MRI-guided Focused Ultrasound Research Articles

Real-world Experience of the Safety of Magnetic Resonance Imaging–guided Focused Ultrasound (MRgFUS)-thalamotomy for Essential Tremor (P3-3.008)

Real-world Experience of the Safety of Magnetic Resonance Imaging–guided Focused Ultrasound (MRgFUS)-thalamotomy for Essential Tremor (P3-3.008)

Long‐term outcome following magnetic resonance imaging‐guided focused ultrasound unilateral thalamotomy for medication‐refractory essential tremor

AbstractObjectiveTo investigate the long‐term outcome 5 years after transcranial magnetic resonance imaging‐guided focused ultrasound (MRgFUS) unilateral ventral intermediate nucleus (Vim) thalamotomy for essential tremor (ET), following our interim reports.MethodsThis was a prospective and open‐labeled study involving a single center. Ten medication‐refractory ET patients (8 men and 2 women, aged 67.1 ± 17.5 years, all right‐handed) underwent left MRgFUS Vim thalamotomy. They were assessed using the Clinical Rating Scale for Tremor (CRST) and the overall health and quality of life (QOL) scale of the Quality of Life in Essential Tremor Questionnaire (QUEST). Additionally, we assessed safety issues during the study period.ResultsRight‐hand tremor improved immediately after the procedure in all patients. The right‐hand CRST score remained significantly improved by 60.2% and 33.5% from baseline at both 1‐ and 5‐years post‐treatment, respectively (both p < 0.05). On the other hand, the left‐hand CRST score and the overall QOL score of QUEST showed no improvement. Adverse events during and immediately after the procedure were mild and reversible. We observed no delayed adverse events.ConclusionMRgFUS unilateral Vim thalamotomy is adopted as one of the therapeutic options for intractable ET. Further investigation of the methodology for accurate targeting and sonication is important to improve long‐term outcomes involving a larger number of patients. In addition, not only unilateral but also bilateral Vim thalamotomy may be necessary to achieve a better quality of life.

Focused ultrasound therapy in movement disorders: management roadmap toward optimal pathway organization.

MRI-guided focused ultrasound (MRgFUS) lesioning is an innovative, safe and effective treatment which provides an innovative development in the field of minimally invasive stereotactic neurosurgery. Based on the application of focused ultrasound energy under full MR planning and thermal imaging control, unilateral lesioning of the thalamus, subthalamic nucleus, and globus pallidus is indicated for the treatment of movement disorders, including essential tremor, Parkinson's disease, and dystonia. We started to apply this technique in February 2019 for the treatment of patients with movement disorders. The authors developed a diagnostic therapeutic care pathway, which is herewith proposed and applied as an explication of standard clinical practice in use. The project was the result of the application of different methods such as Health Technology Assessment (HTA), Strengths, Weaknesses, Opportunities and Threats analysis (SWOT) and Demin -Plan, Do, Check, Act (PDCA) cycle. The aim of this project was to standardize the MRgFUS diagnostic-therapeutic pathway (DTP), describe its application and the appropriateness of different phases (patient selection, intervention phase and follow-up). Here, we described in detail our experience in the DTP application from 2019 up to now in 610 patients with movement disorders.

MRI-Guided Focused Ultrasound for the Treatment of Dystonia: A Narrative Review.

Contemporary surgical management of dystonia includes neuromodulation via deep brain stimulation (DBS) or ablative techniques such as radiofrequency (RF) ablation. MRI-guided focused ultrasound (MRgFUS) is an emerging modality that uses high-intensity ultrasound to precisely ablate targets in the brain; this is incisionless, potentially avoiding the surgical risks of a burr hole and transcortical tract to reach the anatomical target. There is some evidence of efficacy in essential tremor and Parkinson's disease (PD), but, to date, there is no study aggregating the evidence of MRgFUS in dystonia. In this narrative review, we searched Medline, Embase, CINAHL, EBSCO, and ClinicalTrials.gov for primary studies and clinical trials on MRgFUS in the treatment of dystonia. Data were analyzed concerning dystonia phenotype, reported outcomes, and complications. PD-related dystonia was also included within the scope of the review. Using our search criteria, six articles on the use of MRgFUS in adult dystonia and three articles on the use of FUS in dystonia in PD were included. Four trials on the use of FUS in dystonia were also found on ClinicalTrials.gov, one of which was completed in December 2013. All included studies showed evidence of symptomatic improvement, mostly in focal hand dystonia; improvements were also found in dystonia-associated tremor, cervicobrachial dystonia, and dystonia-associated chronic neuropathic painas well as PD-related dystonia. Reported complications included transient neurological deficits and persistent arm pain in one study. However, the evidence is limited to level-4 case series at present. MRgFUS is an emerging modality that appears to be safe and effective, particularly in focal hand dystonia, without major adverse effects. However, the quality of evidence is low at present, and long-term outcomes are unknown. High-quality prospective studies comparing MRgFUS to other surgical techniques will be useful in determining its role in the management of dystonia.

MRI-Guided Focused Ultrasound in Cervical Dystonia

Introduction. MRI-guided focused ultrasound (MRgFUS) is approved for management of various movement disorders, primarily essential tremor and Parkinson’s disease (PD), with favorable long-term outcomes in numerous patients worldwide. However, few case studies describe the use of this modality for symptomatic treatment of dystonias that, as the third most common movement disorder, may be rather disabling.
 Objective: To improve outcomes in patients with cervical dystonia (CD) using MRgFUS.
 Materials and methods. We retrospectively analyzed 13 cases of various CD types managed with MRgFUS in single or multiple sessions. The mean age of the patients was 42 [39; 53] years. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was used to assess patients' statuses and severity of CD symptoms during therapy and the last available observation period. The targets included the pallidothalamic tract and the thalamic ventral oralis complex nucleus or their combination.
 Results. The mean follow-up period was 13.3 ± 3.4 months (July 2021 to April 2023). The mean CD severity sum score (TWSTRS score) was 22 [16; 25] before MRgFUS and 6 [4; 9] in the last observation. Therefore, we report 70.6% [55.6; 76.5] improvement (paired samples t-test p = 0.0025).
 Conclusion. Available data evidence that MRgFUS is efficient and sufficiently safe for symptomatic treatment in pharmacoresistant CD patients. A number of vital aspects of MRgFUS have to be specified in larger CD cohorts in the long-term follow-up.

Outcomes of Focused Ultrasound Thalamotomy in Tremor Syndromes.

The current literature comparing outcomes after a unilateral magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy between tremor syndromes is limited and remains a possible preoperative factor that could help predict the long-term outcomes. The aim was to report on the outcomes between different tremor syndromes after a unilateral MRgFUS thalamotomy. A total of 66 patients underwent a unilateral MRgFUS thalamotomy for tremor between November 2018 and May 2020 at St Vincent's Hospital Sydney. Each patient's tremor syndrome was classified prior to treatment. Clinical assessments, including the hand tremor score (HTS) and Quality of Life in Essential Tremor Questionnaire (QUEST), were performed at baseline and predefined intervals to 36 months. A total of 63 patients, comprising 30 essential tremor (ET), 24 dystonic tremor (DT), and 9 Parkinson's disease tremor (PDT) patients, returned for at least one follow-up. In the ET patients, at 24 months there was a 61% improvement in HTS and 50% improvement in QUEST compared to baseline. This is in comparison to PDT patients, where an initial benefit in HTS and QUEST was observed, which waned at each follow-up, remaining significant only up until 12 months. In the DT patients, similar results were observed to the ET patients: at 24 months there was a 61% improvement in HTS and 43% improvement in QUEST compared to baseline. These results support the use of unilateral MRgFUS thalamotomy for the treatment of DT, which appears to have a similar expected outcome to patients diagnosed with ET. Patients with PDT should be warned that there is a risk of treatment failure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evaluation of the efficacy and safety of MRI-guided focused ultrasound (MRgFUS) for focal hand dystonia: study protocol for an open-label non-randomised clinical trial

IntroductionMRI-guided focused ultrasound (MRgFUS) thalamotomy provides an exciting development in the field of minimally invasive stereotactic neurosurgery. Current treatment options for focal hand dystonia are limited, with potentially more effective...

Magnetic resonance imaging-guided focused ultrasound thalamotomy launch with remote telemedicine international proctorship.

COVID-19 limitations have hindered the implementation of new technologies by preventing proctors from coming to the site. We share our first experience of magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) treatment with an international remote online proctorship, and develop and evaluate the methodology of remote MRgFUS proctorship. This single-center, nonrandomized controlled prospective study included 94 patients: 27 with essential tremor (ET) and 67 with tremor-dominant Parkinson's disease (PD). The coming of proctors was impossible, so we arranged for the remote participation of proctors from the United Kingdom, Spain, and Israel. A total of 38 patients (40.4%) received telemedicine-proctored treatment (proctor group) and 56 received their treatment independently (solo group). We used the Clinical Rating Scale for Tremor (CRST) for ET patients and the Unified Parkinson's Disease Rating Scale (UPDRS) Part III for PD patients. In patients with ET, success rates were 81.8% (proctor group) and 100% (solo group) (p = 0.22). CRST reduction on the treated side was 71.43% [65.83%; 80.56%] (proctor group) versus 60.87% [53.99; 79.58] (solo group) (p = 0.19). None of the patients showed worsening of tremors within 1 year. In patients with PD, the success rates were 92.6% (proctor group) and 100% (solo group) (p = 0.08). The UPDRS Part III improvement was 30.1% (proctor group) versus 39.9% (solo group) (p = 0.003). The 1-year recurrence rate was 40% (proctor group) and 17.5% (solo group) (p = 0.04). No complications were observed at 6 months. We developed a feasible and safe methodology for telemedicine remote online-proctored MRgFUS treatment. No significant difference was observed between the solo and developed remote proctor protocols in terms of complication rate, effect, and long-term results; however, UPDRS Part III improvement was better in the PD solo group. This study demonstrated that the MRgFUS international proctorship can be performed successfully remotely.

What predicts durable symptom relief of uterine fibroids treated with MRI-guided focused ultrasound? A multicenter trial in 8 academic centers.

To identify variables predictive of durable clinical success after MRI-guided focused ultrasound (MRgFUS) treatment of uterine fibroids. In this prospective, multicenter trial, 99 women with symptomatic uterine fibroids were treated using MRgFUS. Pelvic MRI was obtained at baseline and treatment day. The Uterine Fibroid Symptom-Quality of Life questionnaire was used to calculate a symptom severity score (SSS) at baseline and 6, 12, 24, and 36months following treatment. Clinical, imaging, and treatment variables were correlated with symptom reduction sustained through the 12- and 24-month time points using univariable and multivariable logistic regression analyses. A novel parameter, the ratio of non-perfused volume to total fibroid load (NPV/TFL), was developed to determine association with durable outcomes. Post-treatment, mean symptom severity decreased at the 6-, 12-, 24-, and 36-month follow-ups (p < 0.001, all time points). In univariable analysis, three variables predicted treatment success (defined by ≥ 30-point improvement in SSS) sustained at both the 12-month and 24-month time points: increasing ratio of NPV/TFL (p = 0.002), decreasing total fibroid load (p = 0.04), and the absence of T2-weighted Funaki type 2 fibroids (p = 0.02). In multivariable analysis, the NPV/TFL was the sole predictor of durable clinical success (p = 0.01). Patients with ratios below 30% had less improvement in SSS and lacked durable clinical response compared with those between 30-79 (p = 0.03) and ≥ 80% (p = 0.01). Increased non-perfused volume relative to total fibroid volume was significantly associated with durable reduction of symptoms of abnormal uterine bleeding and bulk bother. Patient selection for sustained clinical benefit should emphasize those with likelihood of achieving high ablation ratios, as determined by imaging (e.g., device access, Funaki type) and by considering the total fibroid load, not just the primary symptomatic fibroid. Clinical trial ID: NCT01285960. • Patient selection/treatment approach associated with durable symptom relief in MRI-guided focused ultrasound ablation of uterine fibroids remains unclear. • The ablation ratio, non-perfused volume/total fibroid volume, was positively associated with sustained symptom relief in both bleeding and bulk bother at 1- and 2-year follow-ups. • Selecting patients with imaging features that favor a high ratio of ablation to total fibroid load (including non-targeted fibroids) is the main factor in predicting durability of symptom relief after uterine fibroid treatment.

MRI-guided focused ultrasound ablation of painful lumbar facet joints: a retrospective assessment of safety and tolerability in human subjects.

To evaluate the safety and tolerability of MRI-guided focused ultrasound (MRgFUS) for the treatment of facet joint-mediated pain in human subjects for whom conventional treatment had failed. Secondarily, to evaluate effectiveness of the procedure. Consecutive patients who underwent MRgFUS at our institution were retrospectively identified. Chart review was performed to obtain relevant clinical and technical data. All patients had chronic low back pain and positive comparative medial branch blocks. Twenty-six MRgFUS treatments in 20 patients were included. Mean sonication energy was 1436.6 Joules. The procedure was technically successful in all patients. Of the treated patients, 29.6% experienced short-term worsening of low back pain immediately after the procedure, all by 1-4 points on a 0-10 scale. One patient (3.8%) reported temporary worsening of preexisting radicular symptoms after the procedure. Of 21 treatments with clinical follow-up of at least 3 months available, 12 (57.1%) had >3 months' pain relief, 2 (10%) had <3 months' benefit, 6 (30%) reported no benefit, and 1 (5%) patient was lost to follow-up. In patients who reported at least some benefit with prior conventional radiofrequency ablation, 8/10 (80%) benefited from the MRgFUS procedure. The present study demonstrates that MRgFUS ablation of the lumbar facet joints is a safe and tolerable procedure in human subjects and could provide another option for patients for whom radiofrequency ablation had failed. More than half of all patients received significant durable pain relief, which jumped to 80% for patients who had experienced at least some benefit from prior radiofrequency ablations.

Gray matter alterations in tremor-dominant Parkinson's disease after MRgFUS thalamotomy are correlated with tremor improvement: a pilot study.

Regional differences in gray matter volume (GMV) have been reported to be a reliable marker for diagnosing Parkinson's disease (PD). This study aimed to explore the clinical value of GMV to assess magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy as a treatment for tremor-dominant PD (TDPD). Nine TDPD patients with MRgFUS thalamotomy were recruited for structural magnetic resonance image (MRI) scanning and clinical score evaluation. GMV was calculated. To investigate changes after treatment, voxel- and region of interest (ROI)-wise GMV analyses were performed. Then, GMV with significant differences was extracted from patients to investigate its dynamic alterations by one-way repeated-measures analysis of variance (ANOVA). The nonparametric Spearman rank correlation analysis was used to evaluate the relationship between GMV alterations and tremor improvement after thalamotomy. Tremors were significantly relieved after MRgFUS thalamotomy in nine patients (P<0.05). The treated hand tremor scores improved 74.82% on average in patients from pre-operation to 12 months post-operation. Voxel-wise analysis at the cluster level showed a significant decrease in GMV in the left middle occipital gyrus (MOG) [t=11.81, voxel-level P<0.001, cluster-level Pfamily-wise error (FWE) <0.05] and an increase in GMV in the left precentral gyrus (PreCG) (t=7.99, voxel-level P<0.001, cluster-level PFWE <0.05) in TDPD patients from preoperative to 12 months post-operation, which was significantly correlated with tremor scores (rho =0.346-0.439, P<0.05). ROI-wise analysis showed that GMV related to MRgFUS thalamotomy was associated with long-term structural alterations (P<0.05 with Bonferroni correction), including specific basal ganglia and related nuclei and cerebellum subregions. GMV can be used to reflect tremor improvement after MRgFUS thalamotomy and be helpful to better understand the distant effect of MRgFUS thalamotomy and the involvement of GMV in tremor control in TDPD. ClinicalTrials.gov identifier: NCT04570046.

Treatment of vocal tremor with bilateral magnetic resonance imaging-guided focused ultrasound of the ventral intermediate thalamic nucleus: illustrative case.

Essential vocal tremor is a difficult disease entity to treat with a poor response to existing medical management and limited options for surgical management of the disease. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is an emerging treatment modality with encouraging results for limb tremor in patients with essential tremor, but data are limited for the treatment of vocal tremor. This is the case of a 69-year-old male with a history of essential vocal tremor severely limiting his ability to perform his occupation as an opera singer. He underwent staged bilateral ventral intermediate nucleus of the thalamus thalamotomy with MRgFUS for the treatment of his bilateral upper extremity tremor with near complete resolution of his vocal tremor after a second procedure. Bilateral MRgFUS may be a safe and efficacious option for the treatment of essential vocal tremor. Further research into optimal patient selection, precise target location, and treatment parameters is needed.

Tumor phantom model for MRI-guided focused ultrasound ablation studies.

The persistent development of focused ultrasound (FUS) thermal therapy in the context of oncology creates the need for tissue-mimicking tumor phantom models for early-stage experimentation and evaluation of relevant systems and protocols. This study presents the development and evaluation of a tumor-bearing tissue phantom model for testing magnetic resonance imaging (MRI)-guided FUS (MRgFUS) ablation protocols and equipment based on MR thermometry. Normal tissue was mimicked by a pure agar gel, while the tumor simulator was differentiated from the surrounding material by including silicon dioxide. The phantom was characterized in terms of acoustic, thermal, and MRI properties. US, MRI, and computed tomography (CT) images of the phantom were acquired to assess the contrast between the two compartments. The phantom's response to thermal heating was investigated by performing high power sonications with a 2.4 MHz single element spherically focused ultrasonic transducer in a 3T MRI scanner. The estimated phantom properties fall within the range of literature-reported values of soft tissues. The inclusion of silicon dioxide in the tumor material offered excellent tumor visualization in US, MRI, and CT. MR thermometry revealed temperature elevations in the phantom to ablation levels and clear evidence of larger heat accumulation within the tumor owing to the inclusion of silicon dioxide. Overall, the study findings suggest that the proposed tumor phantom model constitutes a simple and inexpensive tool for preclinical MRgFUS ablation studies, and potentially other image-guided thermal ablation applications upon minimal modifications.

Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Mouse Glioblastoma Model.

An orthotopically allografted mouse GL26 glioma model (Ccr2RFP/wt-Cx3cr1GFP/wt) was used to evaluate the effect of transient, focal opening of the blood-brain barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB opening was induced by magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not exhibit significant changes in cell numbers when compared with tumors in animals not receiving FUS. However, tumors that received two or three sessions of MRgFUS had significantly increased amounts of both CX3CR1-GFP and CCR2-RFP cells. The effect of MRgFUS on immune cell composition was also characterized and quantified using flow cytometry. Glioma implantation resulted in increased amounts of lymphocytes, monocytes and neutrophils in the brain parenchyma. Tumors administered MRgFUS exhibited increased numbers of monocytes and monocyte-derived TAMs. In addition, MRgFUS-treated tumors exhibited more CD80+ cells in monocytes and microglia. In summary, transient, focal opening of the BBB using MRgFUS combined with microbubbles can activate the homing and differentiation of monocytes and induce a shift toward a more pro-inflammatory status of the immune environment in glioblastoma.

501 Patient-Specific Targeting Method for Improved Quality-of-Life Outcomes from MRgFUS Treatment of Essential Tremor

INTRODUCTION: MRI-guided-focused-ultrasound (MRgFUS) ablation of the ventral intermediate nucleus (VIM) is an FDA-approved treatment for essential tremor (ET). However, the VIM cannot be directly visualized on standard imaging, and the ideal ablation zone within the putative VIM varies inter-individually. Suboptimal lesion location can lead to side effects that impair quality of life (QoL). Patient-specific methods to locate the “go-zone” for MRgFUS ablation for ET that can predict QoL outcome could provide significant benefit over current methods. METHODS: We retrospectively studied 26 ET patients treated with MRgFUS at Stanford. Probabilistic tracking from the thalamus to M1 using each subject’s standard, low-resolution preoperative diffusion MRI generated patient-specific cerebello-thalamic-cortical tracts. Within the thalamus, the personalized hotspot with high probability of being connected to M1 defined the “go-zone.” The normative DISTAL-atlas VIM, which some centers use to target deep brain stimulation, provided a comparison. The lesion was segmented in postoperative MRIs and transformed to the preoperative-MRI space. Similarity/overlap between the “go-zone” and lesion was quantified using the Sorensen-Dice coefficient. Postoperative QoL ("better," "same," or "worse") was determined from each subject’s last-available follow-up. RESULTS: Probabilistic thalamus-to-M1 tracking robustly identified cerebello-thalamo-cortical tracts using standard, clinical diffusion MRIs. Lesion similarity to the patient-specific tractographic "go-zone" was associated with better QoL outcomes. Dice coefficients of the "worse" group were significantly lower than of the combined “same”/”better” group (p = 0.014). This was not seen with the DISTAL-atlas VIM. CONCLUSIONS: We proposed a clinically-feasible probabilistic-tractography-based targeting method for MRgFUS treatment of ET. Lesion similarity to the personalized “go-zone” is associated with better QoL outcome, unlike similarity to the normative DISTAL-atlas VIM. This illustrates the value of our patient-specific targeting approach.

Characteristics of Pain During MRI-Guided Focused Ultrasound Thalamotomy.

Magnetic resonance imaging-guided focused ultrasound (MRgFUS) has become popular as an incisionless mode of neurosurgical treatment. However, head pain during sonication is common and its pathophysiology remains poorly understood. To explore the characteristics of head pain occurring during MRgFUS thalamotomy. Our study comprised 59 patients who answered questions about the pain they experienced during unilateral MRgFUS thalamotomy. The location and features of pain were investigated using a questionnaire including the numerical rating scale (NRS) to estimate maximum pain intensity and the Japanese version of the Short Form of McGill Pain Questionnaire 2 to evaluate the quantitative and qualitative dimensions of pain. Several clinical factors were investigated for possible correlation with pain intensity. Forty-eight patients (81%) reported sonication-related head pain, and the degree of pain was severe (NRS score ≥ 7) in 39 patients (66%). The distribution of sonication-related pain was "localized" in 29 (49%) and "diffuse" in 16 (27%); the most frequent location was the "occipital" region. The pain features most frequently reported were those in the "affective" subscale of the Short Form of McGill Pain Questionnaire 2. Patients with diffuse pain had a higher NRS score and lower skull density ratio than did patients with localized pain. The NRS score negatively correlated with tremor improvement at 6 months post-treatment. Most patients in our cohort experienced pain during MRgFUS. The distribution and intensity of pain varied according to the skull density ratio, indicating that the pain might have had different origins. Our results may contribute to the improvement of pain management during MRgFUS.

Evaluation of a Developed MRI-Guided Focused Ultrasound System in 7 T Small Animal MRI and Proof-of-Concept in a Prostate Cancer Xenograft Model to Improve Radiation Therapy.

Focused ultrasound (FUS) can be used to physiologically change or destroy tissue in a non-invasive way. A few commercial systems have clinical approval for the thermal ablation of solid tumors for the treatment of neurological diseases and palliative pain management of bone metastases. However, the thermal effects of FUS are known to lead to various biological effects, such as inhibition of repair of DNA damage, reduction in tumor hypoxia, and induction of apoptosis. Here, we studied radiosensitization as a combination therapy of FUS and RT in a xenograft mouse model using newly developed MRI-compatible FUS equipment. Xenograft tumor-bearing mice were produced by subcutaneous injection of the human prostate cancer cell line PC-3. Animals were treated with FUS in 7 T MRI at 4.8 W/cm2 to reach ~45 °C and held for 30 min. The temperature was controlled via fiber optics and proton resonance frequency shift (PRF) MR thermometry in parallel. In the combination group, animals were treated with FUS followed by X-ray at a single dose of 10 Gy. The effects of FUS and RT were assessed via hematoxylin-eosin (H&E) staining. Tumor proliferation was detected by the immunohistochemistry of Ki67 and apoptosis was measured by a TUNEL assay. At 40 days follow-up, the impact of RT on cancer cells was significantly improved by FUS as demonstrated by a reduction in cell nucleoli from 189 to 237 compared to RT alone. Inhibition of tumor growth by 4.6 times was observed in vivo in the FUS + RT group (85.3%) in contrast to the tumor volume of 393% in the untreated control. Our results demonstrated the feasibility of combined MRI-guided FUS and RT for the treatment of prostate cancer in a xenograft mouse model and may provide a chance for less invasive cancer therapy through radiosensitization.

Beyond the AJR: MRI-Guided Focused Ultrasound Focal Therapy for Intermediate-Risk Prostate Cancer.

Beyond the AJR: MRI-Guided Focused Ultrasound Focal Therapy for Intermediate-Risk Prostate CancerSangeet Ghai, MD1 and Nathan Perlis, MD2Audio Available | Share

Formulation of a kit under Good Manufacturing Practices (GMP) for preparing [111In]In-BnDTPA-trastuzumab-NLS injection: a theranostic agent for imaging and Meitner-Auger Electron (MAE) radioimmunotherapy of HER2-positive breast cancer

Background111In[In]-BnDTPA-trastuzumab-NLS is a radiopharmaceutical with theranostic applications for imaging and Meitner-Auger electron (MAE) radioimmunotherapy (RIT) of HER2-positive breast cancer (BC). Nuclear localization sequence (NLS) peptides route the radiopharmaceutical to the nucleus of HER2-positive BC cells following receptor-mediated internalization for RIT with subcellular range MAEs. The γ-photons emitted by 111In permit tumour imaging by SPECT. Our aim was to formulate a kit under Good Manufacturing Practices conditions to prepare 111In[In]-BnDTPA-trastuzumab-NLS injection for a first-in-human clinical trial.ResultsTrastuzumab was derivatized with p-SCN-BnDTPA to introduce Bn-DTPA for complexing 111In, then modified with maleimide groups for conjugation to the thiol on cysteine in NLS peptides [CGYGPKKKRKVGG]. BnDTPA-trastuzumab-NLS (5 mg in 1.0 mL of 0.05 M ammonium acetate buffer, pH 5.5) was dispensed into unit dose sterile glass vials to produce kits for labeling with 100–165 MBq of 111In[In]Cl3. The kits met specifications for protein concentration (4.5–5.5 mg/mL), volume (0.95–1.05 mL), pH (5.5–6.0), appearance (clear, pale-yellow, particulate-free), BnDTPA substitution level (2.0–7.0 BnDTPA/trastuzumab), purity and homogeneity (SDS-PAGE and SE-HPLC), 111In labeling efficiency (> 90%), binding to HER2-positive SK-BR-3 human breast cancer cells (Ka = 1–8 × 108 L/mmol; Bmax = 0.5–2 × 106 sites/cell), NLS peptide conjugation (upward band shift on SDS-PAGE), sterility (USP Sterility Test) and endotoxins (USP Bacterial Endotoxins Test). 111In-BnDTPA-trastuzumab-NLS injection met specifications for pH (5.5–6.5), radiochemical purity (≥ 90%), radionuclide purity (≥ 99%), appearance (clear, colourless, particle-free) and sterility (retrospective USP Sterility Test). Kits were stable stored at 2–8 °C for up to 661 days (d) meeting all key specifications. Protein concentration remained within or just slightly greater than the specification for up to 139 d. 111In[In]-BnDTPA-trastuzumab-NLS injection was stable for up to 24 h. An expiry of 180 d was assigned for the kits and 8 h for the final radiopharmaceutical.ConclusionA kit was formulated under GMP conditions for preparing 111In[In]-BnDTPA-trastuzumab-NLS injection. This radiopharmaceutical was safely administered to 4 patients with HER2-positive BC to trace the uptake of trastuzumab into brain metastases before and after MRI-guided focused ultrasound (MRIg-FUS) by SPECT imaging.

Complete resolution of chronic cluster headache following central lateral thalamotomy using incisionless MRI-guided focused ultrasound with 6 years of follow-up: illustrative case.

The authors reported the case of a 66-year-old male patient with a 14-year history of right-sided severe episodic and therapy-resistant cluster headache (CH) who underwent bilateral central lateral thalamotomy (CLT) using incisionless transcranial magnetic resonance imaging-guided focused ultrasound (MRgFUS). The patient experienced a single cluster headache attack 5 weeks after the procedure. There were no more pain attacks over the next 6 years of follow-up. This treatment success may indicate a common pathophysiology for CH and neurogenic (neuropathic) pain, which has been treated with CLT for more than 30 years. Further experience is needed to assess the reproducibility of this case.