Distal-vessel fractional flow reserve by computed tomography to monitor epicardial coronary artery disease.

AIMS: Coronary computed tomography angiography (CTA) and fractional flow reserve by computed tomography (FFR-CT) are increasingly utilized to characterize coronary artery disease (CAD). We evaluated the feasibility of distal-vessel FFR-CT as an integrated measure of epicardial CAD that can be followed serially, assessed the CTA parameters that correlate with distal-vessel FFR-CT, and determined the combination of clinical and CTA parameters that best predict distal-vessel FFR-CT and distal-vessel FFR-CT changes. METHODS AND RESULTS: Patients (n = 71) who underwent serial CTA scans at ≥2 years interval (median = 5.2 years) over a 14-year period were included in this retrospective study. Coronary arteries were analysed blindly using artificial intelligence-enabled quantitative coronary CTA. Two investigators jointly determined the anatomic location and corresponding distal-vessel FFR-CT values at CT1 and CT2. A total of 45.3% had no significant change, 27.8% an improvement, and 26.9% a worsening in distal-vessel FFR-CT at CT2. Stepwise multiple logistic regression analysis identified a four-parameter model consisting of stenosis diameter ratio, lumen volume, low density plaque volume, and age, that best predicted distal-vessel FFR-CT ≤ 0.80 with an area under the curve (AUC) = 0.820 at CT1 and AUC = 0.799 at CT2. Improvement of distal-vessel FFR-CT was captured by a decrease in high-risk plaque and increases in lumen volume and remodelling index (AUC = 0.865), whereas increases in stenosis diameter ratio, medium density calcified plaque volume, and total cholesterol presaged worsening of distal-vessel FFR-CT (AUC = 0.707). CONCLUSION: Distal-vessel FFR-CT permits the integrative assessment of epicardial atherosclerotic plaque burden in a vessel-specific manner and can be followed serially to determine changes in global CAD.

Adaptation of the Tumor Antigen Presentation Machinery to Ionizing Radiation.

Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell-mediated immunity, including enhanced expression of MHC class I (MHC-I), ß2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors in vivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and in vivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor-host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

Lung Cancer Screening Among Mammography Patients: Knowledge, Eligibility, Participation, and Interest.

OBJECTIVE: To determine lung cancer screening eligibility, knowledge, and interest and to quantify the effect of the expanded 2021 lung cancer screening eligibility criteria among women presenting for screening mammography, a group with demonstrable interest in cancer screening. METHODS: A single-page survey was distributed to patients presenting for screening mammography, from January-March 2020 and June 2020-January 2021, at 2 academic medical centers on the East and West Coasts. The population served by the East Coast institution has greater poverty, greater ethnic/racial diversity, and lower education levels. Survey questions included age, smoking history, lung cancer screening knowledge, participation, and interest. Lung cancer screening eligibility was determined for both 2013 and 2021 USPSTF guidelines. Descriptive statistics were calculated, and data were compared between groups using the Chi-square test, Mann-Whitney nonparametric test, and the 2-sample t test. RESULTS: 5512 surveys were completed; 33% (1824) of women reported a history of smoking-30% (1656) former smokers and 3% (156) current smokers. Among women with a smoking history, 7% (127/1824) were eligible for lung cancer screening using 2013% and 11% (207/1824) using the 2021 USPSTF criteria. Interest in lung cancer screening was high (73%; 151/207) among eligible women using 2021 USPSTF criteria, but only 42% (87/207) had heard of lung cancer screening and only 28% (57/207) had received prior LDCT screening. CONCLUSION: Eligible screening mammography patients reported high levels of interest in lung cancer screening but low levels of knowledge and participation. Linking mammography and LDCT appointments may improve lung cancer screening participation.

CT-monitored minimal ablative margin control in single-session microwave ablation of liver tumors: an effective strategy for local tumor control.

OBJECTIVES: To investigate the usefulness of minimal ablative margin (MAM) control by intra-procedural contrast-enhanced CT (CECT) in microwave ablation (MWA) of liver tumors. METHODS: A total of 334 consecutive liver tumors (240 hepatocellular carcinomas [HCCs] and 94 colorectal liver metastases [CRLMs]) in 172 patients treated with percutaneous MWA were retrospectively included. MAM of each tumor was assessed after expected ablation completion using intra-procedural CECT, allowing within-session additional ablation to any potentially insufficient margin. On immediate post-MWA MRI, complete ablation coverage of tumor and final MAM status were determined. The cumulative local tumor progression (LTP) rate was estimated by using the Kaplan-Meier method. To identify predictors of LTP, Cox regression analysis with a shared frailty model was performed. RESULTS: Intra-procedural CECT findings prompted additional ablation in 18.9% (63/334) of tumors. Final complete ablation coverage of tumor and sufficient MAM were determined by MRI to be achieved in 99.4% (332/334) and 77.5% (259/334), and their estimated 6-month, 1-year, and 2-year LTP rates were 3.2%, 7.5%, and 12.9%; and 1.0%, 2.1%, and 6.9%, respectively. Insufficient MAM on post-MWA MRI, perivascular tumor location, and tumor size (cm) were independent risk factors for LTP (hazard ratio = 14.4, 6.0, and 1.1, p < 0.001, p = 0.003, and p = 0.011, respectively), while subcapsular location and histology (HCC vs CRLM) were not. CONCLUSIONS: In MWA of liver tumors, intra-procedural CECT monitoring of minimal ablative margin facilitates identification of potentially suboptimal margins and guides immediate additional intra-session ablation to maximize rates of margin-sufficient ablations, the latter being a highly predictive marker for excellent long-term local tumor control. KEY POINTS: • In MWA of liver tumors, intra-procedural CECT can identify potentially suboptimal minimal ablative margin, leading to immediate additional ablation in a single treatment session. • Achieving a finally sufficient ablative margin through the MWA with intra-procedural CECT monitoring of minimal ablative margin results in excellent local tumor control.

Development, diagnostic performance, and interobserver agreement of a 18F-flurpiridaz PET automated perfusion quantitation system.

BACKGROUND: Computerized methodologies standardize the myocardial perfusion imaging (MPI) interpretation process. METHODS: To develop an automated relative perfusion quantitation approach for 18F-flurpiridaz, PET MPI studies from all phase III trial participants of 18F-flurpiridaz were divided into 3 groups. Count distributions were obtained in N = 40 normal patients undergoing pharmacological or exercise stress. Then, N = 90 additional studies were selected in a derivation group. Following receiver operating characteristic curve analysis, various standard deviations below the mean normal were used as cutoffs for significant CAD, and interobserver variability determined. Finally, diagnostic performance was compared between blinded visual readers and blinded derivations of automated relative quantitation in the remaining N = 548 validation patients. RESULTS: Both approaches yielded comparable accuracies for the detection of global CAD, reaching 71% and 72% by visual reads, and 72% and 68% by automated relative quantitation, when using CAD ≥ 70% or ≥ 50% stenosis for significance, respectively. Similar results were observed when analyzing individual coronary territories. In both pharmacological and exercise stress, automated relative quantitation demonstrated significantly more interobserver agreement than visual reads. CONCLUSIONS: Our automated method of 18F-flurpiridaz relative perfusion analysis provides a quantitative, objective, and highly reproducible assessment of PET MPI in normal and CAD subjects undergoing either pharmacological or exercise stress.

Brachial Plexus Tolerance to Single-Session SABR in a Pig Model.

PURPOSE: The single-session dose tolerance of the spinal nerves has been observed to be similar to that of the spinal cord in pigs, counter to the perception that peripheral nerves are more tolerant to radiation. This pilot study aims to obtain a first impression of the single-session dose-response of the brachial plexus using pigs as a model. METHODS AND MATERIALS: Ten Yucatan minipigs underwent computed tomography and magnetic resonance imaging for treatment planning, followed by single-session stereotactic ablative radiotherapy. A 2.5-cm length of the left-sided brachial plexus cords was irradiated. Pigs were distributed in 3 groups with prescription doses of 16 (n = 3), 19 (n = 4), and 22 Gy (n = 3). Neurologic status was assessed by observation for changes in gait and electrodiagnostic examination. Histopathologic examination was performed with light microscopy of paraffin-embedded sections stained with Luxol fast blue/periodic acid-Schiff and Masson's trichrome. RESULTS: Seven of the 10 pigs developed motor deficit to the front limb of the irradiated side, with a latency from 5 to 8 weeks after irradiation. Probit analysis of the maximum nerve dose yields an estimated ED50 of 19.3 Gy for neurologic deficit, but the number of animals was insufficient to estimate 95% confidence intervals. No motor deficits were observed at a maximum dose of 17.6 Gy for any pig. Nerve conduction studies showed an absence of sensory response in all responders and absent or low motor response in most of the responders (71%). All symptomatic pigs showed histologic lesions to the left-sided plexus consistent with radiation-induced neuropathy. CONCLUSIONS: The single-session ED50 for symptomatic plexopathy in Yucatan minipigs after irradiation of a 2.5-cm length of the brachial plexus cords was determined to be 19.3 Gy. The dose-response curve overlaps that of the spinal nerves and the spinal cord in the same animal model. The relationship between the brachial plexus tolerance in pigs and humans is unknown, and caution is warranted when extrapolating for clinical use.

Classes of Drugs that Mitigate Radiation Syndromes.

We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 "hits." Most of these hits could be allocated by maximal common substructure analysis to one of 11 clusters each containing at least three active compounds. Further screening validated 23 compounds as being most active; 15 of these were cherry-picked based on drug availability and tested for their ability to mitigate acute hematopoietic radiation syndrome (H-ARS) in mice. Of these, five bore a 4-nitrophenylsulfonamide motif while 4 had a quinoline scaffold. All but two of the 15 significantly (p < 0.05) mitigated H-ARS in mice. We had previously reported that the lead 4-(nitrophenylsulfonyl)-4-phenylpiperazine compound (NPSP512), was active in mitigating multiple acute and late radiation syndromes in mice of more than one sex and strain. Unfortunately, the formulation of this drug had to be changed for regulatory reasons and we report here on the synthesis and testing of active analogs of NPSP512 (QS1 and 52A1) that have increased solubility in water and in vivo bioavailability while retaining mitigator activity against H-ARS (p < 0.0001) and other radiation syndromes. The lead quinoline 057 was also active in multiple murine models of radiation damage. Taken together, HTS of a total of 150,000 bioactive or chemical substances, combined with maximal common substructure analysis has resulted in the discovery of diverse groups of compounds that can mitigate H-ARS and at least some of which can mitigate multiple radiation syndromes when given starting 24 h after exposure. We discuss what is known about how these agents might work, and the importance of formulation and bioavailability.

Tumor Size Matters-Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy.

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

Existence of a Dose-Length Effect in Spinal Nerves Receiving Single-Session Stereotactic Ablative Radiation Therapy.

PURPOSE: The spinal nerves have been observed to have a similar single-session dose tolerance to that of the spinal cord in pigs. Small-animal studies have shown that spinal cord dose tolerance depends on the length irradiated. This work aims to determine whether a dose-length effect exists for spinal nerves. METHODS AND MATERIALS: Twenty-seven Yucatan minipigs underwent computed tomography and magnetic resonance imaging for treatment planning, followed by single-session stereotactic ablative radiation therapy. A 0.5 cm length of the left-sided C6, C7, and C8 spinal nerves was targeted. The pigs were distributed into 6 groups with prescription doses of 16 Gy (n = 5), 18 Gy (n = 5), 20 Gy (n = 5), 22 Gy (n = 5), 24 Gy (n = 5), or 36 Gy (n = 2) and corresponding maximum doses of 16.7, 19.1, 21.3, 23.1, 25.5, and 38.6 Gy, respectively. Neurologic status was assessed with a serial electrodiagnostic examination and daily observation of gait for approximately 52 weeks. A histopathologic examination of paraffin-embedded sections with Luxol fast blue/periodic acid-Schiff's staining was also performed. RESULTS: Marked gait change was observed in 8 of 27 irradiated pigs. The latency for responding pigs was 11 to 16 weeks after irradiation. The affected animals presented with a limp in the left front limb, and 62.5% of these pigs had electrodiagnostic evidence of denervation in the C6 and C7 innervated muscles. A probit analysis showed the dose associated with a 50% incidence of gait change is 23.9 Gy (95% confidence interval, 22.5-25.8 Gy), which is 20% higher than that reported in a companion study where a 1.5 cm length was irradiated. All symptomatic pigs had demyelination and fibrosis in the irradiated nerves, but the contralateral nerves and spinal cord were normal. CONCLUSIONS: A dose-length effect was observed for single-session irradiation of the spinal nerves in a Yucatan minipig model.

Spinal Nerve Tolerance to Single-Session Stereotactic Ablative Radiation Therapy.

PURPOSE: This study was performed to determine the dose-related incidence of neuropathy from single-session irradiation of the C6-C8 spinal nerves using a pig model and to test the hypothesis that the spinal nerves and spinal cord have the same tolerance to full cross-sectional irradiation. METHODS AND MATERIALS: Twenty-five Yucatan minipigs received study treatment. Each animal underwent computed tomography and magnetic resonance imaging for treatment planning, followed by single-session stereotactic ablative radiation therapy. A 1.5-cm length of the left-sided C6, C7, and C8 spinal nerves was targeted. Pigs were distributed into 5 groups with prescription doses of 16 (n = 7), 18 (5), 20 (5), 22 (5), or 24 (3) Gy with corresponding maximum nerve doses of 17.3, 19.5, 21.6, 24.1, and 26.2 Gy. The neurologic status of all animals was followed for approximately 52 weeks by serial electrodiagnostic examination and daily observation of gait. Histopathologic examination of paraffin-embedded sections with Luxol fast blue/periodic acid-Schiff staining was performed on bilateral spinal nerves and the spinal cord. RESULTS: Marked gait change was observed in 15 of the 25 irradiated pigs. Affected animals presented with a limp in their left front limb, and electromyography demonstrated evidence of denervation in C6 and C7 innervated muscles. Probit analysis showed the ED50 for gait change after irradiation of the spinal nerves to be 19.7 Gy (95% confidence interval, 18.5-21.1). The latency for all responding pigs was 9 to 15 weeks after irradiation. All symptomatic pigs had demyelination and fibrosis in their irradiated nerves, whereas contralateral nerves and spinal cord were normal. CONCLUSIONS: The ED50 for symptomatic neuropathy after full cross-sectional irradiation of the spinal nerves was found to be 19.7 Gy. The dose response of the C6-C8 spinal nerves is not significantly different from that of full cross-sectional irradiation of the spinal cord as observed in companion studies.

The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation.

Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD70/30 doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD70/30 doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.

Building a high-resolution T2-weighted MR-based probabilistic model of tumor occurrence in the prostate.

PURPOSE: We present a method for generating a T2 MR-based probabilistic model of tumor occurrence in the prostate to guide the selection of anatomical sites for targeted biopsies and serve as a diagnostic tool to aid radiological evaluation of prostate cancer. MATERIALS AND METHODS: In our study, the prostate and any radiological findings within were segmented retrospectively on 3D T2-weighted MR images of 266 subjects who underwent radical prostatectomy. Subsequent histopathological analysis determined both the ground truth and the Gleason grade of the tumors. A randomly chosen subset of 19 subjects was used to generate a multi-subject-derived prostate template. Subsequently, a cascading registration algorithm involving both affine and non-rigid B-spline transforms was used to register the prostate of every subject to the template. Corresponding transformation of radiological findings yielded a population-based probabilistic model of tumor occurrence. The quality of our probabilistic model building approach was statistically evaluated by measuring the proportion of correct placements of tumors in the prostate template, i.e., the number of tumors that maintained their anatomical location within the prostate after their transformation into the prostate template space. RESULTS: Probabilistic model built with tumors deemed clinically significant demonstrated a heterogeneous distribution of tumors, with higher likelihood of tumor occurrence at the mid-gland anterior transition zone and the base-to-mid-gland posterior peripheral zones. Of 250 MR lesions analyzed, 248 maintained their original anatomical location with respect to the prostate zones after transformation to the prostate. CONCLUSION: We present a robust method for generating a probabilistic model of tumor occurrence in the prostate that could aid clinical decision making, such as selection of anatomical sites for MR-guided prostate biopsies.

Focal Irradiation and Systemic TGFß Blockade in Metastatic Breast Cancer.

Purpose: This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFß blockade during radiotherapy in metastatic breast cancer patients.Experimental Design: Prospective randomized trial comparing two doses of TGFß blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum.Results: Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; P = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool.Conclusions: TGFß blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. Clin Cancer Res; 24(11); 2493-504. ©2018 AACR.

4-(Nitrophenylsulfonyl)piperazines mitigate radiation damage to multiple tissues.

Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-nitrophenylsulfonamide (NPS) backbone in common that dramatically decrease mortality from the hematopoietic acute radiation syndrome (hARS). The group emerged from an in vitro high throughput screen (HTS) for inhibitors of radiation-induced apoptosis. The lead compound also mitigates against death after local abdominal irradiation and after local thoracic irradiation (LTI) in models of subacute radiation pneumonitis and late radiation fibrosis. Mitigation of hARS is through activation of radiation-induced CD11b+Ly6G+Ly6C+ immature myeloid cells. This is consistent with the notion that myeloerythroid-restricted progenitors protect against WBI-induced lethality and extends the possible involvement of the myeloid lineage in radiation effects. The lead compound was active if given to mice before or after WBI and had some anti-tumor action, suggesting that these compounds may find broader applications to cancer radiation therapy.

Comparison of Triple-Drug Transcatheter Arterial Chemoembolization (TACE) With Single-Drug TACE Using Doxorubicin-Eluting Beads: Long-Term Survival in 313 Patients.

OBJECTIVE: We compared survival outcomes in 313 patients with unresectable hepatocellular carcinoma (HCC) treated with two different transcatheter arterial chemoembolization (TACE) regimens: triple-drug TACE or single-drug TACE using drug-eluting beads. MATERIALS AND METHODS: In this retrospective study, patient selection criteria were uniform. The triple-drug group (n = 166) underwent TACE using ethiodized oil with doxorubicin, cisplatin, and mitomycin-C with a microsphere embolic. The single-drug group (n = 147) underwent TACE using doxorubicin-eluting beads. Group characteristics were classified and analyzed, and survival was calculated using standard statistical methods. All patients were followed until death. Those undergoing orthotopic liver transplant (OLT) were also followed. RESULTS: There were no significant differences between the two groups in terms of demographics, Child-Pugh class, or Okuda stage. With patients undergoing OLT censored (n = 73), the mean (± standard error) survival in the triple-drug group was 23.49 ± 2.38 months, and the median survival was 16.00 ± 1.51 months. Mean survival in the single-drug bead group was 28.16 ± 2.75 months, and the median survival was 15.00 ± 1.50 months (p = 0.168). With patients undergoing OLT censored, the mean and median survival for the total cohort were 26.25 ± 1.97 and 15.00 ± 1.08 months, respectively. In the entire cohort that did not undergo OLT, patients with Child-Pugh class A disease survived significantly longer than did patients with Child-Pugh class B disease. Elevated α-fetoprotein levels were associated with shorter survival, and patients undergoing TACE with drug-eluting beads had shorter hospital stays. Although a greater percentage annual survival was observed in patients undergoing drug-eluting bead TACE who had Child-Pugh class A, Okuda stage I, and Barcelona Clinic Liver Cancer classes A and B disease starting at 36 months, this suggested survival advantage did not reach statistical significance. CONCLUSION: We found no significant survival difference in patients with unresectable HCC treated with triple-drug TACE compared with single-drug TACE using doxorubicin-eluting beads.

Local Hypothermia as a Radioprotector of the Rectal Wall During Prostate Stereotactic Body Radiation Therapy.

PURPOSE: To compare the single-fraction dose-related incidence of rectal obstruction and/or bleeding in normothermic and hypothermic rectums of a rat model. METHODS AND MATERIALS: A 1.9-cm length of rectum was irradiated with a single fraction in 57 Sprague-Dawley rats using a dedicated image-guided small animal irradiator and Monte Carlo-based treatment planning system. All rats had a rectal temperature control apparatus placed during irradiation and were stratified to achieve either a normothermic (37°C) or hypothermic (15°C) rectal wall temperature. Radiation was delivered to a 1-cm-diameter cylindrical volume about the cooling device and rectal wall. The radiation dose was escalated from 16 Gy up to 37 Gy to assess the dose response in each arm. The primary endpoint of this study was rectal obstruction and/or bleeding during a follow-up of 180 to 186 days. Histologic scoring was performed on all study rats. RESULTS: Probit analysis showed a dose associated with a 50% incidence of rectal obstruction of 24.6 Gy and 40.8 Gy for normothermic and hypothermic arms, respectively. The occurrence of obstruction and/or bleeding correlated with the posttreatment histologic score for normothermic rats; however, there was no difference in histologic score between normothermic and hypothermic rats at the highest dose levels evaluated. CONCLUSIONS: A significant radioprotective effect was observed using local hypothermia during a single large dose of radiation for the functional endpoint of rectal obstruction and/or bleeding. A confirmatory study in a large animal model with anatomic and physiologic similarities to humans is suggested.

Knowledge-driven decision support for assessing dose distributions in radiation therapy of head and neck cancer.

PURPOSE: Clinical data that are generated through routine radiation therapy procedures can be leveraged as a source of knowledge to provide evidence-based decision support for future patients. Treatment planning in radiation therapy often relies on trial-and-error iterations, experience, judgment calls and general guidelines. The authors present a knowledge-driven decision support system that assists clinicians by reducing some of the uncertainties associated with treatment planning and provides quantified empirical estimates to help minimize the radiation dose to healthy critical structures surrounding the tumor. METHODS: A database of retrospective DICOM RT data fuels a decision support engine, which assists clinicians in selecting dose constraints and assessing dose distributions. The first step is to quantify the spatial relationships between the tumor and surrounding critical structures through features that account for distance, volume, overlap, location, shape and orientation. These features are used to identify database cases that are anatomically similar to the new patient. The dose profiles of these database cases can help clinicians to estimate an acceptable dose distribution for the new case, based on empirical evidence. Since database diversity is essential for good system performance, an infrastructure for multi-institutional collaboration was also conceptualized in order to pave the way for data sharing of protected health information. RESULTS: A set of 127 retrospective test cases was collected from a single institution in order to conduct a leave-one-out evaluation of the decision support module. In 72 % of these retrospective test cases, patients with similar tumor anatomy were also found to exhibit similar radiation dose distributions. This demonstrates the system's ability to successfully extract retrospective database cases that can estimate the new patient's dose distribution. CONCLUSION: The radiation therapy treatment planning decision support system presented here can assist clinicians in determining good dose constraints and assessing dose distributions by using knowledge gained from retrospective treatment plans.

Two-Point Stretchable Electrode Array for Endoluminal Electrochemical Impedance Spectroscopy Measurements of Lipid-Laden Atherosclerotic Plaques.

Four-point electrode systems are commonly used for electric impedance measurements of biomaterials and tissues. We introduce a 2-point system to reduce electrode polarization for heterogeneous measurements of vascular wall. Presence of endoluminal oxidized low density lipoprotein (oxLDL) and lipids alters the electrochemical impedance that can be measured by electrochemical impedance spectroscopy (EIS). We developed a catheter-based 2-point micro-electrode configuration for intravascular deployment in New Zealand White rabbits. An array of 2 flexible round electrodes, 240 µm in diameter and separated by 400 µm was microfabricated and mounted on an inflatable balloon catheter for EIS measurement of the oxLDL-rich lesions developed as a result of high-fat diet-induced hyperlipidemia. Upon balloon inflation, the 2-point electrode array conformed to the arterial wall to allow deep intraplaque penetration via alternating current (AC). The frequency sweep from 10 to 300 kHz generated an increase in capacitance, providing distinct changes in both impedance (Ω) and phase (ϕ) in relation to varying degrees of intraplaque lipid burden in the aorta. Aortic endoluminal EIS measurements were compared with epicardial fat tissue and validated by intravascular ultrasound and immunohistochemistry for plaque lipids and foam cells. Thus, we demonstrate a new approach to quantify endoluminal EIS via a 2-point stretchable electrode strategy.

Rethinking the Role of Nitroglycerin Ointment in Ischemic Vascular Filler Complications: An Animal Model With ICG Imaging.

PURPOSE: Soft tissue dermal fillers, both temporary and permanent, are used frequently in facial rejuvenation. As the use of fillers increases, ischemic complications including skin necrosis are becoming more prevalent. In the literature, topical nitroglycerin paste has been recommended in the early treatment of patients presenting with ischemia. The purpose of this study was to evaluate the vascular perfusion effects of topical nitroglycerin paste in an animal model using indocyanine green (ICG) imaging. METHODS: After Animal Research Committee approval, a rabbit ear model was used to create filler-associated skin ischemia. Ischemia was confirmed to occur after intra-arterial occlusion. Four commonly used soft tissue fillers were injected intra-arterially: Radiesse (Merz USA, Greensboro NC), Restylane (Galderma, Ft. Worth, TX), Juvederm Ultra (Allergan, Irvine CA), Belotero (Merz USA, Greensboro NC) (0.1 ml). A total of 15 ears were used, 1 control and 4 experimental per product. Thirty minutes after occlusion, nitroglycerin ointment USP, 2%(Nitro-Bid) was applied topically to the experimental ears. Vascular perfusion was evaluated with the SPY System (Novadaq Inc.) using ICG imaging. Perfusion images were obtained at baseline, immediately after, and 30 minutes after intra-arterial filler injection, and at 30, 60, 90, and 120 minutes after application of topical nitroglycerin ointment. RESULTS: In this rabbit ear model, no statistically significant improvement in perfusion was noted after topical application of nitroglycerin paste with ICG imaging. In addition, the skin of the rabbit ear post-nitroglycerin ointment appeared to have more of a congested appearance than the controls. CONCLUSIONS: Ischemic filler complications are becoming increasingly prevalent. Practitioners often treat these complications with topical nitroglycerin paste based on the knowledge that topical nitroglycerin causes vasodilation. In filler-induced tissue ischemia, however, filler product is present within arterioles. Theoretically, applying nitroglycerin paste, at least early, may not improve perfusion and could worsen ischemia with dilation of vessels and further propagation of product into the smaller arterioles and capillaries. In addition, nitroglycerin paste has systemic effects, including hypotension and dizziness, which may not be tolerated by some patients. Therefore, the authors caution the use of topical nitroglycerin paste in patients presenting with filler-associated ischemia. Further studies in the best treatment algorithms for patients presenting with ischemic complications need to be performed.