Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity ...focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors.
We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival.
Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4
Foxp3
, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4
, CD8α
, and CD8α
CD11c
cells, CD11c
in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival,
< 0.0001). This combination treatment significantly also induces CD4
CD44
CD62L
and CD8α
CD44
CD62L
population and is adoptively transferable, imparting immunity, slowing subsequent
tumor engraftment.
Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.
Abstract Variational image registration methods commonly employ a similarity metric and a regularization term that renders the minimization problem well-posed. However, many frequently used ...regularizations such as smoothness or curvature do not necessarily reflect the underlying physics that apply to anatomical deformations. This, in turn, can make the accurate estimation of complex deformations particularly challenging. Here, we present a new highly flexible regularization inspired from the physics of fluid dynamics which allows applying independent penalties on the divergence and curl of the deformations and/or their nth order derivative. The complexity of the proposed generalized div-curl regularization renders the problem particularly challenging using conventional optimization techniques. To this end, we develop a transformation model and an optimization scheme that uses the divergence and curl components of the deformation as control parameters for the registration. We demonstrate that the original unconstrained minimization problem reduces to a constrained problem for which we propose the use of the augmented Lagrangian method. Doing this, the equations of motion greatly simplify and become managable. Our experiments indicate that the proposed framework can be applied on a variety of different registration problems and produce highly accurate deformations with the desired physical properties.
The performance of minimally invasive molecular diagnostic tools in brain tumors, such as liquid biopsy, has so far been limited by the blood-brain barrier (BBB). The BBB hinders the release of brain ...tumor biomarkers into the bloodstream. The use of focused ultrasound in conjunction with microbubbles has been shown to temporarily open the BBB (FUS-BBBO). This may enhance blood-based tumor biomarker levels. This systematic review provides an overview of the data regarding FUS-BBBO-enhanced liquid biopsy for primary brain tumors. A systematic search was conducted in PubMed and Embase databases with key terms "brain tumors", "liquid biopsy", "FUS" and their synonyms, in accordance with PRISMA statement guidelines. Five preclinical and two clinical studies were included. Preclinical studies utilized mouse, rat and porcine glioma models. Biomarker levels were found to be higher in sonicated groups compared to control groups. Both stable and inertial microbubble cavitation increased biomarker levels, whereas only inertial cavitation induced microhemorrhages. In clinical studies involving 14 patients with high-grade brain tumors, biomarker levels were increased after FUS-BBBO with stable cavitation. In conclusion, FUS-BBBO-enhanced liquid biopsy using stable cavitation shows diagnostic potential for primary brain tumors. Further research is imperative before integrating FUS-BBBO for liquid biopsy enhancement into clinical practice.
Purpose:
While respiratory motion compensation for magnetic resonance (MR)‐guided high intensity focused ultrasound (HIFU) interventions has been extensively studied, the influence of slow ...physiological motion due to, for example, peristaltic activity, has so far been largely neglected. During lengthy interventions, the magnitude of the latter can exceed acceptable therapeutic margins. The goal of the present study is to exploit the episodic workflow of these therapies to implement a motion correction strategy for slow varying drifts of the target area and organs at risk over the entire duration of the intervention.
Methods:
The therapeutic workflow of a MR‐guided HIFU intervention is in practice often episodic: Bursts of energy delivery are interleaved with periods of inactivity, allowing the effects of the beam on healthy tissues to recede and/or during which the plan of the intervention is reoptimized. These periods usually last for at least several minutes. It is at this time scale that organ drifts due to slow physiological motion become significant. In order to capture these drifts, the authors propose the integration of 3D MR scans in the therapy workflow during the inactivity intervals. Displacements were estimated using an optical flow algorithm applied on the 3D acquired images. A preliminary study was conducted on ten healthy volunteers. For each volunteer, 3D MR images of the abdomen were acquired at regular intervals of 10 min over a total duration of 80 min. Motion analysis was restricted to the liver and kidneys. For validating the compatibility of the proposed motion correction strategy with the workflow of a MR‐guided HIFU therapy, an in vivo experiment on a porcine liver was conducted. A volumetric HIFU ablation was completed over a time span of 2 h. A 3D image was acquired before the first sonication, as well as after each sonication.
Results:
Following the volunteer study, drifts larger than 8 mm for the liver and 5 mm for the kidneys prove that slow physiological motion can exceed acceptable therapeutic margins. In the animal experiment, motion tracking revealed an initial shift of up to 4 mm during the first 10 min and a subsequent continuous shift of ∼2 mm/h until the end of the intervention. This leads to a continuously increasing mismatch of the initial shot planning, the thermal dose measurements, and the true underlying anatomy. The estimated displacements allowed correcting the planned sonication cell cluster positions to the true target position, as well as the thermal dose estimates during the entire intervention and to correct the nonperfused volume measurement. A spatial coherence of all three is particularly important to assure a confluent ablation volume and to prevent remaining islets of viable malignant tissue.
Conclusions:
This study proposes a motion correction strategy for displacements resulting from slowly varying physiological motion that might occur during a MR‐guided HIFU intervention. The authors have shown that such drifts can lead to a misalignment between interventional planning, energy delivery, and therapeutic validation. The presented volunteer study and in vivo experiment demonstrate both the relevance of the problem for HIFU therapies and the compatibility of the proposed motion compensation framework with the workflow of a HIFU intervention under clinical conditions.
Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, ...successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack of standardisation in protocols applied for establishing the commonly used HSJD-DIPG-007 patient-derived xenograft (PDX) model, based on animal host, injection location, number of cells inoculated, volume, and suspension matrices. This study evaluated the HSJD-DIPG-007 PDX model with respect to its ability to mimic human disease progression for therapeutic testing in vivo. The mice received intracranial injections of HSJD-DIPG-007 cells suspended in either PBS or Matrigel. Survival, tumour growth, and metastases were assessed to evaluate differences in the suspension matrix used. After cell implantation, no severe side effects were observed. Additionally, no differences were detected in terms of survival or tumour growth between the two suspension groups. We observed delayed metastases in the Matrigel group, with a significant difference compared to mice with PBS-suspended cells. In conclusion, using Matrigel as a suspension matrix is a reliable method for establishing a DMG PDX mouse model, with delayed metastases formation and is a step forward to obtaining a standardised in vivo PDX model.
Highlights•Better normal tissue dosimetric sparing was achieved with PBS compared to VMAT. •PBS with posterior fields was highly robust against inter-fraction changes. •Dose differences between ...planned and accumulated PBS doses <5% were calculated. •Larger differences between planned and accumulated full-arc VMAT doses were seen. •Target coverage was not reached for one patient in the accumulated VMAT dose.
Background and PurposeDeformable image registration (DIR) is a core element of adaptive radiotherapy workflows, integrating daily contour propagation and/or dose accumulation in their design. ...Propagated contours are usually manually validated and may be edited, thereby locally invalidating the registration result. This means the registration cannot be used for dose accumulation. In this study we proposed and evaluated a novel multi-modal DIR algorithm that incorporated contour information to guide the registration. This integrates operator-validated contours with the estimated deformation vector field and warped dose. Materials and MethodsThe proposed algorithm consisted of both a normalized gradient field-based data-fidelity term on the images and an optical flow data-fidelity term on the contours. The Helmholtz-Hodge decomposition was incorporated to ensure anatomically plausible deformations. The algorithm was validated for same- and cross-contrast Magnetic Resonance (MR) image registrations, Computed Tomography (CT) registrations, and CT-to-MR registrations for different anatomies, all based on challenging clinical situations. The contour-correspondence, anatomical fidelity, registration error, and dose warping error were evaluated. ResultsThe proposed contour-guided algorithm considerably and significantly increased contour overlap, decreasing the mean distance to agreement by a factor of 1.3 to 13.7, compared to the best algorithm without contour-guidance. Importantly, the registration error and dose warping error decreased significantly, by a factor of 1.2 to 2.0. ConclusionsOur contour-guided algorithm ensured that the deformation vector field and warped quantitative information were consistent with the operator-validated contours. This provides a feasible semi-automatic strategy for spatially correct warping of quantitative information even in difficult and artefacted cases.
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