High-frequency (20 MHz) high-intensity focused ultrasound: New Treatment of actinic keratosis, basal cell carcinoma, and Kaposi sarcoma. An open-label exploratory study.

BACKGROUND: Skin cancer is common, growing, challenging, and in need of progress in early-stage treatment. 20 MHz high-intensity focused ultrasound (HIFU) is new and applied to actinic keratosis (AK) and skin cancers for the first time. HIFU of lower frequency is already used in the treatment of internal cancers. MATERIALS AND METHODS: Eight patients with 201 AK lesions, one patient with 7 basal cell carcinomas (reoccurrences after PDT), and one patient with 7 Kaposi sarcoma lesions (4 treated with radiotherapy in the past) were given 1-3 HIFU treatments. Twenty megahertz HIFU was dosed as 150 ms at 0.6-1.2 J/shot applied to target lesions. Probes with different target depths were available. The preferred shot energy and focal depth in AK were 0.9 J and 1.3 mm. A "Sandwich" strategy with HIFU applied in two depths were tried in cancers. The follow-up period was 3-6 months. RESULTS: All AK cleared except 5, giving a cure rate of 97%. Post-treatment lesion healed in 1-2 weeks with no scar. VAS pain was from 1 to 8, and in any case less than experienced with previous PDT. In both basal cell carcinoma (BCC) and sarcoma, healing was confirmed by histological verification. DISCUSSION/CONCLUSION: 20 MHz HIFU was an effective and safe treatment of AK. This new treatment, applicable to any anatomical site, has promising advantages relative to PDT and has the potential to replace or supplement PDT in future. Case-observations indicated that HIFU can be useful in skin cancers as well.

High-frequency (20 MHz) high-intensity focused ultrasound: New ablative method for color-independent tattoo removal in 1-3 sessions. An open-label exploratory study.

BACKGROUND: High-intensity focused ultrasound (HIFU) operating at 20 MHz is new and potentially applicable to ablative tattoo removal. The method was documented safe and rational in preclinical testing. MATERIALS AND METHODS: High-intensity focused ultrasound was introduced to subjects when lasers and dermatome shaving had failed or caused side effects. Transducers with focal depths between 1.1 mm and 1.7 mm in the skin were used, and settings of 0.4-1.2 J/shot at pulse durations of 150 ms were applied. Tattoos were covered with synergistic "shoulder-by-shoulder" focused ultrasound shots. Effectiveness and side effects were measured. RESULTS: Twenty-two subjects with 67 tattoos were treated. 62% benefitted (19% cleared, 43% partially cleared), and 28% had minor effect. VAS pain was 5-6 versus 7-9 with previous lasers removal. Wound healing was longer after HIFU ablation (1-3 months). 57% of subjects had no scar or minor visible changes of skin surface markings only, while 19% had moderate or major skin thickening. Hypertrophic scar or keloid scars were not observed. DISCUSSION/CONCLUSION: High-intensity focused ultrasound was effective in removal of difficult tattoos of any color where Nd:YAG lasers had failed. The method only needs 1-3 sessions. As an ablative method, the wound healing period is longer than with laser removal and needs attention. Focused ultrasound can be used as a first-line treatment of smaller tattoos independent of color, and second line when Nd:YAG lasers have failed or caused problems. The operator shall be qualified, as with lasers.

High-frequency (20 MHz) high-intensity focused ultrasound system for dermal intervention: A 12-week local tolerance study in minipigs.

BACKGROUND: High-intensity focused ultrasound (HIFU) operating at 20 MHz is new and applicable to skin. Details of use and instrumentation are not documented. MATERIALS AND METHODS: A GLP compliant 12-week study of Göttingen minipigs (n = 3) was undertaken. Effects of HIFU treatment at different focal depths, energy levels and field size (single shot vs 5 × 5 multiple shots) were studied. Clinical scoring and histology of treated sites were made. RESULTS: High-intensity focused ultrasound showed instant and initial effects with wheal and flare responses followed by delayed inflammatory reactions associated with outer skin necrosis, depending on energy dose. HIFU treatment was tunable in the range 0.3-1.5 J, ablative at higher energy level. Transducers with deeper focal points gave more profound effects, while epidermal effects were comparable. Multiple doses of 5 × 5 shots produced stronger reactions than single dose indicating that nearby applied shots were synergistic. Recovery from single doses was faster than in multidose areas. Clinical scarring at the end point was not seen despite occasional fibrous change of dermis. Findings illustrated intended therapeutic use; no special safety issues of concern were raised. CONCLUSION: The new 20 MHz HIFU was reproducible, tunable and produced targeted effects in the outer skin, for example instant wheal and flare followed by inflammation and possibly necrosis depending on energy setting. Reactions recovered during the study with only minor findings at study end. No special safety concerns were raised. The method can be controlled and modulated, and it is ready for clinical testing of dermatological disease indications including conditions presently treated with lasers.

High-frequency (20-MHz) high-intensity focused ultrasound (HIFU) system for dermal intervention: Preclinical evaluation in skin equivalents.

BACKGROUND: High-intensity focused ultrasound (HIFU) for non-invasive treatment of a range of internal pathologies including cancers of major organs and cerebral pathologies is in exponential growth. Systems, however, operate at relatively low frequencies, in the range of 200-2000 kHz as required for deep axial penetration of the body. HIFU utilizing frequencies in excess of 15 MHz has so far not been explored, but presents an opportunity to extend the HIFU modality to target specific dermal lesions and small animal research. MATERIALS AND METHODS: A new 20-MHz HIFU system (TOOsonix ONE-R) with narrow focus corresponding to the dermis was studied in acoustic skin equivalents, for example, in a tissue-mimicking gel and in bovine liver. HIFU lesion geometry, depth, and diameter were determined. The temperature increase in the focal point was measured as a function of acoustic power and the duration of HIFU exposure. RESULTS: The system produces highly reproducible ultrasound lesions with predictable and configurable depths of 1-2 mm, thus corresponding to the depth of the human dermis. The lesion geometry was elongated triangular and sized 0.1-0.5 mm, convergent to a focal point skin deep. Focal point temperature ranged between 40 and 90°C depending on the chosen setting. Observations were confirmed ex vivo in bovine liver and porcine muscle. Variation of acoustic power and duration of exposure produced linear effects in the range of the settings studied. Thus, effects could be adjusted within the temperature interval and spatial field relevant for clinical therapy and experimental intervention targeting the dermal layer of human skin. CONCLUSION: The tested 20-MHz HIFU system for dermal applications fulfilled key prerequisite of narrow-field HIFU dedicated to cutaneous applications regarding reproducibility, geometry, and small size of the applied ultrasound lesions. Controlled adjustment of acoustic lesions within the temperature range 40-90°C qualifies the system for a range of non-ablative and ablative applications in dermatological therapy.

Recalcitrant Basal Cell Carcinoma after Grenz Ray Therapy: Introduction of High-Intensity Focused Ultrasound for Minimally Invasive Management.

Introduction: Grenz ray therapy popular in dermatology decades ago causes multiple and recalcitrant skin cancer in the treated field many years later. The treatment of choice is surgical excision, but limitations especially disfiguring scarring are a major challenge. We introduce 20 MHz high-intensity focused ultrasound (HIFU) as a new therapy overcoming the limitations of excisional surgery. Case Presentation: A 66-year-old female, who in the 1980s had received several grenz ray treatments of the scalp, developed multiple basal cell carcinomas in the field. She had over 30 excisional surgeries including Mohs surgery in the past with many local complications but, nevertheless, recurrent cancers. HIFU treatments applied to eight basal cell carcinomas and two precancerous lesions resulted in complete clearing at 12-month control, but one recurrence after 15 months. Conclusion: The HIFU treatment is convenient, with very few complications, and applicable to field eradication of skin premalignancies and malignancies. HIFU may fill out a hitherto unmet need of both preventive and curative treatment with better long-term control of patients with recalcitrant skin cancer after grenz ray given in the past. HIFU is a new potentially important therapeutic modality in skin oncology, combining curative treatment, field eradication, and prevention in one procedure through treatment of lesions in different states of progression.

Head-to-Head Comparison of Acoustic Properties of Lead-Free and PZT-Based HIFU Transducers Operating at 12 MHz.

A direct comparison of performance and acoustic properties of high-intensity focused ultrasonic transducers utilizing lead-free (sodium bismuth titanate-NBT) and lead-based (lead zirconate titanate-PZT) piezoceramics is discussed. All transducers operate at 12 MHz at third harmonic frequency, having an outer diameter of 20 mm, a central hole of 5 mm in diameter, and a radius of curvature of 15 mm. The electroacoustic efficiency determined by a radiation force balance is evaluated in a range of input power levels up to 15 W. Schlieren tomography as well as hydrophone measurements are used for evaluation of the acoustic field distribution. It is found that the average electroacoustic efficiency of NBT-based transducers is approximately 40%, while it is around 80% in the PZT-based devices. NBT devices show significantly higher inhomogeneity of the acoustic field under schlieren tomography compared to PZT devices. From pressure measurements in the prefocal plane, it was found that the inhomogeneity could be attributed to depoling of significant areas of the NBT piezo-component during the fabrication process. In conclusion, PZT-based devices performed significantly better than those using lead-free material. However, the NBT devices show promise for this application and their electroacoustic efficiency as well as the uniformity of the acoustic field could be improved by employing a low-temperature fabrication process or repoling after processing.

High Intensity Focused Ultrasound (20 MHz) and Cryotherapy as Therapeutic Options for Granuloma Annulare and Other Inflammatory Skin Conditions.

INTRODUCTION: In dermatology, inflammatory skin conditions impose a substantial burden worldwide, with existing therapies showing limited efficacy and side effects. This report aims to compare a novel immunological activation induced by hyperthermic 20 MHz high intensity focused ultrasound (HIFU) with conventional cryotherapy. The bioeffects from the two methods are initially investigated by numerical models, and subsequently compared to clinical observations after treatment of a patient with the inflammatory disease granuloma annulare (GA). METHODS: Clinical responses to moderate energy HIFU and cryotherapy were analysed using numerical models. HIFU-induced pressure and heat transfer were calculated, and a three-layer finite element model simulated temperature distribution and necrotic volume in the skin. Model output was compared to 22 lesions treated with HIFU and 10 with cryotherapy in a patient with GA. RESULTS: Cryotherapy produced a necrotic volume of 138.5 mm3 at - 92.7 °C. HIFU at 0.3-0.6 J/exposure and focal depths of 0.8 or 1.3 mm generated necrotic volumes up to only 15.99 mm3 at temperatures of 68.3-81.2 °C. HIFU achieved full or partial resolution in all treated areas, confirming its hyperthermic immunological activation effect, while cryotherapy also resolved lesions but led to scarring and dyspigmentation. CONCLUSION: Hyperthermic immunological activation of 20 MHz HIFU shows promise for treating inflammatory skin conditions as exemplified by GA. Numerical models demonstrate minimal skin necrosis compared to cryotherapy. Suggested optimal HIFU parameters are 1.3 mm focal depth, 0.4-0.5 J/exposure, 1 mm spacing, and 1 mm margin. Further studies on GA and other inflammatory diseases are recommended.

Healing Process after High-Intensity Focused Ultrasound Treatment of Benign Skin Lesions: Dermoscopic Analysis and Treatment Guidelines.

Background: High-Intensity Focused Ultrasound (HIFU) has emerged as a precise and non-invasive modality for tissue ablation and healing. This study presents a detailed dermoscopic analysis of skin healing post-High-Intensity Focused Ultrasound (HIFU) treatment, focusing on common benign skin lesions, such as seborrheic keratosis, sebaceous hyperplasia, vascular lesions, and sebaceous nevi. Methods: Prior to HIFU treatment, a comprehensive assessment was conducted, integrating ultrasound scanning and clinical evaluations. The TOOsonix System ONE-M was employed for HIFU treatments, with parameters tailored to each lesion type. Results: A common pattern observed across all lesions includes initial whitening post treatment, followed by scab formation and the development of a pink area with reparative vessels. This study, however, highlights distinct differences in fibrosis patterns and healing timelines across different lesion types. Each lesion type exhibited unique fibrosis patterns post treatment. Flatter variants of seborrheic keratosis healed within a month, displaying hypopigmentation and reparative vessels, alongside a distinct lattice fibrosis pattern in more verrucous forms, which took about two months to heal. Sebaceous hyperplasia, characterized by rapid healing within three weeks, demonstrated fibrosis with pink areas and perpendicular white lines, concluding with a slight depression. Vascular lesions varied in healing time based on depth, with superficial ones showing whitening and crust formation, while deeper lesions had vessel occlusion and size reduction accompanied by concentric fibrotic bands. Sebaceous nevi presented the longest healing duration of three months, characterized by amorphous white-gray structures, scab formation, and the emergence of pink areas with branching vessels, leading to clear skin with reduced white lines. Conclusions: in conclusion, this meticulous clinical evaluation highlights the unique healing characteristics and timelines for each skin lesion type treated with HIFU. These insights are invaluable for optimizing follow-up assessments, identifying potential complications, and refining treatment protocols. By providing detailed insights into the healing timelines and patterns for different types of lesions, patients can be better informed about their post-treatment journey.

Treatment of Cutaneous Neurofibromas in Patients with Neurofibromatosis Type 1.

Neurofibromatosis type 1 is a genetic disorder impacting approximately 2.5 million people worldwide, often leading to development of numerous benign yet disfiguring cutaneous neurofibromas (cNF). Removal of cNF is limited to excision or laser ablation with common post-operation complications and scarring. The current case explores a new approach to removal or reduction of cNF by a minimally invasive and pain-reduced treatment modality. A 40-year-old female patient with numerous cNF across her body underwent a single treatment using a 20 MHz dermatologically focused ultrasound device on seven selected cNF on the upper back. Each cNF was treated in a single session of 20-60 s without anesthesia due to manageable pain. Only one minimal adverse reaction in the form of dyspigmentation in a single treated tumor was noted from treatment or during the healing of a thin scab that formed on each cNF a few days after treatment. At the 12-month follow-up, four out of seven treated cNF showed full remission, two showed partial or significant reduction in tumor volume, while two did not respond to treatment. The reason for the variability is not fully understood, but speculations include difference in tissue content, e.g., due to tumor age. The method is concluded to be a promising candidate for a new safe and minimally invasive treatment that can potentially be used for single-session removal/reduction of a large number of cNF. Further research should focus on refining treatment parameters and strategies to enhance response predictability.

Strongly Focused HIFU Transducers With Simultaneous Optical Observation for Treatment of Skin at 20 MHz.

High-intensity focused ultrasound (HIFU) transducers are proposed as a new treatment modality for dermatology. The shape and size of pressure fields generated by strongly focused transducers with an f-number equal to 0.75 operating at frequencies up to 20 MHz are analyzed analytically using the Lucas-Muir model and numerically with the wide-angle Khokhlov-Zabolotskaya-Kuznetsov method. The modeling results under quasi-linear conditions are compared against measurements performed in an acoustic tank with the aid of a fiberoptic hydrophone. The size of the focal zone expressed by their depth of focus and focal diameter is found to be directly controlled by their operating frequency and f-number. Devices manufactured for an operating frequency of 20 MHz are characterized by their 6 dB depth of focus of 490 µm and focal diameter of 80.6 µm. The devices are further studied at high power levels using a polyacrylic tissue-mimicking phantom. The devices are equipped with an optical observation system allowing simultaneous treatment and observation of the skin surface. In comparison to conventional cosmetic applications of HIFU, the devices analyzed are concluded to be ideal for treatment of precisely selected and confined layers of the human skin.

Treatment of superficial benign vascular tumors by high intensity focused ultrasound: Observations in two illustrative cases.

BACKGROUND: Existing therapeutic methods for reduction or removal of superficial vascular malformations and tumors have high risks of scarring and other complications that result in aesthetic appearance less favorable than the baseline. Patients are often cautioned against intervention, which can lead to psychosocial problems and low self-esteem. Improved treatment modalities are therefore relevant from both medical and aesthetic perspectives. METHODS: Two volunteer subjects were treated with a medical 20 MHz high intensity focused ultrasound device developed for dermatological conditions. One patient was given three treatments to remove a superficial congenital hemangioma on the left middle cheek. The other patient was given a single treatment to remove seven cherry angiomas on the thighs. Handpieces with nominal focal depths of 0.8 - 1.8 mm below the skin surface were used to administer acoustic energy of 1.1 - 1.2 J/dose. An integrated dermoscope in the handpiece was used to monitor the treatment in real-time. RESULTS: During treatment, blood in the capillary network of the lesions was coagulated immediately, and capillary walls were collapsed due to the thermal and mechanical effects of the high intensity focused ultrasound. During the healing phase, the areas regenerated a normal skin structure with very limited scar or dyspigmentation. At follow-up, a clear aesthetic improvement was observed over the baseline for all treated targets with the exception of two cherry angiomas, where focal depth and/or dose coverage had not been optimal. CONCLUSION: High intensity focused ultrasound is concluded to be a safe and efficient skin treatment for benign superficial vascular malformations and tumors.

Treatment of Condylomata Acuminata Using a New Non-Vapor-Generating Focused Ultrasound Method following Imiquimod 5% Cream.

Condylomata acuminata is the most common sexually transmitted disease in the world. Physical treatments include excision, cryotherapy, electrocautery and ablative CO2, and Nd:YAG laser ablation, while topical treatments include imiquimod immunotherapy and antimitotic podophyllotoxin or sinecatechins. Efficacies of all methods are low, and recurrences are very common. A new combined method is presented as a single case in a 25-year-old male patient diagnosed with numerous condylomas on the penis, scrotum, and lower abdomen. The treatment consisted of a 7-week topical monotherapy using 5% imiquimod cream followed by local treatment with 20 MHz high-intensity focused ultrasound on remaining recalcitrant lesions. Results showed resolution of approximately 70% of the condylomas after imiquimod treatment, and full resolution of all recalcitrant condylomas treated subsequently with high-intensity focused ultrasound. The method is concluded to be safe and effective and, furthermore, presents a new physical method that does not generate airborne infectious human papillomavirus particles that pose a health risk for the medical team performing therapy. Further studies in larger populations are recommended to confirm the combined efficacy of the proposed method.

Treatment of Seborrheic Keratosis by High Frequency Focused Ultrasound - An Early Experience with 11 Consecutive Cases.

PURPOSE: High intensity focused ultrasound operating at 20 MHz has been demonstrated as a safe and efficient treatment modality for a range of dermatological indications. The method is potentially also applicable to removal of seborrheic keratosis. PATIENTS AND METHODS: A total of 54 seborrheic keratoses in 11 volunteer subjects (8 women and 3 men, average age 51.5 ± 13.2 years) were treated in a single session with a medical 20 MHz high intensity focused ultrasound device developed for dermatological conditions. Handpieces with nominal focal depths of 0.8 mm below the skin surface were used to administer acoustic energy of 0.99-1.2 J/dose. An integrated dermoscope in the handpiece was used to monitor the treatment in real-time. Treatment efficacy and side-effects were assessed directly after treatment and at follow-up 4-15 weeks after treatment. RESULTS: The treatment showed positive results in 96.3% of the cases. About 68.5% of the cases were classified as complete response and 27.8% of the cases as partial response. Two cases (3.7%) did not respond to treatment and were classified as stable condition. No subjects experienced worsening of their condition, and no treatment received the classification of progressive condition. Side effects were primarily redness in the treatment area due to superficial telangiectasia, mild scarring, and persisting and slow-healing lichen planus-like keratosis. No adverse events were observed. CONCLUSION: HIFU is concluded to be a safe and efficient skin treatment for seborrheic keratoses. It has advantages over conventional treatments that can lead to pain during treatment and scarring after healing.

Lead-Free HIFU Transducers.

High-intensity focused ultrasound transducers operating at 4 MHz based on lead-free piezoceramics from the sodium bismuth titanate (NBT) family are described. First, the piezoelectric material (Pz12X) is evaluated from the standpoint of transducer design and its important characteristics, including temperature dependance of several parameters such as dielectric and mechanical coefficients. Then, the performance of six transducers of the same design is evaluated in terms of electro-acoustic efficiency and its dependency on the operating acoustic power level up to 30 W. Overall, the initial electro-acoustic efficiency of three independent transducers is approximately 50% at low acoustic power levels and slightly drops down to 42% as the input electric power reaches 10 W. This process is stable and fully reversible. Moreover, the stability of electro-acoustic efficiency over extended power burst cycling is studied using another two transducers up to 95 × 103 power bursts of 250-ms duration and acoustic power of 10 W. This protocol is beyond the typical clinical use of similar devices in practice. No significant changes in electro-acoustic performance are noted. Additionally, the input electric power and the output acoustic power, together with the temperature of the piezoelectric component, are evaluated simultaneously over the period of one power burst. It is found that the maximum operating temperature over a high-input electric power burst of 600 J is below 60°C, which defines the operational limit for such devices, as the de-poling temperature of the lead-free material is around 85°C. It is found that the lead-free material from the NBT family is also a promising alternative to lead-based PZT-type materials in high-power therapeutic ultrasound.

High-Frequency (20 MHz) Focused Ultrasound: A Novel Method for Noninvasive Tattoo Removal.

Alternatives or complements to laser tattoo removal are needed. Laser removal requires 8-12 sessions and can easily take longer than a year. Some colors cannot be removed, and scars may appear. Applied to allergic reactions in red tattoos, lasers can boost the allergy. A recently developed 20 MHz high-intensity focused ultrasound (HIFU) is introduced as a complementary method to lasers, but also as a stand-alone treatment for selected groups. 20 MHz HIFU allows for application of high-power ultrasound energy to very small focal targets in the dermis, and thereby precise confinement of thermal lesions in the outer layers of human skin, precisely where tattoo inks are deposited. HIFU treatment is "color blind" and can target any type of colored pigment in the dermis. It produces a controlled thermal lesion (up to 65°C) with superficial necrosis followed by an eschar with embedded tattoo pigment. This eschar, containing the tattoo pigment, is discharged over some weeks, and finally replaced by healed skin. HIFU can efficiently remove tattoos of any color in only 1-3 sessions. It can be applied to tattoos when lasers fail to produce efficient removal. The types of side effects are the same as with lasers. The operator shall be trained and knowledgeable. 20 MHz HIFU can furthermore be used in clinical and esthetic dermatology for various other applications, and a range of applications are open in clinical dermatology.

Removal of Common Warts by High-Intensity Focused Ultrasound: An Introductory Observation.

Therapies of common warts are cumbersome and not very effective. Recurrences are common. A new 20 MHz high-intensity focused ultrasound (HIFU) method is introduced as a new potential treatment modality. With HIFU, selected targets in the epidermis and dermis can be treated with full control of the depth and position of the ultrasound lesion and the energy applied to the target. The treatment can be monitored directly in real-time via an integrated dermoscope in the ultrasound probe. Two warts were treated with 8-10 shoulder-by-shoulder treatment doses, focal depth 1.3 mm, and 1.2 J/dose. Pretreatment ultrasound B-mode scanning had shown the thickness and depth of the warts. The treated areas developed a dry wound covered by a crust over the next 1-2 days. After 2 weeks the skin was healed, with no wart and no scar. Observation showed no reoccurrence. HIFU has future potential for treatment of common warts and flat warts, and a broad range of skin lesions being logic further candidates for targeted ablative treatment. One single treatment may suffice. It is, therefore, a new modality in dermatology with a large range of indications.