Percutaneous CT-Guided Cryoablation for Locally Recurrent Prostate Cancer: Technical Feasibility, Safety, and Effectiveness.

PURPOSE: To assess the feasibility and safety of using computed tomography (CT) guidance for ablation of prostate cancer in the salvage setting. MATERIALS AND METHODS: This institutional review board-approved retrospective study of consecutive patients who presented with prostate cancer recurrence and underwent percutaneous CT-guided cryoablation was conducted between July 2020 and September 2022. A total of 18 patients met the inclusion criteria, and a total of 19 procedures were performed. Demographic details; preablation and postablation urinary, rectal, and erectile function assessment; procedure details; and preoperative and postoperative imaging findings and prostate-specific antigen (PSA) values were recorded. RESULTS: The mean treated tumor size was 15.7 mm ± 6.2. Technical success was achieved in 18 of the 19 procedures (94.7%), with 1 procedure aborted due to inability to obtain a safe plane. The mean follow-up time was 10.0 months (range, 2.3-26.7 months) at the time of manuscript preparation. The mean PSA before ablation was 8.1 ng/mL ± 9.3, and postablation PSA nadir was 2.6 ng/mL ± 4.0 (P = .002). Of the 18 patients who had postoperative imaging, 16 (88.9%) had a complete response (ie, no evidence of residual disease), and 2 (11.1%) patients had residual disease. Overall, 16 (88.9%) of the 18 treated patients demonstrated a PSA and/or imaging response to ablation. Mild adverse events occurred in 4 (22%) of the 18 cases. CONCLUSIONS: CT-guided cryoablation appears to be a technically feasible, safe option for treating locally recurrent prostate cancer.

Utility of Intraoperative Neuromonitoring to Protect against Adjacent Nerve Injury in Musculoskeletal and Lymph Nodal Cryoablation.

PURPOSE: To demonstrate the utility of intraoperative neuromonitoring (IONM) as an effective method of passive thermoprotection against cryogenic injury to neural structures during musculoskeletal and lymph node cryoablation. MATERIAL AND METHODS: Twenty-nine patients (16 men; mean age among men, 68.6 years [range, 45-90 years]; mean age among women, 62.6 years [range, 28-88 years]) underwent 33 cryoablations of musculoskeletal and lymph node lesions. Transcranial electrical motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SSEPs) of target nerves were recorded throughout the ablations. Significant change was defined as waveform amplitude reduction greater than 30% (MEP) and 50% (SSEP). The primary outcomes of this study were immediate postprocedural neurologic deficits and frequency of significant MEP and SSEP amplitude reductions. RESULTS: Significant amplitude reductions were detected in 54.5% (18/33) of MEP tracings and 0% (0/33) of SSEP tracings. Following each occurrence of significant amplitude reductions, freeze cycles were promptly terminated. Intraprocedurally, 13 patients had full recovery of amplitudes to baseline, 11 of whom had additional freeze cycles completed. In 5 of 33 (15.2%) cryoablations, there were immediate postprocedural neurologic deficits (moderate adverse events). Unrecovered MEPs conferred a relative risk for neurologic sequela of 23.2 (95% CI, 3.22-167.21; P < .001) versus those with recovered MEPs. All 5 patients had complete neurologic recovery by 12 months. CONCLUSIONS: IONM (with MEP but not SSEP) is a reliable and safe method of passive thermoprotection of neurologic structures during cryoablation. It provides early detection of changes in nerve conduction, which when addressed quickly, may result in complete restoration of MEP signals within the procedure and minimize risk of cryogenic neural injury.

Transitioning the IR Clinic to Telehealth: A Single-Center Experience during the COVID-19 Pandemic.

Telehealth has not previously been widely implemented as a result of regulatory and reimbursement concerns; however, in the current national emergency of the COVID-19 pandemic, the Centers for Medicare and Medicaid Services has relaxed many of its rules, allowing increased adoption of telehealth services, improving the safety and access of outpatient health care. A complete understanding of the regulatory requirements, technologic options, and billing processes of telehealth is required to initiate a successful clinic. A model is presented here based on a single institution's experience with implementing telehealth in the outpatient interventional radiology clinic.

Hepatic Radiofrequency Ablation-induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition.

PURPOSE: To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways. MATERIALS AND METHODS: Rats were used in this institutional animal care and use committee-approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 3½ to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met-negative R3230 tumors for comparison with the native c-Met-positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests. RESULTS: After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor VEGF levels. Compared with RF ablation alone, RF ablation combined with adjuvant PHA-665752 or semaxanib reduced distant tumor growth, proliferation, and microvascular density. For c-Met-negative tumors, hepatic RF ablation did not increase distant tumor growth, proliferation, or microvascular density compared with sham treatment. CONCLUSION: RF ablation of normal liver can stimulate distant subcutaneous tumor growth mediated by HGF/c-Met pathway and VEGF activation. This effect was not observed in c-Met-negative tumors and can be blocked with adjuvant c-Met and VEGF inhibitors.

Effect of thermal dose on heat shock protein expression after radio-frequency ablation with and without adjuvant nanoparticle chemotherapies.

PURPOSE: The aim of this study was to evaluate the effect of different radio-frequency ablation (RFA) thermal doses on coagulation and heat shock protein (HSP) response with and without adjuvant nanotherapies. MATERIALS AND METHODS: First, Fischer rats were assigned to nine different thermal doses of hepatic RFA (50-90 °C, 2-20 min, three per group) or no treatment (n = 3). Next, five of these RF thermal doses were combined with liposomal-doxorubicin (Lipo-Dox, 1 mg intravenously) in R3230 breast tumours, or no tumour treatment (five per group). Finally, RFA/Lipo-Dox was given without and with an Hsp70 inhibitor, micellar quercetin (Mic-Qu, 0.3 mg intravenously) for two different RFA doses with similar coagulation but differing peri-ablational Hsp70 (RFA/Lipo-Dox at 70 °C × 5 min and 90 °C × 2 min, single tumours, five per group). All animals were sacrificed 24 h post-RFA and gross tissue coagulation and Hsp70 (maximum rim thickness and % cell positivity) were correlated to thermal dose including cumulative equivalent minutes at 43 °C (CEM43). RESULTS: Incremental increases in thermal dose (CEM43) correlated to increasing liver tissue coagulation (R2 = 0.7), but not with peri-ablational Hsp70 expression (R2 = 0.14). Similarly, increasing thermal dose correlated to increasing R3230 tumour coagulation for RF alone and RFA/Lipo-Dox (R2 = 0.7 for both). The addition of Lipo-Dox better correlated to increasing Hsp70 expression compared to RFA alone (RFA: R2 = 0.4, RFA/Lipo-Dox: R2 = 0.7). Finally, addition of Mic-Qu to two thermal doses combined with Lipo-Dox resulted in greater tumour coagulation (p < 0.0003) for RFA at 90 °C × 2 min (i.e. greater baseline Hsp70 expression) than an RFA dose that produced similar coagulation but less HSP expression (p < 0.0004). CONCLUSION: Adjuvant intravenous Lipo-Dox increases peri-ablational Hsp70 expression in a thermally dependent manner. Such expression can be exploited to produce greater tumour destruction when adding a second adjuvant nanodrug (Mic-Qu) to suppress peri-ablational HSP expression.

Irreversible electroporation of the lumbar vertebrae in a porcine model: is there clinical-pathologic evidence of neural toxicity?

PURPOSE: To evaluate the effects of irreversible electroporation (IRE) in the porcine spine. MATERIALS AND METHODS: This study was approved by the institutional animal care and use committee. Twenty computed tomographically guided IRE ablations in either a transpedicular location or directly over the posterior cortex were performed in the lumbar vertebrae of 10 pigs by a single operator. T1- and T2-weighted magnetic resonance (MR) imaging was performed with and without contrast material 2 or 7 days after ablation. Mathematical modeling was performed to estimate the extent of ablation. Clinical, radiologic, pathologic, and simulation findings were analyzed. The Miller low-bias back transformation was used to construct 95% confidence intervals for the mean absolute percentage difference between the maximum length and width of the ablation zone on MR images and pathologic measurements by using square-root-transformed data. RESULTS: Bipolar IRE electrode placement and ablation were successful in all cases. The mean distances from the IRE electrode to the posterior wall of the vertebral body or the exiting nerve root were 2.93 mm ± 0.77 (standard deviation) and 7.87 mm ± 1.99, respectively. None of the animals had neurologic deficits. Well-delineated areas of necrosis of bone, bone marrow, and skeletal muscle adjacent to the vertebral body were present. Histopathologic changes showed outcomes that matched with simulation-estimated ablation zones. The percentage absolute differences in the ablation measurements between MR imaging and histopathologic examination showed the following average errors: 24.2% for length and 28.8% for width measurements on T2-weighted images, and 26.1% for length and 33.3% for width measurements on T1-weighted contrast material-enhanced images. CONCLUSION: IRE ablation in the porcine spine is feasible and safe and produces localized necrosis with minimal neural toxicity. Signal intensity changes on images acquired with standard MR imaging sequences demonstrate the ablation zone to be larger than that at histopathologic examination.

Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1α can be suppressed with adjuvant bortezomib or liposomal chemotherapy.

PURPOSE: To characterize upregulation of hypoxia-inducible factor (HIF)-1α after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1α inhibitor (bortezomib) and nanodrugs on modulating RF ablation-upregulated hypoxic pathways. MATERIALS AND METHODS: Fisher 344 rats (n = 68) were used. First, RF ablation-induced periablational HIF-1α expression was evaluated in normal liver or subcutaneous R3230 tumors (14-16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50°C-90°C for 2-20 minutes) on HIF-1α expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1α inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1α. Outcome measures included immunohistochemistry of HIF-1α and heat shock protein 70 (marker of nonlethal thermal injury). RESULTS: RF ablation increased periablational HIF-1α in both normal liver and R3230 tumor, peaking at 24-72 hours. Tumor RF ablation had similar HIF-1α rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1α after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF-1α (rim thickness, 68.7 µm ± 21.5 vs 210.3 µm ± 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm ± 1.5 vs 7.7 mm ± 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation-induced HIF-1α (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1α the most (P < .03). CONCLUSIONS: RF ablation upregulates HIF-1α in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be successfully suppressed with an adjuvant HIF-1α-specific inhibitor, bortezomib, or non-HIF-1α-specific liposomal chemotherapy.

Characterizing Metabolic Heterogeneity of Hepatocellular Carcinoma with Hyperpolarized 13C Pyruvate MRI and Mass Spectrometry.

Purpose To characterize the metabolomic profiles of two hepatocellular carcinoma (HCC) rat models, track evolution of these profiles to a stimulated tumor state, and assess their effect on lactate flux with hyperpolarized (HP) carbon 13 (13C) MRI. Materials and Methods Forty-three female adult Fischer rats were implanted with N1S1 or McA-RH7777 HCC tumors. In vivo lactate-to-pyruvate ratio (LPR) was measured with HP 13C MRI at 9.4 T. Ex vivo mass spectrometry was used to measure intratumoral metabolites, and Ki67 labeling was used to quantify proliferation. Tumors were first compared with three normal liver controls. The tumors were then compared with stimulated variants via off-target hepatic thermal ablation treatment. All comparisons were made using the Mann-Whitney test. Results HP 13C pyruvate MRI showed greater LPR in N1S1 tumors compared with normal liver (mean [SD], 0.564 ± 0.194 vs 0.311 ± 0.057; P < .001 [n = 9]), but not for McA-RH7777 (P = .44 [n = 8]). Mass spectrometry confirmed that the glycolysis pathway was increased in N1S1 tumors and decreased in McA-RH7777 tumors. The pentose phosphate pathway was also decreased only in McA-RH7777 tumors. Increased proliferation in stimulated N1S1 tumors corresponded to a net increase in LPR (six stimulated vs six nonstimulated, 0.269 ± 0.148 vs 0.027 ± 0.08; P = .009), but not in McA-RH7777 (eight stimulated vs six nonstimulated, P = .13), despite increased proliferation and metastases. Mass spectrometry demonstrated relatively increased lactate production with stimulation in N1S1 tumors only. Conclusion Two HCC subtypes showed divergent glycolytic dependency at baseline and during transformation to a high proliferation state. This metabolic heterogeneity in HCC should be considered with use of HP 13C MRI for diagnosis and tracking. Keywords: Molecular Imaging-Probe Development, Liver, Abdomen/GI, Oncology, Hepatocellular Carcinoma © RSNA, 2024 See also commentary by Ohliger in this issue.

Irreversible electroporation ablation: is all the damage nonthermal?

PURPOSE: To determine whether high-dose irreversible electroporation (IRE) ablation induces thermal effects in normal liver tissue. MATERIALS AND METHODS: Animal care and use committee approval was obtained prior to the experiments. IRE ablation (n = 78) was performed by a single four-person team in vivo in 22 porcine livers by applying electric current to two 1.3-cm-diameter circular flat-plate electrodes spaced 1 cm apart. Cardiac-gated IRE pulses (n = 40-360) were systematically applied at varying voltages (1500-2900 V). End temperatures at the ablation zone center were measured and were correlated with ablation time, energy parameters, and resultant treatment effect as determined at gross pathologic and histopathologic examination. Temperatures were then monitored at the center and periphery of four ablations created by using a four-electrode IRE array (3000 V, 90 pulses per electrode pair). Data were analyzed by using multivariate analysis of variance with multiple comparisons and/or paired t tests and regression analysis, as appropriate. RESULTS: Temperature rose above the 34°C baseline after IRE in all flat-plate experiments and correlated linearly (R(2) = 0.39) with IRE "energy dose" (product of voltage and number of pulses) and more tightly in univariate analysis with both voltage and number of pulses. Thus, mean temperatures as high as 86°C ± 3 (standard deviation) were seen for 2500 V and 270 pulses. Ablations of 90 pulses or more at 2500 V produced temperatures of 50°C or greater and classic gross and histopathologic findings of thermal coagulation (pyknotic nuclei and streaming cytoplasm). For lower IRE doses (ie, 2100 V, 90 pulses), temperatures remained below 45°C, and only IRE-associated pathologic findings (ie, swollen sinusoids, dehydrated cells, and hemorrhagic infiltrate) were seen. For the four-electrode arrays, temperatures measured 54.2°C ± 6.1 at the electrode surfaces and 38.6°C ± 3.2 at the ablation zone margin. CONCLUSION: In some conditions of high intensity, IRE can produce sufficient heating to induce "white zone" thermal coagulation. While this can be useful in some settings to increase tumor destruction, further characterization of the thermal profile created with clinical electrodes and energy parameters is therefore needed to better understand the best ways to avoid unintended damage when ablating near thermally sensitive critical structures.

Irreversible electroporation: treatment effect is susceptible to local environment and tissue properties.

PURPOSE: To study the effects of the surrounding electrical microenvironment and local tissue parameters on the electrical parameters and outcome of irreversible electroporation (IRE) ablation in porcine muscle, kidney, and liver tissue. MATERIALS AND METHODS: Animal Care and Use Committee approval was obtained, and National Institutes of Health guidelines were followed. IRE ablation (n = 90) was applied in muscle (n = 44), kidney (n = 28), and liver (n = 18) tissue in 18 pigs. Two electrodes with tip exposure of 1.5-2 cm were used at varying voltages (1500-3000 V), pulse repetitions (n = 70-100), pulse length (70-100 µsec), and electrode spacing (1.5-2 cm). In muscle tissue, electrodes were placed exactly parallel, in plane, or perpendicular to paraspinal muscle fibers; in kidney tissue, in the cortex or adjacent to the renal medulla; and in liver tissue, with and without metallic or plastic plates placed 1-2 cm from electrodes. Ablation zones were determined at gross pathologic (90-120 minutes after IRE) and immunohistopathologic examination (6 hours after) for apoptosis and heat-shock protein markers. Multivariate analysis of variance with multiple comparisons and/or paired t tests and regression analysis were used for analysis. RESULTS: Mean (± standard deviation) ablation zones in muscle were 6.2 cm ± 0.3 × 4.2 cm ± 0.3 for parallel electrodes and 4.2 cm ± 0.8 × 3.0 cm ± 0.5 for in-plane application. Perpendicular orientation resulted in a cross-shaped zone. Orientation significantly affected IRE current applied (28.5-31.7A for parallel, 29.5-39.7A for perpendicular; P = .003). For kidney cortex, ovoid zones of 1.5 cm ± 0.1 × 0.5 cm ± 0.0 to 2.5 cm ± 0.1 × 1.3 cm ± 0.1 were seen. Placement of electrodes less than 5 mm from the medullary pyramids resulted in treatment effect arcing into the collecting system. For liver tissue, symmetric 2.7 cm ± 0.2 × 1.4 cm ± 0.3 coagulation areas were seen without the metallic plate but asymmetric coagulation was seen with the metallic plate. CONCLUSION: IRE treatment zones are sensitive to varying electrical conductivity in tissues. Electrode location, orientation, and heterogeneities in local environment must be considered in planning ablation treatment. Online supplemental material is available for this article.

Adjuvant liposomal doxorubicin markedly affects radiofrequency ablation-induced effects on periablational microvasculature.

PURPOSE: To evaluate the effects of radiofrequency (RF) ablation without and with adjuvant intravenous (IV) liposomal doxorubicin (Doxil) on microvessel morphology and patency and intratumoral drug delivery and retention. MATERIALS AND METHODS: There were 133 tumors/animals used in this experiment. First, single subcutaneous tumors (R3230 in Fischer rats and 786-0 in nude mice) were randomly assigned to receive RF ablation alone or no treatment and sacrificed 0-72 hours after treatment. Next, combined RF ablation and liposomal doxorubicin (1 mg given 15 min after RF ablation) was studied in R3230 tumors at 0-72 hours after treatment. Histopathologic assessment, including immunohistochemical staining for cleaved caspase-3, heat-shock protein 70, and CD34, was performed to assess morphologic vessel appearance, vessel diameter, and microvascular density. Subsequently, tumors were randomly assigned to receive RF ablation alone, RF ablation and liposomal doxorubicin, or no treatment (control tumors), followed by IV fluorescent-labeled liposomes (a surrogate marker) given 0-24 hours after RF ablation to permit qualitative assessment. RESULTS: RF ablation alone resulted in enlarged and dysmorphic vessels from 0-4 hours, peaking at 12-24 hours after RF ablation, occurring preferentially closer to the electrode. The addition of doxorubicin resulted in earlier vessel contraction (mean vessel area, 47,539 µm(2)±9,544 vs 1,854 µm(2)±458 for RF ablation alone at 15 min; P<.05). Combined RF ablation and liposomal doxorubicin produced similar fluorescence 1 hour after treatment (40.88 AU/µm(2)±33.53 vs 22.1 AU/µm(2)±13.19; P = .14) but significantly less fluorescence at 4 hours (24.3 AU/µm(2)±3.65 vs 2.8 AU/µm(2)±3.14; P<.002) compared with RF ablation alone denoting earlier reduction in microvascular patency. CONCLUSIONS: RF ablation induces morphologic changes to vessels within the ablation zone lasting 12-24 hours after treatment. The addition of liposomal doxorubicin causes early vessel contraction and a reduction in periablational microvascular patency. Such changes would likely need to be considered when determining optimal drug administration and imaging paradigms.

PFKFB3-mediated Pro-glycolytic Shift in Hepatocellular Carcinoma Proliferation.

BACKGROUND & AIMS: Metabolic reprogramming, in particular, glycolytic regulation, supports abnormal survival and growth of hepatocellular carcinoma (HCC) and could serve as a therapeutic target. In this study, we sought to identify glycolytic regulators in HCC that could be inhibited to prevent tumor progression and could also be monitored in vivo, with the goal of providing a theragnostic alternative to existing therapies. METHODS: An orthotopic HCC rat model was used. Tumors were stimulated into a high-proliferation state by use of off-target liver ablation and were compared with lower-proliferating controls. We measured in vivo metabolic alteration in tumors before and after stimulation, and between stimulated tumors and control tumors using hyperpolarized 13C magnetic resonance imaging (MRI) (h13C MRI). We compared metabolic alterations detected by h13C MRI to metabolite levels from ex vivo mass spectrometry, mRNA levels of key glycolytic regulators, and histopathology. RESULTS: Glycolytic lactate flux increased within HCC tumors 3 days after tumor stimulation, correlating positively with tumor proliferation as measured with Ki67. This was associated with a shift towards aerobic glycolysis and downregulation of the pentose phosphate pathway detected by mass spectrometry. MRI-measured lactate flux was most closely coupled with PFKFB3 expression and was suppressed with direct inhibition using PFK15. CONCLUSIONS: Inhibition of PFKFB3 prevents glycolytic-mediated HCC proliferation, trackable by in vivo h13C MRI.

Combined thermal ablation and liposomal granulocyte-macrophage colony stimulation factor increases immune cell trafficking in a small animal tumor model.

PURPOSE: To characterize intratumoral immune cell trafficking in ablated and synchronous tumors following combined radiofrequency ablation (RFA) and systemic liposomal granulocyte-macrophage colony stimulation factor (lip-GM-CSF). METHODS: Phase I, 72 rats with single subcutaneous R3230 adenocarcinoma were randomized to 6 groups: a) sham; b&c) free or liposomal GM-CSF alone; d) RFA alone; or e&f) combined with blank liposomes or lip-GM-CSF. Animals were sacrificed 3 and 7 days post-RFA. Outcomes included immunohistochemistry of dendritic cells (DCs), M1 and M2 macrophages, T-helper cells (Th1) (CD4+), cytotoxic T- lymphocytes (CTL) (CD8+), T-regulator cells (T-reg) (FoxP3+) and Fas Ligand activated CTLs (Fas-L+) in the periablational rim and untreated index tumor. M1/M2, CD4+/CD8+ and CD8+/FoxP3+ ratios were calculated. Phase II, 40 rats with double tumors were randomized to 4 groups: a) sham, b) RFA, c) RFA-BL and d) RFA-lip-GM-CSF. Synchronous untreated tumors collected at 7d were analyzed similarly. RESULTS: RFA-lip-GMCSF increased periablational M1, CTL and CD8+/FoxP3+ ratio at 3 and 7d, and activated CTLs 7d post-RFA (p<0.05). RFA-lip-GMSCF also increased M2, T-reg, and reduced CD4+/CD8+ 3 and 7d post-RFA respectively (p<0.05). In untreated index tumor, RFA-lip-GMCSF improved DCs, M1, CTLs and activated CTL 7d post-RFA (p<0.05). Furthermore, RFA-lip-GMSCF increased M2 at 3 and 7d, and T-reg 7d post-RFA (p<0.05). In synchronous tumors, RFA-BL and RFA-lip-GM-CSF improved DC, Th1 and CTL infiltration 7d post-RFA. CONCLUSION: Systemic liposomal GM-CSF combined with RFA improves intratumoral immune cell trafficking, specifically populations initiating (DC, M1) and executing (CTL, FasL+) anti-tumor immunity. Moreover, liposomes influence synchronous untreated metastases increasing Th1, CTL and DCs infiltration.

Morphologically Normal-Appearing Adrenal Glands as a Prevalent Source of Aldosterone Production in Primary Aldosteronism.

BACKGROUND: Normal-appearing adrenal glands on cross-sectional imaging may still be the source of aldosterone production in primary aldosteronism (PA). METHODS: We evaluated the prevalence of aldosterone production among morphologically normal-appearing adrenal glands and the impact of this phenomenon on interpretations of localization studies and treatment decisions. We performed a retrospective cohort study of PA patients with at least 1 normal adrenal gland and reanalyzed contemporary studies to assess interpretations of imaging and adrenal venous sampling (AVS) at the individual patient and adrenal levels. RESULTS: Among 243 patients, 43 (18%) had bilateral normal-appearing adrenals and 200 (82%) had a unilateral normal-appearing adrenal, for a total of 286 normal-appearing adrenal glands. 38% of these normal-appearing adrenal glands were a source of aldosteronism on AVS, resulting in discordance between imaging and AVS findings in 31% of patients. Most patients with lateralizing PA underwent curative unilateral treatment (80%); however, curative treatment was pursued in 92% of patients who had concordant imaging-AVS results but in only 38% who had discordant results (P < 0.05). In young patients, imaging-AVS discordance was detected in 32% of those under 45 years and 21% of those under 35 years. Among 20 contemporary studies (including 4,904 patients and 6,934 normal-appearing adrenal glands), up to 64% of normal-appearing adrenals were a source of aldosteronism resulting in 31% of patients having discordant results. CONCLUSIONS: Morphologically normal-appearing adrenal glands are commonly the source of aldosterone production in PA, even among young patients. The lack of awareness of this issue may result in inappropriate treatment recommendations.

Myofibroblasts: A key promoter of tumorigenesis following radiofrequency tumor ablation.

Radiofrequency ablation (RFA) of intrahepatic tumors induces distant tumor growth through activation of interleukin 6/signal transducer and activator of transcription 3 (STAT3)/hepatocyte growth factor (HGF)/tyrosine-protein kinase Met (c-MET) pathway. Yet, the predominant cellular source still needs to be identified as specific roles of the many types of periablational infiltrating immune cells requires further clarification. Here we report the key role of activated myofibroblasts in RFA-induced tumorigenesis and successful pharmacologic blockade. Murine models simulating RF tumorigenic effects on a macrometastatic tumor and intrahepatic micrometastatic deposits after liver ablation and a macrometastatic tumor after kidney ablation were used. Immune assays of ablated normal parenchyma demonstrated significantly increased numbers of activated myofibroblasts in the periablational rim, as well as increased HGF levels, recruitment other cellular infiltrates; macrophages, dendritic cells and natural killer cells, HGF dependent growth factors; fibroblast growth factor-19 (FGF-19) and receptor of Vascular Endothelial Growth Factor-1 (VEGFR-1), and proliferative indices; Ki-67 and CD34 for microvascular density. Furthermore, macrometastatic models demonstrated accelerated distant tumor growth at 7d post-RFA while micrometastatic models demonstrated increased intrahepatic deposit size and number at 14 and 21 days post-RFA. Multi-day atorvastatin, a selective fibroblast inhibitor, inhibited RFA-induced HGF and downstream growth factors, cellular markers and proliferative indices. Specifically, atorvastatin treatment reduced cellular and proliferative indices to baseline levels in the micrometastatic models, however only partially in macrometastatic models. Furthermore, adjuvant atorvastatin completely inhibited accelerated growth of macrometastasis and negated increased micrometastatic intrahepatic burden. Thus, activated myofibroblasts drive RF-induced tumorigenesis at a cellular level via induction of the HGF/c-MET/STAT3 axis, and can be successfully pharmacologically suppressed.

Adrenocorticotropic Hormone-Stimulated Adrenal Venous Sampling Underestimates Surgically Curable Primary Aldosteronism: A Retrospective Cohort Study and Review of Contemporary Studies.

[Figure: see text].

Intraindividual Variability of Aldosterone Concentrations in Primary Aldosteronism: Implications for Case Detection.

Primary aldosteronism is an underdiagnosed cause of hypertension. Although inadequate screening is one reason for underdiagnosis, another important contributor is that clinicians may inappropriately exclude the diagnosis when screening aldosterone concentrations fall below traditionally established thresholds. We evaluated the intraindividual variability in screening aldosterone concentrations and aldosterone-to-renin ratios, and how this variability could impact case detection, among 51 patients with confirmed primary aldosteronism who had 2 or more screening measurements of renin and aldosterone on different days. There were a total of 137 screening measurements with a mean of 3 (range 2-6) per patient. The mean intraindividual variability, expressed as coefficients of variation, was 31% for aldosterone and 45% for the aldosterone-to-renin ratio. Aldosterone concentrations ranged from 4.9 to 51 ng/dL; 49% of patients had at least one aldosterone measurement below 15 ng/dL, 29% had at least 2 aldosterone measurements below 15 ng/dL, and 29% had at least one measurement below 10 ng/dL. Individual aldosterone-to-renin ratios ranged from 8.2 to 427 ng/dL per ng/mL·hour; 57% had at least one ratio below 30 ng/dL per ng/mL·hour, 27% had at least 2 ratios below 30 ng/dL per ng/mL·hour, and 24% had at least one ratio below 20 ng/dL per ng/mL·hour. Aldosterone concentrations and aldosterone-to-renin ratios are highly variable in patients with primary aldosteronism, with many screening values falling below conventionally accepted diagnostic thresholds. The diagnostic yield for primary aldosteronism may be substantially increased by recalibrating the definition of a positive screen to include more liberal thresholds for aldosterone and the aldosterone-to-renin ratio.

Variability of Aldosterone Measurements During Adrenal Venous Sampling for Primary Aldosteronism.

BACKGROUND: Variability of aldosterone concentrations has been described in patients with primary aldosteronism. METHODS: We performed a retrospective cohort study of 340 patients with primary aldosteronism who underwent adrenal venous sampling (AVS) at a tertiary referral center, 116 of whom also had a peripheral venous aldosterone measured hours before the procedure. AVS was performed by the same interventional radiologist using bilateral, simultaneous sampling, under unstimulated and then stimulated conditions, and each sample was obtained in triplicate. Main outcome measures were: (i) change in day of AVS venous aldosterone from pre-AVS to intra-AVS and (ii) variability of triplicate adrenal venous aldosterone concentrations during AVS. RESULTS: Within an average duration of 131 minutes, 81% of patients had a decline in circulating aldosterone concentrations (relative decrease of 51% and median decrease of 7.0 ng/dl). More than a quarter (26%) of all patients had an inferior vena cava aldosterone of ≤5 ng/dl at AVS initiation. The mean coefficient of variation of triplicate adrenal aldosterone concentrations was 30% and 39%, in the left and right veins, respectively (corresponding to a percentage difference of 57% and 73%), resulting in lateralization discordance in up to 17% of patients if the lateralization index were calculated using only one unstimulated aldosterone-to-cortisol ratio rather than the average of triplicate measures. CONCLUSIONS: Circulating aldosterone levels can reach nadirs conventionally considered incompatible with the primary aldosteronism diagnosis, and adrenal venous aldosterone concentrations exhibit acute variability that can confound AVS interpretation. A single venous aldosterone measurement lacks precision and reproducibility in primary aldosteronism.

Radiology and Political Advocacy: Characterizing Radiology Political Action Committee Donors.

PURPOSE: To identify factors associated with radiologist donations to radiology political action committees (PACs). MATERIALS AND METHODS: A survey was emailed to 4474 radiologists. Factors investigated include demographics, donor history, and knowledge of the federal advocacy process. Logistic regression analysis was performed to determine factors associated with donor behavior. RESULTS: In total, 336 radiologists completed the survey. Overall, 152 (46.2%) radiologists reported donating to a radiology PAC in the past year. Those with annual personal income ≥$450,000 had greater odds to donate than those with annual personal income <$450,000 (odds ratio [OR]: 2.58, 95% confidence interval [CI]: 1.47-4.52; p < 0.001). More than three-quarters (77.2%, n = 254) reported limited or no knowledge of the federal advocacy process. Those with good or excellent knowledge of the federal advocacy process had greater odds to donate than those with no knowledge (OR: 2.63, 95% CI: 1.01-6.84; p = 0.047). Those with awareness that membership dues and foundation funds do not fund Society of Interventional Radiology Political Action Committee had greater odds to donate (OR: 3.54, 95% CI: 2.00, 6.25; p < 0.001). CONCLUSIONS: Radiologists' personal income and knowledge of the federal advocacy process were identified as key factors influencing donations. PAC donation may benefit from raising awareness of the federal advocacy process, as well as from targeted fundraising strategies aimed at higher earners.