Omega-3 polyunsaturated fatty acids: a modified approach for chemo-prevention of bladder cancer in a rat model and molecular studies of antineoplastic mechanisms.

OBJECTIVES: To test the chemo-preventative effects of omega-3 against bladder cancer (BC) induction in a rat model and its potential antineoplastic mechanisms. MATERIAL AND METHODS: Ninety male Fisher rats were divided into three groups during a 22-week protocol: group 1 (control), group 2 (Placebo + N-butyl-N-4- hydroxybutyl nitrosamine (BBN) for induction of BC and group 3 received omega-3 (1200 mg/kg/day) + BBN. At the end, blood samples and bladder tissues were collected and checked for the presence of malignancy, markers of angiogenesis (VEGF relative gene expression), inflammation (IL-6), proliferation (KI-67 expressions), oxidative stress (serum MDA and serum SOD) and epigenetic control (miRNA-145 level). RESULTS: At the end of the study, 60% and 86.6% rats survived in group 2 and 3 with significant weight loss among rats in group 2 when compared with other groups. In group 2, all rats developed visible bladder lesions of which five and 13 developed squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC). In omega3-treated group, only one developed low grade SCC and one developed high grade non- invasive TCC. Bladders from omega-3-treated rats showed lower expression ofKI-67 (p < 0.05), VEGF (p < 0.001) and IL-6 (p < 0.001) and significant higher expression of mi-RNA (p < 0.001). Also, omega-3-treated group showed statistically significant lower MDA level (p < 0.001). CONCLUSION: Omega-3 inhibits bladder tumor growth in the BBN-induced BC rat model, due to anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties together with epigenetic control.

Risk factors of erectile dysfunction and penile vascular changes after surgical repair of penile fracture.

This study was conducted to determine the preoperative and intraoperative risk factors of ED and the underlying penile vascular abnormalities among patients with penile fracture treated surgically. In all, 180 patients with penile fracture were treated surgically and followed up in one center. None of our patients had ED before the penile trauma and only two of them had risk factors for systemic vascular diseases, such as diabetes mellitus (one patient) and hypertension (one patient). After a mean follow-up of 106 months, 11 patients (6.6%) developed ED, 7 had mild ED and 4 had moderate ED. The main risk factors for subsequent ED were aging, >50 years, and bilateral corporal involvement. Among the 11 patients with ED, color Doppler ultrasonography (CDU) showed normal Doppler indices in 4 (36.4%), veno-occlusive dysfunction in 4 (36.4%) and arterial insufficiency in the remaining 3 (27.2%) patients. CDU assessments from the injured and intact sides were comparable. ED of either a psychological or vascular origin can be encountered as a long-term sequel of surgical treatment of penile fracture. Aging, >50 years, at presentation and bilateral corporal involvement is the main risk factors for subsequent development of ED.

Obesity-PSA relationship: a new formula.

To clinically apply the inverse PSA-body mass index (BMI) correlation and enhance PSA sensitivity in obese cases, a new formula is warranted. An innovated BMI-PSA equation is designed. PSA-BMI adjusted formula (named Hekal's equation): measured total PSA (ng ml(-1)) multiplied by age (years) and divided by BMI of the patient. The formula is applied over a randomly chosen 1000 cases of different PSA, BMI, age and trans-rectal ultrasound biopsy results, the yield of new PSA is correlated with pathology and age-specific PSA adjustment values. Among the 988 cases with complete data, obesity (BMI: 30-35 kg m(-2)) in 236 cases (23.8%) and 79 cases (7.9%) have BMI>35 kg m(-2). Mean PSA was 5.8 ng ml(-1) (s.d.+/-8.4 ng ml(-1)). Cases stratified based on their age (every 10 years). The new equation was applied. Obesity is detected in 33.5 and 43.6% of fifth and sixth decade of life respectively (P=0.02), with low measured PSA values (2.1, 3.8 ng ml(-1), respectively). By such PSA measurement biopsy may be omitted, missing 53.3% of malignant cases. In contrast, PSA adjusted were 4 and 9.3 ng ml(-1) within the same group of patients. With such values, the decision of a biopsy could not be missed for the targeted groups. Specificity and sensitivity of adjusted PSA values at cutoff point 4 ng ml(-1) was 41.7 and 70%, respectively. Based on our results, the new PSA-BMI adjusted formula is reproducible, easy applied formula. With such a formula the higher sensitivity of PSA in obese patients could be achieved. The misleading low PSA in obese cases in the fifth and sixth decade will be corrected.

Can prostate cancer be predilected in BHP patients with elevated serum PSA negative initial sextant biopsy? A multivariate analysis study

Objective To define a predictor of prostate cancer in BPH patients with an intermediate PSA (4.1-10 ng/ml) and a negative initial sextant biopsy. Patients and Methods During 1999; 193 BPH patients with an intermediate PSA (4.1-10 ng/ml) underwent TRUS and sextant biopsy. The patients whose initial biopsies were negative for prostate cancer were re-evaluated by serum PSA every 6 months. A total of 76 patients were subjected to an extended 11-core biopsy in view of: (1) PSA velocity ? 1 ng/ml/year; (2) a PSA rise to 10 ng/ml and (3) suspicious biopsy findings (atypical adenomatous hyperplasia or high-grade prostatic intraepithelial neoplasia). Overall; 160 patients were subjected either to TURP (n=127) or open prostatectomy (n=33). Results On initial sextant biopsy; prostate cancer was diagnosed in 22 out of 193 patients (11.4). The specificity of the sextant biopsy was 91.8and its positive predictive value (PPV) was 61.1. A repeat 11-core biopsy revealed prostate cancer in 11 out of 76 patients (14.5). The specificity of the 11-core biopsy was 95.4and its PPV was 78.6. Three cancers out of 160 (2) were discovered on definitive pathology. The PSA velocity cut-off point at 1.4 ng/ml/year and the PSA density cut-off point at 0.12 were optimal for the prediction of cancer using receiver operating characteristic curves. The multivariate analysis (stepwise logistic regression) revealed that PSA density (p=0.011); PSA velocity (p=0.002) and age (p=0.021) were the most significant predictors of cancer when the data were inserted as a continuous format. The sensitivity; specificity and overall accuracy of the model were 80; 98.7and 95.9; respectively. When the data were re-inserted as a coded format; PSA velocity and PSA density were the only predictors. All the analyzed risk factors (age; PSA; DRE; prostate echogenicity and PSA/TZ index) were excluded from the model. Conclusion PSA velocity and PSA density were the most significant predictors of prostate cancer in BPH patients with an intermediate PSA (4.1-10 ng/ml) and a negative initial sextant biopsy

Ketamine anesthesia for short transurethral urologic procedures.

Ketamine (K) is a good analgesic and anesthetic agent in short procedures, but the associated cardiovascular responses and emergence reactions limit its use. Benzodiazepines have been used to improve recovery with favourable reports for midazolam (M). Methylphenidate (MPH), the mild CNS stimulant, improves behaviour and mental concentration and can be used to improve recovery from K anesthesia. This was tested, alone and in combination with M by a double-blind study in 30 patients subjected to short transurethral urologic procedures. Patients were randomized into 3 equal groups to receive K-MPH, K-M or K-M-MPH. M (7.5 mg) was mixed with K and MPH (20 mg) was given at the end of urologic procedures. Perioperative monitoring included pulse rate, blood pressure, ECG, and plasma catecholamines. Recovery was assessed by a triad VAS and recovery area was calculated. Distribution-free statistics were used to assess intergroup differences of similar variables. Ketamine produced satisfactory anesthesia for short transurethral urologic procedures. Addition of M did not change the cardiovascular responses of K but resulted in smooth recovery with no changes in the recovery scores. MPH did not improve the recovery scores but increased the incidence of vomiting, excessive talking, and limb movements.

Prophylactic maltose tetrapalmitate and bacillus Calmette-Guerin immunotherapy of recurrent superficial bladder tumors: preliminary report.

We divided randomly into 3 groups 47 patients with recurrent superficial transitional cell carcinoma of the bladder: group 1-15 controls who underwent transurethral resection only, group 2-17 patients who underwent transurethral resection and bacillus Calmette-Guerin therapy, and group 3-15 patients treated by transurethral resection and maltose tetrapalmitate. Mean followup was 22.93 months for the controls, 28.0 months for group 2 and 24.4 months for group 3. The recurrence rate per 100 patient-months was 11.34 in the controls, 7.4 in group 2 and 7.19 in group 3, and the recurrence index per month was 0.113, 0.070 and 0.072, respectively. The recurrence rate and recurrence index per month were significantly decreased in the treated groups compared to the controls (p less than 0.005). There was no significant difference between the bacillus Calmette-Guerin and maltose tetrapalmitate groups. Invasive carcinoma developed in 60 per cent of the controls, 29.4 per cent of group 2 and 20 per cent of group 3. Invasive carcinoma required cystectomy or definitive radiotherapy. Bacillus Calmette-Guerin caused irritation of the bladder mucosa, while maltose tetrapalmitate did not have any side effects.

Combined cyclophosphamide chemotherapy and maltose tetrapalmitate immunotherapy in the treatment of transplanted bladder and prostate carcinoma of the rat.

Chemoimmunotherapy in two animal models for urological cancers was studied. The models were Dunning R3327A prostatic carcinoma transplanted s.c. in Fischer X Copenhagen F1 hybrids and a well-differentiated bladder carcinoma transplanted orthotopically in the bladder submucosa of female Fischer rats. Cyclophosphamide, cis-platinum, and Adriamycin were initially used as anticancer chemotherapeutic agents, and the most effective ones were used in combination with maltose tetrapalmitate (MTP), which was used as an immunopotentiator. In the case of prostatic carcinoma, cyclophosphamide was the most effective among the anticancer agents in controlling tumor growth after inoculation of either 10(4) or 10(5) tumor cells. Combination of cyclophosphamide with i.p. MTP delayed tumor take and controlled tumor size more effectively than did either of the treatments given alone. Similar results were obtained in the case of bladder tumor. A combination of cis-platinum with MTP significantly controlled bladder tumor size, and a combination of cyclophosphamide with MTP cured 75% of the rats. The remaining 25% of this group had a small tumor that did not increase in size during the subsequent 2 weeks of observation without treatment. The incidence of metastasis of bladder tumor to lymph nodes and lung was reduced by MTP and cis-platinum and eliminated by cyclophosphamide alone and in combination with MTP. Nonspecific immunity as measured by phytohemagglutinin stimulation of spleen lymphocytes and antitumor immunity as measured by cytotoxicity and macrophage migration inhibition assays were highest in rats subjected to cyclophosphamide and MTP combined therapies.

Orthotopic implantation of primary N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide-induced bladder cancer in bladder submucosa: an animal model for bladder cancer study.

Primary bladder tumors induced in Fischer 344 inbred rats by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide were transplanted in syngeneic rats by the intravesical, s.c., i.v., and orthotopic routes. Attempts were made to establish bladder cancer cell lines in vitro. No success was achieved in transplantation by either the s.c., i.v., or intravesical routes when primary tumor cells were transplanted as cell suspensions. Cell suspensions of primary tumors also failed to grow in culture. However, orthotopic implantation into the bladder submucosa gave 45% success. Tumor fragments obtained from either the primary tumor or its lung metastases resulted in 10.6 and 36% tumor takes, respectively, when implanted s.c. However, after one orthotopic passage in the bladder submucosa, the tumor cells injected as cell suspension grew s.c. in 14% and orthotopically in 79% of the animals. Tumor fragments obtained from orthotopic tumors and implanted s.c. resulted in 15% tumor takes. After the second orthotopic passage, tumor cells could be grown in cultures and orthotopically in 100% of animals. The technique of orthotopic implantation as well as the usefulness of this tumor model for bladder cancer studies are described.