Hisham M. Hammouda

Acid Ceramidase Upregulation in Prostate Cancer Cells Confers Resistance to Radiation: AC Inhibition, a Potential Radiosensitizer

Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

Tubularized Incised Plate Repair: Functional Outcome After Intermediate Followup

PURPOSE We describe the functional outcome following tubularized incised plate repair of hypospadias in toilet trained children after an intermediate followup. MATERIALS AND METHODS Children were included in this study only if they were toilet trained and had flow rate data not less than 6 months after primary tubularized incised plate hypospadias repair or 2 months after any secondary procedure to correct complications. Uroflow data (peak flow, voided volume and post-void residuals) were analyzed and plotted on previously determined age-volume dependent nomograms. RESULTS Of the 48 boys 39 required no secondary procedures, while 9 secondary fistula closures were performed in 2, meatotomy in 2 and dilation in 5. After either primary (26) or secondary (7) procedures 33 of the 48 patients (68.7%) had normal peak flow rate and 15 (31.3%) had low peak flow rate. Of the 48 patients 46 had post-void residual urine less than 10% of voided volume. CONCLUSIONS Most children will void efficiently with no straining and no post-void residual (1/2) to 4 years after tubularized incised plate hypospadias repair. Of our patients 68.7% have normal peak flow rate. Intermediate followup of larger series and followup at puberty are recommended to resolve the debate concerning the long-term functional outcome of tubularized incised plate hypospadias repair.

Management of calculus anuria in children: experience of 54 cases.

OBJECTIVE To evaluate the outcome of different treatment plans for calculus anuria in children. PATIENTS AND METHODS Patients were subdivided into three groups, A, B and C. Group A included patients who were critically ill, had serum creatinine> or =3.5mg/dl, blood urea> or =100mg/dl, serum potassium> or =7meq/l and/or blood pH< or =7.1; and they were treated initially by peritoneal dialysis. Patients in groups B and C were stable with serum creatinine<3.5mg/dl, blood urea<100mg/dl, serum potassium level<7meq/l and blood pH>7.1. In group B, the obstructing stone could not be localized, and they were treated either by percutaneous nephrostomy or JJ stent. In group C, stone level was confidently determined and patients were treated by open surgery. RESULTS Fifty-four patients were included. All patients regained normal serum creatinine levels within 72-120h. Overall complication rate in groups A and C was 26% and 13%, respectively. In group B, overall complication rate was 66% for percutaneous nephrostomy and 50% for internal stent. CONCLUSIONS Urinary diversion in children is associated with a high complication rate while dialysis is highly effective in children. Formal surgery in compensated children is associated with a low complication rate with good outcome and early recovery.

Percutaneous nephrolithotomy in children: A preliminary report.

Objectives: The recurrence of pediatric nephrolithiasis, the morbidity of repeated open surgical treatment as well as our experience in percutaneous nephrolithotomy (PNL) in adult patients, all derived us to shift to PNL for managing renal stones >1.5 cm in pediatric patients. Our aim of this study is to evaluate the safety and efficacy of PNL in pediatric patients. Materials and Methods: During the period of the month between May 2011 and April 2013, 38 children (47 renal units) underwent PNL for renal stones 1.5-5 cm in length. Patient demographics, stone characteristics, and clinical outcome were prospectively studied. Data of those who underwent conventional and tubeless PNL were compared. Median follow-up period was 12 months (range: 6-24). Results: The median age at presentation was 8-year (range: 3-12). The operative time ranged from 30 to 120 min (median 90). Overall stone clearance rate was 91.5% after single PNL. The median hospital stay was 3 days. Auxiliary procedures were successful for the remaining 4 patients (nephroscopic clearance in one and shockwave lithotripsy in 3). Tubeless PNL was performed in 17 renal units with a comparable outcome to conventional ones. The perioperative complications were noted in 5/47 (10.6%) of all procedures (Clavien Grade II in 4 and Clavien Grade IIIa in 1) and were managed conservatively. Conclusions: Percutaneous nephrolithotomy for renal stones in pediatric patients is safe and feasible if performed by a well-experienced endourologist. Tubeless PNL is a better choice for children.

Laparoscopic versus open orchiopexy in the management of peeping testis: A multi-institutional prospective randomized study

OBJECTIVE Peeping testis is an inconsistently palpable/seen undescended testis that migrates back and forth at the internal inguinal ring. Both open and laparoscopic orchiopexy are effective forms of management. The present study aimed to evaluate the efficacy and safety of both approaches. PATIENTS AND METHODS Between September 2007 and January 2012, 46 peeping inguinal testes were randomly treated with either open (25 cases) or laparoscopic (21 cases) orchiopexy procedures. Spermatic vessels were preserved for all cases. Operative details, postoperative morbidity and final testicular site and size were recorded. RESULTS The median age of the children was 2.5 years (range 0.5-12.0). The follow-up period ranged from 1.0 to 5.5 years. Of these testes, 20 in the open surgery group and 19 in the laparoscopic group maintained correct intrascrotal position (P = 0.428). Re-do orchiopexy was indicated for two cases in the surgical group (P = 0.493). No cases of testicular atrophy or hernia were encountered. CONCLUSION Open and laparoscopic orchiopexy procedures for peeping testes are fairly comparable. However, laparoscopy is relatively more effective, as two re-do orchiopexies were required in the open surgical group.

Bcl-XL and Bcl-2 expression in bilharzial squamous cell carcinoma of the urinary bladder: which protein is prognostic?

OBJECTIVES Bcl-2 and Bcl-XL are the most important antiapoptotic members of the Bcl-2 family frequently overexpressed in bladder cancer. Overexpression of Bcl-XL bilharzial-related bladder cancer was associated with tumor progression. However, the negative prognostic value of Bcl-2 expression is still questionable. This work studied the expression of Bcl-XL and Bcl-2 immunohistochemically in bilharzial-related squamous cell carcinoma of the urinary bladder and determined their prognostic value in relation to recurrence after radical cystectomy. METHODS A total of 72 patients with muscle-invasive bilharzial squamous cell carcinoma of the urinary bladder underwent radical cystectomy at our institution. The specimens were examined immunohistochemically for Bcl-XL and Bcl-2 expression. The patients were followed up for 3 years or until recurrence. The expression of Bcl-XL and Bcl-2 were related to the other prognostic indicators and patient survival. RESULTS The expressions of both Bcl-2 and Bcl-XL were significantly different according to the grade of malignancy. Bcl-XL expression was significantly related to tumor recurrence, but Bcl-2 expression was not. CONCLUSIONS To our knowledge, the present study is the first report of a negative prognostic value for Bcl-XL in bilharzial squamous cell carcinoma of the urinary bladder. However, this is another negative report on the prognostic value of bcl-2 in bilharzial bladder tumors.

New concept in urethral advancement for anterior hypospadias

OBJECTIVE We report on our experience with urethral mobilization and advancement as a treatment for anterior hypospadias. PATIENTS AND METHODS From January 2004 to March 2007, 55 out of 160 children with anterior hypospadias were managed by urethral mobilization and advancement; 46 had a mean follow-up period of 25 months (range 6-38) and are the subjects of this report. Their ages ranged from 2.5 to 12 years with mean age 4.5 years. The dissection began proximally in the avascular plane above the tunica albuginea covering each corpus cavernosum medially until reaching beneath the corpus spongiosum up to the hypospadiac meatus. Tension-free urethral anastomosis was achieved. The ventral glans was incised deeply at the interballanitic groove. The two glans wings and ventral glanular mucosal flaps were mobilized laterally. Interrupted sutures were placed through the tunica albuginea of corpus spongiosum to the corpora cavernosa. The mobilized urethra was wrapped by dartos fascia. The urethral stent was removed 24h postoperatively. RESULTS Three-fold urethral mobilization was sufficient to achieve tension-free urethral anastomosis. A slit-like orthotopic meatus, with conically shaped glans and straight penis, was achieved in all but one subcoronal case with mid-glans meatal retraction during our early experience. Postoperative urethral fistula was not recorded in any patient. Satisfactory urinary stream for parents and child was reported in 42/46. Peak flow rate was within normal range (upper 50% percentile) in all. CONCLUSION Urethral mobilization should begin proximally. Three-fold penile urethral mobilization, deep interballanitic incision and wide dissection of the glans can provide a slit-like orthotopic meatus with conical glans and straight penis in cases of anterior hypospadias without hypoplastic distal urethra and persistent ventral curvature after penile skin degloving, regardless of the presence of unhealthy, narrow urethral plate, shallow glanular groove, and flat or small glans.

The use of small intestinal submucosa graft for hypospadias repair: Pilot study

Abstract Objective: To evaluate the outcome of using commercially available (SIS) grafts for repairing hypospadias. Collagen-based acellular matrices, including SIS and bladder submucosa matrix, have been used to repair urethral strictures, with varying success, and patients with hypospadias and with inadequate or no genital skin need a substitute tissue for urethroplasty. Patients and methods: This pilot study included 12 patients (mean age 8 years, range 1.5–15) with hypospadias (distal in six, mid-shaft in four and proximal in two). They underwent a repair with four layers of prefabricated SIS as an onlay graft. The outcome was assessed for cosmetic appearance, urinary stream and the postvoid residual volume. The chi-squared and Mann–Whitney U-tests were used to assess the relationship between preoperative factors and the outcome of the repair with SIS grafting. Results: The mean (range) follow-up was 23 (6–36) months. Nine patients ultimately voided normally, with a good cosmetic appearance and no postvoid residual urine. Six patients had a successful repair with no further intervention, whilst three had small fistulae that were treated by simple closure. In three patients the graft failed, by complete disruption or stricture. Graft infection adversely affected the outcome of SIS grafting. Conclusions: The prefabricated SIS graft can be used as an alternative substitute for urethral reconstruction when genital skin is insufficient or lacking, as in circumcised patients or a repeat hypospadias repair. Graft infection is the chief reason for graft failure and should be prevented. Further studies with more patients are needed to confirm these preliminary results.

Can Bcl-XL expression predict the radio sensitivity of Bilharzial-related squamous bladder carcinoma? a prospective comparative study

BackgroundLocal pelvic recurrence after radical cystectomy for muscle invasive bilharzial related squamous cell carcinoma accounts for 75% of treatment failures even in organ confined tumors. Despite the proven value of lymphadenectomy, up to 60% of patients undergoing cystectomy do not have it. These factors are in favor of adjuvant radiotherapy reevaluation. objectives: to evaluate the effect of adjuvant radiotherapy on disease free survival in muscle invasive bilharzial related squamous cell carcinoma of the urinary bladder and to test the predictability of radio-sensitivity using the anti apoptotic protein Bcl-XL.MethodsThe study prospectively included 71 patients, (47 males, 24 females) with muscle invasive bilharzial related squamous cell carcinoma of the bladder (Stage pT2a-T3N0-N3M0) who underwent radical cystectomy in Assiut university hospitals between January 2005 and December 2006. Thirty eight patients received adjuvant radiotherapy to the pelvis in the dose of 50Gy/25 fractions/5 weeks (Group 1), while 33 patients did not receive adjuvant radiotherapy (group 2). Immunohistochemical characterization for bcl-xL expression was done. Follow up was done every 3 months for 12 to 36 months with a mean of 16 ± 10 months. All data were analyzed using SPSS version 16. Three years cumulative disease free survival was calculated and adjusted to Bcl-XL expression and side effects of the treatment were recorded.ResultsThe disease free cumulative survival was 48% for group 1 and 29% for group 2 (log rank p value 0.03). The multivariate predictors of tumor recurrence were the positive Bcl-XL expression (odd ratio 41.1, 95% CI 8.4 - 102.3, p < 0.0001) and radiotherapy (odd ratio 0.19, 95% CI 0.05 - 0.78, p < 0.02). With Cox regression, the only independent multivariate predictor of radio-sensitivity was the Bcl-XL expression with odd ratio 4.6 and a p value < 0.0001. All patients tolerated the treatment with no life threatening or late complications during the period of follow up.ConclusionsAdjuvant radiotherapy for muscle invasive bilharzial related squamous cell carcinoma of the urinary bladder has potential effectiveness and minor side effects. Moreover, Bcl-XL expression is a valuable tool for predicting those who might not respond to this adjuvant treatment.

Primary versus secondary ureteroscopy for pediatric ureteral stones

OBJECTIVE To evaluate the outcome of primary versus secondary ureteroscopy for pediatric ureteral stones. PATIENTS AND METHODS A retrospective chart review study that included 66 children aged less than 12 years, who were subdivided into two groups: Group A, which included 42 children who had undergone primary ureteroscopy without pre-stenting; and Group B, which included 24 children who had undergone ureteroscopy after ureteric stenting. Kidneys, ureters and bladder radiographs were done on the first postoperative day to assess the degree of stone clearance and stent position. RESULTS Age, gender, stone location and stone size were not significantly different between both groups. In Group A, 31 (73.8%) children required ureteric dilation, 13 (31%) had a tight ureter that failed to respond to dilation, 25 (59.5%) displayed complete stone clearance, and of these, 13 (52%) needed postoperative stenting. One child experienced ureteric injury during stone disintegration and was stented for two weeks. Children in Group B experienced a 95.8% complete stone clearance rate, with no ureteric injury reported; postoperative stenting was performed in three (12.5%) children.. CONCLUSION Secondary ureteroscopy is preferable over primary ureteroscopy in pediatric populations because of a significantly lower need for ureteric dilation, shorter procedure time and better stone clearance rate..