Human Adipose-Derived Stromal Cells Delivered on Decellularized Muscle Improve Muscle Regeneration and Regulate RAGE and P38 MAPK.

Volumetric muscle loss (VML) is the acute loss of muscle mass due to trauma. Such injuries occur primarily in the extremities and are debilitating, as there is no clinical treatment to restore muscle function. Pro-inflammatory advanced glycation end-products (AGEs) and the soluble receptor for advanced glycation end-products (RAGE) are known to increase in acute trauma patient's serum and are correlated with increased injury severity. However, it is unclear whether AGEs and RAGE increase in muscle post-trauma. To test this, we used decellularized muscle matrix (DMM), a pro-myogenic, non-immunogenic extracellular matrix biomaterial derived from skeletal muscle. We delivered adipose-derived stromal cells (ASCs) and primary myoblasts to support myogenesis and immunomodulation (N = 8 rats/group). DMM non-seeded and seeded grafts were compared to empty defect and sham controls. Then, 56 days after surgery muscle force was assessed, histology characterized, and protein levels for AGEs, RAGE, p38 MAPK, and myosin heavy chains were measured. Overall, our data showed improved muscle regeneration in ASC-treated injury sites and a regulation of RAGE and p38 MAPK signaling, while myoblast-treated injuries resulted in minor improvements. Taken together, these results suggested that ASCs combined with DMM provides a pro-myogenic microenvironment with immunomodulatory capabilities and indicates further exploration of RAGE signaling in VML.

Automatic Characterization of Pelvic and Sacral Measures from 200 Subjects.

BACKGROUND: An understanding of pelvic and acetabular morphology and orientation is required for accurate surgical reconstruction of the hip and spine, as well for component placement in a total hip arthroplasty. Our objectives were to develop an automated system for measuring pelvic and sacral orientations utilizing computed tomographic (CT) scans and to characterize these measures across 200 asymptomatic subjects. METHODS: An automated feature recognition algorithm was created to identify acetabular and pelvic orientation across 200 scans generated for non-musculoskeletal conditions. Three-dimensional models were generated from CT data to serve as inputs to the algorithm. Acetabular orientation was defined by comparing a plane fit to the acetabular rim with the anterior pelvic plane. Pelvic inclination, pelvic tilt, and sacral slope were defined as the angles between landmarks identified across the pelvis: pubic tubercles, acetabular center, left and right anterior superior iliac spines, and sacral plate. RESULTS: The mean sacral slope was 36.49°, the mean pelvic tilt was 15.60°, and the mean pelvic incidence was 52.05°. The mean sacropubic angle was 32.48° and the mean pelvic-Lewinnek angle was 8.93°. Significant differences between male and female subjects were observed in the sacral slope (mean difference, 4.72°; p < 0.05), pelvic tilt α (mean difference, 4.17°; p < 0.05), pelvic tilt γ (mean difference, 3.06°; p < 0.05), and the pelvic-Lewinnek angle (mean difference, 1.76°; p < 0.05). The comparison of acetabular orientation measures with those in a prior study of the same cohort yielded intraclass correlation coefficients (ICCs) all above 0.97. The validation of sacral orientation via manual measurement also yielded ICC values all at or above 0.97. CONCLUSIONS: Our algorithm showed a high degree of consistency in acetabular orientation measures with respect to a prior study of the same cohort. The measures of pelvic orientation were found to be accurate and reliable when compared with manual measurements of the same data set. All measurements of pelvic orientation were consistent with the means reported in the literature. CLINICAL RELEVANCE: An accurate and reproducible, automated technique for determining pelvic and acetabular orientation provides a way to characterize these measures as an aid in clinical diagnosis and preoperative planning.

Reliability of meniscus tear description: a study using MRI from the Osteoarthritis Initiative.

Despite being one of the most common indications for surgery, data on the types of meniscus tear that should be treated surgically are limited. Improving patient selection requires agreement on meniscus tear description. This study evaluates a simple MRI tear classification system for inter-observer agreement. Knee MRI examinations from 57 subjects from the Osteoarthritis Initiative cohort were reviewed by two sub-specialty trained, musculoskeletal radiologists. Based on two pulse sequences, each meniscus was classified by: tear or no tear; location of tear in anterior, middle or posterior third or multiple thirds; and displaced or non-displaced radial, horizontal, longitudinal or complex tear pattern. A tear was defined as signal abnormality extending to the surface on at least two images and displacement as more than 2 mm of extrusion or separation measured orthogonal to the tear plane. Kappa, weighted Kappa and percentage agreement were calculated. For the medial meniscus, Kappa and percentage agreement estimates were, respectively: the presence of tear, 0.79 and 89.5%; tear with displacement, 0.70 (weighted Kappa) and 66.0%; tear description, 0.47 and 61.4%; tear location, 0.64 and 79.0%. For the lateral meniscus, estimates were: the presence of tear, 0.75 and 89.5%; tear with displacement, 0.81 (weighted Kappa) and 86.0%; tear description, 0.56 and 78.9%; tear location, 0.74 and 87.7%. The strength of agreement between readers was moderate to substantial underscoring the challenge of meniscus tear classification.

Correlation between the accessory anterolateral talar facet, bone marrow edema, and tarsal coalitions.

OBJECTIVE: The purposes of this study was to determine the prevalence of the accessory anterolateral talar facet (AALTF); to evaluate the relationship between AALTF, focal abutting bone marrow edema (FABME), and sinus tarsi edema; and to study the prevalence of tarsal coalitions in patients with the AALTF utilizing ankle MR images. MATERIALS AND METHODS: 5-T ankle MR images were reviewed for the presence of AALTF, FABME, sinus tarsi edema, tarsal coalition, and location and type of coalition (cartilaginous, fibrous, and osseous). Multivariate analysis was performed to examine the correlation between AALTF and the other variables. RESULTS: Three hundred ninety-one consecutive patients were included (age range 5-86 years; mean age 45 years). An AALTF was present in 3.6% (14/391) of patients. The AALTF prevalence was 2% in women and 6.6% in men. There was a significantly association between AALTF and FABME (9/14, p < 0.05), sinus tarsi edema (13/14, p < 0.05), and tarsal coalition (4/14, p < 0.05). CONCLUSION: AALTF is relatively often detected on MRI of the ankle and significantly associated with BME, sinus tarsi edema, and subtalar coalition. Patients with a tarsal coalition should be evaluated for the concurrent presence of an AALTF.

Case report: vertebral foreign body granuloma mimicking a skeletal metastasis.

Intraosseous foreign body granuloma formation related to migrated surgical material is a rarely reported condition with variable imaging appearance. In this case report, we describe a foreign body granuloma that occurred in a lumbar vertebral body one level above a prior surgical fusion. The lytic appearance mimicked a skeletal metastasis in a 65-year-old patient with recently diagnosed renal cell carcinoma. To the best of our knowledge, this is the first reported case of a lumbar vertebral foreign body granuloma occurring distant from the site of surgery, indistinguishable from skeletal metastasis on radiologic examination.

Adipose tissue and muscle attenuation as novel biomarkers predicting mortality in patients with extremity sarcomas.

OBJECTIVES: To assess CT-attenuation of abdominal adipose tissue and psoas muscle as predictors of mortality in patients with sarcomas of the extremities. METHODS: Our study was IRB approved and HIPAA compliant. The study group comprised 135 patients with history of extremity sarcoma (mean age: 53 ± 17 years) who underwent whole body PET/CT. Abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and psoas muscle attenuation (HU) was assessed on non-contrast, attenuation-correction CT. Clinical information including survival, tumour stage, sarcoma type, therapy and pre-existing comorbidities were recorded. Cox proportional hazard models were used to determine longitudinal associations between adipose tissue and muscle attenuation and mortality. RESULTS: There were 47 deaths over a mean follow-up period of 20 ± 17 months. Higher SAT and lower psoas attenuation were associated with increased mortality (p = 0.03 and p = 0.005, respectively), which remained significant after adjustment for age, BMI, sex, tumor stage, therapy, and comorbidities (p = 0.002 and p = 0.02, respectively). VAT attenuation was not associated with mortality. CONCLUSION: Attenuation of SAT and psoas muscle, assessed on non-contrast CT, are predictors of mortality in patients with extremity sarcomas, independent of other established prognostic factors, suggesting that adipose tissue and muscle attenuation could serve as novel biomarkers for mortality in patients with sarcomas. KEY POINTS: • CT-attenuation of adipose tissue and muscle predict mortality in sarcoma patients • CT-attenuation predicts mortality independent of established prognostic factors • Patients with sarcomas often undergo CT for staging or surveillance • Adipose tissue and muscle attenuation could serve as biomarkers for mortality.

Celiac artery stenting to facilitate hepatic yttrium-90 radioembolization therapy.

Radioembolization offers a novel way to treat the nonresectable, liver predominant hepatic malignancies with better tumor response and overall progression-free survival rates. Transarterial catheter-based radioembolization procedure involves the hepatic arterial administration of glass- or resin-based beta emitting Yttirum-90 microspheres. Safe delivery of the tumoricidal radiation dose requires careful angiogram planning and coil embolization to quantify lung shunting and prevent systemic toxicity, respectively. Diagnostic pretreatment angiogram also serves to identify the hepatic arterial variant anatomy and other coexisting pathologies that might require a different or alternative approach. We describe a complex case of celiac artery stenosis with tortuous pancreaticoduodenal arterial arcade precluding access to the right hepatic artery for performing radioembolization. Celiac artery stenting of the stenosis was performed to facilitate subsequent safe and successful Yttrium-90 microsphere radioembolization.

Quantitative proton MR spectroscopy as a biomarker of tumor necrosis in the rabbit VX2 liver tumor.

PURPOSE: To compare metabolic magnetic resonance (MR) imaging findings (ie, quantification of tumor choline concentration) with percentage of necrosis on pathologic examination in rabbits bearing VX2 liver tumors. MATERIALS AND METHODS: VX2 tumors were implanted in the livers of 16 rabbits. MR imaging was performed with a 1.5-T MR scanner and extremity coil, and a hydrogen-1 ((1)H) proton MR spectroscopy ((1)H MRS) imaging protocol was used. Rabbits were euthanized immediately after imaging, and the tumor was harvested and sliced at 4-mm intervals in the axial plane. Choline concentration was calculated and was compared with the percentage of tumor necrosis on pathologic examination. RESULTS: Mean tumor size at pathologic examination was 16 mm (range, 12-22 mm). Mean percentage of necrosis at pathologic examination was 22% (range, 4%-44%). Choline concentration showed a relatively high inverse correlation with percentage of necrosis on pathologic examination, with an r value of 0.78 (P < .002). CONCLUSIONS: Choline concentration showed a relatively high inverse correlation with tumor necrosis on pathologic examination. Therefore, (1)H MRS may be useful to assess tumor necrosis.

Assessment of tumoricidal efficacy and response to treatment with 18F-FDG PET/CT after intraarterial infusion with the antiglycolytic agent 3-bromopyruvate in the VX2 model of liver tumor.

UNLABELLED: The purpose of this study was to determine the effects of 3-bromopyruvate (3-BrPA) on tumor glucose metabolism as imaged with (18)F-FDG PET/CT at multiple time points after treatment and compare them with those after intraarterial control injections of saline. METHODS: Twenty-three New Zealand White rabbits implanted intrahepatically with VX2 tumors were assigned to 1 of 2 groups: 14 rabbits were assigned to the treatment group (TG) and 9 to the saline control group (SG). All animals were infused with 25 mL of either 1.75 mM 3-BrPA or saline over 1 h via a 2-French catheter, which was secured in the hepatic artery. For PET/CT, the animals were injected with 37 MBq of (18)F-FDG at 1 d before treatment and 2 h, 24 h, and 1 wk after treatment. Tumor size, tumor and liver maximal standardized uptake value (SUV(max)), and tumor-to-background ratios were calculated for all studies. Seven TG and 5 SG animals were sacrificed at 1 wk after treatment for histopathologic analysis. RESULTS: Intense (18)F-FDG uptake was seen in untreated tumors. A significant reduction in tumor SUV(max) was noted in TG animals, when compared with SG animals, at 1 wk after treatment (P = 0.006). The tumor-to-liver background ratio in the TG animals, compared with the SG animals, was significantly reduced as early as 24 h after treatment (P = 0.01) and remained reduced at 1 wk (P = 0.003). Tumor SUV(max) increased from the baseline levels at 7 d in controls (P = 0.05). The histopathologic analysis of explanted livers revealed increased tumor necrosis in all TG samples. There was a significant inverse correlation (r(2) = 0.538, P = 0.005) between the percentage of tumor necrosis on histopathology and tumor SUV(max) on (18)F-FDG PET at 7 d after treatment with 3-BrPA. CONCLUSION: Intraarterial injection of 3-BrPA resulted in markedly decreased (18)F-FDG uptake as imaged by PET/CT and increased tumor necrosis on histopathology at 1 wk after treatment in the VX2 rabbit liver tumor. PET/CT appears to be a useful means to follow antiglycolytic therapy with 3-BrPA.

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States.

PURPOSE: This prospective phase II pilot study evaluated safety and efficacy of transarterial chemoembolization (TACE) with drug-eluting beads (DEBs) loaded with doxorubicin in patients with unresectable hepatocellular carcinoma (HCC). METHODS: Twenty patients with unresectable HCC (75% Child's A, 95% Eastern Cooperative Oncology Group performance status 0 to 1, 60% Barcelona Clinic Liver Cancer C, tumor size 6.9 cm) underwent 34 DEB-TACE sessions. Primary endpoints were tumor response, assessed by contrast-enhanced magnetic resonance imaging at 1 month after treatment, using size (response evaluation criteria in solid tumors [RECIST]), contrast-enhancement (European Association for the Study of the Liver) and apparent diffusion coefficient values, and safety assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Secondary endpoints included feasibility, progression-free survival, and overall survival. RESULTS: DEB-TACE was successfully performed in 34 sessions and demonstrated a favorable safety profile. On initial (1 month) postprocedural magnetic resonance imaging, treated lesions had a mean decrease in size of 4% (P = 0.1129). Using RECIST, partial response was achieved in 2 patients (10%), and 18 patients (90%) had stable disease. Treated tumors demonstrated a mean decrease in contrast enhancement of 64% (P < 0.0001). By European Association for the Study of the Liver criteria, 12 patients (60%) had objective tumor response, and 8 (40%) had stable disease. No patients had progression of a treated lesion while undergoing treatment. At 6 months, the disease control rate was 95% using RECIST. Overall survival rates at 1 and 2 years were 65% and 55%, respectively; median overall survival was 26 months. DISCUSSION: DEB-TACE is safe and effective in achieving local tumor control in patients with unresectable HCC.

Diffusion-weighted and Gd-EOB-DTPA-contrast-enhanced magnetic resonance imaging for characterization of tumor necrosis in an animal model.

PURPOSE: To evaluate the role of diffusion-weighted magnetic resonance imaging (MRI) in determining tumor necrosis and contrast-enhanced MRI using gadoxetic acid disodium (Gd-EOB-DTPA) in determining maximum tumor size measurement and tumor delineation compared with criterion-standard histologic measurements in the rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 tumors were implanted in the livers of 13 rabbits. Magnetic resonance imaging was performed using a 1.5-T MRI scanner and an extremity coil. The imaging protocol included T2-weighted fast spin-echo images, 3-dimensional T1-weighted spoiled gradient-echo with and without fat suppression after administration of Gd-EOB-DTPA, and diffusion-weighted echo planar images. Rabbits were killed, and the tumor was harvested and sliced at 4-mm intervals in the axial plane. The MRI parameters evaluated were tumor size, tumor delineation, and tumor apparent diffusion coefficient (ADC) values. Histologic sections were evaluated to quantify tumor necrosis. RESULTS: On contrast-enhanced MRI (obtained from 11 rabbits), the mean tumor sizes were 20, 19, and 20 mm in the arterial, portal venous, and delayed phases, respectively. Tumor delineation was most distinguishable in the delayed phase. On diffusion-weighted MRI (acquired in 13 rabbits), the mean tumor ADC value was 1.84 x 10 mm/s. The mean tumor size at pathology was 16 mm. The mean percent necrosis at the tumor's pathologic condition was 36%. The correlation between ADC value and percent necrosis showed an R value of 0.68. CONCLUSIONS: Contrast-enhanced MRI using Gd-EOB-DTPA may provide additional information about tumor outline in the liver. Moreover, we showed a remarkable correlation between ADC values and tumor necrosis. Thus, diffusion-weighted imaging may be useful to assess tumor necrosis; nevertheless, the search for new modalities remains important.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death.

BACKGROUND: The pyruvic acid analog 3-bromopyruvate (3BrPA) is an alkylating agent known to induce cancer cell death by blocking glycolysis. The anti-glycolytic effect of 3BrPA is considered to be the inactivation of glycolytic enzymes. Yet, there is a lack of experimental documentation on the direct interaction of 3BrPA with any of the suggested targets during its anticancer effect. METHODS AND RESULTS: In the current study, using radiolabeled ((14)C) 3BrPA in multiple cancer cell lines, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as the primary intracellular target of 3BrPA, based on two-dimensional (2D) gel electrophoretic autoradiography, mass spectrometry and immunoprecipitation. Furthermore, in vitro enzyme kinetic studies established that 3BrPA has marked affinity to GAPDH. Finally, Annexin V staining and active caspase-3 immunoblotting demonstrated that apoptosis was induced by 3BrPA. CONCLUSION: GAPDH pyruvylation by 3BrPA affects its enzymatic function and is the primary intracellular target in 3BrPA mediated cancer cell death.

Trends in nontherapeutic laparotomy rates in patients undergoing surgical therapy for hepatic colorectal metastases.

Surgery is the treatment of choice in selected patients with hepatic colorectal metastases. Despite improvements in preoperative imaging, patients can undergo unnecessary nontherapeutic laparotomy. The aim of this study was to examine trends in nontherapeutic laparotomy rates in patients undergoing planned surgical therapy for hepatic colorectal metastases. Data from 530 operations (461 patients) undergoing potentially curative surgical therapy for colorectal liver metastases between 1994 and 2005 were analyzed. The incidence of nontherapeutic laparotomy was determined and factors associated with nontherapeutic laparotomy were identified. Overall, 49 nontherapeutic laparotomies were performed (9.2%). Higher nontherapeutic laparotomy rates were seen in patients with multiple metastases and tumor size >5 cm (both P < 0.05). Preoperative positron emission tomography (PET) imaging was associated with lower risk of nontherapeutic laparotomy [5.6% versus 12.4%, P = 0.009, odds ratio (OR) = 0.42]. At laparotomy, extrahepatic findings were the reason for nontherapeutic laparotomy in 44.9% of cases. The nontherapeutic laparotomy rate significantly decreased over time (14.9% for 1994-1997 versus 9.6% for 1998-2001 versus 4.7% for 2002-2005; P = 0.003). While patients in each time period were similar with regard to tumor specific factors, utilization of PET imaging (P < 0.001) as well as resection plus ablation (P = 0.004) increased over time. We conclude that prevalence of nontherapeutic laparotomy for patients undergoing surgical exploration for hepatic colorectal metastases has decreased significantly in recent years to less than 5%. The reasons for this trend are probably multifactorial and may include improved preoperative assessment, such as PET imaging, as well as salvage surgical options.

Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer.

PURPOSE: To evaluate the anti-glycolytic effects of 3-BrPA on rats bearing RMT mammary tumors, by determining FDG uptake after intravenous administration of the therapeutic dose. MATERIALS AND METHODS: Sixteen rats bearing RMT tumors were treated either with 15 mM 3-BrPA in 2.5 ml of PBS or with 2.5 ml of PBS. After treatment, all rats received FDG and were sacrificed 1 h later. RESULTS: 3-BrPA treatment significantly decreased FDG uptake in tumors by 77% (p = 0.002). FDG uptake did not significantly decrease in normal tissues after treatment. CONCLUSION: Our study showed that 3-BrPA exhibits a strong anti-glycolytic effect on RMT cells implanted in rats.

Receiver operating characteristic analysis of diffusion-weighted magnetic resonance imaging in differentiating hepatic hemangioma from other hypervascular liver lesions.

PURPOSE: To evaluate the role of diffusion-weighted imaging in differentiating between hepatic hemangiomas, both typical and atypical, and other hypervascular liver lesions. METHODS: Retrospective review of 182 hypervascular liver lesions in 117 patients was performed. Diffusion and contrast-enhanced magnetic resonance imaging were performed using a 1.5-T unit. Imaging protocol consisted of T2-weighted fast spin-echo images, breath-hold diffusion-weighted echo-planar images, and breath-hold unenhanced and contrast-enhanced T1-weighted 3-dimensional fat-suppressed spoiled gradient-echo images in the arterial phase (20 seconds) and portal venous phase (60 seconds). Signal intensity changes and apparent diffusion coefficient (ADC) values were evaluated for all lesions. Unpaired t test was used to compare the mean ADC values for different lesions, and statistical significance was set at P < 0.01. Receiver operating characteristic analysis was used to determine the accuracy of diffusion-weighted imaging in differentiating hemangiomas from other hypervascular liver lesions. RESULTS: Lesions included typical and atypical hemangioma (n = 38), hepatocellular carcinoma (HCC; n = 58), focal nodular hyperplasia (FNH; n = 22), and neuroendocrine tumor metastasis (NET; n = 64) with a mean tumor size of 5.3 cm. Mean ADC value for hemangioma, HCC, FNH, and NET was 2.29 x 10(-3), 1.55 x 10(-3), 1.65 x 10(-3), and 1.43 x 10(-3) mm2/s, respectively. There was a statistically significant difference in the ADC value of hemangioma compared with that of FNH (P < 0.001), HCC (P < 0.001), and NET (P < 0.001), respectively. The area under the receiver operating characteristic curve was 0.91. CONCLUSIONS: Diffusion-weighted magnetic resonance imaging and ADC maps can provide rapid quantifiable information to differentiate typical and atypical hemangiomas from other hypervascular liver lesions.

Nonresectable hepatocellular carcinoma: long-term toxicity in patients treated with transarterial chemoembolization--single-center experience.

PURPOSE: To determine the toxicity profile of transarterial chemoembolization (TACE) at 6 months and 1 year after treatment in patients with hepatocellular carcinoma (HCC) in a standardized oncology protocol so that TACE could be compared with systemic chemotherapeutic regimens for liver cancer. MATERIALS AND METHODS: The study was authorized by the institutional review board. Between January 2002 and January 2007, 190 patients (155 men, 35 women; median age, 65 years; age range, 18-84 years) with HCC who underwent TACE treatment were identified from a prospectively collected database. Clinical records of complete blood cell counts and chemical profiles at baseline and at 6 and 12 months after treatment were studied retrospectively. Toxicity was graded according to the common terminology criteria for adverse events (CTCAE). A transition (survival) analysis perspective was used to estimate the distribution of toxicity grades. Patient survival from the first TACE session was calculated with Kaplan-Meier analysis. RESULTS: Grade 3 or 4 toxicity 6 and 12 months, respectively, after treatment included leukocytopenia (7% and 19%); anemia (9% and 19%); thromobocytopenia (13% and 23%); prolonged activated partial thromboplastin time (8% and 18%); elevated aspartate aminotransferase (15% and 18%), alanine aminotransferase (10% and 18%), and alkaline phosphatase (8% and 18%) levels; hypoalbuminemia (10% and 19%); hyperbilirubinemia (10% and 22%); and alopecia (18%). The cumulative survival rate was 58% at 1 year, 39% at 2 years, and 29% at 3 years. These toxicity rates were considerably lower than those reported after treatment with currently used systemic chemotherapeutic agents. CONCLUSION: Study results show that TACE has a favorable long-term toxicity profile in patients with HCC. Data clearly support the role of TACE in the treatment of patients with nonresectable HCC.

Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: evaluation with MR imaging and implication for therapy.

PURPOSE: To test whether different-sized iron oxide-containing Embosphere (IOE) particles can be detected by dedicated magnetic resonance (MR) imaging when injected intraarterially in an animal model of liver cancer and whether their distribution could be accurately predicted by MR imaging before confirmation with histopathologic analysis. MATERIALS AND METHODS: Twenty New Zealand White rabbits implanted with VX2 liver tumor were randomly assigned to undergo embolization with 100-300-microm particles (group S; n = 10) or 300-500-microm particles (group L; n = 10). Embolization was performed with the catheter placed in the proper hepatic artery. T2*-weighted multiplanar MR imaging was performed within 24 hours after the procedure to detect paramagnetic IOE susceptibility artifact. MR imaging interpretation parameters included presence of artifact in the artery and/or at the tumor bed. Hematoxylin and eosin- and Prussian blue-stained pathologic slides were also obtained and the presence of IOE was evaluated similarly. RESULTS: The MR detectability rates for IOEs were 100% in both groups. Paramagnetic susceptibility IOE artifact inside the tumor was detected in 30% of group S animals. On pathologic analysis, IOE particles were detected inside the tumor in 70% of this group. IOEs in group L were found outside the tumor within the hepatic artery on MR imaging and histopathologic study (P < .05). CONCLUSIONS: MR imaging readily detected IOE particles in an animal model of liver cancer regardless of the particle size. The smaller particles (100-300 microm) were delivered inside the tumor or in close proximity to the tumor margin, justifying their use for drug delivery or precise embolization.

Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study.

The aim of this study was to determine the biodistribution and tumor targeting ability of (14)C-labeled 3-bromopyruvate ([(14)C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [(14)C]3-BrPA on tumor and healthy tissue glucose metabolism by determining (18)F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [(14)C]3-BrPA i.a., 1.75 mM [(14)C]3-BrPA i.v., 20 mM [(14)C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [(14)C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [(14)C]3-BrPA was 1.8 +/- 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [(14)C]3-BrPA was 0.03 +/- 0.01% ID/g. After i.a. administration of [(14)C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [(14)C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit.

Evaluation of different calibrated spherical polyvinyl alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in rabbit liver.

PURPOSE: To assess whether porosity and compressibility of calibrated spherical polyvinyl alcohol (PVA) microspheres affect doxorubicin plasma and tumor concentrations after transcatheter arterial chemoembolization (TACE) in a VX2 rabbit model. MATERIALS AND METHODS: Fifteen rabbits were divided into three groups of five rabbits each. Three different types of calibrated spherical PVA microspheres with variable levels of porosity and compressibility were blindly evaluated. TACE was performed by injecting a mixture of doxorubicin (5 mg) and iodized oil (0.5 mL) followed by injection of the embolic material (0.3-0.5 mL). Plasma concentrations of doxorubicin and doxorubicinol were analyzed 20, 40, 60, and 120 minutes and 2 days after TACE, and liver tissue and tumor doxorubicin concentrations were measured 2 days after TACE. RESULTS: All calibrated spherical PVA microspheres showed similar patterns of plasma doxorubicin and doxorubicinol release and tumor concentration of doxorubicin. There were no significant differences of drug levels in either plasma or tumor in each group (P > .05). CONCLUSIONS: After TACE in a rabbit model of liver cancer, testing of three different types of spherical PVA microspheres with varying degrees of porosity and compressibility showed no significant differences in the plasma doxorubicin release pattern and tumor doxorubicin uptake.