Tumor suppression effect of ultrasound-sensitive nanoparticles with focused ultrasound in a pancreas cancer xenograft model.

BACKGROUND: We investigated the tumor suppression effect of an ultrasound-sensitive doxorubicin-loaded liposome-based nanoparticle, IMP301, to enhance the synergistic effect with focused ultrasound (FUS) in an animal model of pancreatic cancer. METHODS: Thirty nude mice with xenografts of PANC-1 human pancreatic cancer cells were randomly and prospectively allocated to 6 different groups (5 per group) each for Study-1 (dose-response test) and Study-2 (synergistic effect test). Study-1 consisted of control, gemcitabine, Doxil with FUS, and three different doses of IMP301 (2, 4, 6 mg/kg) with FUS groups. Study-2 consisted of control, FUS only, gemcitabine, Doxil with FUS, and IMP301 (4 mg/kg) with or without FUS groups. Differences in tumor volume and growth rate were evaluated by one-way ANOVA and Student-Newman-Keuls test. RESULTS: In Study-1, 4 mg/kg or greater IMP301 with FUS groups showed lower tumor growth rates of 14 ± 4 mm3/day (mean ± standard deviation) or less, compared to the control, gemcitabine, and Doxil with FUS groups with rates exceeding 28 ± 5 (p < 0.050). The addition of FUS in Study-2 decreased the tumor growth rate in the IMP301-treated groups from 36 ± 17 to 9 ± 6, which was lower than the control, FUS only, gemcitabine, and Doxil with FUS groups (p < 0.050). CONCLUSIONS: IMP301 combined with FUS exhibited higher tumor growth suppression compared to the use of a conventional drug alone or the combination with FUS. The present study showed the potential of IMP301 to enhance the synergistic effect with FUS for the treatment of pancreatic cancer. RELEVANCE STATEMENT: This article aims to evaluate the synergistic effect of FUS and ultrasound-responsive liposomal drug in tumor growth suppression by using xenograft mouse model of pancreatic ductal adenocarcinoma. FUS-induced ultrasound-sensitive drug release may be a potential noninvasive repeatable treatment option for patients with locally advanced or unresectable pancreatic cancer. KEY POINTS: • Modification of conventional drugs combined with FUS would maximize tumor suppression. • IMP301 with FUS had higher tumor suppression effect compared to conventional chemotherapy. • This image-guided drug delivery would enhance therapeutic effects of systemic chemotherapy.

Clinical value of prostate health index as an indicator for recommending magnetic resonance imaging in patients with gray-zone prostate-specific antigen level.

PURPOSE: To evaluate the usefulness of prostate health index (PHI) as an indicator for recommending magnetic resonance imaging (MRI) in patients with prostate-specific antigen (PSA) gray zone level < 10 ng/mL. METHODS: 443 patients who underwent prostate biopsy (PB) after serum PHI test and MRI between April 2019 and December 2022 were enrolled. For patients with visible lesion on MRI with Prostate Imaging Reporting and Data System Score (PI-RADS) ≥ 3, MRI-targeted PB was performed in addition to systematic 12-core PB. RESULTS: The optimal cutoff value of PHI for predicting PI-RADS ≥ 3 lesions was 39.6, which was significantly associated with overall prostate cancer (OR 3.07, p = 0.018) and clinically significant prostate cancer (csPCa) (OR 4.15, p = 0.006) at MRI-targeted PB cores. When MRI was restricted to patients with PHI ≥ 39.6 alone, 28.7% of unnecessary MRI could be saved at the cost of missing 13.6% of csPCa. When omitting MRI for patients with PHI < 39.6 and PSAD < 0.12 ng/mL2, unnecessary MRI could be reduced by 20.1% with the risk of missing 6.2% of csPCa. With addition of systematic PB, 21.0% of patients with negative MRI-targeted PB were diagnosed as csPCa. CONCLUSIONS: For patients in PSA gray zone, PHI of 39.6 might be an indicator for MRI and further MRI-targeted PB in additional to PSAD of 0.12 ng/mL2, reducing 20.1% of unnecessary MRI with the minimal risk of missing 6.2% of csPCa. To maximize csPCa detection, combining both MRI-targeted and systematic PB should be also considered.

Drug delivery by sonosensitive liposome and microbubble with acoustic-lens attached ultrasound: an in vivo feasibility study in a murine melanoma model.

Conventional chemotherapy methods have adverse off-target effects and low therapeutic efficiencies of drug release in target tumors. In this study, we proposed a combination therapy of doxorubicin (DOX)-loaded ultrasound (US)-sensitive liposomal nanocarriers (IMP301), microbubbles (MBs) under focused US exposure using convex acoustic lens-attached US (LENS) to tumor treatment. The therapeutic effects of each treatment in a murine melanoma model were evaluated using contrast-enhanced US (CEUS) and micro-computed tomography (micro-CT) imaging, bioluminescence and confocal microscopy imaging, and liquid chromatography-mass spectroscopy (LC/MS) analysis. Tumor-bearing mice were randomly assigned to one of the following groups: (1) G1: IMP301 only (n = 9); (2) G2: IMP301 + LENS (n = 9); (3) G3: IMP301 + MB + LENS (n = 9); (4) G4: DOXIL only (n = 9); and (5) G5: IMP301 without DOXIL group as a control group (n = 4). Ten days after tumor injection, tumor-bearing mice were treated according to each treatment strategy on 10th, 12th, and 14th days from the day of tumor injection. The CEUS images of the tumors in the murine melanoma model clearly showed increased echo signal intensity from MBs as resonant US scattering. The relative tumor volume of the G2 and G3 groups on the micro-CT imaging showed inhibited tumor growth than the reference baseline of the G5 group. DOX signals on bioluminescence and confocal microscopy imaging were mainly located at the tumor sites. LC/MS showed prominently higher intratumoral DOX concentration in the G3 group than in other treated groups. Therefore, this study effectively demonstrates the feasibility of the synergistic combination of IMP301, MBs, and LENS-application for tumor-targeted treatment. Thus, this study can enable efficient tumor-targeted treatment by combining therapy such as IMP301 + MBs + LENS-application.

Computer tomography-based shape of tumor contour and texture of tumor heterogeneity are independent prognostic indicators for clinical T1b-T2 renal cell carcinoma.

PURPOSE: To evaluate association between computer tomography (CT)-based features of renal cell carcinoma (RCC) and survival outcomes. METHODS: Data of 958 patients with clinical T1b-T2 RCC who underwent partial/radical nephrectomy from June 2003 to March 2022 were retrospectively evaluated. CT images of patients were reviewed by two radiologists for texture analysis of tumor heterogeneity and shape analysis of tumor contour. Patients were divided into three groups according to patterns of CT-based features: (1) favorable feature group (n = 117); (2) intermediate feature group (n = 606); and (3) unfavorable feature group (n = 235). Kaplan-Meier survival analysis and multivariate Cox regression analysis were performed to evaluate overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS). RESULTS: RCCs with unfavorable CT-based feature showed larger size on CT, higher nuclear grade, higher rate of histologic necrosis, and higher rate of capsular invasion than those in the other two groups (all p < 0.001). Unfavorable feature was associated with poorer OS (p = 0.001), CSS (p < 0.001), and RFS (p < 0.001) on Kaplan-Meier analysis. In multivariate analysis, intermediate and unfavorable features were independent predictors for recurrence (hazard ratio [HR] 2.51, 95% confidence interval [CI] 1.09-5.79, p = 0.031 and HR 3.71, 95% CI 1.58-8.73, p = 0.003, respectively), but not for overall death or RCC-specific death. CONCLUSIONS: A combination of irregular tumor contour feature with heterogeneous tumor texture feature on CT is associated with poor RFS in clinical T1b-T2 RCC preoperatively.

Comparative study of standard and small transrectal transducers for prostate ultrasonography.

PURPOSE: The objective of this study was to evaluate pain and image quality associated with the use of two different ultrasound transducers. METHODS: Fifty healthy male participants aged 30 years or older were prospectively enrolled. All ultrasound procedures were performed using a V8 machine (Samsung Medison, Seoul, Korea) equipped with EA2-11 (conventional) and miniER7 (small-caliber) transrectal transducers, operated by a single genitourinary radiologist. To minimize bias, one group of volunteers underwent ultrasonography with the conventional transducer first, followed by the small transducer. For the remaining participants, the examinations were performed in the opposite order. Ultrasonography, including the measurement of total prostate and transitional zone volumes, was conducted in accordance with standard practice. After testing with both probes, participants were asked to rate their pain on a 10-point numerical rating scale (NRS). A radiologist then evaluated the quality of the images acquired with each probe using a 5-point numeric scale and compared the prostate volume measurements obtained by each method. RESULTS: The mean NRS scores associated with the conventional and small transducers were 4.7±1.8 and 2.7±1.2, respectively (P<0.05). The mean ultrasound image qualities from the two transducers were statistically similar (4.78 and 4.74, P>0.05). The whole prostate gland volume as measured with the conventional transducer (mean±standard deviation, 24.2±9.1 mL) was greater than the measurement (22.1±8.7 mL) obtained with the small-caliber transducer (P<0.05). However, only two of the 50 whole gland volume measurements differed by more than two standard deviations. CONCLUSION: The use of a small transrectal probe significantly reduced pain without compromising image quality.

Tumor contact length with bladder wall provides effective risk stratification for lesions with a VIRADS score of 2-3.

OBJECTIVES: To evaluate the diagnostic performance of the tumor contact length (TCL) in the prediction of MIBC (muscle-invasive bladder cancer) in lesions corresponding to the vesical imaging-reporting and data system (VIRADS) score 2-3. METHODS: This is a single institution, retrospective study targeting 191 consecutive patients assigned of VIRADS score 2-3, who had pre-transurethral resection MRI from July 2019 to September 2021. Logistic regression analyses were performed to determine meaningful predictors of MIBC for this score group, and a nomogram was plotted with those variables. The diagnostic performance of each predictor was compared at predefined thresholds (VIRADS score 3 and TCL 3 cm) using the generalized linear model and ROC analysis. RESULTS: Both VIRADS score and TCL remained independent predictors of MIBC for this score group (odds ratio 7.3 for VIRADS score, and 1.3 for TCL, p < 0.01 for both). The contribution of TCL to the probability of MIBC in the nomogram was greater than that of the VIRADS score. VIRADS score had a sensitivity of 0.54 (14/26), specificity of 0.92 (203/221), and diagnostic accuracy of 0.88 (217/247), and TCL showed a sensitivity of 0.89 (23/26), specificity of 0.95 (209/221), and diagnostic accuracy of 0.94 (232/247). The difference in sensitivity (p = 0.03) and accuracy (p = 0.04) was statistically significant. The AUC was also significantly wider for TCL than for VIRADS (0.97 vs. 0.73, p < 0.01). CONCLUSION: A simple index, TCL, may be helpful in further risk stratification for MIBC in patients with a score of VIRADS 2-3. CLINICAL RELEVANCE STATEMENT: For bladder cancer patients with insufficient qualitative evidence of muscle layer invasion using VIRADS categorization, TCL, a simple quantitative indicator defined as the curvilinear contact length between the bladder wall and the tumor, may be helpful in risk stratification. KEY POINTS: • Even when only lesions with score 2-3 were targeted, VIRADS was still a meaningful indicator of MIBC. • With a predefined threshold of 3 cm applied, TCL outperformed VIRADS in the score 2-3 group, in predicting MIBC. • A longer TCL for a lesion with a VIRADS score 2 may warrant an additional warning for MIBC, whereas a shorter TCL for a lesion with a score 3 may indicate a lower risk of MIBC.

Diagnostic performance of MRI for prediction of recurrent prostate cancer after high-intensity focused ultrasound: a systematic review and meta-analysis.

Purpose: This article aims to evaluate the pooled diagnostic performance control MRI for prediction of recurrent prostate cancer (PCa) after high-intensity focused ultrasound (HIFU). Materials and methods: MEDLINE, EMBASE, and Cochrane library databases up to December 31, 2021, were searched. We included studies providing 2×2 contingency table for diagnostic performance of MRI in predicting recurrent PCa after HIFU, using control biopsy as reference standard. The quality of the included studies was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Sensitivity and specificity were pooled and displayed in a summary receiver operating characteristics (SROC) plot. Meta-regression analysis using clinically relevant covariates was performed for the causes of heterogeneity. Results: Nineteen studies (703 patients) were included. All included studies satisfied at least four of the seven QUADAS-2 domains. Pooled sensitivity was 0.81 (95% CI 0.72-0.90) with specificity of 0.91 (95% CI 0.86-0.96), with area under the SROC curve of 0.81. Larger studies including more than 50 patients showed relatively poor sensitivity (0.68 vs. 0.84) and specificity (0.75 vs. 0.93). The diagnostic performance of studies reporting higher nadir serum prostate-specific antigen levels (>1 ng/mL) after HIFU was inferior, and differed significantly in sensitivity (0.54 vs. 0.78) rather than specificity (0.85 vs. 0.91). Conclusions: Although MRI showed adequate diagnostic performance in predicting PCa recurrence after HIFU, these results may have been exaggerated.

Diagnostic value of multiparametric MRI in detecting residual or recurrent prostate cancer after high-intensity focused ultrasound.

PURPOSE: To evaluate the diagnostic performance of follow-up multiparametric MRI for prediction of recurrent prostate cancer after high-intensity focused ultrasound (HIFU), and to find other, if any, clinical or radiological predictors. MATERIALS AND METHODS: Post-HIFU MRIs of 110 consecutive patients who underwent follow-up biopsies between August 2019 and April 2021 were retrospectively analyzed and the likelihood of recurrence was assessed on a five-point Likert scale by two board-certified uroradiologists. Diagnostic performance of the Likert scale assigned to the post-HIFU MRI was assessed using the follow-up biopsy results as a reference standard. Among the clinical and radiological variables, predictors of the recurrence were examined through logistic regression. RESULTS: In per-patient and per-sector analyses, Likert scale on post-HIFU MRI showed a sensitivity and specificity of 0.37 and 0.97, and 0.42 and 0.87, respectively, in predicting recurrence. Two patients with high suspicion on MRI required additional treatment to regain biochemical control despite negative biopsies. High suspicion on post-HIFU MRI (odds ratio = 1.74; p < 0.01), and more cancer-positive cores on initial biopsy (odds ratio = 1.25; p = 0.03) were independent predictors of recurrence. CONCLUSION: Albeit with low sensitivity, high suspicion on post-HIFU MRI may be clinically important because of its high specificity, especially when considering the possibility of sampling error in biopsies. Patients with a high number of cancer-positive cores at diagnosis should avoid HIFU as they have an increased risk of recurrence.

The Prostate Health Index and multi-parametric MRI improve diagnostic accuracy of detecting prostate cancer in Asian populations.

PURPOSE: The aim of this study was to evaluate the effectiveness of the Prostate Health Index (PHI) and prostate multi-parametric magnetic resonance imaging (mpMRI) in predicting prostate cancer (PCa) and clinically significant prostate cancer (csPCa) during initial prostate biopsy. MATERIALS AND METHODS: In total, 343 patients underwent initial prostate biopsy and were screened by use of PHI and prostate-specific antigen (PSA) levels between April 2019 and July 2021. A subgroup of 232 patients also underwent prostate mpMRI. Logistic regression analysis was performed to evaluate the accuracies of PSA, PHI, and mpMRI as predictors of PCa or csPCa. These predictive accuracies were quantified by using the area under the receiver operating characteristic curve. The different predictive models were compared using the DeLong test. RESULTS: Logistic regression showed that age, PSA, PHI, and prostate volume were significant predictors of both PCa and csPCa. In the mpMRI subgroup, age, PSA level, PHI, prostate volume, and mpMRI were predictors of both PCa and csPCa. The PHI (area under the curve [AUC]=0.693) was superior to the PSA level (AUC=0.615) as a predictor of PCa (p=0.038). Combining PHI and mpMRI showed the most accurate prediction of both PCa and csPCa (AUC=0.833, 0.881, respectively). CONCLUSIONS: The most accurate prediction of both PCa and csPCa can be performed by combining PHI and mpMRI. In the absence of mpMRI, PHI is superior to PSA alone as a predictor of PCa, and adding PHI to PSA can increase the detection rate of both PCa and csPCa.

Diagnostic yield of multiparametric MRI for local recurrence at biochemical recurrence after radical prostatectomy.

Purpose: To validate the diagnostic yield of multiparametric magnetic resonance imaging (mpMRI) for local biochemical recurrence after radical prostatectomy in patients with biochemical recurrence using large consecutive patient data. Materials and methods: Of 4632 patients who underwent radical prostatectomy for prostate adenocarcinoma, 748 patients with prostate-specific antigen > 0.2 ng/mL and second confirmatory level were retrospectively identified. Among them, 468 patients who underwent multiparametric magnetic resonance imaging were analyzed. The primary outcome measure was the diagnostic yield of multiparametric magnetic resonance imaging for local recurrence, and the secondary measure was its accuracy, using the response to salvage radiotherapy as reference. Results: Only 33 patients (7.1%) showed positive imaging findings. The positive and negative predictive values were 84.8% (28/33) and 37.5% (45/120), respectively. The sensitivity and specificity were 27.2% (28/103) and 90% (45/50), respectively. The overall accuracy was 47.7% (73/153). In multivariate logistic regression analysis, prostate-specific antigen level at recurrence was found to be the only factor significantly higher in the positive image findings group. Conclusions: The universal use of multiparametric magnetic resonance imaging resulted in a low-diagnostic yield for local recurrence in patients with biochemical recurrence after radical prostatectomy. The results suggest that selective use of multiparametric magnetic resonance imaging should be considered in patients with a higher prostate-specific antigen threshold.

Diagnostic accuracy of F-18-Fluorocholine PET/CT and multiparametric MRI for prostate cancer.

Background: Positron emission tomography (PET) using different positron-emitting radiopharmaceuticals has emerged as a promising new metabolic diagnostic tool for the evaluation of a variety of malignant diseases. Thus, we investigated the diagnostic efficacy of F-18-Fluorocholine positron emission tomography/computed tomography (PET/CT) and multiparametric magnetic resonance imaging (mpMRI) for the detection and localization of tumors within the prostate with the correlating histopathology as the standard of reference. Methods: Forty patients with histologically proven prostate cancer underwent both F-18-Fluorocholine PET/CT and mpMRI before robot-assisted laparoscopic radical prostatectomy (RARP). The maximum standard uptake values and the tumor-to-background ratio were measured on a sextant basis. In brief, the sextants were defined as right apex, right middle, right base, left apex, left middle, and left base. For each tumor region, the correlation of the tumor localization based on the sextant in both F-18-Fluorocholine PET/CT and mpMRI scans with the histopathological results was determined. Results: The correlation between both imaging modalities and RARP pathology representing (1) all cancer and (2) clinically significant cancer defined as a ≥ International Society of Urological Pathology grade of 2 showed that the sensitivity and the area under the curve (AUC) were higher for mpMRI than for F-18-Fluorocholine PET/CT. In contrast, F-18-Fluorocholine PET/CT had relatively higher specificity than mpMRI. Importantly, we found a very high AUC value of over 0.8 in both imaging modalities. Conclusion: mpMRI had results superior to F-18-Fluorocholine PET/CT in assessing intraprostatic tumor localization. However, F-18-Fluorocholine PET/CT showed superiority in terms of specificity. Thus, using both modalities in conjunction could provide better treatment planning.

Comparison of systematic randomized 12-core transrectal ultrasonography-guided prostate biopsy with magnetic resonance imaging-transrectal ultrasonography fusion-targeted prostate biopsy.

We aimed to compare the complications and pathological outcomes between systematic 12-core transrectal ultrasonography guided prostate biopsy (TRUS-PB) and magnetic resonance imaging-TRUS fusion targeted prostate biopsy (MRI-TRUS FTPB). We examined 10,901 patients who underwent prostate biopsy from May 2003 to December 2017 retrospectively. Among them, 10,325 patients underwent 12-core TRUS-PB and 576 patients underwent MRI-TRUS FTPB. The clinicopathological features and complications in both groups were compared. After propensity score matching, there were no significant differences in the clinical features and complication rates between both groups (P > .05). In the multivariate analyses, the prostate volume was shown to be the only significant predictor of overall complications, infectious complications, bleeding related complications, and Clavien-Dindo grade ≥ 2 complications after prostate biopsy (P < .001). The present study demonstrates the safety of MRI-TRUS FTPB in terms of complications, compared with that of TRUS-PB. Although the combination of MRI-TRUS FTPB and 12-core TRUS-PB provides enhanced diagnostic power, MRI-TRUS FGB alone could provide a reasonable diagnostic value for prostate cancer if the apparent diffusion coefficient suspicious grade of prostate cancer is ≥4. When the Likert suspicious grade of prostate cancer on the apparent diffusion coefficient map of multiparametric MRI was 3, 13.9% (27/194) of the patients were diagnosed with clinically significant prostate cancer (csPCa); 44.4% (12/27) of them were confirmed as csPCa at the MRI-targeted cores. When the apparent diffusion coefficient suspicious grade was ≥4, 43.0% (108/251) were diagnosed with csPCa; 76.8% (83/108) of them were confirmed to have csPCa at the MRI-targeted cores.

Enhanced delivery to brain using sonosensitive liposome and microbubble with focused ultrasound.

Glioblastoma is considered one of the most aggressive and dangerous brain tumors. However, treatment of GBM has been still challenged due to blood-brain barrier (BBB). BBB prevents that the chemotherapeutic molecules are extravasated to brain. In this study, sonosensitive liposome encapsulating doxorubicin (DOX) was developed for enhancement of GBM penetration in combination with focused ultrasound (FUS) and microbubbles. Upon ultrasound (US) irradiation, microbubbles induce cavitation resulting in the tight junction of BBB endothelium to temporarily open. In addition, the composition of sonosensitive liposome was optimized by comparison of sonosensitivity and intracellular uptake to U87MG cells. The optimal sonosensitive liposome, IMP301-DC, resulted 123.9 ± 38.2 nm in size distribution and 98.2 % in loading efficiency. Related to sonosensitivity of IMP301-DC, US-triggered release ratio of doxorubicin was 69.2 ± 12.3 % at 92 W/cm2 of US intensity for 1 min. In the in vivo experiments, the accumulation of DiD fluorescence probe labeled IMP301-DC-shell in the brain through the BBB opening was increased more than two-fold compared to that of Doxil-shell, non-sonosensitive liposome. US exposure significantly increased GBM cytotoxicity of IMP301-DC. In conclusion, this study demonstrated that IMP301-DC could serve as an alternative solution to enhance the penetration to GBM treatment via BBB opening by non-invasive FUS combined with microbubbles.

Adrenal Nodules Detected at Staging CT in Patients with Resectable Gastric Cancers Have a Low Incidence of Malignancy.

Background Guidelines recommending additional imaging for adrenal nodules lack relevant epidemiologic evidence. Purpose To measure the prevalence of adrenal nodules detected at staging CT in patients with potentially resectable gastric cancer and the proportion of patients with malignant nodules among them. Materials and Methods This retrospective study included 10 250 consecutive patients (median age, 63 years; interquartile range, 53-71 years; 6884 men) who underwent staging CT and had potentially resectable gastric cancer in a tertiary center (May 2003 to December 2018). All 10 250 CT studies were retrospectively reviewed, and patients with adrenal nodules (or thickening ≥10 mm) were identified to measure the prevalence of adrenal nodules. Among patients with adrenal nodules, the per-patient proportions of malignant nodules, adrenal metastasis from gastric cancer, and additional adrenal examinations were measured. A secondary analysis was performed by using data from the original CT reports. The same metrics that were used in the retrospective review were assessed. Results The prevalence of adrenal nodules was 4.5% (95% CI: 4.1, 4.9; 462 of 10 250). The proportions of malignant nodules and adrenal metastasis from gastric cancer were 0.4% ( 95% CI: 0.1, 1.6; two of 462) and 0% (95% CI: 0.0, 0.8; 0 of 462), respectively. A total of 27% of the patients (95% CI: 23, 31; 123 of 462) underwent additional adrenal examination. According to original CT reports, the prevalence of adrenal nodules and the proportions of malignant nodules, adrenal metastases from gastric cancer, and additional adrenal examination were 2.7% (95% CI: 2.4, 3.0; 272 of 10 250), 0.7% (95% CI: 0.1, 2.6; two of 272), 0% (95% CI: 0.0, 1.4; 0 of 272), and 42.6% (95% CI: 36.7, 48.8; 116 of 272), respectively. Conclusion Although adrenal nodules were detected frequently on staging CT images of patients with otherwise resectable gastric cancer, these nodules were rarely malignant. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Baumgarten in this issue.

Early response evaluation of doxorubicin-nanoparticle-microbubble therapy in orthotopic hepatocellular carcinoma rat model using contrast-enhanced ultrasound and intravoxel incoherent motion-diffusion MRI.

PURPOSE: This study aimed to apply doxorubicin-loaded nanoparticle microbubble (Dox-NP-MB) therapy in an orthotopic rat model of hepatocellular carcinoma (HCC) and investigate the utility of contrast-enhanced ultrasound (CEUS) and intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI) for response evaluation. METHODS: Twenty-eight N1S1 HCC model rats were treated with either Dox-NP-MB (group [G] 1, n=8), doxorubicin (Dox) alone (G2, n=7), nanoparticle microbubbles alone (G3, n=7), or saline (G4, control, n=6) on days 0 and 7, and were sacrificed on day 11. IVIM-DWI and CEUS were performed before each treatment and before euthanasia. Efficacy was estimated by the percentage of tumor volume growth inhibition compared with control. Toxicity was assessed by body weight changes and blood tests. Post-treatment changes in IVIM-DWI and CEUS parameters were analyzed. RESULTS: Tumor volume growth was inhibited by 48.4% and 90.2% in G1 and G2 compared to G4, respectively. Compared to G2, G1 had a significantly lower degree of body weight change (median, 91.0% [interquartile range, 88.5%-97.0%] vs. 88.0% [82.5%-88.8%], P<0.05) and leukopenia (1.75×103 cells/µL [1.53-2.77] vs. 1.20×103 cells/µL [0.89-1.51], P<0.05). After the first treatment, an increase in peak enhancement, wash-in rate, and wash-in perfusion index on CEUS was observed in G3 and G4 but suppressed in G1 and G2; the apparent diffusion coefficients, true diffusion coefficients, and perfusion fractions significantly increased in G1 and G2 compared to baseline (P<0.05). CONCLUSION: Dox-NP-MB showed reduced Dox toxicity. Early changes in some CEUS and IVIM-DWI parameters correlated with the therapeutic response.

Ultrasound-triggered imaging and drug delivery using microbubble-self-aggregate complexes.

Co-delivery of microbubbles (MBs) with anticancer drugs is a promising theranostic approach that can enhance both the ultrasound contrast and local extravasation of drugs with the sonoporation effect. The simultaneous administration of MBs and hydrophobic drugs, however, is still challenging due to the limitations in drug loading or undesirable stabilization of MBs. In this research, MB-self-aggregate complexes (MB-SAs) were newly fabricated for the encapsulation of hydrophobic drugs, and their theranostic properties are investigated in vitro and in vivo. Glycol chitosan self-aggregates (GC-SAs) loaded with hydrophobic drugs or dyes were chemically conjugated on the surface MBs. Their conjugation ratio was determined to be 73.9%, and GC-SAs on MBs did not affect the stability of MBs. GC-SA attached MBs (GC@MBs) were successfully visualized with low-intensity insonation and showed enhanced cellular uptake via the sonoporation effect. In vivo biodistribution of GC@MBs was examined with tumor-bearing mice, confirming that their accumulation at the tumor site increased by 1.85 times after ultrasound irradiation. The anticancer drug-loaded GC@MBs also exhibited 10% higher cytotoxicity under ultrasound flash. In conclusion, it was expected that GC@MBs could be used both as an ultrasound contrast agent and a drug carrier even with conventional ultrasonic devices.

PMP(Porphyrin-Micelle-PSMA) Nanoparticles for Photoacoustic and Ultrasound Signal Amplification in Mouse Prostate Cancer Xenografts.

Photoacoustic (PA) imaging is used widely in cancer diagnosis. However, the availability of PA agents has not made great progress due to the limitations of the one currently in use, porphyrin. Porphyrin-Micelle (PM), developed by synthesizing porphyrin and PEG-3.5k, confirmed the amplification of the PA agent signal, and added binding affinity in an LNCaP model by attaching prostate-specific membrane antigen PSMA. Compared to the previously used porphyrin, a superior signal was confirmed, and the potential of PMP was confirmed when it showed a signal superior to that of hemoglobin at the same concentration. In addition, in the in vivo mouse experiment, it was confirmed that the signal in the LNCaP xenograft model was stronger than that in the PC-3 xenograft model, and the PMP signal was about three times higher than that of PM and porphyrin.

Comparison of Accuracies between Real-Time Nonrigid and Rigid Registration in the MRI-US Fusion Biopsy of the Prostate.

Magnetic resonance imaging (MRI) is increasingly important in the detection and localization of prostate cancer. Regarding suspicious lesions on MRI, a targeted biopsy using MRI fused with ultrasound (US) is widely used. To achieve a successful targeted biopsy, a precise registration between MRI and US is essential. The purpose of our study was to show any decrease in errors using a real-time nonrigid registration technique for prostate biopsy. Nineteen patients with suspected prostate cancer were prospectively enrolled in this study. Registration accuracy was calculated by the measuring distance of corresponding points by rigid and nonrigid registration between MRI and US, and compared for rigid and nonrigid registration methods. Overall cancer detection rates were also evaluated by patient and by core. Prostate volume was measured automatically from MRI and manually from US, and compared to each other. Mean distances between the corresponding points in MRI and US were 5.32 ± 2.61 mm for rigid registration and 2.11 ± 1.37 mm for nonrigid registration (p < 0.05). Cancer was diagnosed in 11 of 19 patients (57.9%), and in 67 of 266 biopsy cores (25.2%). There was no significant difference in prostate-volume measurement between the automatic and manual methods (p = 0.89). In conclusion, nonrigid registration reduces targeting errors.

Favorable intermediate risk prostate cancer with biopsy Gleason score of 6.

BACKGROUND: To identify potential prognostic factors among patients with favorable intermediate risk prostate cancer with a biopsy Gleason score 6. METHODS: From 2003 to 2019, favorable intermediate risk patients who underwent radical prostatectomy were included in this study. All patients were evaluated preoperatively with MRI. Using PI-RADS scores, patients were divided into two groups, and clinic-pathological outcomes were compared. The impact of preoperative factors on significant pathologic Gleason score upgrading (≥ 4 + 3) and biochemical recurrence were assessed via multivariate analysis. Subgroup analysis was performed in patients with PI-RADS ≤ 2. RESULTS: Among the 239 patients, 116 (48.5%) were MRI-negative (PI-RADS ≤ 3) and 123 (51.5%) were MRI-positive (PI-RADS > 3). Six patients in the MRI-negative group (5.2%) were characterized as requiring significant pathologic Gleason score upgrading compared with 34 patients (27.6%) in the MRI-positive group (p < 0.001). PI-RADS score was shown to be a significant predictor of significant pathologic Gleason score upgrading (OR = 6.246, p < 0.001) and biochemical recurrence (HR = 2.595, p = 0.043). 10-years biochemical recurrence-free survival was estimated to be 84.4% and 72.6% in the MRI-negative and MRI-positive groups (p = 0.035). In the 79 patients with PI-RADS ≤ 2, tumor length in biopsy cores was identified as a significant predictor of pathologic Gleason score (OR = 11.336, p = 0.014). CONCLUSIONS: Among the patients with favorable intermediate risk prostate cancer with a biopsy Gleason score 6, preoperative MRI was capable of predicting significant pathologic Gleason score upgrading and biochemical recurrence. Especially, the patients with PI-RADS ≤ 2 and low biopsy tumor length could be a potential candidate to active surveillance.

Transrectal Ultrasound and Photoacoustic Imaging Probe for Diagnosis of Prostate Cancer.

A combined transrectal ultrasound and photoacoustic (TRUS-PA) imaging probe was developed for the clear visualization of morphological changes and microvasculature distribution in the prostate, as this is required for accurate diagnosis and biopsy. The probe consisted of a miniaturized 128-element 7 MHz convex array transducer with 134.5° field-of-view (FOV), a bifurcated optical fiber bundle, and two optical lenses. The design goal was to make the size of the TRUS-PA probe similar to that of general TRUS probes (i.e., about 20 mm), for the convenience of the patients. New flexible printed circuit board (FPCB), acoustic structure, and optical lens were developed to meet the requirement of the probe size, as well as to realize a high-performance TRUS-PA probe. In visual assessment, the PA signals obtained with the optical lens were 2.98 times higher than those without the lens. Moreover, the in vivo experiment with the xenograft BALB/c (Albino, Immunodeficient Inbred Strain) mouse model showed that TRUS-PA probe was able to acquire the entire PA image of the mouse tight behind the porcine intestine about 25 mm depth. From the ex vivo and in vivo experimental results, it can be concluded that the developed TRUS-PA probe is capable of improving PA image quality, even though the TRUS-PA probe has a cross-section size and an FOV comparable to those of general TRUS probes.