Pyogenic liver abscesses: a contemporary analysis of management strategies at a tertiary institution.

BACKGROUND: Despite equivocal evidence, non-surgical management for pyogenic liver abscess (PLA) has become the standard of care at most institutions with surgery relegated to salvage therapy for those who fail less invasive means. The aim of this study was to describe the outcomes of a step-up approach to PLA management. METHODS: A retrospective chart review was conducted at a single institution for patients diagnosed with PLA over a 10-year period. Demographic, radiologic, microbiological, treatment, and outcomes data were collected and analyzed. RESULTS: 64 patients with PLA were identified. Initial treatment included antibiotics alone (n = 9), percutaneous drainage (PD) (n = 54), and surgery (n = 1). Surgery was ultimately required in 8 patients while 50 were cured with PD and 4 with antibiotics alone. Two (3%) patients died. Overall, PD carried an 85% success rate. CONCLUSION: PLA patients should be initially treated non-operatively, barring indications for emergent surgery or inaccessibility for PD. Surgery can be reserved for failure of PD.

Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model.

PURPOSE: To assess the antiangiogenic effect of bumetanide with dynamic contrast enhanced (DCE)-MRI and a biodegradable macromolecular MRI contrast agent. METHODS: A new polydisulfide containing macrocyclic gadolinium (Gd(III)) chelates, poly([(Gd-DOTA)-DETA]-co-DTBP) (GODP), was synthesized as a safe biodegradable macromolecular MRI contrast agent for DCE-MRI. Nude mice bearing flank HT29 colon cancer xenografts were then treated daily with either bumetanide or saline for a total of 3 weeks. DCE-MRI was performed before and after the treatment weekly. The DCE-MRI data were analyzed using the adiabiatic approximation to the tissue homogeneity (AATH) model to assess the change of tumor vascularity in response to the treatment. Immunohistochemistry (IHC) and western blot were performed to study tumor angiogenic biomarkers and hypoxia. RESULTS: DCE-MRI with GODP revealed that bumetanide reduced vascular permeability and plasma volume fraction by a significantly greater extent than the saline control therapy after 3 weeks of therapy. These changes were verified by the significant decline of CD31 and VEGF expression in the bumetanide treatment group. Despite a significant regression in vascularity, the tumors remained highly proliferative. Overexpression of the transcription factor HIF-1α in response to elevated hypoxia is thought to be the driving force behind the uninterrupted tumor expansion. CONCLUSION: This study demonstrated the effectiveness of DCE-MRI with GODP in detecting vascular changes following the administration of bumetanide. Bumetanide has the potential to curtail growth of the tumor vasculature and can be employed in future therapeutic strategies.

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.

Incidence of hypercoagulable events after image-guided percutaneous cryoablation of renal tumors: a single-center experience.

PURPOSE: To identify retrospectively hypercoagulable events that occurred over time in patients who underwent image-guided percutaneous renal cryoablation and compare the incidence with a cohort of patients who underwent surgical partial nephrectomy (PN) during the same time period. MATERIALS AND METHODS: An electronic medical record database was queried for patients who underwent percutaneous image-guided renal mass cryoablation or PN between September 2006 and June 2012. Records were examined for thrombotic events during the year following the procedure in each group. Incidence rates, Kaplan-Meier estimates, and patient demographic variables were compared using the stratified log-rank test and t test for independent samples. RESULTS: The study comprised 114 cryoablation cases. The cumulative incidence of thrombotic events after 1 year was 4.39%. The incidence per 100 person-years was 4.84. There were 105 PN cases. The cumulative incidence of thrombotic events after 1 year was 1.0%. The incidence per 100 person-years was 1.14. The person-time incidence rate difference for these two groups did not reach statistical significance (P = .0894). CONCLUSIONS: The incidence of thrombotic events in patients who underwent percutaneous renal cryoablation in this study was not significantly different than a comparable cohort who underwent surgical PN during the same time period.

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.

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.

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.

Hypoxia--implications for pharmaceutical developments.

Cells sense oxygen availability using not only the absolute value for cellular oxygen in regard to its energetic and metabolic functions, but also the gradient from the cell surface to the lowest levels in the mitochondria. Signals are used for regulatory purposes locally as well as in the generation of cellular, tissue, and humoral remodeling. Lowered oxygen availability (hypoxia) is theoretically important in the consideration of pharmacology because (1) hypoxia can alter cellular function and thereby the therapeutic effectiveness of the agent, (2) therapeutic agents may potentiate or protect against hypoxia-induced pathology, (3) hypoxic conditions may potentiate or mitigate drug-induced toxicity, (4) hypoxia may alter drug metabolism and thereby therapeutic effectiveness, and (5) therapeutic agents might alter the relative coupling of blood flow and energy metabolism in an organ. The prototypic biochemical effect of hypoxia is related to its known role as a cofactor in a number of enzymatic reactions, e.g., oxidases and oxygenases, which are affected independently from the bioenergetic effect of low oxygen on energetic functions. The cytochrome P-450 family of enzymes is another example. Here, there is a direct effect of oxygen availability on the conformation of the enzyme, thereby altering the metabolism of drug substrates. Indirectly, the NADH/NAD+ ratio is increased with 10% inspired oxygen, leading not only to reduced oxidation of ethanol but also to reduction of azo- and nitro-compounds to amines and disulfides to sulfhydryls. With chronic hypoxia, many of these processes are reversed, suggesting that hypoxia induces the drug-metabolizing systems. Support for this comes from observations that hypoxia can induce the hypoxic inducible factors which in turn alters transcription and function of some but not all cytochrome P-450 isoforms. Hypoxia is identified as a cofactor in cancer expression and metastatic potential. Thus, the effects of hypoxia play an important role in pharmacology, and the signaling pathways that are affected by hypoxia could become new targets for novel therapy or avenues for prevention.

Tissue-based research in kidney cancer: current challenges and future directions.

The past several years have seen unprecedented advances in the application of various therapeutic strategies for the treatment of patients with renal cancer. The availability of active immunotherapy, antiangiogenic therapy, and targeted therapy for this disease has brought front and center issues related to choosing the appropriate treatment for particular patient populations. It is increasingly evident that the most promising treatment selection strategies will incorporate identifying specific features of the tumor itself. To facilitate this move toward personalized medicine, it is critically important to establish some standard principles for renal cancer tissue collection, preparation, and analysis for translational research studies. In this article, we identify and discuss some critical issues related to tissue-based kidney cancer research. We focus on five major areas as follows: (a) surgical and image-guided techniques for tissue collection; (b) quality control of specimen collection, processing, storage, and review; (c) issues related to analysis of paraffin embedded tissues; (d) genomic studies; and (e) assessment of reproducibility of assays across institutions. In addition, some practical implementation strategies are proposed. Although many of the topics discussed are specific for renal cancer, several are also relevant to tissue based biomarker investigations in a broad array of malignancies.

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.

Comparison of Local Injection of Fresh Frozen Plasma to Traditional Methods of Hemostasis in Minimally Invasive Procedures.

RATIONALE AND OBJECTIVES: To evaluate different techniques for reducing hemorrhagic complications in coagulopathic patients with elevated international normalized ratio having an image-guided percutaneous invasive procedure; techniques included systemic transfusion of fresh frozen plasma (FFP), local injection of FFP, percutaneous injection of gelatin sponge, and percutaneous placements of angiographic coils. MATERIALS AND METHODS: Retrospective review of 232 consecutive patients with known coagulopathy undergoing image-guided minimally invasive procedures were selected. Ninety-one patients had local FFP injected, 40 patients underwent local synthetic gelatin injection, 16 patients had percutaneous coil embolization, and 85 patients received systemic FFP. The number of bleeds, complications related to bleeds, and systemic complications were recorded. A 30 cc threshold was used to delineate significant bleeding. RESULTS: No patients experienced clinically significant or insignificant bleeding with local FFP injection (P value <.05). Other local hemostatic methods (Gelfoam, systemic FFP, and coil embolization) were associated with higher levels of bleeding (12.5%, 17.1%, 37.5%, respectively) and complications (7.5%, 31.4%, 37.5%, respectively). Systemic FFP infusion was associated with respiratory, infectious, and mortal complications. CONCLUSIONS: Local injection of blood products provides a safe and efficacious hemostatic agent to reduce the incidence of postprocedural bleeding. The technique is associated with lower rates of bleeding and systemic complications when compared to other local and systemic techniques. Further randomized prospective studies with a larger patient cohort need to be performed to corroborate these initial findings.

Direct Injection of Blood Products Versus Gelatin Sponge as a Technique for Local Hemostasis.

PURPOSE: To provide a method of reducing risk of minimally invasive procedures on patients with abnormal hemostasis and evaluate efficacy of direct fresh frozen plasma injection through a procedure needle tract compared to Gelfoam (gelatin sponge) administration. MATERIALS AND METHODS: Eighty patients with elevated international standardized ratio (INR) undergoing minimally invasive procedures using imaging guidance were selected retrospectively. Forty patients had received Gelfoam as a means of tract embolization during the procedure. The other 40 received local fresh frozen plasma (FFP) through the needle tract. The number of complications and clinically significant bleeding events were recorded. A threshold of 30 cc of blood loss after a procedure was used to identify excess bleeding. RESULTS: No patients experienced clinically significant bleeding after administration of FFP. Five patients experienced postoperative drops in hemoglobin or hematomas after administration of Gelfoam. CONCLUSION: Local injection of blood products can reduce postprocedure bleeding in patients undergoing minimally invasive procedures and provides a safe alternative to the use of synthetic fibrin plugs.

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.

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.

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.

Phase I dose-escalation study of stereotactic body radiotherapy (SBRT) for poor surgical candidates with localized renal cell carcinoma.

PURPOSE: To evaluate the tolerability of escalating doses of stereotactic body radiotherapy (SBRT) for primary treatment of localized renal cell carcinoma (RCC) in poor surgical candidates. PATIENTS AND METHODS: Eligible patients included those with clinically staged radiographic and or pathologically confirmed RCC who had not undergone previous abdominal or pelvic radiotherapy. All patients had comorbid medical conditions which precluded surgery. Median (range) patient age was 77.6years (range 59-89) years and all patients had Karnofsky Performance Status of ⩾60. Median tumor volume was 57.9cm(3) (range 13.8-174.7cm(3)). Dose-limiting toxicity (DLT) was defined as grade 3 or worse gastrointestinal/genitourinary toxicity by Common Terminology Criteria of Adverse Events (version 4). Tumor response was assessed by imaging results using Response Evaluation Criteria In Solid Tumors (RECIST) measurement and percutaneous biopsy. RESULTS: A total of 19 patients (13 men and 6 women) were treated on protocol from June 2006 through August 2011. Groups of 3-6 patients received 24, 32, 40, and 48Gy in 4 fractions. Median (range) follow-up was 13. 7months (5.9-34.7months). For possibly treatment-related acute toxicities, one patient developed grade 2 fatigue and one developed grade 4 duodenal ulcer. For possibly treatment-related late toxicities, 2 patients experienced grade 3 renal toxicity (worsening chronic kidney disease), one reported grade 2 urinary incontinence and one developed grade 4 duodenal ulcer. Among the 15 patients with evaluable response, 3 and 12 had partial response and stable disease, respectively, utilizing RECIST criteria. Among the 11 patients who had post-SBRT biopsy, only one (9%) was negative on first biopsy and an additional one (9%) turned negative without further therapy on second biopsy. CONCLUSIONS: Dose escalation to 48Gy in 4 fractions has been achieved successfully without dose-limiting toxicities. A planned extension of this phase I trial is currently underway treating patients to 60Gy in 3 fractions to further evaluate this experimental therapy.

Noninvasive monitoring of local drug release in a rabbit radiofrequency (RF) ablation model using X-ray computed tomography.

In this study, X-ray computed tomography (CT) was utilized as a noninvasive method to directly examine local drug release kinetics in livers before and following radiofrequency thermal ablation. Iohexol, a CT contrast agent, was used as a drug-mimicking molecule. Release of iohexol in healthy and ablated rabbit livers over 48 h was quantified and correlated with the release profiles from phosphate-buffered saline (PBS) in vitro. The results show that iohexol release in ablated livers is significantly slower than both release in normal livers and in vitro. The time at which 50% of the drug was released (t(1/2)) into ablated liver (20.6+/-5.9 h) was 1.7 times longer than in normal liver (12.1+/-5.4 h) and approximately two times longer than that in PBS (10.1+/-1.2 h). The slower release in ablated livers is a result of severe tissue damage inflicted by thermal ablation, as supported by histological examination. This data suggests that a noninvasive imaging method provides a superior measurement over in vitro release studies in accurately quantifying the local release kinetics of an agent in an altered physiological system in vivo. Because the development of a successful local drug therapy is dependent on the understanding of the agent release kinetics at the implantation site, the noninvasive data may be indispensable in effectively predicting the implant behavior in a physiological system.