Jacob P. Debelak

Hepatic Cryoablation, But Not Radiofrequency Ablation, Results in Lung Inflammation

OBJECTIVE To compare the effects of 35% hepatic cryoablation with a similar degree of radiofrequency ablation (RFA) on lung inflammation, nuclear factor kappaB (NF-kappaB) activation, and production of NF-kappaB dependent cytokines. SUMMARY BACKGROUND DATA Multisystem injury, including acute lung injury, is a severe complication associated with hepatic cryoablation of 30% to 35% or more of liver parenchyma, but this complication has not been reported with RFA. METHODS Sprague-Dawley rats underwent 35% hepatic cryoablation or RFA and were killed at 1, 2, and 6 hours. Liver and lung tissue were freeze-clamped for measurement of NF-kappaB activation, which was detected by electrophoretic mobility shift assay. Serum concentrations of tumor necrosis factor alpha and macrophage inflammatory protein 2 were measured by enzyme-linked immunosorbent assay. Histologic studies of pulmonary tissue and electron microscopy of ablated liver tissue were compared among treatment groups. RESULTS Histologic lung sections after cryoablation showed multiple foci of perivenular inflammation, with activated lymphocytes, foamy macrophages, and neutrophils. In animals undergoing RFA, inflammatory foci were not present. NF-kappaB activation was detected at 1 hour in both liver and lung tissue samples of animals undergoing cryoablation but not after RFA, and serum cytokine levels were significantly elevated in cryoablation versus RFA animals. Electron microscopy of cryoablation-treated liver tissue demonstrated disruption of the hepatocyte plasma membrane with extension of intact hepatocyte organelles into the space of Disse; RFA-treated liver tissue demonstrated coagulative destruction of hepatocyte organelles within an intact plasma membrane. To determine the stimulus for systemic inflammation, rats treated with cryoablation had either immediate resection of the ablated segment or delayed resection after a 15-minute thawing interval. Immediate resection of the cryoablated liver tissue prevented NF-kappaB activation and lung injury; however, pulmonary inflammatory changes were present when as little as a 15-minute thaw interval preceded hepatic resection. CONCLUSIONS Hepatic cryoablation, but not RFA, induces NF-kappaB activation in the nonablated liver and lung and is associated with acute lung injury. Lung inflammation is associated with the thawing phase of cryoablation and may be related to soluble mediator(s) released from the cryoablated tissue. These findings correlate the clinical observation of an increased incidence of multisystem injury, including adult respiratory distress syndrome (ARDS), after cryoablation but not RFA.

Acute lung injury after hepatic cryoablation: Correlation with NF-κB activation and cytokine production

Background: Previous clinical reports have documented multisystem organ injury after hepatic cryoablation. We hypothesized that hepatic cryosurgery, but not partial hepatectomy, induces a systemic inflammatory response characterized by distant organ injury and overproduction of nuclear factor κB (NF-κB)–dependent, proinflammatory cytokines. Methods: In this study, rats underwent either cryoablation of 35% of liver parenchyma or a similar resection of left hepatic tissue. Serum tumor necrosis factor-α and macrophage inflammatory protein-2 levels and NF-κB activation were assessed by electrophoretic mobility shift assay at 30 minutes 1, 2, 6, and 24 hours after either procedure. Results: Cryoablation of 35% of liver (n = 22 rats) resulted in lung injury and a 45% mortality rate within 24 hours of surgery, whereas 7% treated with 35% hepatectomy (n = 15 rats) died during the 24 hours after surgery (P < .05, cryoablation vs hepatectomy). Serum tumor necrosis factor-α and macrophage inflammatory protein-2 levels were markedly increased in rats (n = 10 rats) 1 hour after hepatic cryoablation compared with rats that underwent partial hepatectomy (P < .005). We evaluated NF-κB activation by electrophoretic mobility shift assay in nuclear extracts of liver and lung after cryosurgery and found that NF-κB activation was strikingly increased in the liver but not the lung at 30 minutes and in both organs 1 hour after cryosurgery, and returned to baseline in both organs by 2 hours. In rats undergoing 35% hepatectomy, no increase in NF-κB activation was detected in nuclear extracts of either liver or lung at any time point. Conclusions: These data show that hepatic cryosurgery results in systemic inflammation with activation of NF-κB and increased production of NF-κB–dependent cytokines. Our data suggest that lung injury and death in this animal model is mediated by an exaggerated inflammatory response to cryosurgery. (Surgery 1999:126:518-26.)

Transcatheter arterial chemoembolization as primary treatment for hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma (HCC) in Western populations has historically been associated with poor survival. METHODS In this study, we conducted a 7-year retrospective analysis of patients with HCC undergoing transcatheter arterial chemoembolization (TACE) at our institution and examined demographics, outcomes, and complications. RESULTS During the period of study, 39 patients (25 male [64%], mean age 58 [range 17 to 86]) underwent a total of 78 chemoembolization treatments. During the same time period, an additional 31 patients received supportive care only. The majority of patients had late stage disease (American Joint Committee on Cancer stage III, IVa, or IVb) with no statistical difference noted between the two groups (P = 0.2). However, patients receiving supportive care only had significantly worse hepatic dysfunction by Childs classification (P = 0.005). Twenty-nine patients (74%) had documented cirrhosis, with hepatitis C being the most common cause in 11 of 29 (38%). In patients undergoing TACE, overall actuarial survival was 35%, 20%, and 11% at 1, 2, and 3 years with a median survival of 9.2 months, significantly improved over the group receiving supportive care only (P < 0.0001). Median survival for the group receiving supportive care was less than 3 months. Neither age nor stage had a significant impact on survival. The most common complications of TACE included transient nausea, abdominal pain, vomiting, and fever. CONCLUSIONS TACE is a safe and effective therapeutic option for selected patients with HCC not amenable to surgical intervention.

Hepatic cryoablation-induced multisystem injury: Bioluminescent detection of NF-κB activation in a transgenic mouse model

Hepatic injury from cryoablation has been associated with multisystem injury, including adult respiratory distress syndrome, renal insufficiency, and coagulopathy; but the responsible mechanisms have not been well defined. In the present study we investigated the role of the transcription factor NF-kB in the multiorgan inflammatory response to hepatic cryoablation utilizing a novel in vivo system for determining NF-kB activity. Using transgenic mice expressing photinus luciferase under the control of the 5′ HIV-LTR (an NF-KB-dependent promoter), we measured luciferase activity in the liver, lungs, and kidneys as a marker for NF-kB activity. Luciferase production was determined by in vivo bioluminescence and by luciferase assays of tissue homogenates. After measurement of basal luciferase activity, mice were treated with 35% hepatic cryoablation or sham laparotomy and injected with luciferin (0.75 mg/mouse). Photon emission from the liver, lungs, and kidneys was measured at multiple time points. Hepatic cryoablation induced a significant increase in photon emission by the liver, lungs, and kidneys, which correlated with markedly increased luciferase activity measured from each organ after death. Lung lavage 4 hours after cryoablation showed neutrophilic lung inflammation with increased MIP-2 levels compared with sham surgery. These findings demonstrate that 35% hepatic cryoablation is associated with NF-kB activation in the remnant liver and multiple distant sites, and may be causally related to the multisystem injury that is seen after direct liver injury.

Technical advances toward interactive image-guided laparoscopic surgery

AbstractBackground: Laparoscopic surgery uses real-time video to display the operative field. Interactive image-guided surgery (IIGS) is the real-time display of surgical instrument location on corresponding computed tomography (CT) scans or magnetic resonance images (MRI). We hypothesize that laparoscopic IIGS technologies can be combined to offer guidance for general surgery and, in particular, hepatic procedures. Tumor information determined from CT imaging can be overlayed onto laparoscopic video imaging to allow more precise resection or ablation. Methods: We mapped three-dimensional (3D) physical space to 2D laparoscopic video space using a common mathematical formula. Inherent distortions present in the video images were quantified and then corrected to determine their effect on this 3D to 2D mapping. Results: Errors in mapping 3D physical space to 2D video image space ranged from 0.65 to 2.75 mm. Conclusions: Laparoscopic IIGS allows accurate (<3.0 mm) confirmation of 3D physical space points on video images. This in combination with accurately tracked instruments and an appropriate display may facilitate enhanced image guidance during laparoscopy.