0-MHz Intercept Research Articles

Quantitative Ultrasound for Evaluation of Tumour Response to Ultrasound-Microbubbles and Hyperthermia.

Objectives: Prior study has demonstrated the implementation of quantitative ultrasound (QUS) for determining the therapy response in breast tumour patients. Several QUS parameters quantified from the tumour region showed a significant correlation with the patient's clinical and pathological response. In this study, we aim to identify if there exists such a link between QUS parameters and changes in tumour morphology due to combined ultrasound-stimulated microbubbles (USMB) and hyperthermia (HT) using the breast xenograft model (MDA-MB-231). Method: Tumours grown in the hind leg of severe combined immuno-deficient mice were treated with permutations of USMB and HT. Ultrasound radiofrequency data were collected using a 25 MHz array transducer, from breast tumour-bearing mice prior and post-24-hour treatment. Result: Our result demonstrated an increase in the QUS parameters the mid-band fit and spectral 0-MHz intercept with an increase in HT duration combined with USMB which was found to be reflective of tissue structural changes and cell death detected using haematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labelling stain. A significant decrease in QUS spectral parameters was observed at an HT duration of 60 minutes, which is possibly due to loss of nuclei by the majority of cells as confirmed using histology analysis. Morphological alterations within the tumour might have contributed to the decrease in backscatter parameters. Conclusion: The work here uses the QUS technique to assess the efficacy of cancer therapy and demonstrates that the changes in ultrasound backscatters mirrored changes in tissue morphology.

Quantitative ultrasound imaging of therapy response in bladder cancer in vivo.

Background and AimsQuantitative ultrasound (QUS) was investigated to monitor bladder cancer treatment response in vivo and to evaluate tumor cell death from combined treatments using ultrasound-stimulated microbubbles and radiation therapy.MethodsTumor-bearing mice (n=45), with bladder cancer xenografts (HT- 1376) were exposed to 9 treatment conditions consisting of variable concentrations of ultrasound-stimulated Definity microbubbles [nil, low (1%), high (3%)], combined with single fractionated doses of radiation (0 Gy, 2 Gy, 8 Gy). High frequency (25 MHz) ultrasound was used to collect the raw radiofrequency (RF) data of the backscatter signal from tumors prior to, and 24 hours after treatment in order to obtain QUS parameters. The calculated QUS spectral parameters included the mid-band fit (MBF), and 0-MHz intercept (SI) using a linear regression analysis of the normalized power spectrum.Results and ConclusionsThere were maximal increases in QUS parameters following treatments with high concentration microbubbles combined with 8 Gy radiation: (ΔMBF = +6.41 ± 1.40 (±SD) dBr and SI= + 7.01 ± 1.20 (±SD) dBr. Histological data revealed increased cell death, and a reduction in nuclear size with treatments, which was mirrored by changes in quantitative ultrasound parameters. QUS demonstrated markers to detect treatment effects in bladder tumors in vivo.

Multiparametric monitoring of chemotherapy treatment response in locally advanced breast cancer using quantitative ultrasound and diffuse optical spectroscopy.

PurposeThis study evaluated pathological response to neoadjuvant chemotherapy using quantitative ultrasound (QUS) and diffuse optical spectroscopy imaging (DOSI) biomarkers in locally advanced breast cancer (LABC).Materials and MethodsThe institution's ethics review board approved this study. Subjects (n = 22) gave written informed consent prior to participating. US and DOSI data were acquired, relative to the start of neoadjuvant chemotherapy, at weeks 0, 1, 4, 8 and preoperatively. QUS parameters including the mid-band fit (MBF), 0-MHz intercept (SI), and the spectral slope (SS) were determined from tumor ultrasound data using spectral analysis. In the same patients, DOSI was used to measure parameters relating to tumor hemoglobin and composition. Discriminant analysis and receiver-operating characteristic (ROC) analysis was used to classify clinical and pathological response during treatment and to estimate the area under the curve (AUC). Additionally, multivariate analysis was carried out for pairwise QUS/DOSI parameter combinations using a logistic regression model.ResultsIndividual QUS and DOSI parameters, including the (SI), oxy-hemoglobin (HbO2), and total hemoglobin (HbT) were significant markers for response after one week of treatment (p < 0.01). Multivariate (pairwise) combinations increased the sensitivity, specificity and AUC at this time; the SI + HbO2 showed a sensitivity/specificity of 100%, and an AUC of 1.0.ConclusionsQUS and DOSI demonstrated potential as coincident markers for treatment response and may potentially facilitate response-guided therapies. Multivariate QUS and DOSI parameters increased the sensitivity and specificity of classifying LABC patients as early as one week after treatment.

The Association between Reconstructed Bladder Wall Dose and Chronic Urinary Toxicity Following Prostate Radiotherapy

patients. Histopathological analysis was used to confirm clinical treatment response. Results/Benefits/Challenges: Clinical responders showed a significant increase (p<0.05) in QUS parameters after four weeks of treatments, relative to the baseline: MBF (+7.90 dBr 1.39 [SE]) and 0-MHz intercept (+8.55 dBr 1.84). Spectral slope was however invariant. At similar time intervals, clinical responders also demonstrated significant percent changes to DOSI markers, such as total hemoglobin (HbT, -32.84% 4.07%), water fraction (%Water, -53.97% 3.29%) and scatter power (SP, -45.25% 1.42%). The sensitivity (Sn) and specificity (Sp) for QUS demonstrated that the MBF and 0-MHz intercept were good predictors of response at week 4 (MBF; Sn1⁄492.9%, Sp1⁄4100%, p<0.05), and this also corresponded with HbT (Sn1⁄492.9%, Sp1⁄487.5%, p<0.05) at the same time interval. In addition, QUS and DOSI parameters demonstrated an increase in the Sn/Sp as early as after 1 week of treatment (0-MHz intercept + %Water), (Sn1⁄492.9%, Sp1⁄4100.0%). Conclusion/Impact/Outcomes: QUS and DOSI demonstrated potential, as coincident markers for treatment response and may potentially facilitate response-guided therapies.

Cavity Delineation and Plan Review in Breast Radiotherapy: Concordance between Clinical Specialist Radiation Therapist and Radiation Oncologist

patients. Histopathological analysis was used to confirm clinical treatment response. Results/Benefits/Challenges: Clinical responders showed a significant increase (p<0.05) in QUS parameters after four weeks of treatments, relative to the baseline: MBF (+7.90 dBr 1.39 [SE]) and 0-MHz intercept (+8.55 dBr 1.84). Spectral slope was however invariant. At similar time intervals, clinical responders also demonstrated significant percent changes to DOSI markers, such as total hemoglobin (HbT, -32.84% 4.07%), water fraction (%Water, -53.97% 3.29%) and scatter power (SP, -45.25% 1.42%). The sensitivity (Sn) and specificity (Sp) for QUS demonstrated that the MBF and 0-MHz intercept were good predictors of response at week 4 (MBF; Sn1⁄492.9%, Sp1⁄4100%, p<0.05), and this also corresponded with HbT (Sn1⁄492.9%, Sp1⁄487.5%, p<0.05) at the same time interval. In addition, QUS and DOSI parameters demonstrated an increase in the Sn/Sp as early as after 1 week of treatment (0-MHz intercept + %Water), (Sn1⁄492.9%, Sp1⁄4100.0%). Conclusion/Impact/Outcomes: QUS and DOSI demonstrated potential, as coincident markers for treatment response and may potentially facilitate response-guided therapies.

Abstract CT317: Quantitative ultrasound for personalized chemotherapy in locally advanced breast cancer: Clinical trial results

Abstract Many cancer therapies are intended to induce cell death within a target tumour. A substantial body of research using in vitro and in vivo models has demonstrated that cell death can be detected via quantitative ultrasound techniques. This study investigated the potential to quantify tumour responses to therapy in patients, using quantitative spectral and textural biomarkers extracted from low-frequency ultrasound data (4-10 MHz). Results demonstrate for the first time in a large cohort of patients the ability to predict clinical responders from non-responders as early as one week after the start of chemotherapy with over 95% sensitivity and 95% specificity. A clinical study was undertaken investigating the efficacy of ultrasound to quantify cell death in tumor responses with cancer treatment. Patients (n = 100) with locally advanced breast cancer received anthracyline and taxane-based chemotherapy treatments over four to six months. Data collection consisted of acquiring tumor images and radiofrequency data prior to treatment onset and at 4 times during neoadjuvant chemotherapy (weeks 0, 1, 4, 8 and pre-operatively). Data collection was carried out using an Ultrasonix-RP and an L15-5 6cm transducer pulsed at frequencies of ∼5 and ∼7 MHz, respectively. The majority of patients went on to have a modified radical mastectomy and correlative whole mount histopathology. Results obtained from both ∼5 and ∼7 MHz data indicated considerable increases in ultrasound spectral backscatter power in patients who clinically responded to treatment within one week of starting their chemotherapy. This was accompanied by significant increases in quantitative ultrasound spectral parameters such as mid-band-fit (up to 9.1 ± 1.2 dBr) and 0-MHz intercept (up to 10.8 ± 2.4 dBr). Patients categorized as poor responders clinically demonstrated significantly lower increases (1.9 ± 1.1 dBr and 1.4 ± 2.7 dBr for mid-band-fit and 0-MHz intercept, respectively). Textural biomarkers extracted from quantitative ultrasound spectral parametric maps also demonstrated considerable differences in trend between treatment responding and non-responding patients early after the treatment initiation. Statistically significant differences were found between treatment responding and non-responding patient populations using quantitative ultrasound spectral biomarkers 4 and 8 weeks after treatment initiation. Applying quantitative ultrasound textural biomarkers in order to incorporate response heterogeneities resulted in statistically significant differences between these two populations only one week after the start of chemotherapy. There were also associated survival differences between the two groups of patients. Patients with ultrasound-detected responses at week 1 had an over 90+/-5% 3 year survival whereas patients with no ultrasound-detected response at the same time had a 30+/10% survival (p&amp;lt;0.05). This study demonstrates the potential of ultrasound to quantify changes in tumours in response to cancer treatment administration in a clinical setting. The results indicate that such responses can be detected early during a course of chemotherapy. This can potentially permit ineffective treatments to be changed to more efficacious ones potentially leading to improved treatment outcomes within a framework of personalized medicine. Citation Format: Gregory Jan Czarnota, Ali Sadeghi-Naini, Hadi Tadayyon, Lakshmanan Sannachi, Mehrdad Gangeh, William Tran, Frances Wright, Sonal Gandhi, Kathleen Pritchard, Sunil Verma, Maureen Trudeau. Quantitative ultrasound for personalized chemotherapy in locally advanced breast cancer: Clinical trial results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT317. doi:10.1158/1538-7445.AM2015-CT317

Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy.

It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments. Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively. Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R(2) of 0.9 was observed when quantified cell death was correlated with changes in midband fit. Results from QUS analysis presented in this study confirm that acute tumor response is linked to a vascular effect following high doses of radiation therapy. Overall, this is in agreement with previous reports suggesting that acute tumor radiation response is regulated by a vascular-driven response. Data also suggest that Sunitinib may enhance tumor radiosensitivity through a vascular remodeling process, and that QUS may be sensitive to changes in tissue properties associated with vascular remodeling. Finally, the work also demonstrates the ability of QUS methods to monitor response to radiation-based vascular strategies.

2091464 Quantitative Ultrasound Methods for Lymphedema Assessment

Hypothesis: secondary breast lymphedema produces characteristic tissue features/changes that can be detected using non-invasive image based techniques. Our OBJECTIVES: is to determine which of these tissue features predominate and how they can be used to assess in real-time the spatial and temporal changes occurring in the breast. In order to assess the extent and distribution of breast lymphedema and the potential for therapeutic response in these patients a commercial Radio-Frequency acquisition enabled ultrasound device (Ultrasonix RP, Ultrasonic Medical Corporation, Canada) was used to obtain three-dimensional ultrasound maps of the breast. Radiofrequency data were collected over 5-14 MHz using an L14-5/3.8 mm transducer or when needed an L14-5/6.0 mm transducer. Data obtained were analyzed to generate parametric maps of mid-band fit, 0-MHz intercept and spectral slope. From this data using Gaussian fitting of parameters an estimate of acoustic scatterer size and acoustic scatterer concentration was obtained. Other ultrasound parameters determined from fittings of the generalized gamma-distribution include, the a (scale) and c/v (shape) fit parameters were assessed. Data indicate changes in mid-band fit, spectral slope and 0-MHz intercept in patients with lymphedema compared to normal tissues. There were increases in mid-band fit of 4 +- 1 dBr and similarly for 0-MHz intercept. Spectral slope varied with extent of lymphedema. In summary this investigation supports the viability of being able to assess and track the spatio-temporal anatomic and structural changes with novel non-invasive image based techniques in women presenting with secondary breast lymphedema following breast conservation surgery and adjuvant radiotherapy. Data from this study will enable the development of an image based toolkit for the quantitative assessment of breast-cancer treatment related lymphedema.

Quantitative Ultrasound Spectroscopic Imaging for Characterization of Disease Extent in Prostate Cancer Patients

Three-dimensional quantitative ultrasound spectroscopic imaging of prostate was investigated clinically for the noninvasive detection and extent characterization of disease in cancer patients and compared to whole-mount, whole-gland histopathology of radical prostatectomy specimens. Fifteen patients with prostate cancer underwent a volumetric transrectal ultrasound scan before radical prostatectomy. Conventional-frequency (~5MHz) ultrasound images and radiofrequency data were collected from patients. Normalized power spectra were used as the basis of quantitative ultrasound spectroscopy. Specifically, color-coded parametric maps of 0-MHz intercept, midband fit, and spectral slope were computed and used to characterize prostate tissue in ultrasound images. Areas of cancer were identified in whole-mount histopathology specimens, and disease extent was correlated to that estimated from quantitative ultrasound parametric images. Midband fit and 0-MHz intercept parameters were found to be best associated with the presence of disease as located on histopathology whole-mount sections. Obtained results indicated a correlation between disease extent estimated noninvasively based on midband fit parametric images and that identified histopathologically on prostatectomy specimens, with an r2 value of 0.71 (P<.0001). The 0-MHz intercept parameter demonstrated a lower level of correlation with histopathology. Spectral slope parametric maps offered no discrimination of disease. Multiple regression analysis produced a hybrid disease characterization model (r2=0.764, P<.05), implying that the midband fit biomarker had the greatest correlation with the histopathologic extent of disease. This work demonstrates that quantitative ultrasound spectroscopic imaging can be used for detecting prostate cancer and characterizing disease extent noninvasively, with corresponding gross three-dimensional histopathologic correlation.

Noninvasive Characterization of Locally Advanced Breast Cancer Using Textural Analysis of Quantitative Ultrasound Parametric Images

PURPOSE: The identification of tumor pathologic characteristics is an important part of breast cancer diagnosis, prognosis, and treatment planning but currently requires biopsy as its standard. Here, we investigated a noninvasive quantitative ultrasound method for the characterization of breast tumors in terms of their histologic grade, which can be used with clinical diagnostic ultrasound data. METHODS: Tumors of 57 locally advanced breast cancer patients were analyzed as part of this study. Seven quantitative ultrasound parameters were determined from each tumor region from the radiofrequency data, including mid-band fit, spectral slope, 0-MHz intercept, scatterer spacing, attenuation coefficient estimate, average scatterer diameter, and average acoustic concentration. Parametric maps were generated corresponding to the region of interest, from which four textural features, including contrast, energy, homogeneity, and correlation, were determined as further tumor characterization parameters. Data were examined on the basis of tumor subtypes based on histologic grade (grade I versus grade II to III). RESULTS: Linear discriminant analysis of the means of the parametric maps resulted in classification accuracy of 79%. On the other hand, the linear combination of the texture features of the parametric maps resulted in classification accuracy of 82%. Finally, when both the means and textures of the parametric maps were combined, the best classification accuracy was obtained (86%). CONCLUSIONS: Textural characteristics of quantitative ultrasound spectral parametric maps provided discriminant information about different types of breast tumors. The use of texture features significantly improved the results of ultrasonic tumor characterization compared to conventional mean values. Thus, this study suggests that texture-based quantitative ultrasound analysis of in vivo breast tumors can provide complementary diagnostic information about tumor histologic characteristics.

Quantitative ultrasound evaluation of tumor cell death response in locally advanced breast cancer patients to chemotherapy treatment administration

A clinical study was undertaken investigating the efficacy of ultrasound to quantify cell death in tumor responses with cancer treatment. Patients (n = 25) with locally advanced breast cancer received anthracyline and taxane-based chemotherapy treatments over four to six months. The majority of patients went on to have a modified radical mastectomy and correlative whole mount histopathology. Data collection was carried out using an Ultrasonix-RP and an L15-5 6 cm transducer pulsed at 10 MHz with RF data collected five times during neoadjuvant chemotherapy. Data indicated increases of approximately 9 dBr (+/−1.67) maximally in ultrasound backscatter in patients who clinically responded to treatment. Patients assessed as responding poorly demonstrated significantly lower increases (2.3 +/− 1.7 dBr). Increases in 0-MHz intercept followed similar trends while increases in spectral slope were observed locally from tumor regions demonstrating increases in tissue echogenicity. This study demonstrates the potential of ultrasound to quantify changes in tumors in response to cancer treatment administration in a clinical setting. The results indicate that such responses can be detected early during a course of chemotherapy and should permit ineffective treatments to be changed to more efficacious ones potentially leading to improved treatment outcomes.

Quantitative Ultrasound Evaluation of Tumor Cell Death Response in Locally Advanced Breast Cancer Patients Receiving Chemotherapy

Quantitative ultrasound techniques have been recently shown to be capable of detecting cell death through studies conducted on in vitro and in vivo models. This study investigates for the first time the potential of early detection of tumor cell death in response to clinical cancer therapy administration in patients using quantitative ultrasound spectroscopic methods. Patients (n = 24) with locally advanced breast cancer received neoadjuvant chemotherapy treatments. Ultrasound data were collected before treatment onset and at 4 times during treatment (weeks 1, 4, and 8, and preoperatively). Quantitative ultrasound parameters were evaluated for clinically responsive and nonresponding patients. Results indicated that quantitative ultrasound parameters showed significant changes for patients who responded to treatment, and no similar alteration was observed in treatment-refractory patients. Such differences between clinically and pathologically determined responding and nonresponding patients were statistically significant (P < 0.05) after 4 weeks of chemotherapy. Responding patients showed changes in parameters related to cell death with, on average, an increase in mid-band fit and 0-MHz intercept of 9.1 ± 1.2 dBr and 8.9 ± 1.9 dBr, respectively, whereas spectral slope was invariant. Linear discriminant analysis revealed a sensitivity of 100% and a specificity of 83.3% for distinguishing nonresponding patients by the fourth week into a course of chemotherapy lasting several months. This study reports for the first time that quantitative ultrasound spectroscopic methods can be applied clinically to evaluate cancer treatment responses noninvasively. The results form a basis for monitoring chemotherapy effects and facilitating the personalization of cancer treatment.

Three-dimensional ultrasound-based spectroscopic imaging for the detection of prostate cancer.

234 Background: The objective of this translational research was to investigate the use of real-time novel three-dimension, quantitative ultrasound-based spectroscopic imaging of the prostate as a means of cancer detection. Methods: Fourteen patients with T2-3 prostate cancer underwent a 6–9 MHz trans-rectal ultrasound scan of the prostate prior to radical prostatectomy. Equally spaced axial ultrasound images (0.5 cm separation) corresponding elasticity and spectroscopy data were collected in each patient. Colour-coded spectroscopic parametric maps of 0-Mhz intercept (0-Mhz), mid-band fit (MBF) and slope of line of best fit (slope) were generated indicating where the disease in the prostate gland is hypothetically located. Quantitative data (% volume of cancer over the prostate gland) were compared to whole-mount radical prostatectomy histopathology maps to determine the sensitivity and accuracy in parametrically delineating prostate cancer. Results: Representative data indicate spectral changes were associated with the presence of co-incident disease as located on correlative histopathology whole mount sections. Of the 14 patients enrolled, 7 have been analyzed and presented here. The mean % difference between 0-MHz and MBF, with H&amp;E, was 14% (SD 38%) and 21% (SD 24%), respectively. Gross areas of disease were readily visualized in ultrasound parametric maps and corresponded to a maximum 10dB decrease in 0-MHz or MBF. Parametric maps generated from the spectral slope offered no discrimination of disease. There were differences in scatterer size estimates and scatter concentration estimates between putative disease areas and the remaining tissue. Conclusions: Initial results suggest that there is good correlation between spectroscopic maps with disease on whole-mount specimens. This method may ultimately permit ultrasound-guided targeted biopsies to improve detection rates and non-invasive assessment of disease for radiotherapy planning.

Three-dimensional ultrasound-based spectroscopic imaging for detection of prostate cancer in men.

57 Background: The objective of this translational research was to investigate the use of real-time novel three-dimension, quantitative ultrasound-based spectroscopic imaging of the prostate as a means of cancer detection. Methods: Ten patients with T2-3 prostate cancer underwent a 6-9 MHz trans-rectal ultrasound scan of the prostate prior to radical prostatectomy. Equally spaced axial ultrasound images (0.5 cm separation) corresponding elasticity and spectroscopy data were collected in each patient. Colour-coded spectroscopic parametric maps of 0-Mhz intercept (0-Mhz), mid-band fit (MBF) and slope of line of best fit (slope) were generated indicating where the disease in the prostate gland is hypothetically located. Quantitative data (% volume of cancer over the prostate gland) were compared to whole-mount radical prostatectomy histopathology maps to determine the sensitivity and accuracy in parametrically delineating prostate cancer. Results: Representative data indicate spectral changes were associated with the presence of co-incident disease as located on correlative histopathology whole mount sections. Of the 10 patients enrolled, 7 have been analyzed and presented here. The mean % difference between 0-MHz and MBF, with H&amp;E, was 14% (SD 38%) and 21% (SD 24%), respectively. Gross areas of disease were readily visualized in ultrasound parametric maps and corresponded to a maximum 10dB decrease in 0-MHz or MBF. Parametric maps generated from the spectral slope offered no discrimination of disease. Conclusions: Initial results suggest that there is good correlation between spectroscopic maps with disease on whole-mount specimens. This method may ultimately permit ultrasound-guided targeted biopsies to improve detection rates and non-invasive assessment of disease for radiotherapy planning. No significant financial relationships to disclose.