Clinically-translatable High-fidelity Photoacoustic Tomography Enhanced by Virtual Point Sources

Photoacoustic tomography (PAT), a hybrid imaging modality that acoustically detects the optical absorption contrast, is a promising technology for imaging hemodynamic functions in deep tissues. Particularly, PAT is capable of measuring the blood oxygenation level using hemoglobin as the endogenous contrast. However, the most clinically compatible PAT configuration usually employs a linear ultrasound transducer array and often suffers from the poor image fidelity, mostly due to the limited detection view of the transducer array. PAT can be improved by employing highly-absorbing contrast agents such as droplets and nanoparticles, which, however, have low clinical translation potential due to safety concerns and regulatory hurdles. Moreover, unlike hemoglobin, these exogenous contrast agents cannot report the functional hemodynamic information. In this work, we have developed a new methodology that can improve PAT’s image fidelity without hampering its functional capability or clinical translation potential. By using clinically-approved microbubbles as virtual point sources that strongly scatter the local pressure waves generated by surrounding hemoglobin, we can overcome the limited-detection-view problem and achieve high-fidelity functional PAT in deep tissues, a technology referred to as virtual-point-source PAT (VPS-PAT). We have thoroughly investigated the working principle of VPS-PAT by numerical simulations and phantom validations, showing the acoustic origin of signal enhancement and the superiority over traditional PAT. We have also demonstrated proof-of-concept applications of functional VPT-PAT for in vivo small-animal studies with physiological challenges. We expect that VPS-PAT can find broad applications in biomedical research and accelerated translation to clinical impact.

CTNI-52. RETROSPECTIVE ANALYSIS OF USING RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATING FIELDS FOR CHINESE PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

OBJECTIVES Tumor Treating Fields (TTFields) has been shown to improve the overall survival of newly diagnosed GBM (ndGBM) when combined with Temozolomide (TMZ) in the EF-14 trial. Preclinical studies suggested synergistic effects between TTFields and radiotherapy. This study is aimed to examine the safety and efficacy of combination therapy (chemoradiation concurrent with TTFields treatment) for ndGBM patients in China. METHODS From July 2020 to May 2021, 33 ndGBM patients were treated with combination therapy (radiation target volume following NCCN guidelines). Eight patients had transducer array removed during radiotherapy, others retained transducer array on scalp. All patients had assessment every two months by MRI scan. The adverse reactions and monthly compliance data for TTFields treatment were recorded. RESULTS Twenty-five patients have completed the combination therapy. Three patients retained transducer array during radiotherapy but did not limit the scalp dose (mean: 21.7Gy). As a result, Grade 2 cutaneous adverse reactions developed, and TTFields treatment was suspended. Four patients suspended TTFields treatment due to other adverse reactions. The remaining patients who had limited scalp doses (mean < 20Gy) had no suspension or delay in combination therapy due to cutaneous adverse reactions. The median time of TTFields treatment during radiotherapy is 21.24 hours/day (IQR:19.26,22.08). Two patients had progressive disease, 1 died of pulmonary infection, and 30 had stable disease. The incidence of cutaneous AE was 48.5% (16/33), Grade1: 27.2% (9/33), Grade 2: 21.2% (7/33), and Grade 3: 3% (1/33). CONCLUSIONS The combination therapy was well tolerated in Chinese patients with ndGBM. Removing transducer array during radiotherapy may increase the frequency of array replacement while reducing the patient's daily treatment time. However, retaining transducer array will increase cutaneous adverse reactions. Scalp dose limitation is required yet it allows a maximum duration of TTFields. Further follow-ups are ongoing.

RBIO-01. DEVELOPING THE FRAMEWORK FOR TUMOR TREATING FIELDS (TTFIELDS) TREATMENT PLANNING FOR A PATIENT WITH ASTROCYTOMA IN THE SPINAL CORD

The use of Tumor Treating Fields (TTFields) following resection and chemoradiation has increased survival in patients with Glioblastoma. Patient-specific planning for TTFields transducer array placement has been demonstrated to maximize TTFields dose at the tumor: providing higher TTFields intensity (≥ 1.0 V/cm) and power density (≥ 1.1 mW/cm3) which are associated with improved overall survival. Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed, and the region assigned electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified. Transducer array layouts, in which the arrays were placed on the back of the patient with one array above the tumor and one array below the tumor, yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 3.4mW/cm3 which is well above the threshold dose of 1.1 mW/cm3 reported previously [Ballo et al. Red Jour 2019]. The framework developed for TTFields dosimetry and treatment planning for this spinal tumor will have the potential to increase dose delivery to the tumor bed while optimizing placement that may enhance comfort and encourage device usage.

Investigation of Cylindrical Piezoelectric and Specific Multi-Channel Circular MEMS-Transducer Array Resonator of Ultrasonic Ablation

Background: A cylindrical piezoelectric element and a specific multi-channel circular microelectromechanical systems (MEMS)-transducer array of ultrasonic system were used for ultrasonic energy generation and ablation. A relatively long time is required for the heat to be conducted to the target position. Ultrasound thermal therapy has great potential for treating deep hyperplastic tissues and tumors, such as breast cancer and liver tumors. Methods: Ultrasound ablation technology produces thermal energy by heating the surface of a target, and the heat gradually penetrates to the target’s interior. Beamforming was performed to observe energy distribution. A resonance method was used to generate ablation energy for verification. Energy was generated according to the coordinates of geometric graph positions to reach the ablation temperature. Results: The mean resonance frequency of Channels 1–8 was 2.5 MHz, and the cylindrical piezoelectric ultrasonic element of Channel A was 4.2546 Ω at 5.7946 MHz. High-intensity ultrasound has gradually been applied in clinical treatment. Widely adopted, ultrasonic hyperthermia involves the use of high-intensity ultrasound to heat tissues at 42–45 °C for 30–60 minutes. Conclusion: In the ultrasonic energy method, when the target position reaches a temperature that significantly reduces the cell viability (46.9 °C), protein surface modification occurs on the surface of the target.