Fluoroscopy-guided high-intensity focused ultrasound neurotomy of the lumbar zygapophyseal joints: a prospective, open-label study.

OBJECTIVE: The objective of this study is to investigate safety and effectiveness of a fluoroscopy-guided high-intensity focused ultrasound (HIFU) system for thermal ablation of the lumbar medial branch nerves. METHODS: This dual center prospective cohort study enrolled 30 participants with lumbar zygapophyseal joint syndrome. Each participant previously had a positive response to either a single diagnostic analgesic block or radiofrequency ablation (RFA). The primary effectiveness outcome was individual responder rate, defined as a reduction of two points or more on the pain intensity numerical rating scale without an increase in opioid intake, or a reduction in opioid intake without an increase in pain at 6 months after the intervention. The primary safety outcome was procedure-related or device-related adverse events (AEs). Secondary outcome variables included MRI evidence of tissue ablation, Oswestry Disability Index, 12-Item Short Form Health Survey, Brief Pain Inventory, and Patient Global Impression of Change. RESULTS: The individual responder rate was 89.7% at 2 days, 89.7% at 7 days, 72.4% at 14 days, 82.1% at 30 days, 59.3% at 90 days and 82.6% at 180 days. The average Numeric Rating Scale for pain severity decreased from 7.1 at baseline to 3.0 (N=29) after 2 days, 3.0 (N=29) after 7 days, 3.1 (N=29) after 14 days, 3.2 (N=28) after 30 days, 4.3 (N=27) after 90 days, and 3.3 (N=23) after 180 days. All participants tolerated the procedure well with no significant side effects or complications. CONCLUSIONS: Fluoroscopy-guided HIFU neurotomy achieved clinical responses comparable with RFA, and there were no significant device-related or procedure-related AEs. TRIAL REGISTRATION NUMBER: NCT04129034.

Fluoroscopy-guided high-intensity focused ultrasound ablation of the lumbar medial branch nerves: dose escalation study and comparison with radiofrequency ablation in a porcine model.

BACKGROUND: Radiofrequency ablation (RFA) is a common method for alleviating chronic back pain by targeting and ablating of facet joint sensory nerves. High-intensity focused ultrasound (HIFU) is an emerging, non-invasive, image-guided technology capable of providing thermal tissue ablation. While HIFU shows promise as a potentially superior option for ablating sensory nerves, its efficacy needs validation and comparison with existing methods. METHODS: Nine adult pigs underwent fluoroscopy-guided HIFU ablation of eight lumbar medial branch nerves, with varying acoustic energy levels: 1000 (N=3), 1500 (N=3), or 2000 (N=3) joules (J). An additional three animals underwent standard RFA (two 90 s long lesions at 80°C) of the same eight nerves. Following 2 days of neurobehavioral observation, all 12 animals were sacrificed. The targeted tissue was excised and subjected to macropathology and micropathology, with a primary focus on the medial branch nerves. RESULTS: The percentage of ablated nerves with HIFU was 71%, 86%, and 96% for 1000 J, 1500 J, and 2000 J, respectively. In contrast, RFA achieved a 50% ablation rate. No significant adverse events occurred during the procedure or follow-up period. CONCLUSIONS: These findings suggest that HIFU may be more effective than RFA in inducing thermal necrosis of the nerve.

Past, present and future of Focused Ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting.

Diffuse Intrinsic Pontine Glioma (DIPG), now known as Diffuse Midline Glioma (DMG) is a devastating pediatric brain tumor with limited treatment options and a very poor prognosis. Despite more than 250 clinical trials aimed to treat children diagnosed with DMG, no curative therapies currently exist for this patient population. A major obstacle has been the intact blood brain barrier (BBB) which prevents most therapeutics from crossing into the tumor bed. Focused Ultrasound (FUS) is an emerging, noninvasive medical technology which has been shown in both preclinical and clinical research to disrupt the blood brain barrier safely and temporarily. FUS blood brain barrier opening has been studied in combination with chemotherapies in preclinical DMG models, and this technology is now being investigated in clinical trials for the treatment of pediatric brain tumors. Focused ultrasound has additional mechanisms of action, including sonodynamic therapy and radiation sensitization, that hold promise as future DMG therapies as well. This paper, largely based off the proceedings from a workshop held by the Focused Ultrasound Foundation in October of 2021, summarizes the current state of the field of focused ultrasound for DIPG/DMG, including preclinical, technical, and clinical summaries in addition to recommended next steps for continued advancement of the game changing technology of Focused Ultrasound.

Focused ultrasound for the treatment of glioblastoma.

PURPOSE: Six years ago, in 2015, the Focused Ultrasound Foundation sponsored a workshop to discuss, and subsequently transition the landscape, of focused ultrasound as a new therapy for treating glioblastoma. METHODS: This year, in 2021, a second workshop was held to review progress made in the field. Discussion topics included blood-brain barrier opening, thermal and nonthermal tumor ablation, immunotherapy, sonodynamic therapy, and desired focused ultrasound device improvements. RESULTS: The outcome of the 2021 workshop was the creation of a new roadmap to address knowledge gaps and reduce the time it takes for focused ultrasound to become part of the treatment armamentarium and reach clinical adoption for the treatment of patients with glioblastoma. Priority projects identified in the roadmap include determining a well-defined algorithm to confirm and quantify drug delivery following blood-brain barrier opening, identifying a focused ultrasound-specific microbubble, exploring the role of focused ultrasound for liquid biopsy in glioblastoma, and making device modifications that better support clinical needs. CONCLUSION: This article reviews the key preclinical and clinical updates from the workshop, outlines next steps to research, and provides relevant references for focused ultrasound in the treatment of glioblastoma.

Focused Ultrasound for Pediatric Diseases.

Focused ultrasound (FUS) is a noninvasive therapeutic technology with multiple pediatric clinical applications. The ability of focused ultrasound to target tissues deep in the body without exposing children to the morbidities associated with conventional surgery, interventional procedures, or radiation offers significant advantages. In 2021, there are 10 clinical pediatric focused ultrasound studies evaluating various musculoskeletal, oncologic, neurologic, and vascular diseases of which 8 are actively recruiting and 2 are completed. Pediatric musculoskeletal applications of FUS include treatment of osteoid osteoma and bone metastases using thermal ablation and high-intensity FUS. Pediatric oncologic applications of FUS include treatment of soft tissue tumors including desmoid tumors, malignant sarcomas, and neuroblastoma with high-intensity FUS ablation alone, or in combination with targeted chemotherapy delivery. Pediatric neurologic applications include treatment of benign tumors such as hypothalamic hamartomas with thermal ablation and malignant diffuse intrinsic pontine glioma with low-intensity FUS for blood brain barrier opening and targeted drug delivery. Additionally, low-intensity FUS can be used to treat seizures. Pediatric vascular applications of FUS include treatment of arteriovenous malformations and twin-twin transfusion syndrome using ablation and vascular occlusion. FUS treatment appears safe and efficacious in pediatric populations across many subspecialties. Although there are 7 Food and Drug Administration-approved indications for adult applications of FUS, the first Food and Drug Administration approval for pediatric patients with osteoid osteoma was obtained in 2020. This review summarizes the preclinical and clinical research on focused ultrasound of potential benefit to pediatric populations.

Fluoroscopy-Guided High-Intensity Focused Ultrasound Neurotomy of the Lumbar Zygapophyseal Joints: A Clinical Pilot Study.

OBJECTIVE: To investigate the safety and feasibility of a fluoroscopy-guided, high-intensity focused ultrasound system for zygapophyseal joint denervation as a treatment for chronic low back pain. METHODS: The clinical pilot study was performed on 10 participants diagnosed with lumbar zygapophyseal joint syndrome. Each participant had a documented positive response to a diagnostic block or a previous, clinically beneficial radiofrequency ablation. For a descriptive study, the primary outcome was the safety question. All device- or procedure-related adverse events were collected. Secondary outcome variables included the average numeric rating scale for pain, the Roland-Morris Disability Questionnaire, the Brief Pain Inventory, the Patient Global Impression of Change, the morphine equivalent dose, and the finding of the neurological examination. RESULTS: All participants tolerated the procedure well with no significant device- or procedure-related adverse events; there was one episode of transient pain during the procedure. The average numeric rating scale score for pain decreased from 6.2 at baseline to 2.1 (n = 10) after 1 month, 4.9 (n = 9) after 3 months, 3.0 (n = 8) after 6 months, and 3.0 (n = 6) after 12 months. The ratio of participants who were considered a treatment success was 90% at 1 month, 50% at 3 months, 60% at 6 months, and 40% at 12 months. CONCLUSIONS: The first clinical pilot study using a noninvasive, fluoroscopy-guided, high-intensity focused ultrasound lumbar zygapophyseal neurotomy resulted in no significant device- or procedure-related adverse events and achieved clinical success comparable with that of routine radiofrequency ablation.

MRI-Guided Focused Ultrasound of Osseous Metastases: Treatment Parameters Associated With Successful Pain Reduction.

BACKGROUND: A phase 3 multicenter trial demonstrated that magnetic resonance imaging (MRI)-guided focused ultrasound (US) is a safe, noninvasive treatment that alleviated pain from bone metastases. However, outcomes varied among institutions (from 0%-100% treatment success). PURPOSE: The aim of this study was to identify patient selection, technical treatment, and imaging parameters that predict successful pain relief of osseous metastases after MRI-guided focused US. MATERIALS AND METHODS: This was a secondary analysis of a phase 3 clinical study that included participants who received MRI-guided focused US treatment for painful osseous metastases. Noncontrast CT was obtained before treatment. T2-weighted and T1-weighted postcontrast MRIs at 1.5 T or 3 T were obtained before, at the time of, and at 3 months after treatment. Numerical Rating Scale pain scores and morphine equivalent daily dose data were obtained over a 3-month follow-up period. At the 3-month endpoint, participants were categorized as pain relief responders or nonresponders based on Numerical Rating Scale and morphine equivalent daily dose data. Demographics, technical parameters, and imaging features associated with pain relief were determined using stepwise univariable and multivariable models. Responder rates between the subgroup of participants with all predictive parameters and that with none of the parameters were compared using Fisher exact test. RESULTS: The analysis included 99 participants (mean age, 59 ± 14 years; 56 women). The 3 variables that predicted successful pain relief were energy density on the bone surface (EDBS) (P = 0.001), the presence of postprocedural periosteal devascularization (black band, BB+) (P = 0.005), and female sex (P = 0.02). The subgroup of participants with BB+ and EDBS greater than 5 J/mm2 had a larger decrease in mean pain score (5.2; 95% confidence interval, 4.6-5.8) compared with those without (BB-, EDBS ≤ 5 J/mm2) (1.1; 95% confidence interval, 0.8-3.0; P < 0.001). Participants with all 3 predictive variables had a pain relief responder rate of 93% compared with 0% in participants having none of the predictive variables (P < 0.001). CONCLUSIONS: High EDBS during treatment, postprocedural periosteal devascularization around the tumor site (BB+), and female sex increased the likelihood of pain relief after MRI-guided focused US of osseous metastasis.

Tolerability and Feasibility of X-ray Guided Non-Invasive Ablation of the Medial Branch Nerve with Focused Ultrasound: Preliminary Proof of Concept in a Pre-clinical Model.

Four to six million patients a year in the United States suffer from chronic pain caused by facet joint degeneration. Thermal ablation of the affected facet joint's sensory nerve using radiofrequency electrodes is the therapeutic standard of care. High-intensity focused ultrasound (HIFU) is a novel technology enabling image-guided non-invasive thermal ablation of tissue. Six pigs underwent fluoroscopy-guided HIFU of the medial branch nerve and were followed up for 1 wk (two pigs), 1 mo (two pigs) and 3 mo (two pigs). At the end of each follow-up period, the animals were sacrificed, and targeted tissue was excised and evaluated with computed tomography scans as well as by macro- and micropathology. No significant adverse events were recorded during the procedure or follow-up period. All targets were successfully ablated. X-Ray-guided HIFU is a feasible and promising alternative to radiofrequency ablation of the lumbar facet joint sensory nerve.

Mindfulness with paced breathing reduces blood pressure.

Elevated blood pressure (BP) is a major avoidable cause of premature morbidity and mortality in the United States (US) and worldwide, due primarily to increased risks of stroke as well as myocardial infarction. While there are therapeutic lifestyle changes and adjunctive pharmacologic medications of proven benefit, recent interest has increasingly focused on Complementary and Alternative Medicine, in particular, Mind-Body Interventions. With respect to BP, it is tempting to speculate that mindfulness with paced breathing will have beneficial effects in the short run that may translate into lowered risks of stroke in the long run. Paced breathing is deep diaphragmatic breathing with typical rates equal to or less than 5-7 breaths per minute compared with the usual rate of 12-14. One plausible mechanism of benefit is that paced breathing stimulates the parasympathetic nervous system which alters neuronal function in specific areas of the brain and reduces stress chemicals. The hypothesis that mindfulness with paced slow breathing reduces BP could be directly tested in randomized trials designed a priori to do so. Subsequently, a finding that mindfulness with paced breathing reduces BP would also lead to direct tests in randomized trials of reductions of carotid atherosclerosis and, if so, a larger scale trial to test whether there is a direct impact of mindfulness with paced breathing on reducing the risks of stroke and MI. If rigorous testing of this medical hypothesis led to positive results this would have large and important clinical and policy implications in the US and worldwide.

In vivo measurements of medial branch nerve depth and adjacent osseous structures for ablation of facet-related back pain: Predictors for patient candidacy.

BACKGROUND: Medial branch (MB) targeting during RF ablation for facetogenic back pain is usually performed with flouroscopic guidance yet no specific measurements on the target depth have been published. In order to understand candidacy for other potential ablation methods, we sought to determine the actual MB depth and measurements of adjacent osseous structures. METHODS: CT scans without contrast of the lumbar spine performed in the supine position were retrospectively analyzed in 100 patients. Axial slices less than or equal to 2.5 mm with sagittal and coronal reformations were evaluated. The following distances were measured bilaterally at the L2-L5 levels: The depth from the skin to the MB nerve (anatomic target for RF ablation) at a 15° angulation, the smallest width of the pedicle, and the length, height and width of the transverse process. Age, gender, weight, height, and BMI were correlated with the above measurements. RESULTS: The average distance and 95% CI from skin-to-MB in mm at a 15°angle to the skin increased as the lumbar level increased measuring 64.4 (62.4-66.5) at L2, 72.0 (69.7-74.3) at L3, 79.2 (76.9-81.6) at L4, and 79.1 (76.7-81.5) at L5. The average thickness of the pedicles also increased as the lumbar level increased measuring 9.2 mm at L2 and 16.1 mm at L5. Body weight, lumbar level, and female gender were associated with increased MB depth. Taller stature was associated with more superficial MB depth. We eliminated mild interaction effects between height, weight, and gender by substituting BMI for height and weight without affecting r2. Linear regression revealed the following equation: MB Depth (mm) = 2.2*BMI + 4.9*lumbar vertebral level + 3.6 (if female) - 5.4, which fit the data well (P<0.001, r2 = 0.60). CONCLUSIONS: Our results demonstrate that the MB resides 107 mm or less in depth when measured at a 15° angulation from the skin in > 95% of patients and the distance increases as the lumbar level increases.

Artifact from myomectomy/C-Section on MRI images - what does this mean for MR-guided focused ultrasound candidacy for uterine fibroids?

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) is used for non-surgical treatment of uterine fibroids, often in patients who have had prior myomectomy or Cesarean section. The presence of post-surgical MRI artifacts along the beam path are a common contraindication to MRgFUS treatment. While potential problems arising from superficial cutaneous scars can be circumvented through scar patching and other techniques, deeper artifacts are difficult to bypass. Consequently, many patients with deeper artifacts are often excluded from treatment because of the assumption that these artifacts could deflect the ultrasound beam resulting in off target heating or perturb accurate MR thermometry. We sought to determine if these deep artifacts affect MRgFUS treatment efficacy or safety.Materials and Methods: A search of a MRgFUS center patient database yielded 19 patients with prior uterine surgery who had artifacts along the FUS beam path visible on MRI. Charts, operative reports (when available), screening MRI scans, and MRgFUS treatment scans were reviewed by an experienced MRgFUS treatment physician and artifacts were graded as mild, moderate, or severe.Results: One-way ANOVA showed no significant correlation between artifact severity and percent non-perfused volume (%NPV) (p = .41) or between fibroid size and % NPV (p = .49). There were no adverse events in this patient population except for one case of endometritis that occurred months after the operation, unlikely to be related to the MRgFUS treatments.Conclusion: Patients with uterine fibroids with post-operative susceptibility artifacts in the near-field can be successfully treated with MRgFUS.

Establishing a clinical service for the treatment of osteoid osteoma using magnetic resonance-guided focused ultrasound: overview and guidelines.

Recent studies have demonstrated the effectiveness of magnetic resonance-guided focused ultrasound (MRgFUS) in the treatment of osteoid osteoma (OO), a painful, benign bone tumor. As MRgFUS is a noninvasive and radiation-free treatment, it stands to replace the current standard of care, percutaneous radiofrequency, or laser thermal ablation. Within an institution, creation of a clinical OO MRgFUS treatment program would not only provide cutting edge medical treatment at the current time but would also establish the foundation for an MRgFUS clinical service to introduce treatments currently under development into clinical practice in the future. The purpose of this document is to provide information to facilitate creation of a clinical service for MRgFUS treatment of OO by providing (1) recommendations for the multi-disciplinary management of patients and (2) guidelines regarding current best practices for MRgFUS treatment. This paper will discuss establishment of a multi-disciplinary clinic, patient accrual, inclusion/exclusion criteria, diagnosis, preoperative imaging, patient preparation, anesthesia, treatment planning, targeting and treatment execution, complication avoidance, and patient follow-up to assure safety and effectiveness.

Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results.

BACKGROUND: Pain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases. METHODS: Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher's exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. RESULTS: One hundred forty-seven subjects were enrolled, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day. CONCLUSIONS: This multicenter phase III trial demonstrated that MRgFUS is a safe and effective, noninvasive treatment for alleviating pain resulting from bone metastases in patients that have failed standard treatments.

Leiomyoma shrinkage after MRI-guided focused ultrasound treatment: report of 80 patients.

OBJECTIVE: The purpose of this study was to assess the degree of leiomyoma ablation and shrinkage after MRI-guided focused ultrasound treatment performed according to U.S. Food and Drug Administration protocols for commercial trials. MATERIALS AND METHODS: A total of 147 symptomatic leiomyomas in 80 women (average age, 46 years; range, 34-55 years) were managed with MRI-guided focused ultrasound. The average volume of treated fibroids was 175+/-201 (SD) cm3. Before treatment, T2-weighted MR images in three planes were obtained to measure leiomyoma volume. Immediately after treatment, T1-weighted contrast-enhanced fat-suppressed MR images in three planes were used to measure nonperfused volume ratio. Similar images obtained 6 months after treatment were used to determine leiomyoma shrinkage. Qualitative and quantitative relations between fibroid volume, nonperfused volume ratio at treatment, and 6-month shrinkage were measured. RESULTS: The average nonperfused volume ratio was 55%+/-25% immediately after treatment. Six months after treatment, the average volume of treated fibroids had decreased to 112+/-141 cm3 (n=81) (p<0.0001) with an average volume reduction of 31%+/-28%. A linear regression model showed highly significant correlation between posttreatment nonperfused volume ratio and shrinkage at 6 months (p<0.0001). CONCLUSION: MRI-guided focused ultrasound therapy for leiomyoma can result in nonperfused volume ratio and shrinkage that exceed those in previous clinical trials because the treatment guidelines have been relaxed to allow a greater amount of tissue ablation. The results suggest that a larger nonperfused volume ratio can be achieved, resulting in greater shrinkage and improved relief of symptoms.

Inter- and intrarater reliability in computed axial tomographic grading of splenic injury: why so many grading scales?

OBJECTIVE: After splenic trauma, critical decisions regarding operative intervention are often made with the aid of computed axial tomographic (CT) scan findings. No CT scan-based grading scale has been demonstrated to predict accurately which patients require operative or radiologic intervention for their splenic injuries. We hypothesized that use of the most common grading scale, the American Association for the Surgery of Trauma scale, would be associated with low intra- and interreliability scores. We assessed the ability of experienced trauma radiologists to differentiate grade III from grade IV splenic injuries. METHODS: The films of patients who had undergone abdominal CT scanning before splenectomy for grade III or IV injuries were serially evaluated by four trauma radiology faculty weekly for 3 weeks. We assessed intra- and interrater reliability for grading and for presence of contrast blush. RESULTS: Intrarater reproducibility yielded a weighted kappa score of 0.15 to 0.77. Interrater reliability weighted kappa scores ranged from 0 to 0.84, with a mean value of 0.23. CONCLUSION: CT imaging is not reliable for identifying grades III and IV splenic injury, as experienced radiologists often underestimate the magnitude of injury. Interrater reliability is poor. Factors other than the CT grade of splenic injury should determine whether patients require operative or angiographic therapy.

A prospective randomized study of clinical assessment versus computed tomography for the diagnosis of acute appendicitis.

BACKGROUND: The objective of this study was to determine if routine use of computed tomography (CT) for the diagnosis of appendicitis is warranted. METHODS: During a one-year study period, all patients who presented to the surgical service with possible appendicitis were studied. One hundred eighty-two patients with possible appendicitis were randomized to clinical assessment (CA) alone, or clinical evaluation and abdominal/pelvic CT. A true-positive case resulted in a laparotomy that revealed a lesion requiring operation. A true-negative case did not require operation at one-week follow-up evaluation. Hospital length of stay, hospital charges, perforation rates, and times to operation were recorded. RESULTS: The age and gender distributions were similar in both groups. Accuracy was 90% in the CA group and 92% for CT. Sensitivity was 100% for the CA group and 91% for the CT group. Specificity was 73% for CA and 93% for CT. There were no statistically significant differences in hospital length of stay (CA = 2.4 +/- 3.2 days vs. CT = 2.2 +/- 2.2 days, p = 0.55), hospital charges (CA = 10,728 US dollars +/- 10,608 vs. CT = 10,317 US dollars +/- 7,173, p = 0.73) or perforation rates (CA = 6% vs. CT = 9%, p = 0.4). Time to the operating room was shorter in the CA group, 10.6 +/- 8.4 h vs. CT, 19.0 +/- 19.0 h (p < 0.01). CONCLUSIONS: Clinical assessment unaided by CT reliably identifies patients who need operation for acute appendicitis, and they undergo surgery sooner. Routine use of abdominal/pelvic CT is not warranted. Further research is needed to identify sub-groups of patients who may benefit from CT. Computed tomography should not be considered the standard of care for the diagnosis of appendicitis.