Psychiatric and Substance Use Comorbidity in Treatment-Seeking Injection Opioid Users Referred From Syringe Exchange.

OBJECTIVE: The present study evaluated rates of co-occurring current psychiatric and substance use disorders in a sample of opioid-dependent treatment-seeking injection drug users referred from syringe exchange. METHODS: Participants (N = 208) completed the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-R to assess current (within the past year) psychiatric and substance use disorders and the two most commonly diagnosed personality disorders (antisocial and borderline personality disorders). RESULTS: Forty-eight percent of the sample had a current Axis I psychiatric disorder, and 67% had a co-occurring current substance use disorder. Posttraumatic stress disorder (21%), major depression (17%), and bipolar I (12%) were the most prevalent Axis I psychiatric disorders, and cocaine use disorder (53%) was the most commonly co-occurring substance use disorder. Women were more likely to have diagnoses of most anxiety disorders and less likely to have diagnoses of alcohol use disorder or antisocial personality disorder. The presence of a personality disorder was associated with higher rates of cocaine and sedative use disorder. CONCLUSIONS: Findings suggest the importance of evaluating and treating co-occurring psychiatric and substance use disorders in the treatment of injection drug users with opioid dependence.

Liposomal doxorubicin increases radiofrequency ablation-induced tumor destruction by increasing cellular oxidative and nitrative stress and accelerating apoptotic pathways.

PURPOSE: To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin. MATERIALS AND METHODS: Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation (n = 43), 1 mg of intravenously injected liposomal doxorubicin (n = 26), or combined therapy (n = 30) and were compared with control subjects (n = 11). A subset of animals receiving combination therapy (n = 24) were treated in the presence or absence of N-acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated gammaH2AX, and HSP70 and of markers of oxidative and nitrative stress (8-hydroxydeoxyguanosine [8-OHdG], 4-hydroxynonenal [4-HNE]-modified proteins, and nitrotyrosine [NT]). Statistical analyses, including t tests and analysis of variance for comparisons where appropriate, were performed. RESULTS: By 4 hours after RF ablation alone, a 0.48-mm +/- 0.13 (standard deviation) peripheral band with 57.0% +/- 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm +/- 0.18 band with 77.7% +/- 6.3 positivity was seen for combination therapy (P < .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE-modified proteins, 8-OHdG, NT, and gammaH2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identified peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were significantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm +/- 0.09 band of 25.9% +/- 7.4 positivity vs 0.59-mm +/- 0.11 band of 62.9% +/- 6.0 positivity, P < .001 for both comparisons). CONCLUSION: Combining RF ablation with liposomal doxorubicin increases cell injury and apoptosis in the zone of increased coagulation by using a mechanism that involves oxidative and nitrative stress that leads to accelerated apoptosis.

Does arterial spin-labeling MR imaging-measured tumor perfusion correlate with renal cell cancer response to antiangiogenic therapy in a mouse model?

PURPOSE: To determine whether arterial spin-labeling (ASL) magnetic resonance (MR) imaging findings at baseline and early during antiangiogenic therapy can predict later resistance to therapy. MATERIALS AND METHODS: Protocol was approved by an institutional animal care and use committee. Caki-1, A498, and 786-0 human renal cell carcinoma (RCC) xenografts were implanted in 39 nude mice. Animals received 80 mg sorafenib per kilogram of body weight once daily once tumors measured 12 mm. ASL imaging was performed at baseline and day 14, with additional imaging performed for 786-0 and A498 (3 days to 12 weeks). Mean blood flow values and qualitative differences in spatial distribution of blood flow were analyzed and compared with histopathologic findings for viability and microvascular density. t Tests were used to compare differences in mean tumor blood flow. Bonferroni-adjusted P values less than .05 denoted significant differences. RESULTS: Baseline blood flow was 80.1 mL/100 g/min +/- 23.3 (standard deviation) for A498, 75.1 mL/100 g/min +/- 28.6 for 786-0, and 10.2 mL/100 g/min +/- 9.0 for Caki-1. Treated Caki-1 showed no significant change (14.9 mL/100 g/min +/- 7.6) in flow, whereas flow decreased in all treated A498 on day 14 (47.9 mL/100 g/min +/- 21.1) and in 786-0 on day 3 (20.3 mL/100 g/min +/- 8.7) (P = .003 and .03, respectively). For A498, lowest values were measured at 28-42 days of receiving sorafenib. Regions of increased flow occurred on days 35-49, 17-32 days before documented tumor growth and before significant increases in mean flow (day 77). Although 786-0 showed new, progressive regions with signal intensity detected as early as day 5 that correlated to viable tumor at histopathologic examination, no significant changes in mean flow were noted when day 3 was compared with all subsequent days (P > .99). CONCLUSION: ASL imaging provides clinically relevant information regarding tumor viability in RCC lines that respond to sorafenib.

Parallel imaging enhanced MR colonography using a phantom model.

PURPOSE: To compare various Array Spatial and Sensitivity Encoding Technique (ASSET)-enhanced T2W SSFSE (single shot fast spin echo) and T1-weighted (T1W) 3D SPGR (spoiled gradient recalled echo) sequences for polyp detection and image quality at MR colonography (MRC) in a phantom model. Limitations of MRC using standard 3D SPGR T1W imaging include the long breath-hold required to cover the entire colon within one acquisition and the relatively low spatial resolution due to the long acquisition time. Parallel imaging using ASSET-enhanced T2W SSFSE and 3D T1W SPGR imaging results in much shorter imaging times, which allows for increased spatial resolution. MATERIALS AND METHODS: Using two porcine colon phantoms each with eight simulated 3-10-mm "polyps," baseline reference sequences acquired without ASSET (6-mm slices and readout bandwidth [BW] 62 kHz) were compared with 11 SSFSE and 8 SPGR sequences acquired with 2-fold ASSET acceleration. ASSET-enhanced SSFSE and SPGR sequences comprised BW/matrix combinations ranging from 20-62 kHz/256-352x256, respectively, with slice thicknesses adjusted from 3.0 to 4.5 mm to maintain a 23-26-second acquisition time and 30 cm slab thickness. Two experienced radiologists viewed the datasets in a randomized, blinded fashion. RESULTS: Compared to reference sequences, ASSET-enhanced SSFSE and SPGR sequences facilitated better polyp detection and had similar overall image quality and per-phantom specificity. The two best ASSET-enhanced SSFSE (3 and 4.5 mm slices, each with BW of 62.5 kHz and 352x256 matrices) and three best ASSET-enhanced SPGR BW/slice thickness/matrix combinations of 31 kHz/4.4 msec/192x256; 62/3.4/192x256; and 62/4.0/192x256, respectively, permitted detection of all polyps>or=5 mm. CONCLUSION: Parallel imaging using ASSET-enhanced T2W SSFSE and T1W 3D SPGR improves the ability to detect significant colon polyps in an MRC phantom model.

RF ablation with adjuvant therapy: comparison of external beam radiation and liposomal doxorubicin on ablation efficacy in an animal tumor model.

PURPOSE: To determine the critical thermal dosimetry and relative efficacy for RF ablation combined with external beam radiation (XRT) or liposomal doxorubicin (LD), in an animal tumor model. MATERIALS AND METHODS: This study was performed in two phases, in 13-18 mm diameter R3230 tumors subcutaneously implanted into Fischer rats. In phase 1, tumors (n = 30) were randomized into six groups. RF energy (titrated to 70 degrees C tip temperature) was applied for either 2.5 or 5 min (n = 15, each group). For each duration, one of three adjuvant therapies was applied (n = 5, each): no therapy (control), LD (1 mg intravenously, 30 min post-RF), or XRT (20 Gy at 1 Gy min(-1), within 2 h post-RF), with sacrifice at 48 h for pathologic analysis. In phase 2, thermal mapping was performed in 20 tumors throughout RF application (70 degrees C; 5 min), at 1.5-7 mm distances from the active electrode tip. Temperature profiles throughout the tumor were constructed and were used to interpolate temperatures over time at the critical ablation margin, to derive maximum threshold temperature, AUC (area under the curve) and CEM(43) (cumulative equivalent minutes at 43 degrees C). Ablation sizes and all calculated values were compared within and across experimental groups using MANOVA statistics with pair-wise T-test for individual comparisons. RESULTS: RF/XRT produced the largest coagulation (11.7 +/- 1.5 mm at 2.5 min, >or=15 +/- 0.7 mm at 5 min), followed by RF/LD, and then RF alone (p < 0.001 for all comparisons). RF/XRT demonstrated temperature threshold decreases from RF alone of 11.7 +/- 0.01 degrees C and 12.7 +/- 0.38 degrees C at 2.5 and 5 min respectively (with absolute thresholds of 42 degrees C for XRT compared to 52 degrees C for RF alone). RF/LD had decreases of 4.0 degrees C at 2.5 min and 4.4 degrees C at 5 min. Thermal dose requirements (AUC) decreased by 7.79% or 9.28% for RF/LD compared to >or=19.36% or 25.82% for RF/XRT at 2.5 and 5 min (p < 0.001). CEM(43) values followed similar patterns (p < 0.001), but with a reduction of 10(1) and 10(4) in magnitude for RF/LD and RF/XRT therapies at 5 min, respectively. CONCLUSIONS: For a standardized RF dose, the combination of high dose XRT and RF increased ablation size compared to RF and liposomal doxorubicin or RF alone. Increased ablation size is more closely associated with decreased temperature threshold necessary to induce coagulation, rather than the total thermal dose.

Humoral bone morphogenetic protein 2 is sufficient for inducing breast cancer microcalcification.

Microcalcifications are an important diagnostic marker for breast cancer on mammograms, yet the mechanism of their formation is poorly understood. Indeed, there is presently no short-latency, high-yield, syngeneic rodent model of the process. Bone morphogenetic protein 2 (BMP-2) is a key mediator of physiologic bone formation and pathologic vasculature calcification, but its role in breast cancer microcalcification is unknown. In this study, R3230 rat breast tumors were adapted to cell culture, transduced with adenoviral BMP-2, and inoculated into a syngeneic host. Tumor growth and calcium salt deposition were quantified in living animals over time using micro-computed tomography and probed chemically using near-infrared fluorescence. Plasma BMP-2 levels were quantified over time by enzyme-linked immunosorbent assay. Within 3 weeks, 100% of the breast tumors developed microcalcifications, which were absent from all normal tissues. Importantly, when two tumors were initiated in a single host, the ipsilateral tumor expressing BMP-2 was able to induce microcalcification in the contralateral tumor that was not expressing BMP-2, suggesting that BMP-2 can act humorally. Taken together, we describe the first reproducible rodent model of breast cancer microcalcification, prove that BMP-2 expression is sufficient for initiating the process, and lay the foundation for a new generation of targeted diagnostic agents.

High-power generator for radiofrequency ablation: larger electrodes and pulsing algorithms in bovine ex vivo and porcine in vivo settings.

PURPOSE: To prospectively maximize the extent of tissue coagulation by using a high-power (1000-W, 4000-mA) radiofrequency (RF) generator to optimize pulsing algorithms. MATERIALS AND METHODS: The institutional animal care and use committee approved the use of the animal model in the in vivo portion of this study. RF ablations (n = 258) were performed in ex vivo bovine livers by using a 500-kHz high-power generator. Through internally cooled 3.0-cm single and 2.5- and 4.0-cm cluster electrodes, RF energy was applied for 12 minutes. For each electrode, simplex optimization was used to determine the pulsing algorithms to be used (ie, 5-50-second "on" [energy application] and 10-50-second "off" [cooling without RF heating] periods). Three-dimensional contour maps expressing the relationship between pulsing parameters and resultant coagulation were constructed. Then, 31 RF ablations were performed with optimal settings in vivo in porcine livers, and the results were compared with those obtained in control ablations performed by using a 2000-mA commercial generator. Finally, in 108 experiments, RF energy was applied in ex vivo livers for 6, 12, and 20 minutes with maximum current settings (1000-4000 mA) by using the optimal on and off settings for all three electrodes, and the results were analyzed with multivariate analysis of variance (MANOVA). RESULTS: For all three electrodes, a relationship between the on and off times during the pulsing cycle and the resultant coagulation was established (P < .01). With 3.0-cm single electrodes, maximum coagulation (mean, 5.2 cm +/- 0.1 [standard deviation] ex vivo and 3.6 cm +/- 0.2 in vivo) was achieved with pulse settings of 10-18 seconds on and 11-20 seconds off. With cluster electrodes, greater coagulation was achieved (mean, 6.5 cm +/- 0.6 ex vivo and 3.9 cm +/- 0.3 in vivo with 2.5-cm tip; 8.3 cm +/- 0.3 ex vivo and 5.2 cm +/- 0.8 in vivo with 4.0-cm tip) with optimal pulse settings. Thus, use of the high-power generator yielded substantially increased tissue coagulation in vivo compared with the coagulation achieved with the standard generator. MANOVA revealed that increased maximum current and RF ablation durations of up to 20 minutes were associated with greater coagulation, the size of which also varied according to electrode type (P < .01). CONCLUSION: Markedly larger coagulation zones can be achieved with optimized high-power RF ablation. This may require longer pulsing intervals compared with those previously used.

Chemical tumor ablation with use of a novel multiple-tine infusion system in a canine sarcoma model.

PURPOSE: To determine whether larger confluent zones of ablation can be achieved in chemical ablation with use of a multiple-tine infusion device compared with standard needle infusion in a solid tumor model. MATERIALS AND METHODS: Multiple canine venereal sarcomas (N=42) were implanted in nine mildly immunosuppressed dogs (treated with 10 mg/kg cyclosporin A twice daily). Tumors incubated for 8-12 weeks grew to a diameter of 5.4 cm+/-1.0. With ultrasound guidance, 8-56 mL of 100% ethanol or 15% acetic acid (diluted in saturated saline solution) were injected in aliquots (2-8 mL) at multiple distances (radius of 0-2 cm) from the needle axis with use of a multiple-tine infusion device. Presence of fluid reflux at the needle puncture site and resultant coagulation diameters were measured within 1 hour and compared with the results of infusion with a standard 18-gauge needle. RESULTS: Multiple-tine infusion enabled greater fluid infusion (15 mL+/-3 to 53 mL+/-3 depending on protocol) than standard needle injection (8 mL+/-1) before reflux was observed at the puncture site (P<.01). Additionally, progressive gains in contiguous tumor coagulation were achieved because acetic acid was infused as far as 2 cm from the needle axis with the multiple-tine device (P<.01; R(2)=0.59; y=0.5x+2.9). Optimal coagulation was achieved with the infusion of 4-mL aliquots at 0.5 cm and 1.0 cm from the needle, followed by three 4-mL or 8-mL aliquots (40 degrees rotation between infusions) at 1.5 cm and 2.0 cm from the needle (32 mL+/-0 and 53 mL+/-3 total, respectively). This yielded confluent short-axis coagulation diameters of 4.9 cm+/-1.0 and 5.4 cm+/-1.0, respectively, which were significantly greater than the measurement of 3.1 cm+/-0.4 achieved with standard needle infusion (P<.01). Smaller and noncontiguous foci of coagulation foci (1.7 cm+- 0.5) were seen with the use of ethanol for standard needle and multiple-tine infusions. CONCLUSIONS: Chemical ablation with 15% acetic acid with use of a multiple-tine infusion device resulted in larger diameters of contiguous tumor coagulation and enabled greater volumes of infusion than standard needle infusion or ethanol ablation. This suggests that chemical ablation with acetic acid infused with use of a multiple-tine device may overcome some of the difficulties seen with the use of conventional needle chemical ablation injection alone, such as irregular ablation and fluid reflux up the needle tract.

Radiofrequency ablation: importance of background tissue electrical conductivity--an agar phantom and computer modeling study.

PURPOSE: To determine whether radiofrequency (RF)-induced heating can be correlated with background electrical conductivity in a controlled experimental phantom environment mimicking different background tissue electrical conductivities and to determine the potential electrical and physical basis for such a correlation by using computer modeling. MATERIALS AND METHODS: The effect of background tissue electrical conductivity on RF-induced heating was studied in a controlled system of 80 two-compartment agar phantoms (with inner wells of 0.3%, 1.0%, or 36.0% NaCl) with background conductivity that varied from 0.6% to 5.0% NaCl. Mathematical modeling of the relationship between electrical conductivity and temperatures 2 cm from the electrode (T2cm) was performed. Next, computer simulation of RF heating by using two-dimensional finite-element analysis (ETherm) was performed with parameters selected to approximate the agar phantoms. Resultant heating, in terms of both the T2cm and the distance of defined thermal isotherms from the electrode surface, was calculated and compared with the phantom data. Additionally, electrical and thermal profiles were determined by using the computer modeling data and correlated by using linear regression analysis. RESULTS: For each inner compartment NaCl concentration, a negative exponential relationship was established between increased background NaCl concentration and the T2cm (R2= 0.64-0.78). Similar negative exponential relationships (r2 > 0.97%) were observed for the computer modeling. Correlation values (R2) between the computer and experimental data were 0.9, 0.9, and 0.55 for the 0.3%, 1.0%, and 36.0% inner NaCl concentrations, respectively. Plotting of the electrical field generated around the RF electrode identified the potential for a dramatic local change in electrical field distribution (ie, a second electrical peak ["E-peak"]) occurring at the interface between the two compartments of varied electrical background conductivity. Linear correlations between the E-peak and heating at T2cm (R2= 0.98-1.00) and the 50 degrees C isotherm (R2= 0.99-1.00) were established. CONCLUSION: These results demonstrate the strong relationship between background tissue conductivity and RF heating and further explain electrical phenomena that occur in a two-compartment system.

Radiofrequency tumor ablation: insight into improved efficacy using computer modeling.

OBJECTIVE: To use computer modeling of the Bio-Heat equation to demonstrate factors influencing RF ablation tissue heating. CONCLUSION: Computer modeling demonstrates the importance of energy deposition, tumor and background tissue electrical and thermal conductivity, and perfusion on RF ablation outcomes.

Hybrid radiofrequency and cryoablation device: preliminary results in an animal model.

PURPOSE: To determine whether the simultaneous application of combined bipolar radiofrequency (RF) ablation and cryoablation in a hybrid system produces larger ablation zones than RF or cryoablation alone. MATERIALS AND METHODS: Multiple 15-minute ablations were performed in ex vivo bovine liver (n = 167) with a hybrid applicator system with RF ablation alone (0.3-0.7 A), cryoablation alone (3,500 psi, two freeze/thaw cycles), and combined RF/cryoablation (0.4-0.7 A, 1,000-3,500 psi) with use of a novel applicator consisting of two 2.5-cm active bipolar RF poles located on the same 18-gauge needle separated by two embedded cryoablation nozzles. Resultant coagulation diameters were compared with use of analysis of variance for more than three groups or Student t tests for two groups. Confirmation of the optimal parameters of combination RF/cryoablation was performed by reassessing a range of argon pressure (1,000-3,500 psi) and RF current (0.4-0.7 A) in in vivo porcine liver (n = 36). Arrays of two to four RF/cryoablation applicators were also assessed in ex vivo (n = 54) and in vivo (n = 12) liver. RESULTS: In ex vivo liver, simultaneous RF/cryoablation (0.6 A, 3,000 psi) produced 3.6 cm +/- 0.4 of short-axis coagulation. This was significantly larger than that achieved with optimal RF alone or cryoablation alone (1.5 cm +/- 0.3 and 1.6 cm +/- 0.3, respectively; F = 95; P < .01). The coagulation diameter with simultaneous combination RF/cryoablation was related in parabolic fashion to argon pressure and current with a multivariate r(2) of 0.68. For in vivo liver, optimal combination RF/cryoablation achieved 3.3 cm +/- 0.2 of coagulation, which was significantly larger than that achieved with RF alone (1.1 cm +/- 0.1; P < .01) or cryoablation alone (1.1 cm +/- 0.1 and 1.3 cm +/- 0.1; F = 203; P < .01). The greatest contiguous coagulation was achieved with multiple-applicator arrays. For ex vivo liver, short-axis coagulation measured 5.3 cm +/- 0.1, 6.4 cm +/- 0.1, and 7.6 cm +/- 0.1 for two-, three-, and four-applicator arrays, respectively. For in vivo liver, two-, three-, and four-applicator arrays produced 5.1 cm +/- 0.2, 5.8 cm +/- 0.5, and 7.0 cm +/- 0.5 of confluent coagulation, respectively. CONCLUSION: Simultaneous combination RF and cryoablation with use of a novel applicator design yielded significantly larger zones of coagulation than either modality alone. The large ablation diameters achieved warrant further investigation of the device.

Radiofrequency ablation: Effect of pharmacologic modulation of hepatic and renal blood flow on coagulation diameter in a VX2 tumor model.

PURPOSE: To determine whether pharmacologic agents can be used to modulate blood flow in hepatic and renal tumors sufficiently to alter the extent of radiofrequency (RF)-induced coagulation. MATERIALS AND METHODS: VX2 tumors (8-15 mm) were implanted in the liver (n = 25) or kidney (n = 8) of 33 New Zealand White rabbits. RF was applied to tumors for 6 minutes with use of conventional electrodes (125 mA +/- 35; 90 degrees C +/- 2 degrees C tip temperature). In the hepatic model, blood flow was modulated with use of halothane, epinephrine, or arsenic trioxide (2-6 mg/kg). Laser Doppler flowmetry was used to quantify changes in hepatic blood flow. Correlation of blood flow with induced coagulation diameter was performed. RF ablation was then performed in a renal model with and without arsenic trioxide. RESULTS: For liver tumors, halothane and arsenic trioxide reduced blood flow to 40.3% +/- 17.8% and 29% +/- 15% of normal, respectively, whereas epinephrine increased blood flow to 207.8% +/- 97.9%. Correlation of blood flow to coagulation diameter was demonstrated (R(2) = 0.40). Coagulation measured 7 mm +/- 1 with epinephrine, 10 mm +/- 1 with normal blood flow, 12 mm +/- 3 with halothane, and 13 mm +/- 3 with arsenic trioxide (P <.04 compared with controls). In the renal model, arsenic trioxide decreased blood flow (44% +/- 16%) and increased coagulation diameter (10.9 mm +/- 1) compared with controls (84% +/- 11% and 7.6 mm +/- 1; P <.01, both comparisons). CONCLUSIONS: RF-induced coagulation necrosis in rabbit hepatic and renal tumors is affected by tumor blood flow. Pharmacologic modulation of tumor blood flow may provide a noninvasive way to decrease blood flow during thermally mediated ablation therapy, potentially enabling the creation of larger zones of coagulation necrosis.