Robert G. Uzzo

NEPHRON SPARING SURGERY FOR RENAL TUMORS: INDICATIONS, TECHNIQUES AND OUTCOMES

PURPOSEnA contemporary review of the indications, techniques and outcomes is presented for nephron sparing approaches to solid renal masses, emphasizing their role for the treatment of renal cell carcinoma. We also reviewed the evolving role of minimally invasive forms of parenchymal sparing renal surgery.nnnMATERIALS AND METHODSnMEDLINE and CANCERLIT computerized literature searches, and manual bibliographic reviews were performed to identify published peer reviewed articles pertaining to nephron sparing surgery or partial nephrectomy from 1980 to 2000. Pertinent articles were collated and reviewed.nnnRESULTSnNephron sparing surgery is increasingly being used to treat patients with solid renal lesions. The technical success rate of nephron sparing surgery is excellent, and operative morbidity and mortality are low. For renal cell carcinoma long-term cancer-free survival is comparable to that after radical nephrectomy, particularly for low stage disease. The overall incidence of local recurrence is low at 0% to 10%. For tumors 4 cm. or less local recurrence rates are even less at 0% to 3%. The risk of local recurrence depends primarily on the initial local pathological tumor stage. The reported incidence of multifocal renal cell carcinoma is approximately 15% and it also depends on tumor size, histology and stage. The risk of multifocal disease is low at less than 5% when the maximal diameter of the primary tumor is 4 cm. or less. Recent advances in renal imaging limit the radiographic evaluation necessary when planning complex nephron sparing approaches. Three-dimensional, volume rendered computerized tomography integrates all of the necessary information previously obtained by conventional computerized tomography, angiography, venography and pyelography into a single preoperative test, allowing better operative planning with maximal preservation of unaffected parenchyma in the remnant kidney. Minimally invasive modalities of tumor resection or destruction should be reserved for highly select patients and await improvements in technology, standardization of technique and long-term outcomes data before they may be completely integrated options.nnnCONCLUSIONSnNephron sparing surgery provides effective therapy for patients in whom preservation of renal function is a relevant clinical consideration. The importance of meticulous operative technique for achieving acceptable oncological and functional outcomes is emphasized. Accumulating data in appropriately select patients suggest a long-term functional advantage gained by the maximal preservation of unaffected renal parenchyma without sacrificing cancer control.

3-DIMENSIONAL VOLUME RENDERED COMPUTERIZED TOMOGRAPHY FOR PREOPERATIVE EVALUATION AND INTRAOPERATIVE TREATMENT OF PATIENTS UNDERGOING NEPHRON SPARING SURGERY

PURPOSEnComputerized tomography (CT) is the diagnostic and staging modality of choice for renal neoplasms. Existing imaging modalities are limited by a 2-dimensional (D) format. Recent advances in computer technology now allow the production of high quality 3-D images from helical CT. Nephron sparing surgery requires a detailed understanding of renal anatomy. Preoperative evaluation must delineate the relationship of the tumor to adjacent normal structures and demonstrate the vascular supply to the tumor for the surgeon to conserve as much normal parenchyma as possible. We propose that helical CT combined with 3-D volume rendering provides all of the information required for preoperative evaluation and intraoperative management of nephron sparing surgery cases. We prospectively evaluated the role of 3-D volume rendering CT in 60 patients undergoing nephron sparing surgery for renal cell carcinoma at the Cleveland Clinic Foundation.nnnMATERIALS AND METHODSnTriphasic spiral CT was performed preoperatively in 60 consecutive patients undergoing nephron sparing surgery for renal neoplasms. A 3 to 5-minute videotape was prepared using volume rendering software which demonstrated the position of the kidney, location and depth of extension of the tumor(s), renal artery(ies) and vein(s), and relationship of the tumor to the collecting system. These videotapes were viewed by a radiologist and urologist in the operating room at surgery, and immediately correlated with surgical findings. Corresponding renal arteriograms of 19 patients were retrospectively compared to 3-D volume rendering CT and operative findings.nnnRESULTSnA total of 97 renal masses were identified in 60 cases evaluated with 3-D volume rendering CT before nephron sparing surgery. There were no complications related to the 3-D protocol and 3-D rendering was successful in all patients. The number and location of lesions identified by 3-D volume rendering CT were accurate in all cases, while enhancement and diagnostic characteristics were consistent with pathological findings in 95 of 97 tumors (98%). Of 77 renal arteries identified at surgery 74 were detected by 3-D volume rendering CT (96%). Helical CT missed 3 small accessory arteries, including 1 in a cross fused ectopic kidney. All major venous branches and anomalies were identified, including 3 circumaortic left renal veins. Of 69 renal veins identified at surgery 64 were detected by 3-D volume rendering CT (93%). All 5 renal veins missed by CT were small, short, duplicated right branches of the main renal vein. Renal fusion and malrotation anomalies were correctly identified in all 4 patients.nnnCONCLUSIONSnThe 3-D volume rendering CT accurately depicts the renal parenchymal and vascular anatomy in a format familiar to most surgeons. The data integrate essential information from angiography, venography, excretory urography and conventional 2-D CT into a single imaging modality, and can obviate the need for more invasive imaging. Additionally, the use of videotape in an intraoperative setting provides concise, accurate and immediate 3-D information to the surgeon, and it has become the preferred means of data display for these procedures at our center.

Quality of life and psychological adaptation after surgical treatment for localized renal cell carcinoma: impact of the amount of remaining renal tissue.

OBJECTIVESnTo analyze the quality of life and psychological adjustment after surgical therapy for localized renal cell carcinoma.nnnMETHODSnPostal questionnaires including measures of quality of life (SF-36) and the impact of the stress of cancer (Impact of Events Scale) were completed by 97 patients who had undergone radical or partial nephrectomy for localized renal cell carcinoma. Data were analyzed for the group as a whole and comparing the partial nephrectomy and radical nephrectomy groups. The variables examined included the impact of the type of partial nephrectomy (elective versus mandatory) and the amount of self-reported renal tissue remaining.nnnRESULTSnThe quality of life for the group as a whole was good, with no significant differences between the sample and U.S. norms for an age and sex-matched community sample on both the mental and physical health composite scores. Having undergone a partial versus a radical nephrectomy did not influence the patients overall quality of life. Multiple linear regression modeling demonstrated that having more remaining renal parenchyma was an independent predictor of better self-reported physical health on the SF-36 (P <0.001). The entire sample had low mean scores on both avoidance and intrusion on the Impact of Events Scale, suggesting a lack of daily anxiety about cancer. Multiple linear regression modeling showed that patients who reported having more remaining renal parenchyma had lower intrusion and avoidance scores (P = 0.002 and 0.01, respectively). Multiple logistic regression modeling also demonstrated that the patients perception of their remaining renal parenchyma was associated with less concern about cancer recurrence (P = 0.018) and less impact of cancer on patients overall health (P <0.001).nnnCONCLUSIONSnMost survivors of localized kidney cancer have normal physical and mental health regardless of the type of nephrectomy performed. The quality of life is better for patients with more renal parenchyma remaining after surgery for localized renal cell carcinoma.

Renal cell carcinoma–derived gangliosides suppress nuclear factor-κB activation in T cells

Activation of the transcription factor nuclear factor-kappaB (NFkappaB) is impaired in T cells from patients with renal cell carcinomas (RCCs). In circulating T cells from a subset of patients with RCCs, the suppression of NFkappaB binding activity is downstream from the stimulus-induced degradation of the cytoplasmic factor IkappaBalpha. Tumor-derived soluble products from cultured RCC explants inhibit NFkappaB activity in T cells from healthy volunteers, despite a normal level of stimulus-induced IkappaBalpha degradation in these cells. The inhibitory agent has several features characteristic of a ganglioside, including sensitivity to neuraminidase but not protease treatment; hydrophobicity; and molecular weight less than 3 kDa. Indeed, we detected gangliosides in supernatants from RCC explants and not from adjacent normal kidney tissue. Gangliosides prepared from RCC supernatants, as well as the purified bovine gangliosides G(m1) and G(d1a), suppressed NFkappaB binding activity in T cells and reduced expression of the cytokines IL-2 and IFN-gamma. Taken together, our findings suggest that tumor-derived gangliosides may blunt antitumor immune responses in patients with RCCs.

LAPAROSCOPIC RETROPERITONEAL LIVE DONOR RIGHT NEPHRECTOMY FOR PURPOSES OF ALLOTRANSPLANTATION AND AUTOTRANSPLANTATION

PURPOSEnWe report the technique of and initial experience with retroperitoneal laparoscopic live donor right nephrectomy for purposes of renal allotransplantation and autotransplantation.nnnMATERIALS AND METHODSnA total of 5 patients underwent retroperitoneoscopic live donor nephrectomy of the right kidney for autotransplantation in 4 and living related renal donation in 1. Indications for autotransplantation included a large proximal ureteral tumor, a long distal ureteral stricture and 2 cases of the loin pain hematuria syndrome. In all cases a 3-port retroperitoneal laparoscopic approach and a pelvic muscle splitting Gibson incision for kidney extraction were used. In patients undergoing autotransplantation the same incision was used for subsequent transplantation.nnnRESULTSnAll procedures were successfully accomplished without technical or surgical complications. Total mean operating time was 5.8 hours and average laparoscopic donor nephrectomy time was 3.1 hours. Mean renal warm ischemia time, including endoscopic cross clamping of the renal artery to ex vivo cold perfusion, was 4 minutes. Average blood loss for the entire procedure was 400 cc. Radionuclide scan on postoperative day 1 confirmed good blood flow and function in all transplanted kidneys. Mean analgesic requirement was 58 mg. fentanyl. Mean hospital stay was 4 days (range 2 to 8), and convalescence was completed in 3 to 4 weeks.nnnCONCLUSIONSnIn the occasional patient requiring renal autotransplantation live donor nephrectomy can be performed laparoscopically with renal extraction and subsequent transplantation through a single standard extraperitoneal Gibson incision, thus, minimizing the overall operative morbidity. Furthermore, these data demonstrate that live donor nephrectomy of the right kidney can be performed safely using a retroperitoneal approach with an adequate length of the right renal vein obtained for allotransplantation or autotransplantation.

Renal Cell Carcinoma Invading the Urinary Collecting System: Implications for Staging

PURPOSEnCurrent TNM staging of renal cell carcinoma is based on the tumor propensity for local extension (T), nodal involvement (N) and metastatic spread (M). Locally advanced renal cell carcinoma may involve the perirenal fat, adrenal glands, renal vein, vena cava and/or urinary collecting system. The existing TNM classification does not reflect the ability of renal cell carcinoma to invade the urothelium. We evaluated the incidence and characteristics as well as overall and cancer specific survival of renal cell carcinoma invading the urinary collecting system.nnnMETHODS AND MATERIALSnWe reviewed pathological findings in 504 kidneys from 475 patients with renal cell carcinoma who presented to our institution in a 3-year period. Urothelial involvement required evidence of gross or histological invasion of the renal calices, infundibulum, pelvis or ureter. Demographic and survival data were obtained from medical records and an institutional cancer registry for tumors invading the urothelium. Stage specific survival data were then compared with tumors not involving the urinary collecting system.nnnRESULTSnDefinitive urothelial involvement by the primary tumor was interpretable in 426 of 504 kidneys. Invasion of the collecting system was identified in 61 of 426 cases (14%). Mean diameter of the invading lesions was 10.2 cm. (range 3 to 26). The majority of cases showed clear cell and sarcomatoid histology. Invasion by a papillary lesion was rare. Involvement of the collecting system was most common at the renal poles. Of 61 lesions invading the collecting system 48 (79%) were stage pT3 or greater, while only 13 (21%) were pathologically localized stage pT2 or less. Vascular invasion was identified in 38 renal cell carcinoma cases (62%) with urothelial involvement. A total of 16 cases (26%) were associated with vena caval thrombus. Invading tumors were high Fuhrman grade III or IV in 43 cases (70%). Overall disease specific survival was poor with a median of 19 months. In patients with localized stage pT1 or pT2N0M0 disease and urothelial invasion median disease specific survival was 46 months.nnnCONCLUSIONSnRenal cell carcinoma lesions involving the renal collecting system are characteristically large, high grade and high stage. Clear cell carcinoma most commonly invades, while invasion by papillary tumors is rare. Overall the prognosis for high stage lesions with urothelial involvement is poor and does not appear significantly different from the reported disease specific survival of patients with high stage lesions without urothelial invasion. Localized tumors 4 cm. or less, which are amenable to elective nephron sparing surgery, rarely invade the urothelium. However, when a low stage pT2 or less renal lesion involves the urinary space, survival appears worse than equivalently staged renal cell carcinoma without invasion. Including urothelial invasion into current TNM staging systems for renal cell carcinoma is unlikely to provide significant additional prognostic or therapeutic information.

Comparison of direct hospital costs and length of stay for radical nephrectomy versus nephron-sparing surgery in the management of localized renal cell carcinoma

OBJECTIVESnRecent work has demonstrated comparable surgical results and 5-year cancer-specific survival rates between radical nephrectomy and nephron-sparing surgery (NSS) in the treatment of patients with small (4 cm or smaller) solitary renal cell carcinomas (RCCs). However, differences exist in the intraoperative management and postoperative care of patients undergoing NSS versus radical nephrectomy, and we sought to compare direct hospital costs and length of stay (LOS) between these two groups to determine whether either treatment imparts a specific cost advantage.nnnMETHODSnData were retrieved from medical records and administrative data sets containing billing encounters for all costs incurred during hospitalization at the Cleveland Clinic Foundation. Individual costs were grouped together using nine cost center categories encompassing every aspect of direct hospital care, including anesthesiology, laboratory, radiology, nursing, pharmaceutical, and emergency services, and medical care, surgical care, and miscellaneous costs. Each cost center was further subdivided, and a total of 52 cost subcategories were assessed. The total direct costs of hospitalization were compared using a multivariate regression model in which patient demographics and tumor characteristics, type and year of surgery, LOS, and cost center categories were assessed as single and interactive factors. Postoperative complication and cancer-specific survival rates were also compared to identify any potential therapeutic differences between the two groups.nnnRESULTSnBetween 1991 and 1995, 80 patients underwent surgery at the Cleveland Clinic Foundation for solitary RCCs 4 cm or smaller, including 52 partial and 28 radical nephrectomies. We found no difference in the postoperative complication rate or cancer-specific survival rate between the two surgical groups. Total direct hospital costs and LOS were not statistically different between the NSS and radical nephrectomy groups (P >0.05). This was further supported by our multivariate model, which accounted for 61% of the observed variance in the total costs (F = 12.11, P = 0.0001). The type of surgery was not associated with total cost when controlling for all other factors, including age, sex, year of surgery, tumor size, grade, and stage, and postoperative complications (P = 0.7). There was no significant interaction between the type of surgery and the LOS (P = 0.5).nnnCONCLUSIONSnThis study demonstrated that elective NSS can be performed with equivalent direct hospital costs and LOS when compared with patients undergoing radical nephrectomy for small solitary RCCs. These data have significant economic implications for the comparison of competing surgical treatment strategies for localized RCC.

Caspase-dependent and -independent death pathways in cancer therapy

The majority of current anticancer therapies induce tumor cell death through the induction of apoptosis. Alterations in the apoptotic pathways may determine tumor resistance to these therapies. Activation of the proteolytic cascade involving caspase family members is a critical component of the execution of cell death in apoptotic cells. However, recent studies suggest that cell death can proceed in the absence of caspases. In this review we describe the role of caspase-dependent and -independent pathways as targets for anticancer treatment; better understanding of diverse modes of tumor cell death will help to avoid ineffective treatment and provide a molecular basis for the new strategies targeting caspase-independent death pathways in apoptosis-resistant forms of cancer.

Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes.

Alterations in intracellular Zn2+ concentrations are believed to play a crucial role in modulating apoptosis. The observation that Zn2+ deficiency can induce cell death both in vivo and in vitro has been attributed to the fact that exchange of Zn2+ for Ca2+ and Mg2+ within the nuclei may directly activate endogenous endonucleases therefore inducing DNA fragmentation independent of cytoplasmic factors. Here we show that the membrane-permeable zinc chelator, N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces translocation of cytochrome c from the mitochondrial intramembranous space into the cytosol in human peripheral blood T lymphocytes (PBL) with subsequent activation of caspases-3, -8, and -9. Pretreatment of T lymphocytes with caspase inhibitors Z-VAD.fmk or DEVD.fmk prevented DNA fragmentation in response to TPEN indicating that apoptosis triggered by zinc deficiency is entirely dependent on activation of caspase family members. The release of cytochrome c and activation of downstream caspases precedes changes in the mitochondrial transmembrane potential (Δ Ψm). Therefore, cytoplasmic and mitochondrial events are critical to this process.

Preoperative use of 3D volume rendering to demonstrate renal tumors and renal anatomy.

With increased use of computed tomography (CT) and abdominal ultrasonography, the indications for nephron-sparing surgery are also increasing. Triphasic helical CT and three-dimensional (3D) volume rendering can be combined into a single noninvasive test to delineate renal tumors and normal and complex renal anatomy prior to nephron-sparing surgery. This combination technique has proved accurate and very useful for both preoperative and intraoperative planning by demonstrating renal position, tumor location and depth of tumor extension into the kidney, relationship of the tumor to the collecting system, and renal vascular anatomy. Knowledge of the position of the kidney relative to the lower rib cage, iliac crest, and spine helps in planning the initial surgical incision. By depicting tumor location and depth of extension, helical CT with 3D volume rendering helps ensure complete tumor excision and conservation of adjacent normal renal parenchyma. Depiction of the relationship of the tumor to the collecting system helps anticipate further tumor extension and minimize postoperative complications. Identification of normal renal vasculature and anatomic variants can help minimize ischemic injury and intraoperative bleeding. Radiologists should be familiar with current indications for nephron-sparing surgery and understand what information is required prior to surgery.