laser to treat small-to-medium sized symptomatic BPH demonstrated significant improvements in efficacy parameters and high safety profile within 12 months of follow-up. The procedure entails good hemostasis with minimal blood loss even in patients receiving ongoing anticoagulants.

Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial.

BACKGROUND: Randomized controlled trials (RCTs) addressing varicocele treatment are scarce and have conflicting outcomes. OBJECTIVE: To determine whether varicocele treatment is superior or inferior to no treatment in male infertility from an evidence-based perspective. DESIGN, SETTING, AND PARTICIPANTS: A prospective, nonmasked, parallel-group RCT with a one-to-one concealed-to-random allocation was conducted at the authors' institution from February 2006 to October 2009. Married men 20-39 yr of age who had experience infertility ≥1 yr, had palpable varicoceles, and with at least one impaired semen parameter (sperm concentration <20 million/ml, progressive motility <50%, or normal morphology <30%) were eligible. Exclusions included subclinical or recurrent varicoceles, normal semen parameters, and azoospermia. Sample size analysis suggested 68 participants per arm. INTERVENTION: Participants were randomly allocated to observation (the control arm [CA]) or subinguinal microsurgical varicocelectomy (the treatment arm [TA]). Semen analyses were obtained at baseline (three analyses) and at follow-up months 3, 6, 9, and 12. The mean of each sperm parameter at baseline and follow-ups was determined. MEASUREMENTS: We measured the spontaneous pregnancy rate (the primary outcome), changes from baseline in mean semen parameters, and the occurrence of adverse events (AE-the secondary outcomes) during 12-mo follow-up; p<0.05 was considered significant. RESULTS AND LIMITATIONS: Analysis included 145 participants (CA: n=72; TA: n=73), with a mean age plus or minus standard deviation of 29.3±5.7 in the CA and 28.4±5.7 in the TA (p=0.34). Baseline characteristics in both arms were comparable. Spontaneous pregnancy was achieved in 13.9% (CA) versus 32.9% (TA), with an odds ratio (OR) of 3.04 (95% confidence interval [CI], 1.33-6.95) and a number needed to treat (NNT) of 5.27 patients (95% CI, 1.55-8.99). In CA within-arm analysis, none of semen parameters revealed significant changes from baseline (sperm concentration [p=0.18], progressive motility [p=0.29], and normal morphology [p=0.05]). Conversely, in TA within-arm analysis, the mean of all semen parameters improved significantly in follow-up versus baseline (p<0.0001). In between-arm analysis, all semen parameters improved significantly in the TA versus CA (p<0.0001). No AEs were reported. CONCLUSIONS: Our RCT provided level 1b evidence of the superiority of varicocelectomy over observation in infertile men with palpable varicoceles and impaired semen quality, with increased odds of spontaneous pregnancy and improvements in semen characteristics within 1-yr of follow-up.

The clinicopathologic patterns of prostatic diseases and prostate cancer in Saudi patients.

OBJECTIVE: To determine the clinicopathologic patterns of prostatic diseases in Saudi patients, with special emphasis on prostate cancer (PCa). METHODS: The records of patients who underwent histopathological examinations of their prostatic specimens in King Abdulaziz University Medical City and King Faisal Specialist Hospital, Jeddah, Kingdom of Saudi Arabia, between June 2003 and June 2008 were reviewed retrospectively. The age, indications for biopsy, histological diagnosis, and Gleason grading of cancer patients, were studied. RESULTS: The study included 330 patients aged 37-100 years (median=68). Specimens included 233 transrectal ultrasound (TRUS) biopsies, 85 transurethral resection of the prostate (TURP), 8 simple prostatectomies, 3 radical prostatectomies, and one radical cystoprostatectomy. Indications for TRUS guided biopsy in PCa patients were elevated prostate specific antigen (PSA) (85.2%), abnormal digital rectal examination (5.5%) or both (9.3%). Prostate specific antigen values <4 ng/ml were found in 13.6% of PCa patients. Among others, adenocarcinoma was found in 28.5%, benign prostatic hyperplasia (BPH) alone in 43.3%, BPH with inflammation in 20.3% and inflammation alone in 4.2%. In specimens of TURP or simple prostatectomy for apparently benign disease, incidental PCa was detected in 14/93 (15%). The Gleason sum of > or = 6 was found in 92.8% of patients. CONCLUSION: The incidence of prostate cancer in Saudi Arabia is low compared to the western countries. However, incidental PCa detected in presumed benign disease appears to be rising. Further future studies addressing this issue are needed to confirm the potential rising trend, and its possible etiology. Our findings support the recommendations to lower the PSA cutoff value for prostatic biopsy to 2.5 rather than 4 ng/ml.

Shock wave lithotripsy in patients with renal calculi.

OBJECTIVE: To demonstrate the efficacy of shock wave lithotripsy (SWL) in the primary treatment of 1647 patients with renal calculi using a Dornier Doli U/50 lithotripter. METHODS: One thousand and six hundred forty-seven patients underwent SWL as day-cases at King Abdulaziz University Hospital in Jeddah, Saudi Arabia between October 2001 and July 2007, using intravenous sedation (Pethidine 1mg/kg and Midazolam 5-10mg) for analgesia in 85.5% of the patients. The treatment outcome of 2241 renal calculi was analyzed and stratified according to the size and the site of the stones. Recorded data included shock waves intensity, number of shocks, treatment time, analgesia, stone related factors such as size, site, number, nature, composition, and any related complications. The stones were grouped into 5 groups according to the largest stone size in the kidney. Patients were followed up for 6-18 months, mean of 13 months. RESULTS: Complete clearance of the stones occurred in 2154 kidneys (89.5%). At 3-months follow up. The overall re-treatment rate was 57.2% and for each group it was 132 (23.5%) for Group I, 254 (36.1%) for Gourp II, 473 (85.5%) for Group III, 278 (100%) for Group IV and 147 100% for Group V. Treatment failed in 87 patients with stone size of 20-29mm in 57 patients, and in 30 patients with stone size of 30-39mm. Fifty-six were solitary pelvic stones treated with ureteroscopy, while 31 were calyceal stones treated by other modalities such as percutaneousnephro-lithotomy. The most common complication was pyelonephritis with or without obstruction. CONCLUSION: Shock wave lithotripsy treatment was a successful primary management of renal stones of variable sizes in 89.5% of the treated kidneys.