Shmuel Cytron

Human CTL Epitopes Prostatic Acid Phosphatase-3 and Six-Transmembrane Epithelial Antigen of Prostate-3 as Candidates for Prostate Cancer Immunotherapy

Specific immunotherapy of prostate cancer may be an alternative or be complementary to other approaches for treatment of recurrent or metastasized disease. This study aims at identifying and characterizing prostate cancer-associated peptides capable of eliciting specific CTL responses in vivo. Evaluation of peptide-induced CTL activity in vitro was done following immunization of HLA-A2 transgenic (HHD) mice. An in vivo tumor rejection was tested by adoptive transfer of HHD immune lymphocytes to nude mice bearing human tumors. To confirm the existence of peptide-specific CTL precursors in human, lymphocytes from healthy and prostate cancer individuals were stimulated in vitro in the presence of these peptides and CTL activities were assayed. Two novel immunogenic peptides derived from overexpressed prostate antigens, prostatic acid phosphatase (PAP) and six-transmembrane epithelial antigen of prostate (STEAP), were identified; these peptides were designated PAP-3 and STEAP-3. Peptide-specific CTLs lysed HLA-A2.1+ LNCaP cells and inhibited tumor growth on adoptive immunotherapy. Furthermore, peptide-primed human lymphocytes derived from healthy and prostate cancer individuals lysed peptide-pulsed T2 cells and HLA-A2.1+ LNCaP cells. Based on the results presented herein, PAP-3 and STEAP-3 are naturally processed CTL epitopes possessing anti-prostate cancer reactivity in vivo and therefore may constitute vaccine candidates to be investigated in clinical trials.

Color Doppler sonography: its real role in the evaluation of children with highly suspected testicular torsion

Abstract. The goal of this study was to assess the reliability of color Doppler imaging in boys who presented with acute scrotal pain and borderline clinical findings. The second purpose of the study was to evaluate the potential change in diagnostic accuracy as a result of employing radiological staff with varying levels of experience. Thirty-eight consecutive patients with highly suspected testicular torsion were enrolled in this prospective study. Clinical examination was followed by color Doppler US (7.5-MHz transducer ). The staff of radiologists included four residents and three experienced radiologists. All patients underwent surgical exploration. All original reports of residents were reviewed by experienced radiologists and sensitivity with specificity were determined and compared. Original interpretations of color Doppler imaging yielded sensitivity of 77.8% and specificity of 85%, which changed after review to 88.9 and 90%, respectively. Clinical assessment was accurate only in 47.4%. Agreement between original and retrospective color Doppler diagnosis was obtained in 20 of 23 (86.9%) reviewed cases. Color Doppler US may prevent unnecessary surgery in the cases with conclusive normal and increased blood flow. In all other situations scrotal exploration should be performed.

Active Rectal Wall Protection Using Direct Transperineal Cryo-Needles for Histologically Proven Prostate Adenocarcinomas

INTRODUCTION AND OBJECTIVES Cryosurgical ablation of the prostate is a promising new modality for the treatment localized prostate cancer. However, better protection of the rectal wall during cryoablation of the peripheral zone of the prostate (PZP) may permit deeper freezing of the PZP and for longer time, rendering the procedure safer and more effective. We present a modified cryoablation technique of the prostate using the SeedNet system (Galil Medical, Uniondale, NY, USA), in which the rectum is actively protected during cryoablation. PATIENTS AND METHODS During a 12-month period, 31 patients (32 procedures) with localized and histologically proven prostate adenocarcinoma of various stages and grades were treated in this fashion. We evaluated the feasibility of a new method of active rectal wall protection during cryoablation of the prostate. Fourteen ultrathin, 17-gauge, probes, cryo-needles were percutaneously introduced under transrectal ultrasound (TRUS) guidance into the prostate. Peripheral region of the prostate and the area between the prostate and rectal wall were real time monitored for temperature changes. Two cryo-needles placed between the prostate and rectal wall served for active warming using the thawing mode when the temperatures dropped to approximately 0 degrees C, and rectal lumen washing with hot water (+40 degrees C) when the temperature reading dropped further to -8 degrees C or -10 degrees C. RESULTS Active protection of the rectal wall using the cryosurgical modification of active thawing by the two additional cryo-needles placed in the space between the prostate and rectum, while freezing the prostate was performed in every patient, thus enabling us a safe generation of an iceball at the peripheral zone of the prostate with an average temperature ranging from -35 degrees C to -60 degrees C, for 10 min per cycle. During a follow-up of up to 18 months (mean 13.2 months) there was a PSA decrease to values equal or less than 0.5ng/ml in 25 patients (80.6%) and to values equal or less than 1 ng/ml in 21 patients (67.7%). There were no cases of rectal injury or postoperative rectal pain in any of these patients. CONCLUSIONS This new cryotechnique of active rectal wall protection during cryotherapy of the prostate was safe and simple to perform, resulting in no rectal injuries. It was also very effective in ablating the prostate gland, as expressed by the low follow up PSA values.

Interstitial biodegradable balloon for reduced rectal dose during prostate radiotherapy: results of a virtual planning investigation based on the pre- and post-implant imaging data of an international multicenter study.

PURPOSE To evaluate dose reduction caused by the implantation of an interstitial inflatable and biodegradable balloon device aiming to achieve lower rectal doses with virtual 3D conformal external beam radiation treatment. MATERIALS AND METHODS An inflatable balloon device was placed, interstitially and under transrectal ultrasound guidance, into the rectal-prostate interspace prior treatment initiation of 26 patients with localized prostate cancer, who elected to be treated with radiotherapy (3D CRT or IMRT). The pre- and post-implant CT imaging data of twenty two patients were collected (44 images) for the purpose of the 3D conformal virtual planning presented herein. RESULTS The dorsal prostate-ventral rectal wall separation resulted in an average reduction of the rectal V70% by 55.3% (± 16.8%), V80% by 64.0% (± 17.7%), V90% by 72.0% (± 17.1%), and V100% by 82.3% (± 24.1%). In parallel, rectal D2 ml and D0.1 ml were reduced by 15.8% (± 11.4%) and 3.9% (± 6.4%), respectively. CONCLUSIONS Insertion of the biodegradable balloon into the prostate-rectum interspace is similar to other published invasive procedures. In this virtual dose distribution analysis, the balloon insertion resulted in a remarkable reduction of rectal volume exposed to high radiation doses. This effect has the potential to keep the rectal dose lower especially when higher than usual prostate dose escalation protocols or hypo-fractionated regimes are used. Further prospective clinical investigations on larger cohorts and more conformal radiation techniques will be necessary to define the clinical advantage of the biodegradable interstitial tissue separation device.

Laparoscopic laser soldering for repair of ureteropelvic junction obstruction in the porcine model.

BACKGROUND AND PURPOSE Laparoscopic pyeloplasty is used for the repair of ureteropelvic junction (UPJ) obstruction. Our objective was to introduce laser soldering to this procedure. MATERIALS AND METHODS We developed a system based on a CO2 laser, an infrared detector, and two infrared transmitting optical fibers to obtain temperature-controlled laser soldering of cuts in tissues. The system was used for laparoscopic soldering of incisions in the kidneys of pigs. RESULTS We carried out laparoscopic pyeloplasty successfully in a porcine model using fiberoptic laser soldering. Laparoscopic laser soldering was found to be faster than suturing. It was easier to use and provided watertight bonding. CONCLUSIONS This technique will be useful in pyeloplasty as well as other laparoscopic surgical procedures.

Increased incidence of diabetes mellitus in the patients with transitional cell carcinoma of urinary bladder

The progression of bladder cancer to invasive disease is highly dependent on its ability to penetrate basement membrane of urothelium. Studies on diabetic nephropathy have shown a reduction in proteoglycan content of the glomerular basement membrane. Based on the well-known fact that proteoglycans are one of the main components of basement membrane and extracellular matrix we assessed the relationship between diabetes mellitus, bladder cancer incidence and its behavior. These studies include 252 patients with microscopically confirmed transitional cell carcinoma of bladder, and 549 patients with other urological disorders who served as controls. The prevalence of diabetes mellitus in each group was assessed. The group of patients suffering from transitional cell carcinoma was divided according to etiological risk factors such as cigarette smoking, diabetes and patients that were non-smokers and did not suffer from diabetes mellitus. We assessed the features of bladder cancer behavior in each group. Logistic regression model estimation for statistical analysis was used, with transitional cell carcinoma as a dependent binary variable and age, sexes smoking and diabetes as independent variables. Statistical significance was considered at two levels: p <-0.001 and p <-0.05. Odds ratio (OR) adjusted to age, sex, cigarette smoking, diabetes mellitus and 95% Confidence Interval (CI) were calculated for TCC. In the TCC group 22.2% of the patients suffered from diabetes mellitus. In the control group 10.38% suffered from diabetes mellitus. Logistic regression analysis, OR and 95% CI showed a statistically significant relationship between diabetes and TCC. These data are comparable only with smoking (OR -2.3; 95% CI -1.6 –3.5 and OR-1.58; 95% CI -1.08 –2.4 correspondingly). Based on these data we suggest that diabetes mellitus may be considered an etiological risk factor for bladder cancer development.

Effect of short-term dutasteride therapy on prostate vascularity in patients with benign prostatic hyperplasia: a pilot study.

OBJECTIVES In this study we assessed the possible influence of dutasteride (types 1 and 2 isoenzymes of 5-alpha-reductase inhibitors) on prostate tissue vascularity. We also attempted to evaluate whether preoperative treatment with dutasteride could help to avoid excessive bleeding in patients undergoing transurethral resection of prostate (TUR-P). METHODS This pilot study has 3 phases. All patients enrolled in the study had a prostate-specific antigen < 4 ng/mL and normal digital rectal examination. In the first phase we included 10 patients with benign prostatic hyperplasia treated with alpha-blockers. The end point of this phase was to choose the preset that could exclude noise signals and be reproducible. In the second phase, we included 32 patients in whom color Doppler sonography (CDS) was performed before and 6 weeks after treatment with 0.5 mg dutasteride per day. We counted every discrete color Doppler signal (CD-spot). To compare the CDS data, we used the Student t test, and P < .05 was considered significant. Afterward, 46 patients joined the third phase. Patients were assigned to the control and study groups according to sequentially numbered sealed envelopes. Patients in the study group received 0.5 mg dutasteride 6 weeks before TUR-P. RESULTS In the first phase: color Doppler preset with pulse repetition frequency of 0.3 kHz was chosen as the most sensible. In the second phase, a significant decline in CD-spots count was detected in 23 (72%) patients (P < .05) and was more distinctive in the periurethral zone. In the third phase, only 43 of the patients continued with TUR-P (in 3 patients, voiding symptoms improved). Operating time and volume of irrigation fluid were significantly different (50.55 minutes/42.65 minutes, P = .014; 8.03/13.10 L, P = .047). CONCLUSIONS Six weeks of dutasteride treatment may reduce prostate tissue vascularity in the periurethral area proximal to the verumontanum. The third phase of our study confirmed that preoperative treatment with dutasteride could improve operative performance and avoid TUR syndrome.

Using gray-scale and two different techniques of color Doppler sonography to detect prostate cancer

OBJECTIVES To correlate the findings of prostate color Doppler sonography (CDS) with those of site-specific transrectal ultrasound-guided core biopsy; to evaluate the significance of two different color presets in detecting prostate cancer compared with gray-scale transrectal ultrasonography; and to compare the accuracy of conventional gray-scale transrectal ultrasound (CGS)-guided biopsy with CDS-guided biopsy. METHODS Seventy patients were enrolled in this prospective study. CDS was performed before biopsy. Two color presets were used: CDS-1 (high sensitivity) and CDS-2 (high specificity). The color flow was graded on a scale from 0 to 2+. At the completion of the color grading, color maps were constructed. In each case, CDS-guided biopsy was performed followed by CGS-guided biopsy (six sextant biopsies and focal lesional biopsies). RESULTS The cancer detection rate was 33%, 31%, and 27% for CGS-guided biopsy, CDS-1, and CDS-2, respectively. CDS-1 was more sensitive than CDS-2 (81% versus 60%) but both presets had similar specificities (79% versus 82%). CGS-guided biopsy yielded a sensitivity of 90%, a specificity of 38%, and a positive and negative predictive value of 34% and 83%, respectively. A biopsy strategy combining hypoechoicity with increased color flow increased the specificity to 97%, positive predictive value to 68%, and negative predictive value to 84%, but its sensitivity was low (18%). CONCLUSIONS Our experience suggests that low-velocity, high-sensitivity color is superior to all other CDS settings. The presence of focal peripheral zone hypervascularity at CDS is associated with a high likelihood of prostate cancer. However, only a combination of CDS guidance with six sextant biopsies may achieve maximal sensitivity and specificity.

Fiberoptic infrared spectroscopy: a novel tool for the analysis of urine and urinary salts in situ and in real time.

OBJECTIVES To use infrared fiberoptic spectroscopy for the analysis of urinary salts in real time and with no sample processing; and to assess the practical role of this method for the quantitative measurement of the composition of urine and for the diagnosis of urolithiasis in patients. METHODS Urine samples were obtained from two groups of patients: 24 patients with stone formation after shock wave lithotripsy and 24 normal subjects of similar age. Infrared absorption measurements were performed in real time, using infrared transmitting silver halide fibers. The absorption data were compared with the infrared absorption spectra of aqueous solutions prepared in our laboratory, with known concentrations of known urinary salts. The results were used for the study of the chemical composition of these salts in the urine samples and for a quantitative analysis of the concentration of the salts. RESULTS We determined the composition of the stones in 20 of the 24 patients on the basis of the characteristic absorption peaks for the oxalates, carbonates, urates, and phosphates observed in their urinary samples. Using the method mentioned above, we found the concentration of different salts in urine with an average error of 20%. CONCLUSIONS Fiberoptic infrared spectroscopy could be used as a new diagnostic tool for detecting different urinary salts in urine, finding their chemical composition, and determining their concentrations, without any sample preparation.

Transrectal Ultrasonography-Guided Injection of Long-Acting Steroids in the Treatment of Recurrent/Resistant Anastomotic Stenosis After Radical Prostatectomy

BACKGROUND AND PURPOSE Different techniques have been used for the treatment of patients with anastomotic stenosis after radical prostatectomy (RP). In this retrospective study, we analyzed our experience with urethral dilation and consecutive transrectal ultrasonography (TRUS)-guided injections of long-acting steroids in the scar area. PATIENTS AND METHODS We reviewed the records of patients who underwent RP in our department from 2002 to 2010 and presented to the outpatient clinics with symptomatic anastomotic stenosis. Patients were treated with: Urethral dilation, cold knife (CK) urethrotomy, transurethral resection (TUR) of stenosis and dilation/resection of the strictures with consecutive TRUS-guided injection of a long-acting steroid (dilation+TRUS-steroids). Patients remained under follow-up, which included the assessment of voiding and continence patterns, as well as cystourethroscopy. RESULTS In 32 (10.8%) patients, symptomatic anastomotic stenosis was diagnosed. Initial urethral dilation succeeded in only 3 (10.3%) patients; thus, 29 remained with recurrent/resistant stenosis. Urethral dilation+TRUS-steroids was performed in 14 patients, while 8 patients underwent CK and in 7 TUR was performed. Patients in the dilation+TRUS-steroids group had lower re-treatment rates, and none of these patients became incontinent. Patients in the TUR group needed no re-treatment; however, they had the highest incontinence rate (57.1%). As a result, the highest efficiency quotient was in the dilation+TRUS-steroids with the lowest in the TUR group. CONCLUSION Urethral dilation with consecutive TRUS-guided injections of steroids has the highest efficiency quotient and can be performed under local anesthesia with a low risk of incontinence.