Laparoscopic partial nephrectomy for hilar tumors: technique and results

BACKGROUND: Laparoscopic partial nephrectomy for hilar tumors is a cutting edge procedure for which little data is available in the current literature. OBJECTIVE: To describe our technique and results of laparoscopic partial nephrectomy for renal hilar tumors. DESIGN, SETTING, AND PARTICIPANTS: Between April 2000 and September 2006, 94 partial laparoscopic nephrectomies were performed at our institution. A total of 18 (19.1%) patients had hilar tumors. A hilar tumor was defined as a lesion suspicious for renal cell carcinoma in contact with a major renal vessel on preoperative cross-sectional imaging. In 3 (16.7%) of the patients, the indication for nephron-sparing surgery was imperative. Mean tumor size was 3cm (range, 2-4.5). Eight (44.4%) surgeries were performed with renal artery perfusion for cold ischemia; the remaining surgeries were performed under warm ischemia. INTERVENTION(S): After occluding the renal artery and controlling the renal vein by using separate rubber band tourniquets, we excised the tumor mass including delicate mobilization away from the blood vessels. Although we used to insert a ureteral stent at the beginning of our experience with laparoscopic partial nephrectomies, we no longer do so. All surgeries were performed by a single urologist (G.J.). MEASUREMENTS: Operative time, ischemia time, blood loss, renal function using the Cockroft formula as well as renal scans, operative and post-operative complications, pathology parameters. RESULTS AND LIMITATIONS: All surgeries were completed laparoscopically. Mean surgical time was 238min (range, 150-420). Mean ischemia times were 42.5min (range, 27-63) and 34.1min (range, 24-56) for the cold and warm ischemia groups, respectively. Estimated intraoperative blood loss was 165ml (range, 50-500). There were two (11%) entries into major vessels during tumor excision, namely a segmental renal artery in one patient and a segmental renal vein in another. Both of these occurrences were managed laparoscopically. One patient necessitated laparoscopic reexploration for urine extravasation in the immediate postoperative period. All postoperative nuclear scans (available in 12 of 18 patients) showed functional kidney moiety. Mean split renal function was 38.6% (range, 24-50) on the operated side. Histopathological examination confirmed renal cell carcinoma in 14 (77.8%) of the patients. One (7.1%) patient had a positive surgical margin on the surface that was adjacent to the renal artery. In a median follow-up of 26 mo (range, 1-59), no local recurrence or systemic progression occurred. CONCLUSION: Laparoscopic partial nephrectomy for hilar tumors is a feasible and safe procedure in the hands of experienced laparoscopic surgeons. Oncological results seem excellent, but further follow-up is needed for accurate long-term assessment of this surgical approach.     

Long-term results of a multicenter randomized study on direct versus crossover bypass for unilateral iliac artery occlusive disease

OBJECTIVE: To compare late patency after direct and crossover bypass in good-risk patients with unilateral iliac occlusive disease not amenable to angioplasty. METHODS: Between May 1986 and March 1991, 143 patients with unilateral iliac artery occlusive disease and disabling claudication were randomized into two surgical treatment groups, ie, crossover bypass (n = 74) or direct bypass (n = 69). The size of the patient population was calculated to allow detection of a possible 20% difference in patency in favor of direct bypass with a one-sided alpha risk of 0.05 and a beta risk of 0.10. Patients underwent yearly follow-up examinations using color flow duplex scanning with ankle-brachial systolic pressure index measurement. Digital angiography was performed if hemodynamic abnormalities were noted. Median follow-up was 7.4 years. Primary endpoints were primary patency and assisted primary patency estimated by the Kaplan-Meier method with 95% confidence interval. Secondary endpoints were secondary patency and postoperative mortality and morbidity. RESULTS: Cardiovascular risk factors, preoperative symptoms, iliac lesions TASC class (C in 87 [61%] patients and D in 56 [39%] patients), and superficial femoral artery (SFA) run-off were comparable in the two treatment groups. One patient in the direct bypass group died postoperatively. Primary patency at 5 years was higher in the direct bypass group than in the crossover bypass group (92.7 +/- 6.1% vs 73.2 +/- 10%, P = .001). Assisted primary patency and secondary patency at 5 years were also higher after direct bypass than crossover bypass (92.7 +/- 6.1% vs 84.3 +/- 8.5%, P = .04 and 97.0 +/- 3.0% vs 89.8 +/- 7.1%, P = .03, respectively). Patency at 5 years after crossover bypass was significantly higher in patients presenting no or low-grade SFA stenosis than in patients presenting high-grade (> or =50%) stenosis or occlusion of the SFA (74.0 +/- 12% vs 62.5 +/- 19%, P = .04). In both treatment groups, patency was comparable using polytetrafluoroethylene (PTFE) and polyester grafts. Overall survival was 59.5 +/- 12% at 10 years. CONCLUSION: This study showed that late patency was higher after direct bypass than crossover bypass in good-risk patients with unilateral iliac occlusive disease not amenable to angioplasty. Crossover bypass should be reserved for high-risk patients with unilateral iliac occlusion not amenable to percutaneous recanalization.     

Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles

Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor alpha (TNF-alpha) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-alpha release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF-alpha production.     

Risk of second cancers in the era of modern radiation therapy: does the risk/benefit analysis overcome theoretical models?

In the era of modern radiation therapy, the compromise between the reductions in deterministic radiation-induced toxicities through highly conformal devices may be impacting the stochastic risk of second malignancies. We reviewed the clinical literature and evolving theoretical models evaluating the impact of intensity-modulated radiation therapy (IMRT) on the risk of second cancers, as a consequence of the increase in volumes of normal tissues receiving low doses. The risk increase (if any) is not as high as theoretical models have predicted in adults. Moreover, the increase in out-of-field radiation doses with IMRT could be counterbalanced by the decrease in volumes receiving high doses. Clinical studies with short follow-up have not corroborated the hypothesis that IMRT would drastically increase the incidence of second cancers. In children, the risk of radiation-induced carcinogenesis increases from low doses and consequently the relative risk of second cancers after IMRT could be higher than in adults, justifying current developments of proton therapy with priority given to this population. Although only longer follow-up will allow a true assessment of the real impact of these modern techniques on radiation-induced carcinogenesis, a comprehensive risk-adapted strategy will help minimize the probability of second cancers.     

Analysis of a large fMRI cohort: Statistical and methodological issues for group analyses

The aim of group fMRI studies is to relate contrasts of tasks or stimuli to regional brain activity increases. These studies typically involve 10 to 16 subjects. The average regional activity statistical significance is assessed using the subject to subject variability of the effect (random effects analyses). Because of the relatively small number of subjects included, the sensitivity and reliability of these analyses is questionable and hard to investigate. In this work, we use a very large number of subject (more than 80) to investigate this issue. We take advantage of this large cohort to study the statistical properties of the inter-subject activity and focus on the notion of reproducibility by bootstrapping. We asked simple but important methodological questions: Is there, from the point of view of reliability, an optimal statistical threshold for activity maps? How many subjects should be included in group studies? What method should be preferred for inference? Our results suggest that i) optimal thresholds can indeed be found, and are rather lower than usual corrected for multiple comparison thresholds, ii) 20 subjects or more should be included in functional neuroimaging studies in order to have sufficient reliability, iii) non-parametric significance assessment should be preferred to parametric methods, iv) cluster-level thresholding is more reliable than voxel-based thresholding, and v) mixed effects tests are much more reliable than random effects tests. Moreover, our study shows that inter-subject variability plays a prominent role in the relatively low sensitivity and reliability of group studies.     

MRI monitoring of focal cerebral ischemia in peroxisome proliferator-activated receptor (PPAR)-deficient mice

Peroxisome proliferator-activated receptors (PPARs) are a potential target for neuroprotection in focal ischemic stroke. These nuclear receptors have major effects in lipid metabolism, but they are also involved in inflammatory processes. Three PPAR isotypes have been identified: alpha, beta (or delta) and gamma. The development of PPAR transgenic mice offers a promising tool for prospective therapeutic studies. This study used MRI to assess the role of PPARalpha and PPARbeta in the development of stroke. Permanent middle cerebral artery occlusion induced focal ischemia in wild-type, PPARalpha-null mice and PPARbeta-null mice. T(2)-weighted MRI was performed with a 7 T MRI scan on day 0, 1, 3, 7 and 14 to monitor lesion growth in the various genotypes. General Linear Model statistical analysis found a significant difference in lesion volume between wild-type and PPAR-null mice for both alpha and beta isotypes. These data validate high-resolution MRI for monitoring cerebral ischemic lesions, and confirm the neuroprotective role of PPARalpha and PPARbeta in the brain.