Simon Kimm

Management of Distal Ureter in Laparoscopic Nephroureterectomy—A Comprehensive Review of Techniques

Approximately 5% of all urothelial tumors in adults arise from the upper tracts. While the gold standard treatment is open nephroureterectomy, laparoscopic nephroureterectomy is becoming increasingly popular. Oncologic principles dictate that complete excision of the transmural ureter and bladder cuff and avoidance of urine spillage are paramount. This can be challenging laparoscopically and multiple techniques have been described. We review described surgical techniques, published oncologic data, as well as advantages and disadvantages for each technique including open excision, cystoscopic detachment and ligation, laparoscopic stapling, ureteral intussusception, transurethral resection of ureteral orifice (TURUO) and modifications of TURUO. To date, no controlled studies have been performed demonstrating one techniques superiority.

Suppressive roles of calreticulin in prostate cancer growth and metastasis.

Calreticulin is an essential, multifunctional Ca(2+)-binding protein that participates in the regulation of intracellular Ca(2+) homeostasis, cell adhesion, and chaperoning. Calreticulin is abundantly expressed and regulated by androgens in prostate epithelial cells. Given the importance of both calreticulin in multiple essential cellular activities and androgens in prostate cancer, we investigated the possibility of a role for calreticulin in prostate cancer progression. Immunohistochemistry revealed the down-regulation of calreticulin in a subset of human prostate cancer specimens. Prostate cancer cells overexpressing exogenous calreticulin produced fewer colonies in both monolayer culture and soft agar. Furthermore, calreticulin overexpression also inhibited tumor growth in the orthotopic PC3 xenograft tumor model and macroscopic lung metastasis in the rat Dunning AT3.1 prostate tumor model. To address the potential mechanism of calreticulin suppression of prostate cancer, we generated calreticulin mutants with different functional domains deleted. The calreticulin mutants containing the P-domain, which binds to other endoplasmic reticulum chaperone proteins, were sufficient for the suppression of PC3 growth in colony formation assays. Overall, our data support the hypothesis that calreticulin inhibits growth and/or metastasis of prostate cancer cells and that this suppression requires the P-domain.

Reconstitution of Lethally Irradiated Adult Mice with Dominant Negative TGF-β Type II Receptor-Transduced Bone Marrow Leads to Myeloid Expansion and Inflammatory Disease

TGF-β regulation of immune homeostasis has been investigated in the context of cytokine knockout (TGF-β null) mice, in which particular TGF-β isoforms are disrupted throughout the entire organism, as well as in B and T cell-specific transgenic models, but to date the immunoregulatory effects of TGF-β have not been addressed in the context of an in vivo mouse model in which multi-isoform TGF-β signaling is abrogated in multiple leukocyte lineages while leaving nonhemopoietic tissue unaffected. Here we report the development of a murine model of TGF-β insensitivity limited to the hemopoietic tissue of adult wild-type C57BL/6 mice based on retroviral-mediated gene transfer of a dominant negative TGF-β type II receptor targeting murine bone marrow. Unlike the lymphoproliferative syndrome observed in TGF-β1-deficient mice, the disruption of TGF-β signaling in bone marrow-derived cells leads to dramatic expansion of myeloid cells, primarily monocytes/macrophages, and is associated with cachexia and mortality in lethally irradiated mice reconstituted with dominant negative receptor-transduced bone marrow. Surprisingly, there was a notable absence of T cell expansion in affected animals despite the observed differentiation of most cells in the T cell compartment to a memory phenotype. These results indicate not only that TGF-β acts as a negative regulator of immune function, but that lack of functional TGF-β signaling in the myeloid compartment of adult mice may trigger suppression of lymphocytes, which would otherwise proliferate when rendered insensitive to TGF-β.

Comparison of Holding Strength of Suture Anchors on Human Renal Capsule

INTRODUCTION The use of surgical clips as suture anchors has made laparoscopic partial nephrectomy (LPN) technically simpler by eliminating the need for intracorporeal knot tying. However, the holding strength of these clips has not been analyzed in the human kidney. Therefore, the safety of utilizing suture anchors is unknown as the potential for clip slippage or renal capsular tears during LPN could result in postoperative complications including hemorrhage and urinoma formation. With the above in mind, we sought to compare the ability of Lapra-Ty clips and Hem-o-lok clips to function as suture anchors on human renal capsule. METHODS Fresh human cadaveric kidneys with intact renal capsules were obtained. A Lapra-Ty clip (Ethicon, Cincinnati, OH) or a Hem-o-lok clip (Weck, Raleigh, NC) was secured to a no. 1 Vicryl suture (Ethicon) with and without a knot, as is typically utilized during the performance of LPN. The suture was then placed through the renal capsule and parenchyma and attached to an Imada Mechanical Force Tester (Imada, Northbrook, IL). The amount of force required both to violate the renal capsule and to dislodge the clip was recorded separately. RESULTS Six Lapra-Ty clips and six Hem-o-lok clips were tested. The mean force in newtons required to violate the renal capsule for the Lapra-Ty group was 7.33 N and for the Hem-o-lok group was 22.08 N (p < 0.001). The mean force required to dislodge the clip from the suture for the Lapra-Ty group was 9.0 N and for the Hem-o-lok group was 3.4 N (p < 0.001). When two Hem-o-lok clips were placed on the suture in series, the mean force required to dislodge the clips was 10.6 N. CONCLUSION When compared with Lapra-Ty clips, using two Hem-o-lok clips may provide a more secure and cost-effective method to anchor sutures on human renal capsule when performing LPN.

The Unidirectional Barbed Suture for Renorrhaphy During Laparoscopic Partial Nephrectomy: Stanford Experience

PURPOSE Using barbed suture represents a novel technical modification in the performance of minimally invasive partial nephrectomy. Our purpose of this study was to evaluate the safety and efficacy of this suture for renorrhaphy during laparoscopic partial nephrectomy (LPN). PATIENTS AND METHODS Thirteen consecutive patients underwent LPN using V-Loc™ 180 (Covidien, Dublin, Ireland) suture, and a nonconsecutive control group of 24 patients, matched according to tumor size and R.E.N.A.L. nephrometry score, underwent LPN using absorbable polyglactin suture. All 37 patients underwent LPN performed by a single surgeon. Perioperative and postoperative indicators of morbidity, estimated blood loss, and warm ischemia time (WIT) were compared between the groups. RESULTS Baseline characteristics including age, body mass index, American Society of Anesthesiologists score, tumor size, laterality, and R.E.N.A.L nephrometry score were identical between the groups. On multivariable analysis, there were no significant differences between the two groups with regard to operative time, estimated blood loss, transfusion rates, rates of surgical complications, and length of hospital stay. However, mean WIT was significantly shorter in the V-Loc group compared with the control group (24.5±5.3 minutes versus 31.9±8.9 minutes, P=.01). CONCLUSIONS The use of V-Loc sutures for renorrhaphy during LPN is safe and feasible and, in our series, significantly reduces WIT. Further studies are needed to corroborate these findings, but these results indicate a promising development in reducing WIT during minimally invasive partial nephrectomy.

Feasibility of Catheter-Directed Intraluminal Irreversible Electroporation of Porcine Ureter and Acute Outcomes in Response to Increasing Energy Delivery

PURPOSE To evaluate the feasibility of focal intraluminal irreversible electroporation (IRE) in the ureter with a novel electrode catheter and to study the treatment effects in response to increasing pulse strength. MATERIALS AND METHODS Five IRE treatment settings were each evaluated twice for the ablation of normal ureter in 5 Yorkshire pigs (n = 1-4 ablations per animal; total of 10 ablations) with the use of a prototype device under ultrasound and fluoroscopic guidance. Animals received unilateral or bilateral treatment, limited to a maximum of 2 ablations in any 1 ureter. Treatment was delivered with increasing pulse strength (from 1,000 V to 3,000 V in increments of 500 V) while keeping the pulse duration (100 μs) and number of pulses (n = 90) constant. Ureter patency was assessed with antegrade ureteropyelography immediately following treatment. Animals were euthanized within 4 hours after treatment, and treated urinary tract was harvested for histopathologic analysis with hematoxylin and eosin and Masson trichrome stains. RESULTS IRE was successfully performed in all animals, without evidence of ureteral perforation. Hematoxylin and eosin analysis of IRE treatments demonstrated full-thickness ablation at higher field strengths (mucosa to the adventitia). Masson trichrome stains showed preservation of connective tissue at all field strengths. CONCLUSIONS Intraluminal catheter-directed IRE ablation is feasible and produces full-thickness ablation of normal ureters. There was no evidence of lumen perforation even at the maximum voltages evaluated.

The Prognostic Impact of a Positive Vascular Margin on pT3 Clear Cell Renal Cell Carcinoma

PURPOSE We examined the impact of positive vascular margins in patients with pT3 clear cell renal cell carcinoma. MATERIALS AND METHODS After excluding patients with nonvascular positive margins, metastasis, lymph node involvement, neoadjuvant therapy or nonclear cell histology, we identified 224 patients with venous tumor invasion through our institutional database from 1999 to 2013. Kaplan-Meier analysis and log rank tests were used to evaluate whether positive vascular margins were associated with progression-free survival or cancer specific survival. RESULTS There were 41 patients (18%) with a positive vascular margin. Margin status was directly related to the level of invasion (p <0.0001). Compared to the negative vascular margin group the positive group had a significantly worse progression-free survival (p=0.01) but not cancer specific survival (p=0.3). Similarly the level of vascular thrombus invasion was significantly associated with worse progression-free survival (p=0.02) but not cancer specific survival (p=0.4). The 3-year progression-free survival was worst with inferior vena cava invasion and best with segmental/muscular venous branch invasion (54%, 95% CI 34-70 vs 76%, 95% CI 64-85). Among patients with only main renal vein thrombus, vascular margin status was not associated with progression-free survival (p=0.5) or cancer specific survival (p=0.2). CONCLUSIONS In patients with pT3N0/XM0 clear cell renal cell carcinoma positive vascular margins are associated with risk of disease progression. However, the risk of relapse associated with positive vascular margins is driven by the extent of vascular thrombus invasion. These findings suggest that the clinical significance of vascular margin status as currently defined in pT3 clear cell renal cell carcinoma is minimal.

Nonthermal Ablation by Using Intravascular Oxygen Radical Generation with WST11: Dynamic Tissue Effects and Implications for Focal Therapy

Purpose To examine the hypothesis that vascular-targeted photodynamic therapy (VTP) with WST11 and clinically relevant parameters can be used to ablate target tissues in a non-tumor-bearing large-animal model while selectively sparing blood vessels and collagen. Materials and Methods By using an institutional animal care and use committee-approved protocol, 68 ablations were performed in the kidneys (cortex and medulla) and livers of 27 adult pigs. Posttreatment evaluation was conducted with contrast material-enhanced computed tomography in the live animals at 24 hours. Immunohistochemistry was evaluated and histologic examination with hematoxylin-eosin staining was performed at 4 hours, 24 hours, and 7 days. Intravenous infusion of WST11 (4 mg per kilogram of body weight) was followed by using near-infrared illumination (753 nm for 20 minutes) through optical fibers prepositioned in target tissues by using a fixed template. Treated areas were scanned, measured, and statistically analyzed by using the Student t test and two-way analysis of variance. Results Focal WST11 VTP treatment in the liver and kidney by using a single optical fiber resulted in well-demarcated cylindrical zones of nonthermal necrosis concentrically oriented around the light-emitting diffuser, with no intervening viable parenchymal cells. The radius of ablated tissue increased from approximately 5 mm at 150 mW to approximately 7 mm at 415 mW (P < .01). Illumination through fiber triads at 1-cm separation resulted in confluent homogeneous necrosis. Patterns of acute injury within 24 hours were consistent with microcirculatory flow arrest and collagen preservation (demonstrated with trichrome staining). In the peripheral ablation zone, blood vessels at least 40 μm in diameter were selectively preserved and remained functional at 7 days. Ablated tissues exhibited progressive fibrosis and chronic inflammatory cell infiltrates. No histologic changes consistent with thermal injury were observed in blood vessels or collagen. The renal hilum and collecting system did not show treatment effect, despite treatment proximity. Conclusion WST11 VTP induces nonthermal tissue ablation in target tissue while preserving critical organ structures and bystander blood vessels within solid organs. (©) RSNA, 2016 Online supplemental material is available for this article.

Bombesin Antagonist-Based Radiotherapy of Prostate Cancer Combined with WST-11 Vascular Targeted Photodynamic Therapy

Purpose: DOTA-AR, a bombesin-antagonist peptide, has potential clinical application for targeted imaging and therapy in gastrin-releasing peptide receptor (GRPr)–positive malignancies when conjugated with a radioisotope such as 90Y. This therapeutic potential is limited by the fast washout of the conjugates from the target tumors. WST-11 (Weizmann STeba-11 drug; a negatively charged water-soluble palladium-bacteriochlorophyll derivative, Tookad Soluble) vascular targeted photodynamic therapy (VTP) is a local ablation approach recently approved for use in early-stage prostate cancer. It generates reactive oxygen/nitrogen species within tumor blood vessels, resulting in their instantaneous destruction followed by rapid tumor necrosis. We hypothesize that the instantaneous arrest of tumor vasculature may provide a means to trap radiopharmaceuticals within the tumor, thereby improving the efficacy of targeted radiotherapy. Experimental Design: GRPr-positive prostate cancer xenografts (PC-3 and VCaP) were treated with 90Y-DOTA-AR with or without VTP. The uptake of radioisotopes was monitored by Cherenkov luminescence imaging (CLI). The therapeutic efficacy of the combined VTP and 90Y-DOTA-AR in PC-3 xenografts was assessed. Results: CLI of 90Y-DOTA-AR demonstrated longer retention of radiotracer within the VTP-treated PC-3 xenografts compared with the non–VTP-treated ones (P < 0.05) at all time points (24–144 hours) after 90Y-DOTA-AR injection. A similar pattern of retention was observed in VCaP xenografts. When 90Y-DOTA-AR administration was combined with VTP, tumor growth delay was significantly longer than for the control or the monotherapy groups. Conclusions: Tumor vascular arrest by VTP improves 90Y-DOTA-AR retention in the tumor microenvironment thereby enhancing therapeutic efficacy. Clin Cancer Res; 23(13); 3343–51. ©2017 AACR.

Improved Intraoperative Visualization of Nerves through a Myelin-Binding Fluorophore and Dual-Mode Laparoscopic Imaging

The ability to visualize and spare nerves during surgery is critical for avoiding chronic morbidity, pain, and loss of function. Visualization of such critical anatomic structures is even more challenging during minimal access procedures because the small incisions limit visibility. In this study, we focus on improving imaging of nerves through the use of a new small molecule fluorophore, GE3126, used in conjunction with our dual-mode (color and fluorescence) laparoscopic imaging instrument. GE3126 has higher aqueous solubility, improved pharmacokinetics, and reduced non-specific adipose tissue fluorescence compared to previous myelin-binding fluorophores. Dosing and kinetics were initially optimized in mice. A non-clinical modified Irwin study in rats, performed to assess the potential of GE3126 to induce nervous system injuries, showed the absence of major adverse reactions. Real-time intraoperative imaging was performed in a porcine model. Compared to white light imaging, nerve visibility was enhanced under fluorescence guidance, especially for small diameter nerves obscured by fascia, blood vessels, or adipose tissue. In the porcine model, nerve visualization was observed rapidly, within 5 to 10 minutes post-intravenous injection and the nerve fluorescence signal was maintained for up to 80 minutes. The use of GE3126, coupled with practical implementation of an imaging instrument may be an important step forward in preventing nerve damage in the operating room.