Timothy Tran

Targeted Imaging of Urothelium Carcinoma in Human Bladders by an ICG pHLIP Peptide Ex vivo

Significance Bladder cancer is the fifth most common cancer. Timely diagnosis and appropriate early management protocols are of paramount significance for improving patient outcomes. This study shows efficient pH-dependent near-infrared imaging of bladder malignant tumors without targeting of normal tissue. Our results demonstrate that the indocyanine green pH low insertion peptide (pHLIP) construct is suitable for use as a predictive clinical marker, specifically staining human bladder tumors after intravesical administration ex vivo. The targeting allows delivery of various imaging probes, which may offer early diagnosis and improve the outcomes of endoscopic and radical surgical resection of urothelial carcinomas. In addition, delivery of therapeutic molecules to cancer cells by pHLIP might open an opportunity for novel targeted treatment of bladder cancers. Bladder cancer is the fifth most common in incidence and one of the most expensive cancers to treat. Early detection greatly improves the chances of survival and bladder preservation. The pH low insertion peptide (pHLIP) conjugated with a near-infrared fluorescent dye [indocyanine green (ICG)] targets low extracellular pH, allowing visualization of malignant lesions in human bladder carcinoma ex vivo. Cystectomy specimens obtained after radical surgery were immediately irrigated with nonbuffered saline and instilled with a solution of the ICG pHLIP construct, incubated, and rinsed. Bladders were subsequently opened and imaged, the fluorescent spots were marked, and a standard pathological analysis was carried out to establish the correlation between ICG pHLIP imaging and white light pathological assessment. Accurate targeting of bladder lesions was achieved with a sensitivity of 97%. Specificity is 100%, but reduced to 80% if targeting of necrotic tissue from previous transurethral resections or chemotherapy are considered as false positives. The ICG pHLIP imaging agent marked high-grade urothelial carcinomas, both muscle invasive and nonmuscle invasive. Carcinoma in situ was accurately diagnosed in 11 cases, whereas only four cases were seen using white light, so imaging with the ICG pHLIP peptide offers improved early diagnosis of bladder cancers and may also enable new treatment alternatives.

Calculated insulin resistance correlates with stone-forming urinary metabolic changes and greater stone burden in high-risk stone patients.

AIMS Metabolic syndrome and diabetes are associated with nephrolithiasis. Proposed mechanisms of lithogenesis include insulin resistance causing low urine pH and hyperinsulinemia leading to hypercalciuria. Herein, we sought to determine whether insulin resistance was associated with differences in stone burden and lithogenic changes on 24-hour urine samples. MATERIALS AND METHODS All patients that underwent comprehensive metabolic workup including 24-hour urine samples and fasting insulin levels were included. Insulin resistance was defined as a homeostasis model assessment of insulin resistance value > 5 (HOMA-IR = (glucose×insulin)/405). Patients on active metabolic therapy were excluded or the 24-hour urine sample predating treatment was utilized for analysis. Stone burden was determined by totaling the maximal diameter of all stones noted on CT. RESULTS 18 of 30 patients (60.0%) had HOMA-IR > 5. Among patients with calculated insulin resistance, stone burden was greater (17.6 mm vs. 6.3 mm, p = 0.002) and 24-hour urine samples revealed higher urine calcium (293 mg/d vs. 159 mg/d, p = 0.02) and lower urine pH and citrate (454 mg/d vs. 639 mg/d, p = 0.04 and 5.83 vs. 6.33, p = 0.04, respectively). CONCLUSIONS Previous studies have demonstrated a correlation between metabolic syndrome, diabetes, and nephrolithiasis. This report demonstrates a quantitative increase in stone burden among patients with calculated insulin resistance. The pathway for this greater stone burden may be related to the urinary metabolic changes noted among patients with insulin resistance. In the future, targeting reduction of fasting insulin levels may represent a key element of stone disease prevention.

Modern Outcomes with Modified PCNL

Percutaneous nephrolithotomy (PCNL) is the treatment of choice for patients with renal calculi ≥ 2 cm as well as larger lower pole calculi [1,2]. The armamentarium of specialized rigid and flexible nephroscopes and powerful lithotripters allow for greater stone-free rates in the treatment of patients with large stone burdens [3]. However, in comparison to shockwave lithotripsy and ureteroscopy, PCNL is associated with greater morbidity, particularly with respect to bleeding risk. This is attributed to the creation of a nephrostomy tract with subsequent tract dilation resulting in shearing of renal parenchyma and bleeding [4]. As such, percutaneous surgery using smaller tracts has been explored as a means to limit the morbidity of PCNL. An assortment of options ranging from micro-, to ultramini-, to miniPCNL have been described [5-7]. Recent series have demonstrated improvements in bleeding risk [8], postoperative pain scores [9] and hospital length of stay [10] compared with standard PCNL. However, despite these benefits, technical limitations apply. Smaller access tracts require miniaturized instruments, precluding the use of many efficient stone fragmentation and retrieval devices routinely used in standard PCNL. Therefore, while reported stone-free rates are generally high, these studies are often limited to patients with stone burdens between 10-20 mm [5,6,8].

PD35-06 CAN CT IMAGING PREDICT STONE IMPACTION?

INTRODUCTION AND OBJECTIVES: There are many techniques for laser lithotripsy of urinary stones. The “popcorn” method involves placing a laser fiber in the center of a collection of stones and firing continuously, allowing fragments to further dust into smaller particles. Our aim was to examine different locations and laser settings on the efficiency of this lithotripsy method. METHODS: Pre-fragmented BegoStone phantoms were created between 2-4mm in size to mimic typical popcorning conditions. A 0.5g collection of fragments was placed into two 3D-printed models (a 2 cm spherical calyx model and 4x2 cm ellipsoid pelvis model, Figure 1) and a 200mm laser fiber was positioned at the top of the stones. The laser was fired for 2 minutes with constant irrigation, with 5 trials performed at each setting: 0.2J/50Hz, 0.5J/20Hz, 0.5J/40Hz, 1J/20Hz. The fragmentation efficiency was determined by calculating the mass of stones reduced to sub-2mm particles after 48h of drying. Statistical analysis was performed with ANOVA and Student’s T-test. Additionally, high-speed photography was used to examine the mechanism of the popcorn effect. RESULTS: The trials within the calyx model were significantly more efficient compared to the pelvis model (0.18g vs 0.13g, p<0.05). When comparing laser settings, there was a difference between groups by one-way ANOVA (F[3,36] 1⁄4 7.92, p 1⁄4 0.0003). Post hoc tests showed that 20W settings were significantly more efficient than 0.2J/ 50Hz (p<0.05) although 0.5J/20Hz was not significantly less efficient than the 20W settings (Figure 2). High-speed imaging shows the majority of fragmentation is due to intermittent stone contact with the laser as opposed to stone-stone interaction. CONCLUSIONS: The popcorn effect is most efficient in a smaller space as in the calyx model and as such we recommend displacement of stones into a calyx for popcorning. The 0.5J/20Hz setting produces efficient popcorning at a lower power of 10W, reducing fiber burnback and potential for injury, and is our recommended setting. Source of Funding: None

PD16-11 PERCUTANEOUS MANAGEMENT OF CALYCEAL DIVERTICULA: ASSOCIATED FACTORS AND OUTCOMES

INTRODUCTION AND OBJECTIVES: The choice of treatment for symptomatic calyceal diverticula (CD) depends on size, location, and degree of stone burden. Percutaneous treatment is preferred for large CD, lower pole CD, and CD with a large stone burden, but its safety for anterior CD has not been evaluated. In addition, the necessity to treat the diverticular neck and the need for metabolic evaluation remains controversial. We sought to shed some light on these issues based on our significant experience. METHODS: We identified 51 patients in our IRB approved Endourology database with stone bearing CD that were treated percutaneously by a single experienced surgeon. We separated patients into those with stones only in their CD (CD only) and those who also had renal calculi outside of their diverticulum (CD plus). Demographic data, size and location of the CD, treatment of the diverticular neck, intra-operative and post-operative outcomes, stone analysis, and 24-hr urine parameters were recorded. Urine parameters were also compared to stone formers without CD (non-CD). RESULTS: CD only patients are younger (44 vs. 54 y, p1⁄40.024), have lower BMI (23.2 vs. 27, p1⁄40.032), and are more often female (71% vs. 44%, p 1⁄4 0.046) compared to non-CD patients. Anterior CD (66%) were more common than posterior, and 52% of the CD were found in the upper pole. Average CD size was 2.5cm with a stone burden of 1.47 cm. PCNL was performed safely and completely in 98% of the patients, with a complication rate of 4%. The diverticular neck was dilated in 44% of the cases. In follow-up there was 1 symptomatic recurrence managed by ureteroscopy. Calcium phosphate was contained in 82% of stones. All CD patients had at least one metabolic derangement, similar to regular stone formers, but with unusually high levels of urinary calcium and pH (Table 1). CONCLUSIONS: Percutaneous treatment of CD is safe and effective regardless of size or location (including anterior CD). Infundibular neck dilation does not appear to be necessary. A significant proportion of CD patients have metabolic abnormalities. Stone formation is likely a result of stasis and metabolic factors, and CD patients are at risk for future renal calculi.

PD35-01 A RANDOMIZED DOUBLE-BLIND CONTROLLED STUDY ASSESSING ELECTRO-ACUPUNCTURE FOR THE MANAGEMENT OF POST-OPERATIVE PAIN AFTER PERCUTANEOUS NEPHROLITHOTOMY

INTRODUCTION AND OBJECTIVES: Percutaneous nephrolithotomy (PCNL) is the gold standard procedure for large renal calculi, but post-operative pain remains a major concern. Modifications of the PCNL technique have been developed in part to decrease pain. More recently, acupuncture has been described as an adjunct to reduce pain following abdominal, spinal, and orthopedic surgeries. Among the benefits of acupuncture are its ease of performance, non-invasiveness, and lack of significant side effects. In comparison to traditional acupuncture, electro-acupuncture has shown enhanced efficacy, possibly due to central endorphin release. We sought to investigate the effects of electro-acupuncture on patients undergoing PCNL. METHODS: A double blind, randomized, sham controlled study design was used. Fifty patients undergoing PCNL by a single surgeon were randomized to one of three groups: true electro-acupuncture (EA, n1⁄4 17), sham electro-acupuncture (Sham, n 1⁄4 20), and no acupuncture (Control, n 1⁄4 13). Acupuncture was performed by a licensed acupuncturist 1 hr prior to surgery. All study personnel, except the acupuncturist were blinded to the intervention. PCNL was performed according to standard protocol and without intra-operative nerve block or local anesthetic. Pain scores (visual analog scale (VAS)), narcotic use (morphine equivalents (ME)), and side effects were recorded at set intervals post-operatively. RESULTS: Mean VAS scores for flank and abdomen in the EA group were lower at all time periods compared to sham and control groups. In fact, 2 patients in the EA group did not require any postoperative narcotics. Mean cumulative opioid usage was lower in the EA group immediately post-operatively compared to both sham and control groups (Table 1). No differences between groups were found for nausea and vomiting. No adverse effects of EA were noted. CONCLUSIONS: Electro-acupuncture significantly reduces acute post-operative pain and narcotic usage without any adverse effects. This promising adjunct for post-operative pain control warrants further validation.

MP23-15 EARLY DISCHARGE FOLLOWING DECOMPRESSION FOR SEPSIS AND AN OBSTRUCTING STONE? A MULTI-INSTITUTIONAL STUDY TO IDENTIFY PREDICTORS OF ANTIBIOTIC SENSITIVITY

INTRODUCTION AND OBJECTIVES: Patients presenting with sepsis and an obstructing stone undergo urgent urinary tract decompression. Following this, patients are hospitalized for hemodynamic support and broad spectrum antibiotics. Urine culture results are used to tailor outpatient antibiotic therapy. At times patients achieve early clinical stability but remain hospitalized while awaiting antibiotic sensitivities. We sought to identify predictors of antibiotic resistance that may allow clinicians to select candidates for discharge on empiric oral antibiotics prior to culture results being available. METHODS: All patients that underwent emergent urinary tract decompression for sepsis and an obstructing ureteral stone over the last 2 years at the two above institutions were included. Clinical factors, including urine culture sensitivities and patient demographics were recorded. Student’s t-test and the chi-squared test were used to identify statistical difference. RESULTS: 134 patients were identified that met inclusion criteria. Eighty-four patients (62.7%) had urine cultures with antibiotic resistance. Comparison was made between patients with pan-sensitive and resistant urine cultures (Table 1). Patients with resistant cultures were more likely to have had previous urologic surgery (44.7% vs. 22.0%, p 1⁄4 0.008) the most notable difference was in patients that had had previous ureteroscopy (38.9% vs. 8.0%, p 1⁄4 0.0002). Those with resistant cultures were more likely to require postoperative ICU-level care (27.1% vs. 12.0%, p 1⁄4 0.039), have bacteremia (48.2% vs. 24.0%, p 1⁄4 0.005) and a longer length of stay (5.4 vs. 3.4 days, p 1⁄4 0.026). Resistance patterns were noted to be similar between the two institutions (Table 2). CONCLUSIONS: Patients that have had previous urologic surgery, especially ureteroscopy, appear to be poor candidates for early discharge on empiric antibiotics prior to the completion of urine culture results due to a higher likelihood of having antibiotic resistance. These results were noted to be consistent at both institutions participating in this study. Source of Funding: none

MP90-09 THE METABOLIC SYNDROME AND ITS IMPACT ON CALCIUM OXALATE STONE TYPE

HRQOL) in each of the domains. With multivariate analysis, these differences maintained their significance (mean domain scores were higher by 2.5, 2.8, 2.8, 1.3 points, respectively, all p<0.0001). In itemlevel analysis, patients prescribed potassium citrate were less likely than those not prescribed it to report any nausea, stomach upset or cramps (43% vs 55%, p<0.001). Multivariate logistic regression showed a 40% lower likelihood of having GI complaints among patients prescribed potassium citrate, p1⁄40.001, when controlling for the aforementioned factors. CONCLUSIONS: Among chronic stone forming patients, the use of potassium citrate is associated with higher HRQOL across all domains of the WISQOL. Those prescribed potassium citrate appear less likely to endorse GI complaints compared to those not. These findings may be useful when encouraging patients to consider initiating potassium citrate therapy.