Nicholas G. Cost

The Impact of Targeted Molecular Therapies on the Level of Renal Cell Carcinoma Vena Caval Tumor Thrombus

BACKGROUND Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases. OBJECTIVE To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi. MEASUREMENTS The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT. RESULTS AND LIMITATIONS Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction. CONCLUSIONS TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.

Algorithm for comprehensive approach to hypospadias reoperation using 3 techniques.

PURPOSE We describe comprehensive hypospadias reoperation based on presence or absence of a supple urethral plate using the 3 surgical techniques of transurethral incised plate, 1-stage inlay graft and 2-stage buccal graft. MATERIALS AND METHODS We reviewed prospective data from all reoperative hypospadias urethroplasties performed by one of us (WTS) between 2000 and 2008. Patient age, number of operations, indications for additional surgery, meatal location, reoperative surgical technique and outcomes were extracted. RESULTS A total of 133 patients underwent reoperation by transurethral incised plate (69), 1-stage inlay graft (16) or 2-stage buccal graft (48) urethroplasty. Mean number of prior failed repairs was 1.1, 1.9 and 4.3, respectively. Followup was available in 121 patients (91%), with 90 (74%) undergoing 1 successful reoperative urethroplasty. Complications occurred in 19%, 15% and 38% of patients, respectively, and most often consisted of fistulas or glans dehiscence. CONCLUSIONS Hypospadias reoperation can be accomplished using these 3 techniques without skin flaps, a potential advantage given the relative paucity of skin after failed repair. Fistulas after transurethral incised plate urethroplasty correlate with barrier layers used, while glans dehiscence is more likely in 2-stage buccal graft repairs when cheek rather than lip is used within the glans.

TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma

Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca(2+) influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca(2+) and Zn(2+) fluxes inhibit miR-214, which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 directly through miR-204 and indirectly through another miR-204 target, Caveolin 1 (CAV1).

Analysis of risk factors for glans dehiscence after tubularized incised plate hypospadias repair

PURPOSE We determined the incidence of glans dehiscence and the associated risk factors after tubularized incised plate hypospadias repair. MATERIALS AND METHODS All data for patients undergoing tubularized incised plate hypospadias repair, surgical details and postoperative outcomes were prospectively maintained in databases. Data were analyzed with simple and multiple logistic regression to determine if patient age, preoperative testosterone use, meatal location (distal, mid shaft or proximal), glansplasty sutures (chromic catgut vs polyglactin) or primary vs revision tubularized incised plate procedure was associated with an increased risk of glans dehiscence. RESULTS Glans dehiscence occurred in 32 of 641 patients (5%). Age at surgery, preoperative testosterone use and glansplasty suture did not impact the risk of glans dehiscence. Glans dehiscence occurred in 20 of 520 distal (4%), 1 of 47 mid shaft (2%) and 11 of 74 proximal (15%) tubularized incised plate repairs, with the odds of glans dehiscence being 3.6 times higher in patients with proximal vs distal meatal location. Patients undergoing reoperative (9 of 64, 14%) vs primary tubularized incised plate (23 of 577, 4%) had a 4.7-fold increased risk of glans dehiscence. CONCLUSIONS Proximal meatal location and revision surgery, most commonly for prior glans dehiscence, increase the odds of glans dehiscence by 3.6 and 4.7-fold, respectively, suggesting anatomical and/or host factors (wound healing) are more important than age, type of suture or preoperative testosterone use in the development of this postoperative complication.

Pediatric Testicular Torsion: Demographics of National Orchiopexy Versus Orchiectomy Rates

PURPOSE While the timely diagnosis and management of pediatric torsion can lead to testicular salvage, limited data exist on rates of orchiopexy vs orchiectomy and associated factors. Thus, we examined the Pediatric Health Information System database for torsion outcomes and demographics at American pediatric hospitals. MATERIALS AND METHODS Using the Pediatric Health Information System database we performed a 7-year retrospective cohort study in children 1 to 17 years old with a primary ICD-9 diagnosis of torsion, assessing CPT codes for orchiopexy and orchiectomy. Data were analyzed with SPSS®, version 17.0. RESULTS Of 2,876 patients who underwent surgery for an ICD-9 diagnosis code of testicular torsion 918 (31.9%) underwent orchiectomy at a mean age of 10.7 years and 1,958 (68.1%) underwent orchiopexy at a mean age of 12.6 years (p <0.0001). In the age groups 1 to 9, 10 to 13 and 14 years or greater 274 (49.9%), 311 (29.4%) and 333 patients (26.2%), respectively, underwent orchiectomy. A higher orchiectomy rate was seen at age 1 to 9 vs 10 years or greater. Torsion and orchiectomy rates did not vary by season or geographic region. A higher orchiectomy rate was seen in black vs white children (37.6% vs 28.1%) and in patients without vs with private insurance (36.7% vs 27.0%). Multivariate analysis revealed an association of age (p <0.0001), race (p <0.0001) and insurance status (p <0.001) with orchiectomy. CONCLUSIONS Nationally an average of 32% of the 411 pediatric torsion cases explored annually result in orchiectomy. Identified factors increasing the orchiectomy risk included age 1 to 9 years, black race and lack of private insurance. Efforts should continue to identify modifiable variables that can increase testicular salvage in patients with testicular torsion.

Radiofrequency ablation of small renal cortical tumours in healthy adults: renal function preservation and intermediate oncological outcome

To present the glomerular filtration rate (GFR) and oncological outcomes in a series of patients with cT1a renal cortical tumours treated with radiofrequency ablation (RFA), a non‐ischaemic minimally invasive ablative method, as nephron‐sparing surgery gives excellent oncological outcomes and preserves renal function.

Pediatric standard and robot-assisted laparoscopic pyeloplasty: a comparative single institution study.

PURPOSE We report our experience and compare the outcomes between standard and robot-assisted laparoscopic pyeloplasty to treat ureteropelvic junction obstruction in children. MATERIALS AND METHODS A retrospective cohort study was performed of all children who underwent standard or robot-assisted laparoscopic pyeloplasty for ureteropelvic junction obstruction at a single institution from October 2007 to January 2012. Indications for surgery included symptomatic obstruction and abnormal diuretic renal scan. A successful outcome was defined as resolution of clinical symptoms, improvement of hydronephrosis on ultrasound, stable ultrasound with resolution of symptoms or improvement of the drainage curve on diuretic renal scan. RESULTS We reviewed 18 patients (median age 8.1 years) who underwent standard and 46 (8.8 years) who underwent robot-assisted laparoscopic pyeloplasty (p = 0.194). Median operative time was 298 minutes (range 145 to 387) for standard and 209 minutes (106 to 540) for robot-assisted laparoscopic pyeloplasty (p = 0.008). Mean hospitalization was similar between the groups (1 day for standard vs 2 days for robot-assisted laparoscopic pyeloplasty, p = 0.246). Narcotic use was similar between the groups. Median followup was 43 months for standard and 22 months for robot-assisted laparoscopic pyeloplasty (p <0.01). Renal ultrasound showed postoperative improvement of hydronephrosis in 85% and stable disease in 15% of patients following robot-assisted laparoscopic pyeloplasty, and improvement in 89.5% and stable disease in 10.5% after standard laparoscopic pyeloplasty. Symptoms resolved in 100% of patients (38 of 38) after robot-assisted laparoscopic pyeloplasty and 87.5% of patients (7 of 8) after standard laparoscopic pyeloplasty. CONCLUSIONS Robot-assisted laparoscopic pyeloplasty and standard laparoscopic pyeloplasty are effective techniques to correct ureteropelvic junction obstruction, with similar outcomes. Robot-assisted laparoscopic pyeloplasty had a shorter operative time, and its success and complication rates are comparable to standard laparoscopic pyeloplasty.

Tamsulosin and Spontaneous Passage of Ureteral Stones in Children: A Multi-Institutional Cohort Study

PURPOSE Tamsulosin is associated with increased passage of ureteral stones in adults but its effectiveness in children is uncertain. We determined the association between tamsulosin and the spontaneous passage of ureteral stones in children. MATERIALS AND METHODS We performed a multi-institutional retrospective cohort study of patients 18 years or younger who presented between 2007 and 2012 with ureteral stones up to 10 mm and who were treated with tamsulosin or oral analgesics alone. The outcome was spontaneous stone passage, defined as radiographic clearance and/or patient report of passage. Subjects prescribed tamsulosin were matched with subjects prescribed analgesics alone, using nearest neighbor propensity score matching to adjust for treatment selection. Conditional logistic regression models were used to estimate the association between tamsulosin and spontaneous passage of ureteral stones, adjusting for stone size and location. RESULTS Of 449 children with ureteral stones 334 were eligible for inclusion, and complete data were available for 274 patients from 4 institutions (99 receiving tamsulosin, 175 receiving analgesics alone). Following case matching, there were no differences in age, gender, weight, height, stone size or stone location between the 99 subjects prescribed tamsulosin and the 99 propensity score matched subjects prescribed analgesics alone. In the tamsulosin cohort 55% of ureteral stones passed, compared to 44% in the analgesics alone cohort (p=0.03). In multivariate analysis adjusting for stone size and location tamsulosin was associated with spontaneous passage of ureteral stones (OR 3.31, 95% CI 1.49-7.34). CONCLUSIONS The odds of spontaneous passage of ureteral stones were greater in children prescribed tamsulosin vs analgesics alone.

A Comparison of Renal Function Outcomes After Nephron-sparing Surgery and Radical Nephrectomy for Nonsyndromic Unilateral Wilms Tumor

OBJECTIVE To better understand the impact of nephron-sparing surgery (NSS) on renal function in patients with nonsyndromic unilateral Wilms tumor (uWT), a group of such patients treated with NSS were compared with a stage-matched cohort managed with radical nephrectomy (RN). The recommended management of nonsyndromic uWT is RN. However, NSS may decrease the risk of long-term renal disease and associated comorbidities. MATERIALS AND METHODS An international, multi-institutional review was conducted of nonsyndromic uWT cases managed with NSS and compared with a stage-matched RN cohort. Data were collected on demographics, oncologic characteristics and outcomes, serum creatinine, and estimated glomerular filtration rate (eGFR) calculated via Schwartz formula. RESULTS Fifteen patients who underwent NSS (6 females and 9 males) met study criteria and were diagnosed at a median age of 2.5 years (range, 0.2-8.2 years) and followed for a median of 8.4 years (range, 0.5-31.8 years). The stage-matched RN cohort consisted of 15 patients (8 females and 7 males) diagnosed at a median age of 3.7 years (0.3-7.4) and followed for a median of 2.1 years (0.6-10.5 years). The median preoperative eGFR was 91.7 (39.4-237.7) and 149.9 (93.8-215.9) for NSS and RN, respectively, P=.026. The median eGFR at last follow-up was 135.3 (57.5-185.8) and 131.0 (98.6-161.2) for NSS and RN, respectively, P=.95. The median change in eGFR during the study period was a gain of 28.6 (-51.9 to 83.0) for the NSS cohort vs a loss of 19.1 (-54.7 to 25.2) for the RN cohort, P=.007. CONCLUSION In a highly selected patient population with nonsyndromic uWT, NSS provides excellent renal function preservation when compared with RN. These data require validation via prospective investigation on a larger scale.

A comparison of pediatric, adolescent, and adult testicular germ cell malignancy.

Testicular germ cell tumors (T‐GCTs) occur from infancy to adulthood, and are the most common solid tumor in adolescent and young adult males. Traditionally, pediatric T‐GCTs were perceived as more indolent than adult T‐GCTs. However, there are few studies comparing these groups and none that specifically evaluate adolescents.