Impact of the COVID-19 Lockdown Strategy on Vascular Surgery Practice: More Major Amputations than Usual.

BACKGROUND: The aim of this study is to investigate the impact of the coronavirus disease 2019 (COVID-19) lockdown period on the number and type of vascular procedures performed in the operating theater. METHODS: A total of 38 patients who underwent 46 vascular procedures during the lockdown period of March 16th until April 30th, 2020, were included. The control groups consisted of 29 patients in 2019 and 54 patients in 2018 who underwent 36 and 66 vascular procedures, respectively, in the same time period. Data were analyzed using SPSS Statistics. RESULTS: Our study shows that the lockdown during the COVID-19 pandemic resulted in a significant increase in the number of major amputations (42% in 2020 vs. 18% and 15% in 2019 and 2020, respectively; P-value 0.019). Furthermore, we observed a statistically significant difference in the degree of tissue loss as categorized by the Rutherford classification (P-value 0.007). During the lockdown period, patients presented with more extensive ischemic damage when than previous years. We observed no difference in vascular surgical care for patients with an aortic aneurysm. CONCLUSIONS: Measurements taken during the lockdown period have a significant effect on non-COVID-19 vascular patient care, which leads to an increased severe morbidity. In the future, policy makers should be aware of the impact of their measurements on vulnerable patient groups such as those with peripheral arterial occlusive disease. For these patients, medical care should be easily accessible and adequate.

Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.

Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer.

Antiglycolytic therapy combined with an image-guided minimally invasive delivery strategy for the treatment of breast cancer.

PURPOSE: The antiglycolytic agent 3-bromopyruvate (3-BrPA) promotes anticancer effects in multiple tumor models. This study evaluated the therapeutic efficacy of ultrasound (US)-guided intratumoral delivery of 3-BrPA in an orthotopic tumor model of breast cancer. MATERIALS AND METHODS: Human breast cancer cell line MDA MB 231 was used for in vitro and in vivo studies. The anticancer effect of 3-BrPA was evaluated by viability assay, quantification of adenosine triphosphate (ATP) and lactate levels, and activity of matrix metalloproteinase (MMP)-9. In animal experiments, 15 nude mice with MDA MB 231 breast tumors were divided into three groups for US-guided intratumoral treatment with 1.75 mM 3-BrPA (group 1), 5 mM 3-BrPA (group 2), and saline solution (group 3). Tumor size was measured and subjected to histopathologic examination. RESULTS: In vitro, treatment with 3-BrPA resulted in a dose-dependent decrease in cell viability. A decrease in ATP and lactate levels, invasion, and MMP9 activity and expression was observed after treatment with concentrations of 3-BrPA that did not affect cell viability. In vivo, a significant difference in tumor volume was observed between 3-BrPA-treated and control animals. At the end of the study, tumor volumes in the 3-BrPA groups were 1,876 mm(3)±346 and 426 mm(3)±180 in the 1.75-mM and 5-mM 3-BrPA groups, respectively, versus 4,447 mm(3)±571 in the control group (P< .05). CONCLUSIONS: US-guided intratumoral injection of 3-BrPA effectively blocks breast cancer progression in an orthotopic mouse tumor model.

Phase 2 trial of concurrent bevacizumab and transhepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Vascular endothelial growth factor is up-regulated in hepatocellular carcinoma (HCC) and is further up-regulated after transhepatic arterial chemoembolization. The authors of this report conducted a phase 2 trial to evaluate the safety and efficacy of bevacizumab combined with chemoembolization in patients with unresectable HCC. METHODS: Patients who had an Eastern Cooperative Oncology Group performance of status 0 to 2, a Child-Pugh score of A or B, and Barcelona Clinic Liver Cancer stage B or C HCC were eligible. Treatment consisted of bevacizumab every 2 weeks and chemoembolization during the third week of a 6-week cycle for up to 3 cycles over 6 months. The primary endpoints were safety and efficacy. RESULTS: Twenty-five patients received chemoembolization and bevacizumab. The most common grade 3 and 4 events after the first treatment cycle were leukocytopenia (12%), fatigue (12%), and hyponatremia (12%). Serious toxicities that had a known association with bevacizumab were observed in 4 patients. Thirty-day mortality was 0%. The median time to tumor progression for the targeted lesions was not reached, and overall survival was 10.8 months. The objective response rate was 60% using enhancement response evaluation criteria, and the disease control rate was 100%. CONCLUSIONS: Concurrent treatment with bevacizumab and chemoembolization was safe in carefully selected patients and demonstrated antitumor activity in patients with unresectable HCC. These results support the further development of bevacizumab combined with chemoembolization as a treatment for unresectable HCC.

Spontaneous tumor regression in a syngeneic rat model of liver cancer: implications for survival studies.

PURPOSE: To characterize tumor growth of N1S1 cells implanted into the liver of Sprague-Dawley rats to determine if this model could be used for survival studies. These results were compared with tumor growth after implantation with McA-RH7777 cells. MATERIALS AND METHODS: N1S1 or McA-RH7777 cells were implanted into the liver of Sprague-Dawley rats (n = 20 and n = 12, respectively) using ultrasound (US) guidance, and tumor growth was followed by using US. Serum profiles of 19 cytokines were compared in naive versus tumor-bearing rats. RESULTS: Both types of tumors were visible on US 1 week after tumor implantation, but the mean tumor volume of N1S1 tumors was larger compared to McA-RH7777 tumors (231 mm(3) vs 82.3 mm(3), respectively). Tumor volumes in both groups continued to increase, reaching means of 289 mm(3) and 160 mm(3) in N1S1 and McA-RH7777 groups, respectively, 2 weeks after tumor implantation. By week 3, tumor volumes had decreased considerably, and six tumors (50%) in the McA-RH7777 had spontaneously regressed, versus two (10%) in the N1S1 group. Tumor volumes continued to decrease over the following 3 weeks, and complete tumor regression of all tumors was seen 5 weeks and 6 weeks after tumor implantation in the McA-RH7777 and N1S1 groups, respectively. In an N1S1-implanted rat, multiple cytokines that have been shown to correlate with the ability of the tumor to survive in a hostile environment were increased by as much as 50%, whereas the average increase in cytokine levels was 90%. These findings suggest that the net cytokine environment favors an antitumor immune response. A similar trend was observed in a rat with a McA-RH7777 tumor, and the increase in cytokine levels was considerably more pronounced, with an average increase of 320%. CONCLUSIONS: The model of N1S1 cell implantation in the liver of Sprague-Dawley rats is not ideal for survival studies and should only be used with great caution in short-term studies that involve cancer therapies.

Human hepatocellular carcinoma in a mouse model: assessment of tumor response to percutaneous ablation by using glyceraldehyde-3-phosphate dehydrogenase antagonists.

PURPOSE: To characterize tumor response to percutaneous injection of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antagonists in a mouse model of human hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Animal experiments were approved by the Johns Hopkins University Animal Care and Use Committee. Luciferase (luc) gene-expressing Hep3B tumor-bearing athymic nude mice were randomly divided into four groups of six mice each. Tumor-specific GAPDH inhibition was achieved by using percutaneous injection of GAPDH antagonists-3-bromopyruvate (3-BrPA) or GAPDH-specific short hairpin RNA (shRNA). Tumor response to treatment was assessed by using bioluminescence imaging and analysis of GAPDH function and apoptotic markers (caspase-3, caspase-9, and positive staining for terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling). HCC samples from 34 patients were obtained from the Johns Hopkins tumor bank, as approved by the Institutional Review Board, for GAPDH expression analysis. Statistical analysis was performed by using a two-sample t test or Spearman rank correlation coefficient. RESULTS: In vitro, 3-BrPA affected Hep3B cell viability (half maximal inhibitory concentration = 0.15 mmol/L), and GAPDH shRNA suppressed (45.5%) colony formation. In vivo, percutaneous injection of GAPDH antagonists into luc-Hep3B tumors decreased bioluminescence imaging signal and viability (3-BrPA, P < .0001; GAPDH shRNA, P = .03). The 3-BrPA treatment primarily inhibited GAPDH activity (74.5%) compared with its expression (34.3%), whereas GAPDH shRNA inhibited both activity (60.6%) and expression (44.4%). Targeted inhibition of GAPDH by using 3-BrPA or shRNA induced apoptosis. HCC samples from patients demonstrated a strong correlation between GAPDH upregulation and the proto-oncogene c-jun expression (r = 0.543, P = .003). CONCLUSION: Percutaneous injection of GAPDH antagonists induces apoptosis and blocks Hep3B tumor progression, which demonstrates the therapeutic potential of targeting GAPDH in human HCC.

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.

3-Bromopyruvate induces endoplasmic reticulum stress, overcomes autophagy and causes apoptosis in human HCC cell lines.

BACKGROUND: Autophagy, a cellular response to stress, plays a role in resistance to chemotherapy in cancer cells. Resistance renders systemic chemotherapy generally ineffective against human hepatocellular carcinoma (HCC). Recently, we reported that the pyruvate analog 3-bromopyruvate (3-BrPA) promoted tumor cell death by targeting GAPDH. In continuance, we investigated the intracellular response of two human HCC cell lines (Hep3B and SK-Hep1) that differ in their status of key apoptotic regulators, p53 and Fas. METHODS AND RESULTS: 3-BrPA treatment induced endoplasmic reticulum (ER) stress, translation inhibition and apoptosis based on Western blot and qPCR, pulse labeling, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and active caspase-3 in both the cell lines. However, electron microscopy revealed that 3-BrPA treated SK-Hep1 cells underwent classical apoptotic cell death while Hep3B cells initially responded with the protective autophagy that failed to prevent eventual apoptosis. CONCLUSION: 3-BrPA treatment promotes apoptosis in human HCC cell lines, irrespective of the intracellular response.

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.

The pyruvic acid analog 3-bromopyruvate interferes with the tetrazolium reagent MTS in the evaluation of cytotoxicity.

3-Bromopyruvate (3BrPA) is a pyruvate analog known for its alkylating property. Recently, several reports have documented the antiglycolytic and anticancer effects of 3BrPA and its potential for therapeutic applications. 3BrPA-mediated cytotoxicity has been evaluated in vitro by various methods including tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)-based assays such as MTT, MTS, and so on. However, growing body of evidences has shown that tetrazolium reagent may interfere with the test compounds. In this study, we investigated whether the tetrazolium reagent interferes with the assessment of 3BrPA cytotoxicity. The results of the tetrazolium-based MTS assay were compared with 3 distinct cell viability detection methods, that is, Trypan Blue staining, ATP depletion, and Annexin V staining in 2 different cell lines, Vx-2 and HepG2. The MTS assay data showed false positive results by indicating increased cell viability at 1 mM and 2 mM 3BrPA whereas the other cell viability assays demonstrated that both Vx-2 and HepG2 cells are not viable at the same treatment conditions. In order to validate the direct interaction of 3BrPA with MTS reagent, we tested cell-free media incubated with different concentrations of 3BrPA. The results of cell-free media showed an increase in absorbance in a dose-dependent manner confirming the interaction of MTS with 3BrPA. Thus, our data clearly demonstrate that 3BrPA interferes with the accuracy of MTS-based cytotoxicity evaluation. Hence, we suggest that employing multiple methods of biochemical as well as morphological cytotoxicity assays is critical to evaluate 3BrPA-mediated cell death.

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.

Percutaneous US-guided implantation of Vx-2 carcinoma into rabbit liver: a comparison with open surgical method.

PURPOSE: To evaluate technical feasibility and experimental usefulness of percutaneous US-guided implantation of Vx-2 carcinoma in rabbit liver. MATERIALS AND METHODS: Forty-eight New Zealand White male rabbits were used. Solid tumor mass of Vx-2 carcinoma was harvested from carrier rabbit, and minced tumor cells were implanted. Twenty-four rabbits underwent percutaneous US-guided tumor implantation, and the same number of rabbits underwent open laparotomy tumor implantation. Tested parameters included technical success, procedural time, amount of anesthesia, recovery time, complications, tumor size, and regional tumor seeding. RESULTS: A new percutaneous US-guided implantation was technically feasible in all rabbits. Evaluation parameters showed that the percutaneous US-guided implantation method is less invasive than the open laparotomy method. Targeting rate for left lateral lobe of implantation site was comparable in both methods (91.7% of percutaneous US-guided; 95.8% in open laparotomy). The success rate of tumor growth in the liver was 100% in both groups. However, in the group with US-guidance, tumor seeding developed more frequently in five of 24 rabbits (20.8%) than in open laparotomy group (2/24, 8.3%). Five rabbits had thoracoabdominal wall needle tract seeding, and two rabbits had tumor seeding at both thoracoabdominal wall and intraperitoneal space. CONCLUSIONS: Percutaneous US-guided implantation of Vx-2 carcinoma in rabbit liver is a less invasive alternative to open laparotomy, achieving equally successful tumor growth in the liver. Although percutaneous US-guidance implantation method may not be considered for long-term survival study design because of the possibility of tumor seeding, it can be considered for nonsurvival study design.

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.

Considerations for implantation site of VX2 carcinoma into rabbit liver.

PURPOSE: To assess whether the implantation site of VX2 carcinoma into rabbit liver affects successful vessel selection for transcatheter arterial interventions. MATERIALS AND METHODS: Twenty-four New Zealand White rabbits were randomly assigned to two groups. All implantations were performed by open laparotomy with minced tumor cells inserted into a 16-gauge Angiocath needle. Group I rabbits (n = 12) had tumor implanted into the left medial lobe of the liver and group II rabbits (n = 12) had tumor implanted into the left lateral lobe. Two weeks after implantation, selective angiography was performed for subsequent chemoembolization, which was part of a different study. Tested variables included maximum tumor diameter, tumor feeding artery size, and tumor vascularity. RESULTS: Successful tumor growth was achieved in all rabbits. Selective angiography was possible in 33.3% of rabbits in group I and 66.6% of rabbits in group II (P < .05). Tumor size and vascularity were similar between groups. Mean lengths of tumor feeder arteries from the bifurcation of the left hepatic artery were 4.1 mm +/- 1.2 in group I (left medial lobe) and 10.8 mm +/- 3.0 in group II (left lateral lobe; P < .05). The angulation of the left medial lobar artery (group I) off the left hepatic artery was acute in eight of 12 rabbits (66.6%), but only four of 12 rabbits in group II (33.3%) showed acute angulation of the left lateral lobar artery off the left hepatic artery (P < .05). Mean angiography time was significantly shorter in group II. CONCLUSIONS: For selective hepatic arterial interventions, the left lateral lobe of the liver may be favorable as an implantation site for VX2 tumors in rabbits.

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.