Efficiency of combined blocking of aerobic and glycolytic metabolism pathways in treatment of N1-S1 hepatocellular carcinoma in a rat model.

BACKGROUND/AIM: The aim of this study was to determine whether the addition of bumetanide (BU), a glycolytic metabolism pathway inhibitor, to arterial embolization improves tumor necrosis of N1-S1 hepatocellular carcinoma in a rat model. MATERIALS AND METHODS: N1-S1 tumors were surgically implanted in the liver of 14 Sprague-Dawley rats. The rats were divided into three groups: In control group (n = 5), 1 ml of normal saline was injected intra-arterially. The tumor in the transarterial embolization group (TAE, n = 4) was embolized using 10 mg of 50-150 µ polyvinyl alcohol (PVA) particles and embolization plus BU group (TAE + BU, n = 5) were embolized with 10 mg of PVA plus 0.04 mg/kg of BU. Tumor volume was measured using two-dimensional ultrasound before intervention and twice a week afterward. Relative tumor volume after the intervention was calculated as the percentage of preinterventional tumor volume. After 4 weeks of observation, the rats were sacrificed for histopathological evaluation. RESULTS: No statistically significant difference was detected in the preintervention tumor sizes between the three groups (P > 0.05). In the control group, the relative tumor volume increased to 142.5% larger than baseline measurements. In the TAE group, the tumor volume decreased by 18.2 ± 12.2%. The tumor volume in the TAE + BU group decrease by 90.4 ± 10.2%, which was 72.2% more than in TAE only group (P < 0.0001). Histopathological evaluation demonstrated no residual tumor in the TAE + BU group. CONCLUSION: Tumor necrosis significantly increased in N1-S1 tumor that received BU at the time of TAE when compared to TAE alone.

Cinnamic Acid Derivatives Enhance the Efficacy of Transarterial Embolization in a Rat Model of Hepatocellular Carcinoma.

INTRODUCTION: We hypothesize that the combination of transarterial embolization (TAE) plus inhibition of lactate export will limit anaerobic metabolism and reduce tumor survival compared to TAE alone. The purpose of this study was to test this hypothesis in a rat model of hepatocellular carcinoma (HCC). METHODS: Rat N1-S1 hepatoma cells were assayed in vitro using the Seahorse XF analyzer to measure extracellular acidification (lactate excretion) comparing effects of the addition of caffeic acid (CA) or ferulic acid (FA) or UK-5099 with control. Monocarboxylate transporter Slc16a3 was knocked down by RNAi. N1S1 tumors were orthotopically implanted in rats and 4 groups evaluated: (1) Control, (2) TAE-only, (3) TAE plus CA, and (4) TAE plus FA. Tumor size was determined by ultrasound and analyzed by repeated measures statistics. Tumors harvested at 4 weeks were examined by microscopy. RESULTS: Seahorse assays showed that CA and FA caused a significant reduction by >90% in lactate efflux by N1S1 tumor cells (p < 0.01). Knockdown of Slc16a3 prevented inhibition by CA. In vivo tumors grew 30-fold in volume over 4 weeks in untreated controls. By comparison, TAE resulted in near cessation of growth (10% in 4-week time period). However, both TAE + CA and TAE + FA caused a significant reduction of tumor volumes (87 and 72%, respectively) compared to control and TAE (p < 0.05). Pathologic evaluation revealed residual tumor in the TAE group but no residual viable tumor cells in the TAE + CA and TAE + FA groups. CONCLUSION: Addition of CA or FA enhances the effectiveness of TAE therapy for HCC in part by blocking lactate efflux.

ALPHA glycolytic vasculogenesis better correlates with MRI and CT imaging techniques than the traditional oxygen vasculogenesis theory.

OBJECTIVE: Traditional vasculogenesis has many contradictions related to treatment and imaging. This occurs because cancer also uses glycolysis, which does not need oxygen or arteries. Glycolytic lactate supports many procancer processes but high levels of it inhibit glycolysis. CONCLUSION: To avoid this, lactate induces vascular growth factors that initiate glycolytic vasculogenesis ALPHA (acidic lactate sequentially induces first lymphangiogenesis, phlebogenesis, and then arteriogenesis). The sequence of vessel development is lymphatics, veins, and then arteries. Modern contrast imaging depends more on veins than arteries, which is more consistent with ALPHA than the traditional theory.

Squamous cell carcinoma arising from ovarian mature cystic teratoma and causing small bowel obstruction.

Malignant transformation of mature cystic teratoma (MCT) is a rare phenomenon with incidence of approximately 1-3%. We report a 48-year-old woman who presented to the emergency room with symptoms of bowel obstruction. She underwent computed tomography scan for the evaluation of obstruction, which demonstrated diffuse ascites accompanying a cystic pelvic to lower abdominal mass which had invaded into the adjacent small bowel causing partial small bowel obstruction. Histologically, the mass demonstrated a MCT within which aroused a well-differentiated squamous cell carcinoma. Exploratory laparotomy was performed to confirm the diagnosis and debulking of the mass was performed.

Real-time monitoring of radiofrequency ablation and postablation assessment: accuracy of contrast-enhanced US in experimental rat liver model.

PURPOSE: To examine the accuracy of the unenhanced zone at contrast material-enhanced ultrasonography (US) in predicting coagulative necrosis during and 21 days after radiofrequency (RF) ablation by using radiologic-pathologic comparison. MATERIALS AND METHODS: Animal studies were approved by the Institutional Animal Care and Use Committee. The livers of 28 rats underwent US-guided RF ablation. In four animals, contrast-enhanced US was performed during ablation and 2 hours and 2, 7, 14, and 21 days after ablation. The unenhanced zone area on US images was measured. DiI-labeled microbubbles were administered during ablation at 2, 4, and 6 minutes or at 2 hours and 2, 7, 14, and 21 days after ablation in the remaining 24 animals (n = 3 at each time point). One minute later, the animal was euthanized, and the ablated liver was harvested. Tissue samples were imaged to quantify total fluorescence, and NADH staining was performed on the same slice. Hematoxylin-eosin staining was also performed. The findings on fluorescence images, NADH-stained images, and hematoxylin-eosin-stained images were compared. The areas of DiI bubble-negative zones, NADH-negative zones, and lightly NADH-staining zones were measured. Data were analyzed by using one-way analysis of variance. RESULTS: The area of the unenhanced zone on contrast-enhanced US images increased during RF ablation and reached a maximum within 2 days after ablation. At histopathologic examination, a transition zone manifested adjacent to the coagulation zone until 2 days after ablation. The DiI-bubble negative zone on fluorescence images and the damaged zone (transition zone plus coagulation zone) on NADH-stained images increased rapidly within 2 hours after ablation, then slowly reached the maximum on day 2. The ratios of the mean areas of these two zones at hour 2 to those at day 2 were 94.6% and 95.6%, respectively. High uniformity between the damaged zone on NADH-stained images and the DiI bubble-negative zone on fluorescence images was noted at all time points. CONCLUSION: The temporary transition zone in NADH staining is partially damaged and should transition to nonviability 2 days after ablation. These results demonstrate that contrast-enhanced US can help delineate the maximum area of cell damage (to within 5% of the maximum) as early as 2 hours after ablation. Contrast-enhanced US may be a simple and accurate tool for monitoring the effects of RF ablation and quantifying the size of thermal damage after treatment.

Acidic lactate sequentially induced lymphogenesis, phlebogenesis, and arteriogenesis (ALPHA) hypothesis: Lactate-triggered glycolytic vasculogenesis that occurs in normoxia or hypoxia and complements the traditional concept of hypoxia-based vasculogenesis.

Our hypothesis, ALPHA (Acidic Lactate sequentially induced Lymphogenesis, PHlebogenesis, and Arteriogenesis) proposes that lactate triggers vasculogenesis to manage lactate levels and complements the traditional vasculogenesis hypothesis. The teleologic basis for glycolytic vasculogenesis is primariy to produce drainage vessels, initially lymphatics but subsequently veins.

Pneumodissection: an alternative protective technique for the percutaneous cryoablation of small renal masses.

INTRODUCTION: Percutaneous cryoablation is an emerging treatment option for the small renal mass. It poses a risk of thermal injury to adjacent tissues, limiting its application. We describe pneumodissection, a novel technique for preventing thermal injury during percutaneous cryoablation. MATERIALS AND METHODS: The cases of 4 patients who underwent percutaneous renal cryoablation and pneumodissection were retrospectively reviewed. RESULTS: Pneumodissection mechanically separated four tumors from overlying bowel segments (mean distance 1.2 ± 0.4 cm), permitting successful cryoablation. There were no complications or recurrences with 7.5 months of follow-up. CONCLUSIONS: Pneumodissection is a feasible displacement technique that facilitates percutaneous cryoablation in at-risk patients. Further study is warranted.

Image-guided biopsy of small renal masses in the era of ablative therapies.

OBJECTIVE: To further evaluate the accuracy, safety, and impact of image-guided renal biopsies on clinical decision making and management of the indeterminate small renal masses. METHODS: A total of 145 patients (males 99, females 46) with small renal masses suspicious for malignancy were evaluated during the study period. The patients' mean age was 67.2 (± 11.6) years. Computed tomography guided biopsies were carried out in all cases by an experienced interventional radiologist. An experienced genitourinary pathologist reviewed all pathological specimens. Patients' demographic characteristics, tumor histology and subsequent intervention, as well as periprocedural morbidities were recorded and analyzed. RESULTS: A total of 145 renal biopsy procedures were carried out. The small renal masses mean size was 2.4 ± 1.1 cm. Biopsy was diagnostic in 126 (86.9%) cases and non-diagnostic in 19 (13.1%) cases. Of diagnostic biopsies, 107 (84.9%) were malignant, 84.1% of which were primary renal cell carcinoma. Histological subtyping and grading of tumor was possible in 100% and 52.2% of renal cell carcinomas, respectively. The major renal cell carcinoma subtype was clear cell (63.3%) followed by papillary (24.4%) and chromophobe (8.8%). Repeat biopsy was carried out in nine of 19 non-diagnostic cases, and diagnosis was possible in 66.7%. Sensitivity of percutaneous renal biopsy was 91%, and its accuracy was 85.5%. Overall, patients' age, sex, tumor size, and location were not related to non-diagnostic biopsy results and/or tumor pathology. No cases of hemorrhage, seeding of biopsy tract, infection or mortalities were observed. CONCLUSIONS: Our findings showed that image-guided biopsy of indeterminate small renal masses is safe and can provide the correct diagnosis with a high degree of accuracy. Thus, this procedure can play an important role in establishing a histopathological diagnosis before treatment of enhancing small renal masses with ablative technologies. Furthermore, repeat biopsy can alter the clinical management of non-diagnostic biopsies.

Radiofrequency ablation: effect of tumor- and organ-specific pharmacologic modulation of arterial and portal venous blood flow on coagulation diameter in an N1-S1 tumor model.

PURPOSE: To investigate inherent differences in vasculature of tumors versus normal parenchyma and efficacy of radiofrequency (RF) ablation with glucagon, adenosine, and a combination of the two compared with normal saline solution (NS) controls in an N1-S1 tumor model implanted in Sprague-Dawley rat livers. MATERIALS AND METHODS: A total of 17 tumors were established in the left lobes of rats. Tumor perfusion relative to surrounding liver parenchyma was evaluated with contrast-enhanced ultrasound with intermittent-bolus technique before and after administration of glucagon, adenosine, a combination of the two, or NS. Tumors were ablated with a 22-gauge RF probe with 1 cm of exposed tip at 80 °C for 2 min. Tumor size, zone of necrosis, and viable tumor were measured in tumors after 2,3,5-triphenyltetrazolium chloride staining. Results were compared with degree of tumor perfusion. RESULTS: The normalized tumor perfusion ratio did not significantly change with administration of NS (1.38% ± 3.93). Vasomodulation resulted in significant decreases in normalized tumor perfusion ratio: 66.22% ± 24.57 (P < .01) with glucagon, 71.45% ± 22.72 (P < .01) with adenosine, and 74.98% ± 16.58 (P < .01) with glucagon plus adenosine. After tumor ablation, there was an increase in size of the ablated area by 100%-165% in the three treatment groups compared with NS controls. Differences among treatment groups were not statistically significant. CONCLUSIONS: Tumor blood flow may be significantly altered by using systemic injection of appropriate medications. This tumor- and organ-specific approach to tumor vasomodulation may be used to enhance current therapeutic options.

Differentiation of benign periablational enhancement from residual tumor following radio-frequency ablation using contrast-enhanced ultrasonography in a rat subcutaneous colon cancer model.

Benign periablational enhancement (BPE) response to thermal injury is a barrier to early detection of residual tumor in contrast enhanced imaging after radio-frequency (RF) ablation. The objective of this study was to evaluate the role of quantitative of contrast-enhanced ultrasound (CEUS) in early differentiation of BPE from residual tumor in a BD-IX rat subcutaneous colon cancer model. A phantom study was first performed to test the validity of the perfusion parameters in predicting blood flow of two US contrast imaging modes-contrast harmonic imaging (CHI) and microflow imaging (MFI). To create a simple model of BPE, a peripheral portion of the tumor was ablated along with surrounding normal tissue, leaving part of the tumor untreated. First-pass dynamic enhancement (FPDE) and MFI scans of CEUS were performed before ablation and immediately, 1, 4 and 7 days after ablation. Time-intensity-curves in regions of BPE and residual tumor were fitted to the function y = A(1-exp[-ß{t-t0}])+C, in which A, ß, t0 and C represent blood volume, flow speed, time to start and baseline intensity, respectively. In the phantom study, positive linear correlations were noted between A, ß, Aß and contrast concentration, speed and flow rate, respectively, in both CHI and MFI. On CEUS images of the in vivo study, the unenhanced ablated zone was surrounded by BPE and irregular peripheral enhancement consistent with residual tumor. On days 0, 4 and 7, blood volume (A) in BPE was significantly higher than that in residual tumor in both FPDE imaging and MFI. Significantly greater blood flow (Aß) was seen in BPE compared with residual tumor tissue in FPDE on day 7 and in MFI on day 4. The results of this study demonstrate that qualitative CEUS can be potentially used for early detection of viable tumor in post-ablation assessment.

Hemostasis effects of direct intraparenchymal injection of platelets and fresh frozen plasma before cutting needle biopsy in an animal model.

PURPOSE: To evaluate the effectiveness of direct intraparenchymal injection of platelets or fresh frozen plasma (FFP) into the needle tract before cutting needle biopsy to decrease postprocedural blood loss in pigs with normal and abnormal hemostasis. MATERIALS AND METHODS: A total of 12 Yorkshire-cross pigs were anesthetized and maintained on a respirator. The pigs were divided into three groups: three with normal hemostasis, five treated with warfarin anticoagulation, and four treated with aspirin. Four types of biopsies were performed in the exposed livers and kidneys with 14-gauge Tru-Cut needles. The first was a standard (ie, control) biopsy, and the other three were performed with 2 mL normal saline solution, porcine FFP, or platelet-rich porcine plasma injected into the planned needle tract. Biopsy was then performed in the same needle tract. Blood loss was measured with gauze sponges. RESULTS: Significantly decreased postbiopsy blood loss was noted after FFP and platelet injection in the livers and kidneys of all groups except the kidney biopsy group after platelet injection in pigs with normal hemostasis. There was no significant difference in blood loss between the control and saline solution control groups in any of the pigs. CONCLUSIONS: Local injection of platelets or FFP significantly decreases postbiopsy blood loss in pigs with impaired hemostasis.

Percutaneous cryoablation of renal masses: impact of patient selection and treatment parameters on outcomes.

OBJECTIVES: To evaluate whether the trend in patient selection or perioperative parameters were associated with treatment outcomes after percutaneous cryoablation (PCA) of renal masses. METHODS: We retrospectively analyzed our urological oncology database and identified 52 patients treated for a total of 54 renal masses. Univariate analysis was performed to evaluate whether the variables of age, gender, tumor size, number of probes used, total freezing time, preoperative creatinine, American Society of Anesthesia class, body mass index, or age-adjusted Charlson comorbidity index (CCI) score had an impact on the outcomes of treatment failure or the complication rate. RESULTS: During a mean follow-up of 21 months, recurrence-free, overall, and disease-specific (based on radiographic follow-up and biopsy) survival were 96.2%, 98.1% and 100%, respectively. The mean age-adjusted CCI score for patients with postoperative complications was 6.5, compared with a mean score of 3.0 in patients without postoperative complications (P = .02). The complication rate was also significantly higher when a greater number of cryoprobes were used during PCA (P < .005). None of the variables analyzed were predictive of treatment failure. CONCLUSIONS: Of the pre- and intraoperative variables studied, age-adjusted CCI score and number of cryoprobes used were the only variables with predictive value for outcomes in regard to treatment failure or complications. As investigators continue using cryoablation to treat renal masses, it is important to be able to completely and honestly counsel patients regarding the likelihood of complications and need for subsequent therapy in the setting of treatment failure.

Percutaneous computed tomography guided cryoablation of the celiac plexus as an alternative treatment for intractable pain caused by pancreatic cancer.

Computed Tomography (CT)-guided percutaneous cryoablation was performed in a 43-year-old patient with intractable epigastric abdominal pain caused by advanced adenocarcinoma of the pancreas and extensive celiac trunk involvement. Initial treatment with celiac plexus nerve neurolysis using local ethanol injection was unsuccessful. A 17-gauge 17-cm cryoablation probe (Galil Medical Inc. Plymouth Meeting, PA) was placed into the expected location of the celiac plexus through a left paraspinal approach under CT guidance and two cycles of freeze-thaw were performed. Patient's pain decreased from 10 of 10 (subjective pain scoring using a visual analog scale; VAS; 0-10) to 3. No post-procedure complication was observed. His pain has remained stable after 6 months of follow up. Percutaneous cryoablation appears to be an effective alternative to neurolytic celiac plexus block for palliative treatment of celiac plexus involvement. Further study with larger number of patients is needed to evaluate the safety and efficacy.

Dynamic evolutionary changes in blood flow measured by MDCT in a hepatic VX2 tumor implant over an extended 28-day growth period: time-density curve analysis.

RATIONALE AND OBJECTIVES: The enhancement pattern of malignant tumors has been studied in short-term animal models (7-14 days), but the reported results have been variable and inconsistent. The purpose of this study was to investigate the changing blood flow characteristics of VX2 tumors implanted in rabbit livers with contrast-enhanced multidetector computed tomography (MDCT) to establish a predictable pattern of vascular evolution over an extended 28-day growth period. MATERIALS AND METHODS: VX2 carcinoma was implanted in livers of 10 male New Zealand White rabbits. Dynamic CT (2/seconds x 60 seconds) was conducted on days 7, 14, 21, and 28 after tumor implantation. Enhancement parameters of time-density curve (TDC), time to start (T0), time to peak (TP), maximum enhancement (DeltaH), slope of enhancement (SLe), and washout (SLw) in tumor center, tumor rim, and normal liver were analyzed. Tumor samples corresponding to CT images of one tumor on days 14 and 21 and seven tumors on day 28 were stained with hematoxylin and eosin and anti-CD31 monoclonal antibody. The relationship between enhancement parameters and histology parameters (thickness of tumor border, extent of blood stasis, and luminar vessel density) was analyzed. RESULTS: Consistent growth, appearance, and vascular changes occurred in 7 of 10 animals over the 4-week observation period. Peripheral rim-like enhancement was noted in CT images. TDC analysis showed that tumor rim enhancement was pronounced and more rapid than normal liver initially but this difference diminished with tumor progression. The SLe, SLw, and DeltaH decreased from 10.03 +/- 3.25 Hu/second, 0.42 +/- 0.25 Hu/sec, and 58.00 +/- 25.27 Hu on day 7 to 5.86 +/- 2.73 Hu/second, 0.10 +/- 0.13 Hu/second, and 37.78 +/- 8.89 Hu/second on day 28, respectively. TP increased from 12.71 +/- 4.85 seconds on day 7 to 25.57 +/- 7.75 seconds on day 28. No significant changes were noted on the TDC parameters in normal liver. The maximum density difference between tumor rim and normal liver (D(rim-liver)) appeared 10.5 +/- 2.1 seconds after contrast injection. The maximum D(rim-liver) decreased from 54.33 +/- 37.86 Hu on day 7 to 11.16 +/- 13.03 Hu on day 28. On histological analysis, viable tumor cells were found in tumor rim with few luminar vessels. The tumor border showed desmoplastic reaction, vascular dilation and proliferation, inflammatory cell infiltration, and blood stasis. These findings were more obvious on day 28 than those on day 14. TP showed significant positive correlations with the extent of blood stasis in tumor border and adjacent liver and the maximum thickness of the tumor border (r = 0.945 and 0.893 respectively, P < .05). CONCLUSION: The rabbit VX2 liver tumor is a hypovascular tumor with perilesional enhancement over its lifespan as imaged by MDCT. Consistent changes in the measured vascular parameters correlated with the size/age of the tumor implants. These findings suggest that the accuracy of CT enhancement imaging for VX2 liver tumor detection might be decreased with tumor development.

Radiofrequency ablation: post-ablation assessment using CT perfusion with pharmacological modulation in a rat subcutaneous tumor model.

RATIONALE AND OBJECTIVES: Inflammatory reaction surrounding the ablated area is a major confounding factor in the early detection of viable tumor after radiofrequency (RF) ablation. A difference in the responsiveness of normal and tumor blood vessels to vasoactive agents may be used to distinguish these regions in post-ablation follow-up. The goal of this study was to examine longitudinal perfusion changes in untreated viable tumor and the peripheral hyperemic rim of RF-ablated tumor in response to a vasoconstrictor (phenylephrine) or vasodilator (hydralazine) in a subcutaneous rat tumor model. MATERIALS AND METHODS: Bilateral subcutaneous shoulder tumors were inoculated in 24 BDIX rats and evenly divided into two groups (phenylephrine and hydralazine groups). One tumor in each animal was completely treated with RF ablation (at 90 +/- 2 degrees C for 3 minutes), and the other remained untreated. Computed tomographic perfusion scans before and after phenylephrine (10 microg/kg) or hydralazine (5 mg/kg) administration were performed 2, 7, and 14 days after ablation. Four rats per group were euthanized on each scan day, and pathologic evaluation was performed. The changes of blood flow in the peripheral rim of ablated tumor and untreated viable tumor in response to phenylephrine or hydralazine at each time point were compared. The diagnostic accuracy of viable tumor using the percentage change of blood flow in response to phenylephrine and hydralazine was compared using receiver-operating characteristic analysis. RESULTS: The peripheral rim of ablated tumor presented with a hyperemic reaction with dilated vessels and congestion on day 2 after ablation, numerous inflammatory vessels on day 7, and granulation tissue formation on day 14. Phenylephrine significantly decreased the blood flow in the peripheral hyperemic rim of ablated tumor on days 2, 7, and 14 by 16.3 +/- 9.7% (P = .001), 24.0 +/- 22.6% (P = .007), and 31.1 +/- 25.4% (P = .045), respectively. In untreated viable tumor, the change in blood flow after phenylephrine was irregular and insignificant. Hydralazine decreased the blood flow in the peripheral rim of both ablated tumor and untreated viable tumor. Receiver-operating characteristic analysis showed that reliable tumor diagnosis using the percentage change of blood flow in response to phenylephrine was noted on days 2 and 7, for which the areas under the curve were 0.82 (95% confidence interval, 0.64-1.00) and 0.81 (95% confidence interval, 0.56-1.00), respectively. However, tumor diagnosis using the blood flow change in response to hydralazine was unreliable. CONCLUSION: Phenylephrine markedly decreased blood flow in the peripheral hyperemic rim of ablated tumor but had little effect on the untreated viable tumor. Computed tomographic perfusion with phenylephrine may be useful in the long-term treatment assessment of RF ablation.

Vasomodulation of tumor blood flow: effect on perfusion and thermal ablation size.

Blood flow is a key factor in the efficacy of radiofrequency (RF) ablation treatment of solid tumors. We hypothesized that vasoactive drugs can modulate tumor blood flow and thereby improve the outcome of this thermal ablation approach. To verify this hypothesis, we measured the tumor perfusion changes in response to phenylephrine (PE) and hydralazine (HYZ) using a CT perfusion method in a rat subcutaneous tumor model. The coagulation sizes induced by RF ablation alone, RF ablation with PE and RF ablation with HYZ were compared. Results demonstrated that HYZ produced a marked decrease in entire tumor and tumor rim blood flow of 31.1 and 29.1%; while PE insignificantly change tumor blood flow (5.1% decrease in whole tumor and 6.0% decrease in tumor rim). A markedly greater coagulation area (0.59 cm2 +/- 0.24) was observed when HYZ was administered before RF ablation. No difference was noted in the coagulation area induced by RF ablation alone or the combination of PE injection followed by RF ablation (0.29 cm2 +/- 0.13 vs. 0.30 cm2 +/- 0.18). Results suggest that HYZ decreases subcutaneous tumor blood flow and enhances the coagulation size induced by RF ablation. PE has little influence on tumor blood flow and does not improve ablation.

Combination of sensitizing pretreatment and radiofrequency tumor ablation: evaluation in rat model.

PURPOSE: To prospectively determine, in an animal tumor model, if the block copolymer Pluronic P85 (BASF, Shreveport, La) sensitizes cancer cells to hyperthermia and if intratumorally or intravenously administered copolymer improves the therapeutic outcome of radiofrequency (RF) ablation tumor treatment. MATERIALS AND METHODS: The effects of Pluronic P85 and mild hyperthermia in vitro were tested in DHD/K12/TRb rat colorectal carcinoma cells. Cells were incubated at 37 degrees C or 43 degrees C for 15-60 minutes with 0%, 7%, or 10% wt/wt Pluronic P85, and cell viability was assessed by using a mitochondrial enzyme assay. In vivo experiments were performed as approved by the Institutional Animal Care and Use Committee at Case Western Reserve University and according to all applicable guidelines on animal use. Bilateral subcutaneous tumors in rats were treated with either intratumoral (13 tumors) or intravenous (15 tumors) Pluronic P85 followed by ablation or with ablation alone (14 tumors) and were monitored for 14 days by using volumes estimated from caliper measurements of tumor diameter. Acute effects of Pluronic P85 on the size of ablation-induced coagulation were measured after 24 hours in additional tumors (six tumors each treated according to the protocol for the ablation-only, intratumoral injection, and intravenous injection groups). Statistical testing was performed by using linear regression analysis and two-sided t tests with a significance level of .05. RESULTS: At 43 degrees C, 7% and 10% Pluronic P85 reduced in vitro cell viability by 22% +/- 5 (standard error of the mean) (P < .001) and 28% +/- 5 (P < .001), respectively, compared with the viability of control cells. At day 14, the volume of tumors ablated after local and systemic Pluronic P85 pretreatment changed by -55% +/- 14 (P = .03) and -59% +/- 14 (P = .02), respectively, compared with an increase of 16% +/- 28 for tumors treated with ablation alone. Coagulation area at 24 hours was reduced by 44% relative to that in control tumors (P = .03) after intratumoral Pluronic P85 but was unchanged after systemic Pluronic P85. CONCLUSION: Tumor pretreatment with Pluronic P85 improved the outcome of RF ablation by decreasing the tumor volume and residual tumor in an experimental carcinoma model.

Injectable polymer depot combined with radiofrequency ablation for treatment of experimental carcinoma in rat.

OBJECTIVE: The purpose of this study was to investigate whether an intralesional chemotherapy depot with or without a chemosensitizer could improve the efficacy of radiofrequency (RF) ablation in treatment of experimental carcinoma in rats. MATERIALS AND METHODS: Eighteen BD-IX rats were inoculated with bilateral subcutaneous tumors via injection of DHD/K12TRb rat colorectal carcinoma cells in suspension. Four weeks after inoculation, one tumor in each rat was treated with RF ablation at 80 degrees C for 2 minutes and the other with RF ablation followed by intralesional chemotherapy with carboplatin. The drug was administered via 2 different in situ-forming poly(D,L-lactide-coglycolide) (PLGA) depot formulations either with or without a chemosensitizer. Treatment efficacy was assessed by comparing the change in tumor diameter compared with control, percent of coagulation necrosis and a rating of treatment completeness. RESULTS: Tumors treated with ablation and carboplatin + sensitizer (n = 9) showed a diameter decrease of 49.4 +/- 24.5% at the end point relative to ablation control, while those treated with ablation and carboplatin only (n = 8) showed a 7.1 +/- 12.6% decrease. Use of sensitizer also showed increased tissue necrosis (81.9 +/- 9.7% compared with 68.7 +/- 26.7% for ablation only) and double the number of complete treatments (6/9 or 66.7%) compared with ablation control (3/9 or 33.3%). CONCLUSIONS: From these results, we conclude that intralesional administration of a carboplatin and sensitizer-loaded polymer depot after RF ablation has the potential to improve the outcome of ablation by increasing effectiveness of local adjuvant chemotherapy in preventing progression of tumor unaffected by the ablation treatment.

Combined tumor therapy by using radiofrequency ablation and 5-FU-laden polymer implants: evaluation in rats and rabbits.

PURPOSE: To evaluate the use of 5-fluorouracil (5-FU)-laden polymer implants as an adjunct to radiofrequency (RF) ablation for tumor treatment. MATERIALS AND METHODS: All animal studies were performed in compliance with the Case Western Reserve University Institutional Animal Care and Use Committee guidelines. Three studies were performed to investigate (a) in vitro dissolution of 5-FU-laden polymer implants in saline and bovine serum, (b) tissue distribution of 5-FU and its metabolite, 5-fluorouridine (5-FUrd), in the ablated liver tissue of rats (n = 4), and (c) efficacy of combined approach (n = 4) compared with that of ablation alone (n = 6) for VX2 liver tumor model in rabbits. Characterization of 5-FU release in vitro and distribution of 5-FU in rat liver tissue were analyzed by using high performance liquid chromatography; in vivo efficacy was assessed by using computed tomography and pathologic examination. RESULTS: Results of the in vitro dissolution study showed that a 75% release of 5-FU occurred in 2 days when exposed to bovine serum and in 9 days when exposed to phosphate-buffered saline. In the ablated rat liver, the 5-FU level was higher at the center and lower at the periphery of the tissue both at 24 hours (41.0 mg per kilogram tissue vs 15.0 mg per kilogram tissue, respectively) and at 48 hours (8.0 mg per kilogram tissue vs 2.0 mg per kilogram tissue, respectively). The 5-FUrd concentration was twofold higher peripherally than centrally and was higher at 48 hours than at 24 hours. In rabbits, local delivery of 5-FU immediately after RF ablation provided a significant (P < .05) reduction in tumor size compared with ablation alone (1.80 cm3 +/- 0.28 [standard error] vs 3.53 cm3 +/- 0.52, respectively; P = .034) and a more than 20-fold reduction in tumor size compared with the control (1.80 cm3 +/- 0.28 vs 41.95 cm3 +/- 11.58, respectively; P = .018). CONCLUSION: Combined treatment by using 5-FU polymer implants and RF ablation shows uniform sustained release of 5-FU for 48 hours at least 8 mm from the edge of the ablation zone and appears to be successful at controlling the growth of an experimental tumor in rabbits appreciably better than does ablation alone.

Interventional CT: 30 years' experience.

CT-guided procedures remain an important tool for diagnosis and tissue acquisition for primary diagnosis and molecular/tissue correlation. New imaging devices such as MDCT and PET/CT will improve diagnosis but percutaneous procedures will be needed to confirm and support new molecular and DNA treatments. Coagulopathic patients can be treated with LIBE a new method to prevent bleeding. Vasoactive drugs can be used to improve differentiation of malignant and benign diseases.