Cryoablation of Primary Breast Cancer in Patients Ineligible for Clinical Trials: A Multiinstitutional Study.

BACKGROUND. Breast cancer cryoablation clinical trials have strict inclusion criteria that exclude patients with potentially treatable disease. OBJECTIVE. The purpose of this study was to evaluate the safety and outcomes of breast cancer cryoablation without surgical excision in patients ineligible for prospective cryoablation clinical trials due to unfavorable patient or tumor characteristics. METHODS. This retrospective study included women who underwent cryoablation of biopsy-proven unifocal primary breast cancer with locally curative intent, without surgical excision, despite being ineligible for (and thus excluded from) cryoablation clinical trials, across seven institutions between January 1, 2000, and August 26, 2021. Adverse events (AEs) were recorded. Cryoablation procedures were classified as technically successful if they were not prematurely terminated and achieved intended treatment parameters and if the first follow-up imaging examination showed no evidence of residual disease. The results of follow-up biopsies were recorded. Ipsilateral breast tumor recurrences (IBTRs) diagnosed during follow-up were identified and classified as true recurrence or new primary disease. A competing-risk model was used to estimate the cumulative incidence of IBTR accounting for death before IBTR as a competing risk. RESULTS. The final study sample included 112 patients (median age, 71 years). A total of seven of 112 (6.3%) patients had a minor AE; no moderate or major AEs occurred. A total of 110 of 112 cryoablation procedures (98.2%) were technically successful. During a median follow-up of 2.0 years, 22 of 110 patients (20.0%) underwent biopsy for suspicious imaging findings in the ipsilateral breast, which yielded benign concordant findings in nine of 22 patients (40.9%) and IBTR in 12 of 22 patients (54.5%). Overall, 12 of 110 patients (10.9%) experienced IBTR, including seven with true recurrence and five with new primary disease; three of 12 patients (25.0%) with IBTR had received earlier adjuvant or neoadjuvant therapy. When death was accounted for as a competing risk, the cumulative incidence of IBTR was 5.3%, 12.2%, and 18.2% at 1, 2, and 3 years, respectively. CONCLUSION. In select individuals with unfavorable patient or tumor characteristics, breast cancer cryoablation provides a safe alternative to surgery and has good outcomes. These findings may be particularly relevant in patients who are also poor surgical candidates. CLINICAL IMPACT. Breast cancer cryoablation can be safely applied in a larger patient populations than those defined by clinical trial inclusion criteria.

Generating and monitoring mild hyperthermia using a ring array ultrasound transducer.

OBJECTIVE: To demonstrate the feasibility of using a ring array ultrasound (US) transducer, guided by ultrasound tomography (UST), for generating and monitoring mild hyperthermia (MHTh). METHODS: In silico and in vitro experiments were designed to evaluate the efficacy of a ring array US transducer for generating MHTh and monitoring changes in temperature. In a series of in silico studies, we compared the acoustic focal profiles produced by a ring array US transducer transmitting at different frequencies and further investigated the effectiveness of UST-guidance in implementing aberration correction to enhance the focal profile. In vitro experiments evaluated the capability of using a ring array US transducer to generate and maintain MHTh and the accuracy of using UST to monitor temperature changes. RESULTS: The simulations demonstrated that a ring array US transducer achieves symmetrical and localized acoustic focusing. In a heterogenous tissue model, a ring array US transducer achieved a superior acoustic focus by implementing aberration correction with guidance from UST. In vitro experiments demonstrated the capability of a ring array US transducer to generate MHTh in a tissue-mimicking phantom in an average of 117 ± 18 s and subsequently maintain MHTh. Lastly, a ring array US transducer utilized UST to track temperature changes in a preheated water-filled inclusion while it passively cooled from 45 °C to 25 °C, with a maximum error of 0.58 °C. CONCLUSION: A ring array US transducer can noninvasively generate and monitor MHTh, overcoming many limitations of current clinical systems. The closed geometry of the transducer is optimal for acoustic focusing and UST-guidance allows for improved aberration correction in a heterogenous medium. Utilizing UST thermometry with the same ring array US transducer will allow for implementing an image-guided, temperature-controlled, all-acoustic MHTh system.

Methylene Blue/Collagen Mixture for CT-Guided Presurgical Lung Nodule Marking: High Efficacy and Safety.

PURPOSE: To assess outcomes of computed tomography (CT)-guided methylene blue/collagen marking of preoperative lung nodules before video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracic surgery (RATS). MATERIALS AND METHODS: A retrospective cohort study assessing 25 methylene blue/collagen solution CT-guided lung nodule localization procedures on 26 nodules in 25 patients was performed. The procedures were performed by a fellowship-trained radiologist 1-2 hours before scheduled surgery under local anesthesia. Approximately 4-6 ml of methylene blue/collagen solution was injected in a perinodular location under CT guidance with a 19-gauge trocar needle and along the track to the visceral pleural surface. Post-procedural CT images confirmed appropriate lung nodule location marking. RESULTS: Perinodular CT-guided trocar needle placement was achieved in all marking procedures (n = 26/26). Increased consolidation near the target nodule was also demonstrated in all patients on the post-procedural localized CT scans. One patient with moderate emphysema developed a small to moderate-sized pneumothorax (∼20%-30%), and an 8-Fr thoracentesis catheter was placed under CT guidance before surgery. There was no bleeding or hemoptysis in any patient. Methylene blue/collagen solution was readily visible by the thoracic surgeon in association with all target nodules. One patient required conversion to open procedure due to the proximal portion of the right lower lobe pulmonary artery segmental branch. Of the 26 identified nodules, pathology specimens confirmed the adequacy of nodule resection in all cases. CONCLUSIONS: Preoperative CT-guided methylene blue/collagen solution injection offers a safe and highly effective technique for marking subpleural lung nodules undergoing VATS or RATS.

Percutaneous Cryoablation of Renal Tumors: Is It Time for a New Paradigm Shift?

PURPOSE: To retrospectively assess long-term outcomes of percutaneous renal cryoablation, including factors affecting complications and local recurrence rates. MATERIALS AND METHODS: A total of 357 computed tomographic (CT) fluoroscopy-guided percutaneous cryoablation procedures were performed for 382 masses in 302 outpatients; 347 were biopsy-proven renal-cell carcinoma (RCC) or Bosniak category > III masses (n = 28). Benign pathologic conditions (n = 18) or metastatic non-RCC disease (n = 17) were included to analyze procedural complication rate, but recurrence rates, tumor staging, and nephrometry score were limited to RCCs. The average tumor diameter was 2.9 cm (range, 1-10.3 cm), and median nephrometry score for RCC was 8 (mean, 7.4). Protection of adjacent vital structures was performed in 34% of procedures (n = 121), and ureteral stent placement was performed for 9.2% (n = 33). All major complications were graded per surgical Clavien-Dindo criteria. RESULTS: The average CT-visible cryoablation zone diameter was 5 cm (range, 2.5-10.5 cm). Grade ≥ 3 complications occurred in 2.8% of procedures (n = 10), and appeared related to only high nephrometry scores (P = .0086) and larger tumors (P = .0034). No significant changes in renal function before and after the procedure were noted (P = .18). At a mean follow-up of 31.8 months, the local tumor recurrence rate was 3.2% (11 of 347) for RCC, and no significant difference was noted between tumors larger or smaller than 3 cm (P = .15). The difference reached significance only among the small number of stage ≥ T2 RCC tumors (P = .0039). CONCLUSIONS: Long-term follow-up of percutaneous renal cryoablation demonstrates low recurrence rates with preserved renal function, even for patients with high nephrometry scores and body mass index, assuming thorough cytotoxic technique and protection measures.

Cryoablation of Abdominal Wall Endometriosis: A Minimally Invasive Treatment.

OBJECTIVE: The objective of this study is to present cryoablation as a minimally invasive definitive treatment for abdominal wall endometriosis. We describe our experience with the outpatient application of cryoablation to treat symptomatic abdominal wall endometriosis in three patients. CONCLUSION: This feasibility study shows that minimally invasive cryoablation treated abdominal wall endometriosis in three patients and provided a prompt clinical response.

Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-clip hypertensive rats.

Renal artery stenosis is increasing in prevalence. Angioplasty plus stenting has not proven to be better than medical management. There has been a reluctance to use available denervation methodologies in this condition. We studied conscious, chronically instrumented, two-kidney, one-clip (2K-1C) Goldblatt rats, a model of renovascular hypertension, to test the hypothesis that renal denervation by cryoablation (cryo-DNX) of the renal nerve to the clipped kidney decreases mean arterial pressure (MAP), plasma and tissue ANG II, and contralateral renal sympathetic nerve activity (RSNA). Five-week-old male Sprague-Dawley rats underwent sham (ShC) or right renal artery clipping (2K-1C), placement of telemetry transmitters, and pair-feeding with a 0.4% NaCl diet. After 6 wk, rats were randomly assigned to cryo-DNX or sham cryotreatment (sham DNX) of the renal nerve to the clipped kidney. MAP was elevated in 2K-1C and decreased significantly in both ShC cryo-DNX and 2K-1C cryo-DNX. Tissue norepinephrine was ∼85% lower in cryo-DNX kidneys. Plasma ANG II was higher in 2K-1C sham DNX but not in 2K-1C cryo-DNX vs ShC. Renal tissue ANG II in the clipped kidney decreased after cryo-DNX. Baseline integrated RSNA of the unclipped kidney was threefold higher in 2K-1C versus ShC and decreased in 2K-1C cryo-DNX to values similar to ShC. Maximum reflex response of RSNA to baroreceptor unloading in 2K-1C was lower after cryo-DNX. Thus, denervation by cryoablation of the renal nerve to the clipped kidney decreases not only MAP but also plasma and renal tissue ANG II levels and RSNA to the contralateral kidney in conscious, freely moving 2K-1C rats.

Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes.

Breast Tomographic Ultrasound: The Spectrum from Current Dense Breast Cancer Screenings to Future Theranostic Treatments.

This review provides unique insights to the scientific scope and clinical visions of the inventors and pioneers of the SoftVue breast tomographic ultrasound (BTUS). Their >20-year collaboration produced extensive basic research and technology developments, culminating in SoftVue, which recently received the Food and Drug Administration's approval as an adjunct to breast cancer screening in women with dense breasts. SoftVue's multi-center trial confirmed the diagnostic goals of the tissue characterization and localization of quantitative acoustic tissue differences in 2D and 3D coronal image sequences. SoftVue mass characterizations are also reviewed within the standard cancer risk categories of the Breast Imaging Reporting and Data System. As a quantitative diagnostic modality, SoftVue can also function as a cost-effective platform for artificial intelligence-assisted breast cancer identification. Finally, SoftVue's quantitative acoustic maps facilitate noninvasive temperature monitoring and a unique form of time-reversed, focused US in a single theranostic device that actually focuses acoustic energy better within the highly scattering breast tissues, allowing for localized hyperthermia, drug delivery, and/or ablation. Women also prefer the comfort of SoftVue over mammograms and will continue to seek out less-invasive breast care, from diagnosis to treatment.

Percutaneous image-guided cryoablation of painful metastases involving bone: multicenter trial.

BACKGROUND: This study sought to describe the results of a single-arm multicenter clinical trial using image-guided percutaneous cryoablation for the palliation of painful metastatic tumors involving bone. METHODS: Over a 44-month period, 61 adult patients with 1 or 2 painful bone metastases with a score of 4 or more on a scale of 0 to 10 (≥4/10) worst pain in a 24-hour period who had failed or refused conventional treatment were treated with percutaneous image-guided cryoablation. Patient pain and quality of life was measured using the Brief Pain Inventory prior to treatment, 1 and 4 days after the procedure, weekly for 4 weeks, and every 2 weeks thereafter for a total of 6 months. Patient analgesic use was also recorded at these same follow-up intervals. Complications were monitored. Analysis of the primary endpoint was undertaken via paired comparison procedures. RESULTS: A total of 69 treated tumors ranged in size from 1 to 11 cm. Prior to cryoablation, the mean score for worst pain in a 24-hour period was 7.1/10 with a range of 4/10 to 10/10. At 1, 4, 8, and 24 weeks after treatment, the mean score for worst pain in a 24-hour period decreased to 5.1/10 (P < .0001), 4.0/10 (P < .0001), 3.6/10 (P < .0001), and 1.4/10 (P < .0001), respectively. One of 61 (2%) patients had a major complication with osteomyelitis at the site of ablation. CONCLUSIONS: Percutaneous cryoablation is a safe, effective, and durable method for palliation of pain due to metastatic disease involving bone.

Soft-tissue cryoablation in diffuse locations: feasibility and intermediate term outcomes.

PURPOSE: To assess whether diverse tumor location(s) show differences in percutaneous cryoablation (PCA) outcomes of cancer control, morbidity, and ablation volume reduction for many soft-tissue tumor types. MATERIALS AND METHODS: A total of 220 computed tomography (CT)- and/or ultrasonography-guided percutaneous cryotherapy procedures were performed for 251 oligometastatic tumors from multiple primary cancers in 126 patients. Tumor location was grouped according to regional sites: retroperitoneal, superficial, intraperitoneal, bone, and head and neck. PCA complications were graded according to Common Terminology Criteria for Adverse Events (version 4.0). Local tumor recurrence and involution were calculated from ablation zone measurements, grouped into 1-, 3-, 6-, 12-, 18-, and 24-month (or later) statistical bins. RESULTS: Tumor and procedure numbers for each site were 75 and 69 retroperitoneal, 76 and 62 superficial, 39 and 32 intraperitoneal, 34 and 34 bone, and 27 and 26 head and neck. Average diameters of tumor and visible ice during ablation were 3.4 and 5.5 cm, respectively. Major complications (ie, grade >3) attributable to PCA occurred after five procedures (2.3%). At 11 months average follow-up (range, 0-82 mo), a 10% total recurrence rate (26 of 251) was noted; three occurred within the ablation zone, for a local progression rate of 1.2%. Average time to recurrence was 4.9 months, and, at 21 months, the initial ablation zone had reduced in volume by 93%. CONCLUSIONS: CT-guided PCA is a broadly safe, effective local cancer control option for oligometastatic disease with soft-tissue tumors in most anatomic sites. Other than bowel and nerve proximity, PCA also shows good healing if proper visualization and precautions are followed.

Knowledge of breast density and awareness of related breast cancer risk.

Little is known about women's knowledge of breast density or between-race differences in this knowledge. In the current study, we examined knowledge of breast density and awareness of its role as a breast cancer risk factor among women who had previously taken part in a breast imaging study. Seventy-seven women (54.5 % Black) returned a survey assessing perceptions and accuracy of breast density knowledge, knowledge of one's own breast density, and breast cancer risk awareness. White women had greater perceived knowledge of breast density compared to Black women; however, differences in the accuracy of definitions of breast density were due to education. Black women were less likely to know how dense their own breasts were. Black and White women both lacked awareness that having dense breast increased breast cancer risk. The results highlight the need to disseminate information regarding breast density to women, while ensuring that the information is equally accessible to both Black and White women.

Mesenteric fat cryolipolysis attenuates insulin resistance in the Ossabaw swine model of the metabolic syndrome.

BACKGROUND: The rising prevalence of insulin resistance (IR), metabolic syndrome, and type 2 diabetes are associated with increases in abdominal mesenteric fat. Adipocytes are sensitive to low temperatures, making cryolipolysis of mesenteric fat an attractive treatment modality to potentially reduce IR. OBJECTIVES: We aimed to determine whether (1) cryolipolysis is safe in reducing the volume of the mesenteric fat and (2) reduction in mesenteric fat volume reduces indices of IR and glycemic dysfunction. SETTING: Indiana University School of Medicine. METHODS: A novel cooling device and method delivered cryolipolysis in a controlled manner to avoid tissue ablative temperatures. Ossabaw pigs (n = 8) were fed a high-fat diet for 9 months to develop visceral obesity, IR, and metabolic syndrome. Following laparotomy, mesenteric fat cryolipolysis (MFC) was performed in 5 pigs, while 3 served as sham surgery controls. The volume of the mesenteric fat was measured by computed tomography and compared with indices of glucose intolerance before and at 3 and 6 months postprocedure. RESULTS: MFC safely reduced mesenteric fat volume by ∼30% at 3 months, which was maintained at 6 months. Body weight did not change in either the MFC or sham surgery control groups. Measure of glycemic control, insulin sensitivity, and blood pressure significantly improved after MFC compared with sham controls. CONCLUSION: MFC reduces the volume of mesenteric fat and improves glycemic control in obese, IR Ossabaw pigs, without adverse effects.

Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy.

Although breast density decline with tamoxifen therapy is associated with greater therapeutic benefit, limited data suggest that endocrine symptoms may also be associated with improved breast cancer outcomes. However, it is unknown whether endocrine symptoms are associated with reductions in breast density after tamoxifen initiation. We evaluated treatment-associated endocrine symptoms and breast density change among 74 women prescribed tamoxifen in a 12-month longitudinal study. Treatment-associated endocrine symptoms and sound speed measures of breast density, assessed via novel whole breast ultrasound tomography (m/s), were ascertained before tamoxifen (T0) and at 1-3 (T1), 4-6 (T2), and 12 months (T3) after initiation. CYP2D6 status was genotyped, and tamoxifen metabolites were measured at T3. Using multivariable linear regression, we estimated mean change in breast density by treatment-associated endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline density. Significant breast density declines were observed in women with treatment-associated endocrine symptoms (mean change (95% confidence interval) at T1:-0.26 m/s (-2.17,1.65); T2:-2.12 m/s (-4.02,-0.22); T3:-3.73 m/s (-5.82,-1.63); p-trend = 0.004), but not among women without symptoms (p-trend = 0.18) (p-interaction = 0.02). Similar declines were observed with increasing symptom frequency (p-trends for no symptoms = 0.91; low/moderate symptoms = 0.03; high symptoms = 0.004). Density declines remained among women with detectable tamoxifen metabolites or intermediate/efficient CYP2D6 metabolizer status. Emergent/worsening endocrine symptoms are associated with significant, early declines in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations predict clinical outcomes. If confirmed, endocrine symptoms may be a proxy for tamoxifen response and useful for patients and providers to encourage adherence.

Percutaneous cryoablation of metastatic lesions from non-small-cell lung carcinoma: initial survival, local control, and cost observations.

PURPOSE: To assess feasibility, complications, local tumor recurrences, overall survival (OS), and estimates of cost effectiveness for multisite cryoablation (MCA) of oligometastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 49 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 60 tumors in 31 patients (19 women and 12 men) with oligometastatic NSCLC. Average patient age was 65 years. Tumor location was grouped according to common metastatic sites. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. RESULTS: Total numbers of tumors and cryoablation procedures for each anatomic site were as follows: lung, 20 and 18; liver, nine and seven; superficial, 12 and 11; adrenal, seven and seven; paraaortic/isolated, two and two; and bone, 10 and seven. A mean of 1.6 procedures per patient were performed, with a median clinical follow-up of 11 months. Major complication and local recurrence rates were 8% (four of 49) and 8% (five of 60), respectively. Median OS for MCA was 1.33 years, with an estimated 1-year survival rate of approximately 53%. MCA appeared cost-effective even when added to the cost of best supportive care or systemic regimens, with an adjunctive cost-effectiveness ratio of $49,008-$87,074. CONCLUSIONS: MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, and possibly increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic NSCLC.

Percutaneous cryoablation of metastatic renal cell carcinoma for local tumor control: feasibility, outcomes, and estimated cost-effectiveness for palliation.

PURPOSE: To assess complications, local tumor recurrences, overall survival (OS), and estimates of cost-effectiveness for multisite cryoablation (MCA) of oligometastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 60 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 72 tumors in 27 patients (three women and 24 men). Average patient age was 63 years. Tumor location was grouped according to common metastatic sites. Established surgical selection criteria graded patient status. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. RESULTS: Total number of tumors and cryoablation procedures for each anatomic site are as follows: nephrectomy bed, 11 and 11; adrenal gland, nine and eight; paraaortic, seven and six; lung, 14 and 13; bone, 13 and 13; superficial, 12 and nine; intraperitoneal, five and three; and liver, one and one. A mean of 2.2 procedures per patient were performed, with a median clinical follow-up of 16 months. Major complication and local recurrence rates were 2% (one of 60) and 3% (two of 72), respectively. No patients were graded as having good surgical risk, but median OS was 2.69 years, with an estimated 5-year survival rate of 27%. Cryoablation remained cost-effective with or without the presence of systemic therapies according to historical cost comparisons, with an adjunctive cost-effectiveness ratio of $28,312-$59,554 per LYG. CONCLUSIONS: MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, with apparent increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic RCC.

Breast ultrasound tomography versus MRI for clinical display of anatomy and tumor rendering: preliminary results.

OBJECTIVE: The objective of our study was to determine the clinical display thresholds of an ultrasound tomography prototype relative to MRI for comparable visualization of breast anatomy and tumor rendering. SUBJECTS AND METHODS: Thirty-six women were imaged with MRI and our ultrasound tomography prototype. The ultrasound tomography scan generated reflection, sound-speed, and attenuation images. The reflection images were fused with the components of the sound-speed and attenuation images that achieved thresholds to represent parenchyma or solid masses using an image arithmetic process. Qualitative and quantitative comparisons of MRI and ultrasound tomography clinical images were used to identify anatomic similarities and optimized thresholds for tumor shapes and volumes. RESULTS: Thresholding techniques generated ultrasound tomography images comparable to MR images for visualizing fibrous stroma, parenchyma, fatty tissues, and tumors. In 25 patients, tumors were cancerous and in 11, benign. Optimized sound-speed thresholds of 1.46±0.1 and 1.52±0.03 km/s were identified to best represent the extent of fibroglandular tissue and solid masses, respectively. An arithmetic combination of attenuation images using a threshold of 0.16±0.04 dB/cm (mean±SD) further characterized benign from malignant masses. No significant difference in tumor volume was noted between benign or malignant masses by ultrasound tomography or MRI (p>0.1) using these universal thresholds. CONCLUSION: Ultrasound tomography is able to image and render breast tissues in a manner comparable to MRI. Using universal ultrasound tomography threshold values for rendering the size and distribution of benign and malignant tissues appears feasible without IV contrast material.

Feasibility of ultrasound tomography-guided localized mild hyperthermia using a ring transducer: Ex vivo and in silico studies.

BACKGROUND: As of 2022, breast cancer continues to be the most diagnosed cancer worldwide. This problem persists within the United States as well, as the American Cancer Society has reported that ∼12.5% of women will be diagnosed with invasive breast cancer over the course of their lifetime. Therefore, a clinical need continues to exist to address this disease from a treatment and therapeutic perspective. Current treatments for breast cancer and cancers more broadly include surgery, radiation, and chemotherapy. Adjuncts to these methods have been developed to improve the clinical outcomes for patients. One such adjunctive treatment is mild hyperthermia therapy (MHTh), which has been shown to be successful in the treatment of cancers by increasing effectiveness and reduced dosage requirements for radiation and chemotherapies. MHTh-assisted treatments can be performed with invasive thermal devices, noninvasive microwave induction, heating and recirculation of extracted patient blood, or whole-body hyperthermia with hot blankets. PURPOSE: One common method for inducing MHTh is by using microwave for heat induction and magnetic resonance imaging for temperature monitoring. However, this leads to a complex, expensive, and inaccessible therapy platform. Therefore, in this work we aim to show the feasibility of a novel all-acoustic MHTh system that uses focused ultrasound (US) to induce heating while also using US tomography (UST) to provide temperature estimates. Changes in sound speed (SS) have been shown to be strongly correlated with temperature changes and can therefore be used to indirectly monitor heating throughout the therapy. Additionally, these SS estimates allow for heterogeneous SS-corrected phase delays when heating complex and heterogeneous tissue structures. METHODS: Feasibility to induce localized heat in tissue was investigated in silico with a simulated breast model, including an embedded tumor using continuous wave US. Here, both heterogenous acoustic and thermal properties were modeled in addition to blood perfusion. We further demonstrate, with ex vivo tissue phantoms, the feasibility of using ring-based UST to monitor temperature by tracking changes in SS. Two phantoms (lamb tissue and human abdominal fat) with latex tubes containing varied temperature flowing water were imaged. The measured SS of the water at each temperature were compared against values that are reported in literature. RESULTS: Results from ex vivo tissue studies indicate successful tracking of temperature under various phantom configurations and ranges of water temperature. The results of in silico studies show that the proposed system can heat an acoustically and thermally heterogenous breast model to the clinically relevant temperature of 42°C while accounting for a reasonable time needed to image the current cross section (200 ms). Further, we have performed an initial in silico study demonstrating the feasibility of adjusting the transmit waveform frequency to modify the effective heating height at the focused region. Lastly, we have shown in a simpler 2D breast model that MHTh level temperatures can be maintained by adjusting the transmit pressure intensity of the US ring. CONCLUSIONS: This work has demonstrated the feasibility of using a 256-element ring array transducer for temperature monitoring; however, future work will investigate minimizing the difference between measured SS and the values shown in literature. A hypothesis attributes this bias to potential volumetric average artifacts from the ray-based SS inversion algorithm that was used, and that moving to a waveform-based SS inversion algorithm will greatly improve the SS estimates. Additionally, we have shown that an all-acoustic MHTh system is feasible via in silico studies. These studies have indicated that the proposed system can heat a tumor within a heterogenous breast model to 42°C within a narrow time frame. This holds great promise for increasing the accessibility and reducing the complexity of a future all-acoustic MHTh system.

Rapid Reductions in Breast Density following Tamoxifen Therapy as Evaluated by Whole-Breast Ultrasound Tomography.

PURPOSE: Women whose mammographic breast density declines within 12-18 months of initiating tamoxifen for chemoprevention or adjuvant treatment show improved therapeutic responses compared with those whose density is unchanged. We tested whether measuring changes in sound speed (a surrogate of breast density) using ultrasound tomography (UST) could enable rapid identification of favorable responses to tamoxifen. METHODS: We evaluated serial density measures at baseline and at 1 to 3, 4 to 6, and 12+ months among 74 women (aged 30-70 years) following initiation of tamoxifen for clinical indications, including an elevated risk of breast cancer (20%) and diagnoses of in situ (39%) or invasive (40%) breast carcinoma, enrolled at Karmanos Cancer Institute and Henry Ford Health System (Detroit, MI, USA). For comparison, we evaluated an untreated group with screen negative mammography and frequency-matched on age, race, and menopausal status (n = 150), at baseline and 12 months. Paired t-tests were used to assess differences in UST sound speed over time and between tamoxifen-treated and untreated patients. RESULTS: Sound speed declined steadily over the 12 month period among patients receiving tamoxifen (mean (SD): -3.0 (8.2) m/s; p = 0.001), whereas density remained unchanged in the untreated group (mean (SD): 0.4 (7.1) m/s; p = 0.75 (relative change between groups: p = 0.0009)). In the tamoxifen group, we observed significant sound speed reductions as early as 4-6 months after tamoxifen initiation (mean (SD): -2.1 (6.8) m/s; p = 0.008). Sound speed reductions were greatest among premenopausal patients (P-interaction = 0.0002) and those in the middle and upper tertiles of baseline sound speed (P-interaction = 0.002). CONCLUSIONS: UST can image rapid declines in sound speed following initiation of tamoxifen. Given that sound speed and mammographic density are correlated, we propose that UST breast imaging may capture early responses to tamoxifen, which in turn may have utility in predicting therapeutic efficacy.

The Potential Role of the Fat-Glandular Interface (FGI) in Breast Carcinogenesis: Results from an Ultrasound Tomography (UST) Study.

This study explored the relationship between the extent of the fat-glandular interface (FGI) and the presence of malignant vs. benign lesions. Two hundred and eight patients were scanned with ultrasound tomography (UST) as part of a Health Insurance Portability and Accountability Act (HIPAA)-compliant study. Segmentation of the sound speed images, employing the k-means clustering method, was used to help define the extent of the FGI for each patient. The metric, α, was defined as the surface area to volume ratio of the segmented fibroglandular volume and its mean value across patients was determined for cancers, fibroadenomas and cysts. ANOVA tests were used to assess significance. The means and standard deviations of α for cancers, fibroadenomas and cysts were found to be 4.0 ± 2.0 cm-1, 3.1 ± 1.7 cm-1 and 2.3 ± 0.9 cm-1, respectively. The differences were statistically significant (p < 0.001). The separation between the groups increased when α was measured on only the image slice where the finding was most prominent, with values for cancers, fibroadenomas and cysts of 5.4 ± 3.6 cm-1, 3.6 ± 2.3 cm-1 and 2.4 ± 1.5 cm-1, respectively. Of the three types of masses studied, cancer was associated with the most extensive FGIs, suggesting a potential role for the FGI in carcinogenesis, a subject for future studies.