Ultrasound frequency-controlled microbubble dynamics in brain vessels regulate the enrichment of inflammatory pathways in the blood-brain barrier.

Microbubble-enhanced ultrasound provides a noninvasive physical method to locally overcome major obstacles to the accumulation of blood-borne therapeutics in the brain, posed by the blood-brain barrier (BBB). However, due to the highly nonlinear and coupled behavior of microbubble dynamics in brain vessels, the impact of microbubble resonant effects on BBB signaling and function remains undefined. Here, combined theoretical and prospective experimental investigations reveal that microbubble resonant effects in brain capillaries can control the enrichment of inflammatory pathways that are sensitive to wall shear stress and promote differential expression of a range of transcripts in the BBB, supporting the notion that microbubble dynamics exerted mechanical stress can be used to establish molecular, in addition to spatial, therapeutic windows to target brain diseases. Consistent with these findings, a robust increase in cytotoxic T-cell accumulation in brain tumors was observed, demonstrating the functional relevance and potential clinical significance of the observed immuno-mechano-biological responses.

The roles of thermal and mechanical stress in focused ultrasound-mediated immunomodulation and immunotherapy for central nervous system tumors.

BACKGROUND: Focused ultrasound (FUS) is an emerging technology, offering the capability of tuning and prescribing thermal and mechanical treatments within the brain. While early works in utilizing this technology have mainly focused on maximizing the delivery of therapeutics across the blood-brain barrier (BBB), the potential therapeutic impact of FUS-induced controlled thermal and mechanical stress to modulate anti-tumor immunity is becoming increasingly recognized. OBJECTIVE: To better understand the roles of FUS-mediated thermal and mechanical stress in promoting anti-tumor immunity in central nervous system tumors, we performed a comprehensive literature review on focused ultrasound-mediated immunomodulation and immunotherapy in brain tumors. METHODS: First, we summarize the current clinical experience with immunotherapy. Then, we discuss the unique and distinct immunomodulatory effects of the FUS-mediated thermal and mechanical stress in the brain tumor-immune microenvironment. Finally, we highlight recent findings that indicate that its combination with immune adjuvants can promote robust responses in brain tumors. RESULTS: Along with the rapid advancement of FUS technologies into recent clinical trials, this technology through mild-hyperthermia, thermal ablation, mechanical perturbation mediated by microbubbles, and histotripsy each inducing distinct vascular and immunological effects, is offering the unique opportunity to improve immunotherapeutic trafficking and convert immunologically "cold" tumors into immunologically "hot" ones that are prone to generate prolonged anti-tumor immune responses. CONCLUSIONS: While FUS technology is clearly accelerating concepts for new immunotherapeutic combinations, additional parallel efforts to detail rational therapeutic strategies supported by rigorous preclinical studies are still in need to leverage potential synergies of this technology with immune adjuvants. This work will accelerate the discovery and clinical implementation of new effective FUS immunotherapeutic combinations for brain tumor patients.

Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors.

Effective drug delivery in brain tumors remains a major challenge in oncology. Although local hyperthermia and stimuli-responsive delivery systems, such as thermosensitive liposomes, represent promising strategies to locally enhance drug delivery in solid tumors and improve outcomes, their application in intracranial malignancies remains unexplored. We hypothesized that the combined abilities of closed-loop trans-skull Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS) hyperthermia with those of thermosensitive drugs can alleviate challenges in drug delivery and improve survival in gliomas. Methods: To conduct our investigations, we first designed a closed loop MR-guided Focused Ultrasound (MRgFUS) system for localized trans-skull hyperthermia (ΔT < 0.5 °C) in rodents and established safety thresholds in healthy mice. To assess the abilities of the developed system and proposed therapeutic strategy for FUS-triggered chemotherapy release we employed thermosensitive liposomal Dox (TSL-Dox) and tested it in two different glioma tumor models (F98 in rats and GL261 in mice). To quantify Dox delivery and changes in the transvascular transport dynamics in the tumor microenvironment we combined fluorescent microscopy, dynamic contrast enhanced MRI (DCE-MRI), and physiologically based pharmacokinetic (PBPK) modeling. Lastly, to assess the therapeutic efficacy of the system and of the proposed therapeutic strategy we performed a survival study in the GL261 glioma bearing mice. Results: The developed closed-loop trans-skull MRgFUS-hyperthermia system that operated at 1.7 MHz, a frequency that maximized the brain (FUS-focus) to skull temperature ratio in mice, was able to attain and maintain the desired focal temperature within a narrow range. Histological evidence (H&E and Nissl) suggests that focal temperature at 41.5 ± 0.5 °C for 10 min is below the threshold for tissue damage. Quantitative analysis of doxorubicin delivery from TSLs with MRgFUS-hyperthermia demonstrated 3.5-fold improvement in cellular uptake in GL261 glioma mouse tumors (p < 0.001) and 5-fold increase in delivery in F98 glioma rat tumors (p < 0.05), as compared to controls (TSL-Dox-only). Moreover, PBPK modeling of drug transport that was calibrated using the experimental data indicated that thermal stress could lead to significant improvement in the transvascular transport (2.3-fold increase in the vessel diffusion coefficient; P < 0.001), in addition to promoting targeted Dox release. Prospective experimental investigations with DCE-MRI during FUS-hyperthermia, supported these findings and provided evidence that moderate thermal stress (≈41 °C for up to 10 min) can promote acute changes in the vascular transport dynamics in the brain tumor microenvironment (Ktrans value for control vs. FUS was 0.0097 and 0.0148 min-1, respectively; p = 0.026). Crucially, survival analysis demonstrated significant improvement in the survival in the TSL-Dox-FUS group as compared to TSL-Dox-only group (p < 0.05), providing supporting evidence on the therapeutic potential of the proposed strategy. Conclusions: Our investigations demonstrated that spatially controlled thermal stress can be attained and sustained in the mouse brain, using a trans-skull closed-loop MRgFUS system, and used to promote the effective delivery of chemotherapy in gliomas from thermosensitive drugs. This system also allowed us to conduct mechanistic investigations that resulted in the refinement of our understanding on the role of thermal stress in augmenting mass and drug transport in brain tumors. Overall, our study established a new paradigm for effective drug delivery in brain tumors based on closed-loop ultrasound-mediated thermal stress and thermosensitive drugs.

Synchrotron Radiation-Based Refraction-Contrast Tomographic Images Using X-ray Dark-Field Imaging Optics in Human Lung Adenocarcinoma and Histologic Correlations.

The aim of this study was to evaluate the clinical implication of synchrotron radiation imaging techniques for human lung adenocarcinoma in comparison with pathologic examination. A refraction-based tomographic imaging technique called the X-ray dark-field imaging (XDFI) method was used to obtain computed tomographic images of human lung adenocarcinoma at the beam line at Photon Factory BL 14B at the High Energy Accelerator Research Organization (KEK) in Tsukuba, Japan. Images of normal lung tissue were also obtained using the same methods and reconstructed as 3D images. Both reconstructed images were compared with pathologic examinations from histologic slides which were made with identical samples. Pulmonary alveolar structure including terminal bronchioles, alveolar sacs, and vasculatures could be identified in synchrotron radiation images of normal lung. Hyperplasia of interstitial tissue and dysplasia of alveolar structures were noticed in images of lung adenocarcinoma. Both synchrotron radiation images were considerably correlated with images from histologic slides. Lepidic patterns of cancer tissue were distinguished from the invasive area in synchrotron radiation images of lung adenocarcinoma. Refraction-contrast tomographic techniques using synchrotron radiation could provide high-resolution images of lung adenocarcinoma which are compatible with those from pathologic examinations.

Use of the rectal retractor to reduce the rectal dose in high dose rate intracavitary brachytherapy for a carcinoma of the uterine cervix.

Commercially available rectal retractors can be used in high dose rate intracavitary brachytherapy (HDR ICR) as one of the methods for reducing the rectal dose in radiotherapy for a uterine cervical cancer. However, the extent of the rectal protection achieved using these rectal retractors has not been reported. The aim of the study was to examine the effect of a rectal retractor on reducing the rectal dose in HDR ICR. Thirty patients were treated with HDR ICR using rectal retractors. Tandem and ovoids were applied in 15 patients and ovoids only were used in the other 15 patients. During the simulation, the rectum was filled with barium, and anteroposterior and lateral radiographs were then taken with and without the rectal retractor. Along the anterior rectal wall outlined, 4 to 8 points (median 6) were chosen to calculate the dose for each patient including the rectal point (RP), which is an author-defined rectal point modified from the definition of the rectal reference point in the ICRU report 38. The length of the measured rectum was 3-7 cm (median 5 cm). The bladder point (BP) dose was measured as recommended by the ICRU. The prescription doses to point A varied from 3.5 to 5 Gy (median 4 Gy). Paired comparisons were made on the individual patients by calculating the normalized mean doses of the RP, the maximal point (MP), and the longitudinal average (LA) with and without the rectal retractor. The doses to the bladder points (BP) were also calculated in parallel to the rectal points. The anterior rectal walls were displaced posteriorly after inserting the rectal retractor. In the tandem and ovoids group, the number of patients with a reduced dose in the RP, MP and LA were 14 (93.3%), 12 (80.0%) and 13 (86.7%), respectively. In the ovoids only group, the corresponding figures were 14 (93.3%), 14 (93.3%) and 14 (93.3%). In the tandem and ovoids group, the reduced dose in the RP, MP, and LA dose were 0.52 Gy (13.0%), 0.50 Gy (12.5%), and 0.39 Gy (9.8%), respectively (p < 0.05). In the ovoids only group, the RP, MP, and LA dose were reduced by 0.62 Gy (15.5%), 0.92 Gy (23.0%), and 0.54 Gy(13.5%), respectively (p < 0.05). There was no significant change in the bladder point doses when the rectal retractor was applied, although the mean BP dose were 0.27 Gy and 0.09 Gy lower for the tandem and ovoids group and for ovoids only group, respectively (p > 0.05). The mean RP, MP, and LA dose reduction rates of the patient subgroup where the RP dose was < 70% of the prescription dose were compared with the subgroup where the RP dose was > 70%. The effect of the rectal dose reduction was significant only in the subgroup of patients who received > 70% of the prescription dose (p < 0.05). The use of the rectal retractor was a simple and an effective method for reducing the rectal dose. It was also considered to be a highly reproducible method, which can replace the time-consuming vaginal gauze packing in HDR-ICR.

Value of external irradiation for locally advanced papillary thyroid cancer.

PURPOSE: To look for the possible efficacy of external beam irradiation (EBRT) for locally advanced papillary thyroid cancers. MATERIALS AND METHODS: Between August 1981 and September 1997, 91 patients with locally advanced papillary thyroid cancers (pathologic Stage T4 or N1) were treated with surgical resection. After surgery, 23 patients received postoperative EBRT with or without ablative radioiodine therapy, and 68 patients were treated with ablative radioiodine therapy alone. The distribution of age, gender, and stage was comparable in both groups. RESULTS: The overall survival rates at 7 years were not significantly different statistically between the two groups at 98.1% for the no-EBRT group and 90% for the EBRT group (p = 0.506). The locoregional control rates at 5 years were significantly different (EBRT 95.2% and no EBRT 67.5%; p = 0.0408). Analysis of the prognostic factors, age, gender, stage, and use of radioiodine ablative therapy, indicated these were not significant variables, except for EBRT. CONCLUSIONS: Adjuvant postoperative EBRT did not affect overall survival, but significantly improved locoregional control in patients with locally advanced papillary thyroid cancer (Stage pT4 or lymph node involvement).