Chemoembolization Beyond Hepatocellular Carcinoma: What Tumors Can We Treat and When?

Liver metastases are the most common malignancy found in the liver and are 20 to 40 times more common than primary hepatic tumors, including hepatocellular carcinoma. Patients with liver metastases often present with advanced disease and are not eligible for curative-intent surgery or ablative techniques. The unique hepatic arterial blood supply of liver metastases allows interventional radiologists to target these tumors with transarterial therapies. Transarterial chemoembolization (TACE) has been studied in the treatment of liver metastases originating from a variety of primary malignancies and has demonstrated benefits in terms of hepatic progression-free survival, overall survival, and symptomatic relief, among other benefits. Depending on the primary tumor from which they originate, liver metastases may have different indications for TACE, may utilize different TACE regimens and techniques, and may result in different post-procedural outcomes. This review offers an overview of TACE techniques and specific considerations in the treatment of liver metastases, provides an in-depth review of TACE in the treatment of liver metastases originating from colorectal cancer, neuroendocrine tumor, and uveal melanoma, which represent some of the many tumors beyond hepatocellular carcinoma that can be treated by TACE, and summarizes data regarding when one should consider TACE in their treatment algorithms.

Contrast-enhanced US Evaluation of Hepatocellular Carcinoma Response to Chemoembolization: A Prospective Multicenter Trial.

Background Contrast-enhanced (CE) US has been studied for use in the detection of residual viable hepatocellular carcinoma (HCC) after locoregional therapy, but multicenter data are lacking. Purpose To compare two-dimensional (2D) and three-dimensional (3D) CE US diagnostic performance with that of CE MRI or CT, the current clinical standard, in the detection of residual viable HCC after transarterial chemoembolization (TACE) in a prospective multicenter trial. Materials and Methods Participants aged at least 21 years with US-visible HCC scheduled for TACE were consecutively enrolled at one of three participating academic medical centers from May 2016 to March 2022. Each underwent baseline 2D and 3D CE US before TACE, 2D and 3D CE US 1-2 weeks and/or 4-6 weeks after TACE, and CE MRI or CT 4-6 weeks after TACE. CE US and CE MRI or CT were evaluated by three fellowship-trained radiologists for the presence or absence of viable tumors and were compared with reference standards of pathology (18%), angiography on re-treatment after identification of residual disease at 1-2-month follow-up imaging (31%), 4-8-month CE MRI or CT (42%), or short-term (approximately 1-2 months) CE MRI or CT if clinically decompensated and estimated viability was greater than 50% at imaging (9%). Diagnostic performance criteria, including sensitivity and specificity, were obtained for each modality and time point with generalized estimating equation analysis. Results A total of 132 participants were included (mean age, 64 years ± 7 [SD], 87 male). Sensitivity of 2D CE US 4-6 weeks after TACE was 91% (95% CI: 84, 95), which was higher than that of CE MRI or CT (68%; 95% CI: 58, 76; P < .001). Sensitivity of 3D CE US 4-6 weeks after TACE was 89% (95% CI: 81, 94), which was higher than that of CE MRI or CT (P < .001), with no evidence of a difference from 2D CE US (P = .22). CE MRI or CT had 85% (95% CI: 76, 91) specificity, higher than that of 4-6-week 2D and 3D CE US (70% [95% CI: 56, 80] and 67% [95% CI: 53, 78], respectively; P = .046 and P = .023, respectively). No evidence of differences in any diagnostic criteria were observed between 1-2-week and 4-6-week 2D CE US (P > .21). Conclusion The 2D and 3D CE US examinations 4-6 weeks after TACE revealed higher sensitivity in the detection of residual HCC than CE MRI or CT, albeit with lower specificity. Importantly, CE US performance was independent of follow-up time. Clinical trial registration no. NCT02764801 © RSNA, 2023 Supplemental material is available for this article.

A 5-Year Update on the IR Residency Match: 2022 National Survey Results of Program Directors and Matched Applicants Compared with 2017.

PURPOSE: To characterize the experiences of matched applicants (MAs) and program directors (PDs) in the 2022 interventional radiology (IR) residency Match and compare with 2017 data. METHODS: Surveys were distributed to IR PDs and MAs from the 2022 Match. Findings were compared with those of 2017 using the 2-sample t test and Fisher exact test. RESULTS: In total, 68 MAs (40%) and 47 PDs (52%) responded. Collected demographic traits were similar, including ongoing male predominance (77% of MAs, 83% of PDs). Moreover, 86% of MAs and 87% of PDs were "satisfied" with Match outcomes. Compared with those in 2017, MAs applied to more IR programs (P < .001). MAs reported more research (P = .003) and abstracts/publications (P < .001) and ranked these as more important than PDs did (P < .001 for both). Approximately 82% of PDs gave special attention to candidates who completed a visiting rotation at their institution; 60% of MAs and 95% of PDs believed virtual interviews resulted in overinterviewing (P < .001); both agreed they provided convenience and accessibility. Furthermore, 63% of MAs believed a Step 1 pass/fail system will be less equitable for applicants. Additional data on demographics, medical school experiences, applications, interviews, intern year, and rank process were reported. CONCLUSIONS: Satisfaction with Match results remained high from 2017 to 2022, although efforts are needed to improve applicants' ability to navigate the application process, address overapplying, and evaluate concerns regarding the Step 1 pass/fail system. These survey findings will help inform applicants and PDs for future match cycles.

Iatrogenic Renal Artery Injury in 90 Cases: Arteriographic Findings and Outcomes after Embolization for Bleeding.

PURPOSE: To evaluate differences in arteriographic findings and outcomes after embolization among patients with a suspected iatrogenic renal arterial injury (IRAI). MATERIALS AND METHODS: Patients at the authors' institution who underwent renal arteriography for suspected IRAIs after partial nephrectomy, biopsy, or percutaneous access over a 20-year period were included. Records, imaging, and outcomes were reviewed. Data analysis was performed using the Fisher exact or Kruskal-Wallis test. RESULTS: Ninety arteriograms were performed on 83 patients after partial nephrectomy (n = 32), biopsy (n = 27), or percutaneous access (n = 24), including for nephrostomy/ureterostomy and stone removal. The median number of days between the index procedure and arteriogram was highest (15 days) after partial nephrectomy and lowest (5 days) after biopsy (P = .0001). Embolization was performed during 76% of arteriograms. If prearteriographic imaging showed positive results for IRAIs, embolization was performed in 67% versus 33% if imaging showed negative results (P = .005). The transfusion rate was higher after biopsy than after partial nephrectomy or percutaneous access (P = .002). Acute kidney injury after arteriogram occurred in 7% of patients; however, all returned to baseline by 1 week. CONCLUSIONS: Despite the different mechanism of IRAIs in partial nephrectomy, biopsy, and percutaneous access, arteriographic findings and outcomes were overall similar among groups. Prearteriographic imaging can help identify IRAIs but cannot supersede the clinical judgment regarding indication for embolization. IRAIs can present acutely or after a long interim, although patients who underwent biopsy presented earlier and more frequently required a blood transfusion. IRAIs can be treated with embolization without permanent deleterious effects on renal function.

Variability in biopsy quality informs translational research applications in hepatocellular carcinoma.

In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7-10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10-75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.

Demographic Trends in Female Interventional Radiology Trainees With the Advent of the Integrated Interventional Radiology Residency.

OBJECTIVE: Examine changes in gender representation in the interventional radiology (IR) training pool since the advent of the integrated IR residency in 2015 to 2020. METHODS: Electronic Residency Application Service and ACGME Data Resource Book records from 2015 to 2020 were reviewed for integrated IR residency and vascular and interventional radiology (VIR) fellowship applicant data and active IR resident and VIR fellow data, respectively. The Society of Interventional Radiology (SIR) 2018 registry data were reviewed for SIR membership data. Two-tailed Fisher's exact tests and χ2 analyses were used to compare trainees between application cycles. RESULTS: In the 2017 application cycle, 23% (247 of 1,062) of integrated IR residency applicants were female, with similar interest in the 2018, 2019, and 2020 cycles (χ2[3, n = 2,863] = 5.1, P = .17). In comparison, female VIR fellowship applicants were 12% from 2017 to 2020. Female integrated IR residents represented 13% to 18% of all integrated IR residents in the 2016 to 2020 academic years compared with the period before the integrated IR residency when female IR trainees represented 8% (23 of 275) of all IR trainees in 2015 to 2016 (P = .0002). Although in 2018, the total active SIR female membership was 9% (319 of 3,622), the female resident membership was 17% (131 of 793), and the female medical student membership was 25% (389 of 1,573). DISCUSSION: With the advent of the integrated IR residency, there is an increasing female constituency, at the medical student, IR applicant, and IR resident levels, with more than a doubling of female IR trainees, portending a continued reduction in the IR gender disparity in the future.

Infection Rates Following Hepatic Embolotherapy in Patients with Prior Biliary Interventions: Comparison of Single-Drug Moxifloxacin and Multidrug Antibiotic Prophylaxis.

PURPOSE: To investigate the incidence of infection in patients with prior biliary interventions undergoing hepatic embolotherapy following extended antibiotic prophylaxis using moxifloxacin monotherapy or a multidrug regimen. MATERIAL AND METHODS: Under an Institutional Review Board-approved protocol, retrospective review of a quality assurance database identified all liver-directed therapies (LDTs) at a tertiary care center between 2010 and 2019 with biliary intervention prior to LDT Records were reviewed for infectious complications within 3 months of chemo- or radioembolization. Patients were categorized based on extended antibiotic prophylaxis regimen: oral moxifloxacin monotherapy or multidrug regimen of levofloxacin and metroniodazole plus preprocedural neomycin and erythromycin. Procedures without at least 2 months of clinical follow-up, hepatic ablation, and procedures without extended antibiotic prophylaxis were excluded Regression analysis was used to analyze multivariate data to detect a difference in infection rate. RESULTS: Twenty-four chemoembolization and 58 radioembolization procedures were performed on 55 patients with prior biliary interventions. Forty-four used monotherapy and 38 used multidrug regimen. The incidence of infection was 16.7% (4/24) after chemoembolization and 13.8% (8/58) after radioembolization The incidence of infection in patients did not differ between antibiotic prophylaxis regimens (18.2% [8/44] with moxifloxacin monotherapy and 10.5% [4/38] multidrug regimen, P = .3) or between types of biliary interventions (24.1% [7/29] with bilioenteric anastomosis and 23.8% [5/21] biliary stenting, P = .3). CONCLUSIONS: The types of extended antibiotic prophylaxis (moxifloxacin monotherapy vs multitherapy), prior biliary intervention, and embolotherapy were not found to be associated with differences in the incidence of infectious complications in this population.

US-triggered Microbubble Destruction for Augmenting Hepatocellular Carcinoma Response to Transarterial Radioembolization: A Randomized Pilot Clinical Trial.

Background US contrast agents are gas-filled microbubbles (MBs) that can be locally destroyed by using external US. Among other bioeffects, US-triggered MB destruction, also known as UTMD, has been shown to sensitize solid tumors to radiation in preclinical models through localized insult to the vascular endothelial cells. Purpose To evaluate the safety and preliminary efficacy of combining US-triggered MB destruction and transarterial radioembolization (TARE) in participants with hepatocellular carcinoma (HCC). Materials and Methods In this pilot clinical trial, participants with HCC scheduled for sublobar TARE were randomized to undergo either TARE or TARE with US-triggered MB destruction 1-4 hours and approximately 1 and 2 weeks after TARE. Enrollment took place between July 2017 and February 2020. Safety of US-triggered MB destruction was evaluated by physiologic monitoring, changes in liver function tests, adverse events, and radiopharmaceutical distribution. Treatment efficacy was evaluated by using modified Response Evaluation Criteria in Solid Tumors (mRECIST) on cross-sectional images, time to required next treatment, transplant rates, and overall survival. Differences across mRECIST reads were compared by using a Mann-Whitney U test, and the difference in prevalence of tumor response was evaluated by Fisher exact test, whereas differences in time to required next treatment and overall survival curves were compared by using a log-rank (Mantel-Cox) test. Results Safety results from 28 participants (mean age, 70 years ± 10 [standard deviation]; 17 men) demonstrated no significant changes in temperature (P = .31), heart rate (P = .92), diastolic pressure (P = .31), or systolic pressure (P = .06) before and after US-triggered MB destruction. No changes in liver function tests between treatment arms were observed 1 month after TARE (P > .15). Preliminary efficacy results showed a greater prevalence of tumor response (14 of 15 [93%; 95% CI: 68, 100] vs five of 10 [50%; 95% CI: 19, 81]; P = .02) in participants who underwent both US-triggered MB destruction and TARE (P = .02). Conclusion The combination of US-triggered microbubble destruction and transarterial radioembolization is feasible with an excellent safety profile in this patient population and appears to result in improved hepatocellular carcinoma treatment response. © RSNA, 2020.

Medical Student Education During the COVID-19 Pandemic: Initial Experiences Implementing a Virtual Interventional Radiology Elective Course.

RATIONALE AND OBJECTIVES: In response to the COVID-19 pandemic reducing medical student presence on clinical services and in classrooms, academic institutions are utilizing a virtual format to continue medical student education. We describe a successful initial experience implementing a virtual elective in interventional radiology (IR) and provide the course framework, student feedback, and potential improvements. MATERIALS AND METHODS: A 2-week virtual IR elective curriculum was created utilizing a combination of synchronous and asynchronous learning and the "flipped" classroom educational model. Students virtually participated in daily IR resident education conferences, resident-led case review sessions, and dedicated lectures. Asynchronous prelearning material consisted of text and video correlating to lecture topics. Anonymous precourse and postcourse surveys were sent to all participating students (n = 10). RESULTS: Ten students (100%) completed precourse and seven (70%) completed postcourse surveys. Enrolled students were considering residencies in surgery (50%), internal medicine (40%), interventional radiology (30%), and/or diagnostic radiology (30%). Students' understanding of what IRs do and the procedures they perform (p < 0.001), when to consult IR for assistance in patient management (p = 0.005), and the number of IR procedures students could recall (p = 0.015) improved after the course. Case-review sessions and virtual lectures ranked as having the highest education value. Students recommended additional small-group case workshops. CONCLUSION: This successful virtual IR elective provides a framework for others to continue IR medical student education during the pandemic and grow the specialty's presence within an increasingly virtual medical school curriculum. The described model may be modified to improve IR education beyond the COVID-19 era.

Interventional Oncology Approach to Hepatic Metastases.

Metastatic liver disease is one of the major causes of cancer-related morbidity and mortality. Locoregional therapies offered by interventional oncologists alleviate cancer-related morbidity and in some cases improve survival. Locoregional therapies are often palliative in nature but occasionally can be used with curative intent. This review will discuss important factors to consider prior to palliative and curative intent treatment of metastatic liver disease with locoregional therapy. These factors include those specific to the tumor, liver function, liver reserve, differences between treatment modalities, and patient-specific considerations.

Comparison of Clinical Performance of VectorFlow and Palindrome Symmetric-Tip Dialysis Catheters: A Multicenter, Randomized Trial.

PURPOSE: To compare clinical performance of 2 widely used symmetric-tip hemodialysis catheters. MATERIALS AND METHODS: Patients with end-stage renal disease initiating or resuming hemodialysis were randomized to receive an Arrow-Clark VectorFlow (n = 50) or Palindrome catheter (n = 50). Primary outcome was 90-d primary unassisted catheter patency. Secondary outcomes were Kt/V ([dialyzer urea clearance × total treatment time]/total volume of urea distribution), urea reduction ratio (URR), and effective blood flow (QB). RESULTS: Primary unassisted patency rates with the VectorFlow catheter at 30, 60, and 90 d were 95.5% ± 3.3, 87.2% ± 7.3, and 80.6% ± 9.8, respectively, compared with 89.1% ± 6.2, 79.4% ± 10.0, and 71.5% ± 12.6 with the Palindrome catheter (P = .20). Patients with VectorFlow catheters had a mean Kt/V of 1.5 at 30-, 60-, and 90-day time points, significantly higher than the mean Kt/V of 1.3 among those with Palindrome catheters (P = .0003). URRs were not significantly different between catheters. Catheter QB rates exceeded National Kidney Foundation-recommended thresholds of 300 mL/min at all time points for both catheters and were similar for both catheters (median, 373 mL/min). Catheter failure, ie, poor flow rate requiring guide-wire exchange or removal, within the 90-day primary outcome occurred in 3 VectorFlow subjects and 5 Palindrome subjects (P = .72). Infection rates were similar, with 0.98 infections per 1,000 catheter days for VectorFlow catheters compared with 2.62 per 1,000 catheter days for Palindrome catheters (P = .44). CONCLUSIONS: The 90-day primary patency rates of Palindrome and VectorFlow catheters were not significantly different, and both achieved sustained high QB through 90 day follow-up. However, dialysis adequacy based on Kt/V was consistently better with the VectorFlow catheter versus the Palindrome.

Diagnosis and Treatment of Nonmaturing Fistulae for Hemodialysis Access via Transradial Approach: A Case-Control Study.

PURPOSE: To compare outcomes of transradial access for endovascular treatment of nonmaturing hemodialysis fistulae compared to brachial arteriography followed by unidirectional or bidirectional fistula access for intervention. MATERIALS AND METHODS: In this institutional review board-approved, retrospective, case-control study, 56 consecutive patients with nonmaturing arteriovenous fistulae underwent percutaneous intervention between 2015 and 2018. The transradial group (n = 28) underwent radial artery access for diagnostic fistulography and intervention. The control group (n = 28) underwent retrograde brachial artery access for fistulography followed by unidirectional/bidirectional fistula access for intervention. Both groups had similar demographics, fistula characteristics, and stenosis locations. RESULTS: Fewer punctures were required in the transradial group compared to controls (1.2 vs 2.4, P < .0001), and procedure time was shorter (64.9 vs 91.3 minutes, P = .0016). Anatomic, technical, and clinical success rates trended higher in the transradial group compared to controls (93% vs 86%, 96% vs 89%, and 82% vs 64%, respectively). Nonmaturation resulting in fistula abandonment was lower in the transradial group (3.7% vs 25%, P = .025). Primary unassisted patency at 3, 6, and 12 months was 77.1% ± 8.2%, 73.1% ± 8.7%, and 53.3% ± 10.6% in the transradial group, respectively, and 63.0% ± 9.3%, 55.6% ± 9.6%, and 48.1% ± 9.6% in the control group, respectively (P = .76). Primary assisted patency at 12 months was 92.3% ± 5.3% in the transradial group compared to 61.8% ± 9.6% at 12 months in the control group (P = .021). No major complications occurred. Minor complications were lower in the transradial group than in the control group (14% vs 39%, P = .068). CONCLUSIONS: Treatment of nonmaturing fistulae via a transradial approach was safe, improved midterm patency, and was associated with lower rates of fistula abandonment.

Nonfemoral Arterial Hemostasis Following Percutaneous Intervention Using a Focused Compression Device.

PURPOSE: Upper extremity and tibiopedal arterial access are increasingly used during endovascular therapies. Balloon compression hemostasis devices in these anatomic locations have been described, but most utilize a compression surface extending well beyond the puncture site. We report single-center experience with an arterial puncture-focused compression device following upper extremity and tibiopedal access. PATIENTS AND METHODS: A series of 249 focused compression hemostasis devices (VasoStat, Forge Medical, Bethlehem, Pennsylvania, USA) were used in 209 patients following lower extremity (n = 63) and upper extremity (n = 186; radial: 90%) arterial access procedures using 4-7 French sheaths. Demographic, operative, and follow-up data were collected. Logistic regression was used to evaluate potential association between patient/operative variables and time to hemostasis. RESULTS: Primary hemostasis was achieved in 97.2% (242/249) following sheath removal; in 7 cases (2.8%) puncture site oozing occurred after initial device removal and required reapplication. Secondary hemostasis was 100% (249/249). Seven complications (2.8%) were recorded: 5 minor hematomas (2%) and 2 transient access artery occlusions (0.8%). Mean time to hemostasis enabling device removal was 55 ± 28 min. Elevated body mass index (BMI) was not associated with increased time to hemostasis (p = 0.31). Accessed artery, sheath size, and heparin dose were also not associated with time to hemostasis (p = 0.64; p = 0.74; p = 0.75, respectively). CONCLUSIONS: The focused compression hemostasis device enabled rapid hemostasis with a low complication rate. Time to hemostasis was independent of BMI, access site, sheath size, or heparin dose.

Iatrogenic celiac and hepatic artery dissections during intra-arterial regional tumor therapies: a 16-year retrospective review.

PURPOSE: To identify the incidence and outcomes of iatrogenic celiac and hepatic artery dissections during transarterial therapies, including bland embolization, chemoembolization, radioembolization (TARE), and pre-TARE scintigraphic mapping. METHODS: The institution's quality assessment database, electronic medical record, and picture archiving and communication system were reviewed to identify all patients who underwent transarterial locoregional therapy from 1/2001 to 7/2017 and to determine the incidence of iatrogenic dissection, to assess patency of the arteries after dissection, and to assess the ability to complete therapy. RESULTS: 2253 patients underwent 3776 transarterial hepatic oncology procedures. Among 3776 procedures, 40 (1.1%) were associated with dissection of the visceral vasculature, affecting 39 patients (1.7%). The incidence of flow-limiting dissections was 0.3% (13/3776) and non-flow-limiting dissections was 0.7% (27/3776). After dissection, 68% (27/40) of treatments were completed the same day. Among the 13 aborted treatments, 8 (62%) were completed on a subsequent encounter. Follow-up imaging was obtained in 26 of 40 cases at median time of 63 days. Complete resolution of the dissection was seen in 15/26 cases (58%), near complete resolution (< 30% luminal narrowing) in 3/26 (12%), unchanged appearance of a non-flow-limiting dissection in 4/26 (15%), progressive luminal narrowing in 3/26 (12%), and complete occlusion in 1/26 (4%). CONCLUSION: Iatrogenic dissections of visceral arteries rarely occur during tumor embolization procedures. 35/39 (90%) of patients underwent successful treatment despite the dissection.

Venous Stents: Current Status and Future Directions.

Venous outflow obstruction is a dominant contributor to chronic venous disease. Treatment of venous disease has historically been limited by available vascular stent technology not specifically designed for the venous system. The ideal venous stent must provide requisite flexibility, strength, and accurate deployment for the anatomical and pathophysiological conditions of chronic venous disease. Venous stent technology is advancing with multiple dedicated venous stents currently available in Europe and with investigational device exemption studies ongoing in the United States. These technological advancements are promising for patients suffering from chronic venous disease. This article discusses the current status and future directions of venous stents.

Metastatic Liver Disease: Indications for Locoregional Therapy and Supporting Data.

Metastatic liver disease is a major cause of cancer-related morbidity and mortality. Surgical resection is considered the only curative treatment, yet only a minority is eligible. Patients who present with unresectable disease are treated with systemic agents and/or locoregional therapies. The latter include thermal ablation and catheter-based transarterial interventions. Thermal ablation is reserved for those with limited tumor burden. It is used to downstage the disease to enable curative surgical resection, as an adjunct to surgery, or in select patients it is potentially curative. Transarterial therapies are indicated in those with more diffuse disease. The goals of care are to palliate symptoms and prolong survival. The indications and supporting data for thermal ablation and transarterial interventions are reviewed, technical and tumor factors that need to be considered prior to intervention are outlined, and finally several cases are presented.

Rapid and profound potentiation of Apo2L/TRAIL-mediated cytotoxicity and apoptosis in thoracic cancer cells by the histone deacetylase inhibitor Trichostatin A: the essential role of the mitochondria-mediated caspase activation cascade.

Apo2L/TRAIL is actively investigated as a novel targeted agent to directly induce apoptosis of susceptible cancer cells. Apo2L/TRAIL-refractory cells can be sensitized to the cytotoxic effect of this ligand by cytotoxic chemotherapeutics. The aim of this study was to evaluate the in vitro tumoricidal activity of the Apo2L/TRAIL + Trichostatin A in cultured thoracic cancer cells and to elucidate the molecular basis of the synergistic cytotoxicity of this combination. Concurrent exposure of cultured cancer cells to sublethal concentrations of Apo2L/TRAIL and Trichostatin A resulted in profound enhancement of Apo2L/TRAIL-mediated cytotoxicity in all cell lines regardless of their intrinsic susceptibility to this ligand. This combination was not toxic to primary normal cells. While Apo2L/TRAIL alone or Trichostatin A alone mediated < 20% cell death, 60 to 90% of cancer cells were apoptotic following treatment with TSA + Apo2L/TRAIL combinations. Complete translocation of Bax from the cytosol to the mitochondria compartment was mainly observed in combination-treated cells and this was correlated with robust elevation of caspase 9 proteolytic activity indicative of activation of the mitochondria apoptogenic effect. Profound TSA + Apo2L/TRAIL-mediated cytotoxicity and apoptosis were completely abrogated by either Bcl2 over-expression or by the selective caspase 9 inhibitor, highlighting the essential role of mitochondria-dependent apoptosis signaling cascade in this process. Moreover, increased caspase 8 activity observed in cells treated with the TSA + Apo2L/TRAIL combination was completely suppressed by Bcl-2 over-expression or by the selective caspase 9 inhibitor indicating that the elevated caspase 8 activity in combination-treated cells was secondary to a mitochondria-mediated amplification feedback loop of caspase activation. These finding form the basis for further development of HDAC inhibitors + Apo2L/TRAIL combination as novel targeted therapy for thoracic malignancies.

NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR.

Phencyclidine (PCP) administration elicits positive and negative symptoms that resemble those of schizophrenia and is widely accepted as a model for the study of this human disorder. Group II metabotropic glutamate receptor (mGluR) agonists have been reported to reduce the behavioral and neurochemical effects of PCP. The peptide neurotransmitter, N-acetylaspartylglutamate (NAAG), is a selective group II agonist. We synthesized and characterized a urea-based NAAG analogue, ZJ43. This novel compound is a potent inhibitor of enzymes, glutamate carboxypeptidase II (K(i) = 0.8 nM) and III (K(i) = 23 nM) that deactivate NAAG following synaptic release. ZJ43 (100 microM) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP-induced motor activation, falling while walking, stereotypic circling behavior, and head movements. To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co-administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Additionally, LY341495 alone increased PCP-induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR. These data support the view that NAAG peptidase inhibitors may represent a new therapeutic approach to some of the components of schizophrenia that are modeled by PCP.