Omer A. Raheem

Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.

Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled‐Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC‐3 cells with 5‐Aza‐CdR reactivated 39 genes (≥ 2‐fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high‐grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7/69), p < 0.0001) and BPH (11.43% (4/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.

Comparison of rates and risk factors for development of osteoporosis and fractures after radical or partial nephrectomy.

OBJECTIVE To examine incidence of and risk factors for development of osteoporosis and fractures in patients who underwent radical nephrectomy (RN) and partial nephrectomy (NSS), as osteoporosis is an important cause of morbidity in chronic kidney disease. METHODS This was a retrospective review of 905 patients (mean age 57.5 years, mean follow-up 6.4 years) who underwent RN or NSS for renal tumors at 2 institutions from July 1987 to June 2007. Demographics, renal function, metabolic parameters, and history of preoperative and postoperative osteoporosis and fractures were recorded. Data were analyzed within subgroups based on treatment (RN vs NSS). Multivariate analysis was conducted to elucidate risk factors for developing osteoporosis following surgery. RESULTS A total of 610 patients underwent RN and 295 underwent NSS. Tumor size (cm) was significantly larger for RN (RN 7.0 vs NSS 3.7, P<.0001). No significant differences were noted with respect to demographic factors and preoperative osteoporosis (RN 8.7% vs NSS 9.5%, P=.785) and fractures (RN 1.7% vs NSS 0.7%, P=.382). Postoperatively, significantly less osteoporosis (NSS 12.5% vs RN 22.6%, P<.001) and fewer fractures (NSS 4.4% vs RN 9.8%, P=.007) developed in the NSS cohort. MVA demonstrated female (OR 1.85, P=.001), Caucasian (OR 2.33, P<.0001), preoperative eGFR<60 mL/min/1.73 m2, (OR=3.02, P<.0001), preoperative metabolic acidosis (OR=4.22, P=.0006), and RN (OR 2.59, P<.0001) were risk factors for developing osteoporosis. CONCLUSIONS Patients undergoing RN had a significantly higher incidence of osteoporosis and fractures compared with a well-matched cohort of patients who underwent NSS. In addition to RN, female gender, Caucasian background, preoperative eGFR<60, and preoperative metabolic acidosis were associated with developing osteoporosis.

A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions

Prostate cancer metastasizes to bone in the majority of patients with advanced disease leading to painfully debilitating fractures, spinal compression and rapid decline. In addition, prostate cancer bone metastases often become resistant to standard therapies including androgen deprivation, radiation and chemotherapy. There are currently few models to elucidate mechanisms of interaction between the bone microenvironment and prostate cancer. It is, thus, essential to develop new patient-derived, orthotopic models. Here we report the development and characterization of PCSD1 (Prostate Cancer San Diego 1), a novel patient-derived intra-femoral xenograft model of prostate bone metastatic cancer that recapitulates mixed osteolytic and osteoblastic lesions.MethodsA femoral bone metastasis of prostate cancer was removed during hemiarthroplasty and transplanted into Rag2-/-;γc-/- mice either intra-femorally or sub-cutaneously. Xenograft tumors that developed were analyzed for prostate cancer biomarker expression using RT-PCR and immunohistochemistry. Osteoblastic, osteolytic and mixed lesion formation was measured using micro-computed tomography (microCT).ResultsPCSD1 cells isolated directly from the patient formed tumors in all mice that were transplanted intra-femorally or sub-cutaneously into Rag2-/-;γc-/- mice. Xenograft tumors expressed human prostate specific antigen (PSA) in RT-PCR and immunohistochemical analyses. PCSD1 tumors also expressed AR, NKX3.1, Keratins 8 and 18, and AMACR. Histologic and microCT analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions. PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture.ConclusionsPCSD1 xenografts tumors were characterized as advanced, luminal epithelial prostate cancer from a bone metastasis using RT-PCR and immunohistochemical biomarker analyses. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely resembled the bone lesions in the patient. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study metastatic disease in the bone and to develop novel therapies for inhibiting prostate cancer growth in the bone-niche.

PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche.

IntroductionProstate cancer bone metastasis occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with therapy resistance and rapid decline. Androgen deprivation therapy (ADT) is standard of care for advanced prostate cancer, however, bone metastatic prostate cancer (PCa) often becomes resistant to ADT. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. Here we report the castrate resistant growth in the bone niche of PCSD1, a patient-derived intra-femoral xenograft model of prostate bone metastatic cancer treated with the anti-androgen, bicalutamide.MethodsPCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2−/−;γc−/− mice intra-femorally (IF) or sub-cutaneously (SC). At 5 weeks post-transplantation mice received bicalutamide or vehicle control for 18 days. Tumor growth of PCSD1 was measured with calipers. PSA expression in PCSD1 xenograft tumors was determined using quantitative RT-PCR and immunohistochemistry. Expression of AR and PSMA, were also determined with qPCR.ResultsPCSD1 xenograft tumor growth capacity was 24 fold greater in the bone (intra-femoral, IF) than in the soft tissue (sub-cutaneous, SC) microenvironment. Treatment with the anti-androgen, bicalutamide, inhibited tumor growth in the sub-cutaneous transplantation site. However, bicalutamide was ineffective in suppressing PCSD1 tumor growth in the bone-niche. Nevertheless, bicalutamide treatment of intra-femoral tumors significantly reduced PSA expression (p < =0.008) and increased AR (p < =0.032) relative to control.ConclusionsPCSD1 tumors were castrate resistant when growing in the bone-niche compared to soft tissue. Bicalutamide had little effect on reducing tumor burden in the bone yet still decreased tumor PSA expression and increased AR expression, thus, this model closely recapitulated castrate-resistant, human prostate cancer bone metastatic disease. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche.

Feasibility of Transrectal Hybrid Natural Orifice Transluminal Endoscopic Surgery (NOTES) Nephrectomy in the Cadaveric Model

OBJECTIVE To examine feasibility of transrectal hybrid natural orifice transluminal endoscopic surgery (NOTES) nephrectomy in human cadavers in the evolution of this technique, as transrectal hybrid NOTES nephrectomy has been demonstrated in the porcine model. METHODS Four hybrid transrectal NOTES nephrectomies were performed on 4 cadavers (3 female/1 male, 2 right/2 left). Pneumoperitoneum was created by periumbilical 12-mm trocar, through which a laparoscope was advanced to obtain intra-abdominal visualization. A 4-cm horizontal incision was made 2-cm above the dentate line and a submucosal tunnel was created in the posterior rectal wall/presacral space. A dual-channel gastroscope was advanced through the submucosal tunnel and retroperitoneum to the level of the kidney using air insufflation. A peritoneal window was created and renal mobilization was completed. A transumbilically applied laparoscopic 45-mm stapler was used to transect the ureter and renal hilum. A specimen entrapment bag was deployed transrectally for specimen extraction, followed by transrectal incision closure. RESULTS Transrectal NOTES nephrectomy was successfully performed in all cases, with intact specimen extraction. Median weight was 77 kg (range 74-85 kg); median body mass index (BMI) was 30.1 kg/m(2) (range 25.6-31.2 kg/m(2)). Mean operative time was 175 minutes (range 150-210 minutes). Median transrectal access time was 36 minutes (range 24-47 minutes). Median dimensions of removed kidneys were length 11.2 cm (range 10-12 cm), width 5 cm (range 4.5-6 cm), and thickness 3.8 cm (range 3-4.5 cm). CONCLUSION Transrectal hybrid NOTES nephrectomy in the cadaver model is feasible with intact specimen extraction and acceptable operative times. Preclinical survival studies are requisite to assess sterility and complications. This approach may be an alternative to transvaginal access.

What Do I Tell Patients About Saw Palmetto for Benign Prostatic Hyperplasia

Saw palmetto is widely used to treat lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Although there is passionate support for herbal and complementary therapies for LUTS, clinical evidence is mixed. Because there is a well-recognized, profound placebo effect in tests of efficacy for agents treating LUTS, it is imperative that all therapies be tested in placebo-controlled trials. This article reviews evidence of the efficacy and safety of saw palmetto for men with LUTS caused by BPH, with particular emphasis on published randomized clinical trials and the upcoming Complementary and Alternative Medicine for Urologic Symptoms (CAMUS) trial.

Clinical predictors of nocturia in the sleep apnea population

Objectives: This study aims to evaluate clinical predictors of nocturia in patients with obstructive sleep apnea (OSA). Materials and Methods: In retrospective manner, a total of 200 patients with OSA were randomly included. Group I contained 100 patients with OSA and no nocturia, and Group II included 100 patients with OSA and nocturia. Bivariate logistic analyses were used to identify variables most likely to contribute to nocturia. Multivariate logistic regression of age, waist circumference, STOP score (Snore, Tired, Obstruction and Pressure), and Apnea–Hypopnea Index (AHI) was performed to evaluate predictors of nocturia. Statistical significance was defined as P < 0.05. Results: Median nocturia episodes were 2.2 in Group II. Patients were younger in Group I, with a mean age of 45 vs 50 years (P = 0.008). Mean BMI of 30 was similar in both groups, but there were more overweight patients in Group II (28% vs 18%). AHI approached significance between groups—18 vs 23 in group I and II, respectively (P = 0.071). In multivariate analysis, age over 70 years and moderate AHI were statistically significant predictors of nocturia (coefficients 0.6 and –0.2 with P = 0.003 and 0.03, respectively). Conclusions: This study identifies age and AHI score as predictors of nocturia in patients with OSA. This may indicate the usefulness of incorporating nocturia in the screening of patients with OSA. Future studies are needed to further evaluate mechanism of action, clinical significance, and effect of treatment for nocturia in patients with OSA.

Partial orchiectomy and testis intratubular germ cell neoplasia: World literature review.

Approximately 5% of all patients diagnosed with testicular cancer may have contralateral intratubular germ cell neoplasia (ITGCN) and may develop contralateral germ cell tumor. Here, we present a historical review and current literature regarding ITGCN and partial orchiectomy. The PubMed world literature search was performed for articles written in the English language. Search terms used were: Partial orchiectomy and ITGCN, with a return of 322 articles. Articles obtained were from the United States, Germany, Denmark and the Netherlands as well as a few case reports from Australia, France, Turkey and Spain. A critical review of the literature was performed. Partial orchiectomy is an option for the management of testicular malignancy in a select group of patients in whom radical orchiectomy is not desirable, including those with a solitary testicle, bilateral concurrent malignancies and a desire for paternity or being independent from androgen supplementation. Reports have demonstrated the feasibility of partial orchiectomy, but there are strict surgical criteria; tumor less than 2 cm in size, maintenance of cold ischemia, meticulous dissection to maintain testicular blood supply and biopsying of adjacent testicular parenchyma to ensure negative margins and absence of concurrent ITGCN. Partial orchiectomy is followed by testicular irradiation of 18-20 Gy; this radiation dose reduces fertility but maintains leydig cell function with androgen independence. Patients with a history of testicular carcinoma have a 5% chance of developing a metachronous contralateral tumor. Partial orchiectomy is a technically challenging procedure that requires close follow-up, but may represent a reasonable management option in selected patients.

Management of pelvic lymphoceles following robot-assisted laparoscopic radical prostatectomy.

Pelvic lymphocele is a potential complication of radical prostatectomy. Although lymphoceles often regress spontaneously, many may progress, precipitate clinical symptoms, and ultimately require intervention. To date, the best treatment of pelvic lymphoceles has not yet been fully defined. However, laparoscopic marsupialization is a definitive and efficacious surgical alternative to percutaneous drainage. It is effective, results in minimal patient morbidity, and allows for rapid recovery. We report our experience with management of clinically symptomatic pelvic lymphoceles following robotic-assisted prostatectomy using laparoscopic marsupialization.

Surgical management of adolescent varicocele: Systematic review of the world literature

Historically, idiopathic varicocele is the most commonly diagnosed pre-pubertal andrological condition. The clinical presentation of varicocele may vary from dull and dragging unilateral or bilateral testicular pain to visible varicose veins lying over the hemiscrotum. Over the last decade, significant strides were made in managing symptomatic varicoceles, particularly minimal invasive procedures and surgeries. We sought to review the published literature in a systematic manner to gain an overview and streamline the presentations and main treatment modalities.