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

Round 1

Reviewer 1 Report

This is a very interesting review paper pertaining to a promising shift in how US technology is utilized for breast cancer screening. The theranostic aspect also seems to show certain advantages for future clinical purposes. On the other hand, only future studies will demonstrate whether SoftVue can adequately increase cancer detection and concurrently decrease the burden of unnecessary biopsies.

The manuscript is well-written, notwithstanding multiple minor linguistic errors that I shall mention here, including suggested corrections:

p3, l122 – Remove „a“ before „cost-effective“.

p3, l127 – Replace „r“ with „R“, ie. the capital for the BRCA acronym.

p4, l127 – Replace „a“ with „an“ before „FDA“.

p4, l161 – Replace „whose reflections“ with „reflections of which“.

p6, l215 – I recommend to rephrase „on only a“ as „only on a“.

p6, l227 – Insert „an“ before „input“.

p9, Table 2. – In Ultrasound BI-RADS, under „Masses“, remove „Oval“ after „Shape“.

p13, l385 – Remove the comma between „energy“ and „in“.

p13, l388 – Rewrite „fine tune“ as „fine-tune“.

p13, l393 – Insert „a“ or „the“ before „heterogeneous“.

p14, l423 – I presume you mistyped „with“ as „will“.

p14, l425 – Remove the comma between „SoftVue“ and „from“.

p14, l425 – Replace „a“ with „an“ before „FDA“.

p14, l425 – Remove the comma between „screening“ and „to“.

p14, l433 – It is superfluous to have the word „focusing“ repeated within the same sentence.

Author Response

We are grateful that Reviewer #1 found our paper interesting and appreciative for the multiple linguistic corrections.  We have followed every suggested correction by Reviewer #1, which can be seen from the corrected attached manuscript with track changes that awaits permission for further submission.  This attached draft also contains all the fully implemented corrections suggested by the other reviewers.  Formatting corrections of table 2 as suggested the editors’ office have also been completed, including removal of unnecessary self references.  We hope this fulfills all concerns.

Reviewer 2 Report

[General comments]

This is a nice review on the SoftVue breast tomographic ultrasound (BTUS) system and associated techniques developed by the group led by Prof. Duric over the past 20 years. The results are promising and the manuscript is generally well written.

[Major comments]

1.   As the acoustic attenuation, sound speed, and tissue stiffness measured by SoftVue are quantitative ultrasound parameters, providing a color bar (just like the one in the right part of Figure 11) for each of these parameters in figures like Figure 2 may be helpful for the readers.

2.   The authors are working on BTUS BI-RADS (Under development). This is interesting. As shown in Tables 2 and 3, this reviewer is wondering why the authors still use qualitative descriptions for BTUS BI-RADS features. BI-RADS is mainly based on B-mode ultrasound, which is qualitative, but there are several quantitative ultrasound parameters measured by SoftVue. Why not consider combining these quantitative ultrasound parameters for categorizing the breast tumor? An example is the stiffness measured by FibroScan which has been used for staging liver fibrosis.

3.   Although the authors focused on the only FDA-cleared BTUS system, i.e., SoftVue, mentioning (comparing with) other BTUS systems may be helpful for the readers. Moreover, discussing the potential reasons why these systems are not yet FDA-cleared may also be helpful.

4.   Please proofread the manuscript. Following are just some examples.

[Minor comments]

5.   Lines 62-64. Please consider rephrasing the sentence “The initial screening trial approved SoftVue improved improvements in both sensitivity and specificity when interpreted in combination with mammography.”

6.   Line 105. Pleas correct “hand-held devices (HHUS)” to “hand-held ultrasound (HHUS).”

7.   Line 115. Please correct “BIRADS” to “BI-RADS.”

8.   Line 131. Please correct “510K” to “510(k).”

9.   Lines 151-152. Please consider rephrasing the sentence “We only highlight our results with SoftVue do its extensive clinical documentation [15-29].”

10. Line 163. There are two periods for the sentence.

11. Line 201. “x-ray” to “X-ray”

12. Line 210-212. There are “m/sec” and “m/s.” Please change “m/sec” to “m/s.”

13. Line 210. “7.4% (118/1585 m/s)” Here, “118/1585” seems an explanation for “7.4%,” so it should have a unit “m/s.”

14. Line 211. “0.7% (11/1563 m/s)” Please refer to the above comment. “m/s” should be removed.

15. No need to use a period in the title or in the caption of a section, or to use a colon in the caption of a subsection. Please check this.

Minor editing needed.

Author Response

We appreciate reviewer#2’s comments and are grateful for all the suggested minor linguistic changes that have all been followed.  We will address all the major comments individually.  All corrections can be seen in the corrected attached manuscript with track changes that awaits permission for further submission.

Major comment #1: We really appreciate the good suggestion of placing an additional color bar for all images that contain Stiffness Fusion (SF).  We agree that this makes SF images more clearly related to the evaluation of tissue hardness or softness in each image and have tried to place the color bar similar to its appearance on the clinical scanner.  These new color bars can be seen in figures 2, 5-8 of the attached manuscript draft.

Major comment #2: The suggestion of using a possible quantitative ultrasound parameter for gaining BI-RADS BTUS, similar to staging the liver fibrosis by FibroScan, is very interesting but beyond the scope of this review article at this time.

Major comment #3:The attached draft also contains all the fully implemented corrections suggested by the other reviewers.  Formatting corrections of table 2 as suggested by the editors’ office have also been completed, including removal of unnecessary self references.  We hope this fulfills all concerns.

Reviewer 3 Report

Introduction

    • For a better understanding of the study, it is suggested to add a brief description of the purpose and importance of the study at the end of the introduction. 

SoftVue – Breast Density, Risk, Screening and Specificity.

    • 59: Figure 1 should be after it is mentioned in the text. Avoid putting figures in the following format: [Figure X].

    • 62-69: Demonstrate this paragraph quantitatively and add references to support the statements made in the text.

    • 77: Consider providing a brief explanation of the Breast Imaging Reporting and Data System (BI-RADS).

    • 86: Consider providing a brief introduction or background on digital breast tomosynthesis (DBT).

    • 92-93: Add sensitivity and specificity values. 

    • 115: It is important to give context to the BI-RADS score for the reader. 

Understanding SoftVue Image Sequences: Tissue Acoustics and Clinical Imaging.

    • 146-148: Add a brief explanation of how the imaging sequences help in detecting breast abnormalities and improving diagnosis.

    • 171-174: Provide specific examples of common artifacts in ultrasonography and explain how SoftVue eliminates them for better visualization of breast anatomy.

    • 181-182: Add in figure "3a" and "3b".

    • 188-191:Explain or add some reference as to why 3 MHz frequency is considered optimal to allow adequate breast tissue penetration and high image resolution.

    • 196-197: Adds a brief explanation of how the velocity of sound in breast tissue can influence the detection and characterization of breast masses.

    • 207: Place the table after mentioning it in the text. 

    • 207-208: Brief highlights the relevance of these measurements for breast tissue evaluation.

    • 227: Figure 4 should be after it is mentioned in the text. 

    • 236-241: Provide a more detailed explanation of how the Wafer technique works to improve breast mass detection, including how pixel values are calculated and how the relationship between reflection and sound velocity is used.

SoftVue UST and US BI-RADS – Review of common breast masses

    • 310-312: Add justification as to why the comparison between BI-RADS ultrasound parameters and the parameters proposed by SoftVue BTUS has been performed. Include a brief explanation of the technical or clinical rationale supporting the comparison.

    • The colors shown in Table 3 can be confused with the colors of the color Doppler technique.

The Future of Dynamic Focusing for Therapy

    • Discuss potential ethical considerations associated with the transition of SoftVue from medical imaging device to therapeutic device.

    • 436: Figure 11 should be after it is mentioned in the text. 

Conclusion

    • The conclusion should cover more about screening and diagnostic imaging for breast cancer, as four of the sections of the review focus on that, and it is the most supported and researched approach as described in the manuscript. 

    • As a general recommendation, it would be nice if the manuscript had a brief section on technical specifications, image format, PACS usage, equipment lifetime, specific infrastructure, etc. 

Minor spelling and typos

Author Response

Responses to Reviewer #3 are answered here and below in bolded italics in order to address each point to make sure that they have all been addressed to the reviewer's satisfaction.  Where possible, a single sentence was used to answer the concern for brevity and clarity.  All corrections can be found in the attached tracked changes version of the manuscript, which also includes the corrections for Reviwers #1&2.

 For a better understanding of the study, it is suggested to add a brief description of the purpose and importance of the study at the end of the introduction. 

We have provided 2 sentences at the end of the Introduction addressing the purpose and importance of this review of BTUS technology.

• 59: Figure 1 should be after it is mentioned in the text. Avoid putting figures in the following format: [Figure X].

Figure 1 now follows the first paragraph where it was mentioned.  We believe we have understood the second sentence as referring to figures and sentences instead of brackets and done so for the remainder of the manuscript.

• 62-69: Demonstrate this paragraph quantitatively and add references to support the statements made in the text.

Even though the significant improvements in sensitivity and specificity were mentioned in section 2.2, we have also now included the 20% improvement in sensitivity and 8% improvement in specificity has requested.  These are now found on line 65-67. 

• 77: Consider providing a brief explanation of the Breast Imaging Reporting and Data System (BI-RADS).

A sentence has now been added with associated new reference #7 to allow the acronym BI-RADS to be defined by itself.  See the new line 82-100. 

• 86: Consider providing a brief introduction or background on digital breast tomosynthesis (DBT).

A sentence has now been added explaining DBT as 3D mammography, which allows partial removal of overlying then structures.  See the new line 93-96. 

• 92-93: Add sensitivity and specificity values. 

That sentence already has sensitivity and specificity values that we left in place.  See also mentioning those values above. 

• 115: It is important to give context to the BI-RADS score for the reader.

As noted above, align has already been added given context to BI-RADS with associated reference. 

• 146-148: Add a brief explanation of how the imaging sequences help in detecting breast abnormalities and improving diagnosis.

A sentence has been added to better understand the diagnostic flow of detection and mass characterization has seen in new lines 159-163. 

• 171-174: Provide specific examples of common artifacts in ultrasonography and explain how SoftVue eliminates them for better visualization of breast anatomy.

We believe this entire paragraph and the associated Figure 3 specifically addresses the common artifacts of "shadowing" and "through-transmission" as now seen on the new lines 189-198. 

• 181-182: Add in figure "3a" and "3b".

Changed as noted. 

• 188-191:Explain or add some reference as to why 3 MHz frequency is considered optimal to allow adequate breast tissue penetration and high image resolution.

Attenuation decreases with decreasing frequency. At around 3 MHZ ultrasound signals can penetrate the whole breast, a requirement for imaging the whole breast. Decreasing frequency also means decreasing resolution. So, 3 MHz is the sweet spot for high resolution (submm) imaging of the entire breast.  This has been added in lines 211-214.  

• 196-197: Adds a brief explanation of how the velocity of sound in breast tissue can influence the detection and characterization of breast masses.

As noted in the new lines 221-223, the separation of dense tissues in a 3D format by SoftVue is comparable to the better mass detection and characterization by DBT.  That said, similar dense tissues (i.e. high sound speed) can still obscure mass margins of a similar sound speed adjacent mass. 

• 207: Place the table after mentioning it in the text.

Done 

• 207-208: Brief highlights the relevance of these measurements for breast tissue evaluation.

See now new lines 230-232 as relative tissue differences highlight their visual conspicuity.

• 227: Figure 4 should be after it is mentioned in the text.

Done  

• 236-241: Provide a more detailed explanation of how the Wafer technique works to improve breast mass detection, including how pixel values are calculated and how the relationship between reflection and sound velocity is used.

The following is placed into lines 265-271:
"Wafer embodies two functions. The first is to remove fat signals by using information from the sound speed image to mitigate the hypoechoic nature of fat at these frequencies. It is essentially a form of fat correction which makes masses more conspicuous.  The second function is to enhance masses further by taking the gradient of the sound speed image, which under a constant density assumption, represents changes in acoustic impedance which serves to enhance mass edges. The combination of these actions generates more contrast for mass detection." 

• 310-312: Add justification as to why the comparison between BI-RADS ultrasound parameters and the parameters proposed by SoftVue BTUS has been performed. Include a brief explanation of the technical or clinical rationale supporting the comparison.

The following has been placed in the beginning of Section 4:

“SoftVue generates multiple parameters assess mass characterization. SoftVue Reflection mode is akin to B-mode and can use standard US BIRADS when it comes to echogenicity and shape. On the other hand, the SoftVue sequences of Sound Speed and Stiffness Fusion have no counterparts in B-mode and needed new criteria. Thus, a comparison was needed to highlight both familiar criteria as well as the new criteria.”   

• The colors shown in Table 3 can be confused with the colors of the color Doppler technique.

The colors have been removed and replaced with Bold font. 

• Discuss potential ethical considerations associated with the transition of SoftVue from medical imaging device to therapeutic device.

We found “ethical considerations” not clear to respond. From an ethics perspective, we do not anticipate any issue to transform a screening/diagnostic device into a theranostic system to better serve the patients. In general, there is a significant interest to combine diagnostic and therapeutic devices into theranostic platforms, especially when a single hardware can be used for both applications.  We suspect that the reviewer meant to question the “safety and regulatory” aspect of the device modification and repurposing, which we believe is a useful technology insight warranting further discussion with appropriate references..  We therefore added a final additional paragraph to Section 5, lines 487-506 as noted. 

• 436: Figure 11 should be after it is mentioned in the text.

Moved as requested. 

• The conclusion should cover more about screening and diagnostic imaging for breast cancer, as four of the sections of the review focus on that, and it is the most supported and researched approach as described in the manuscript. 

We agree and have included an additional first paragraph to the conclusion as noted on lines 508-520, covering screening and diagnostic aspects of the review. 

• As a general recommendation, it would be nice if the manuscript had a brief section on technical specifications, image format, PACS usage, equipment lifetime, specific infrastructure, etc.

We had an additional sentence in Section 3.1 referring to the detailed Table 1 in our stiffness manuscript [23].  As previously mentioned, we also added a more technical paragraph to Section 5 giving technical specifics of the required changes being made to the future theranostic system.

Round 2

Reviewer 3 Report

Dear Editor,

Upon conducting a thorough review, the authors have addressed significant issues, resulting in a substantial improvement in the paper. While there remain minor areas for enhancement, it is deemed suitable for publication following a minor spelling revision.

Kind regards,

Minor spelling revision needed.