What could transform an underdog into a winner?
Author and Curator: Dror Nir, PhD
Many feedbacks to my last post reflected radiologists’ perception of ultrasound as a low-tech, unreliable imaging device.
Ultrasounds most manifested limitation by radiologists is that its performance is too-much user-dependent. This opinion finds support in numerous clinical studies concluding that ultrasound-based assessment of a cancer patient varies with the operator.
How come that an imaging technology that is not only low-cost, simple to operate and risk-free to the patient, but has also gained a leading position in certain domain, like obstetrics, is perceived as the underdog when it comes to cancer assessment? Could it be because of its positioning as a “multi-purpose” system, which requires only very basic training?
If indeed this is the case, it doesn’t require “rocket-science” to turn it around. It only needs designing dedicated ultrasound machines who offer a comprehensive solution to one specific clinical need. Using such machines will require highly skilled operators who will enjoy a superior workflow, reporting tools and proven clinical guidelines.
The unsatisfactory reality of mammography-based breast cancer screening, as evident by epidemiology data and expert-panels’ reports, opens the opportunity to transform ultrasound into a winner in the niche-market of breast cancer screening and diagnosis. It’s a significant market that justifies the investment in ultrasound systems dedicated to detection and characterisation of breast cancer lesions.
No doubt, that the ability to provide accurate and standardized interpretation of such ultrasound systems’ scans is a pre-requisite. Ultrasound-based tissue characterisation is a must for any application aiming at standardized image interpretation. A sample out-of present ultrasound-based technologies aiming at providing some level of tissue-characterisation are listed below. Recent clinical studies show promising results using these technologies. It is worth watching carefully to see if any of those could be part of a future ultrasound-based solution to breast cancer screening.
Solid Breast Lesions: Clinical Experience with US-guided Diffuse Optical Tomography Combined with Conventional US
Results: Of the 136 biopsied lesions, 54 were carcinomas and 82 were benign. The average total hemoglobin concentration in the malignant group was 223.3 μmol/L ± 55.8 (standard deviation), and the average hemoglobin concentration in the benign group was 122.5 μmol/L ± 80.6 (P = .005). When the maximum hemoglobin concentration of 137.8 μmol/L was used as the threshold value, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of DOT with US localization were 96.3%, 65.9%, 65.0%, 96.4%, and 76.5%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of conventional US were 96.3%, 92.6%, 89.7%, 97.4%, and 93.4%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of conventional US combined with DOT were 100%, 93.9%, 91.5%, 100%, and 96.3%, respectively.
Conclusion: US-guided DOT combined with conventional US improves accuracy compared with DOT alone.
Breast Lesions: Quantitative Elastography with Supersonic Shear Imaging—Preliminary Results
Results: All breast lesions were detected at Supersonic Shear Imaging. Malignant lesions exhibited a mean elasticity value of 146.6 kPa ± 40.05 (standard deviation), whereas benign ones had an elasticity value of 45.3 kPa ± 41.1 (P < .001). Complicated cysts were differentiated from solid lesions because they had elasticity values of 0 kPa (no signal was retrieved from liquid areas).
Conclusion: Supersonic Shear Imaging provides quantitative elasticity measurements, thus adding complementary information that potentially could help in breast lesion characterization with B-mode US.
Distinguishing Benign from Malignant Masses at Breast US: Combined US Elastography and Color Doppler US—Influence on Radiologist Accuracy
Results: The Az of B-mode US, US elastography, and Doppler US (average, 0.844; range, 0.797–0.876) was greater than that of B-mode US alone (average, 0.771; range, 0.738–0.798) for all readers (P = .001 for readers 1, 2, and 3; P < .001 for reader 4; P = .002 for reader 5). When both elastography and Doppler scores were negative, leading to strict downgrading, the specificity increased for all readers from an average of 25.3% (75.4 of 298; range, 6.4%–40.9%) to 34.0% (101.2 of 298; range, 26.5%–48.7%) (P < .001 for readers 1, 2, 4, and 5; P = .016 for reader 3) without a significant change in sensitivity.
Conclusion: Combined use of US elastography and color Doppler US increases both the accuracy in distinguishing benign from malignant masses and the specificity in decision-making for biopsy recommendation at B-mode US.
Evaluation of breast lesions by contrast enhanced ultrasound: Qualitative and quantitative analysis
A 57-year-old woman with a no-palpable lesion in the outer upper quadrant of left breast. (a) Gray scale image show an indistinct, hypo-echoic lesion. (b) Contrast enhanced image obtained 35 s after contrast agent injection showing a homogeneously and hyper-enhanced lesion. (c) Micro flow image obtained 38 s after contrast agent injection showing the enhanced mass with several radial vessels (arrow). (d) The time-intensity curve analysis show the peak intensity is 145.69 (intensity/1000), time to peak is 15.08 s, ascending slope is 8.98, descending slope is 1.03, the area under the curve is 7783.34. Pathologic analyses show this is an invasive ductal carcinoma.
Results: Histopathologic analysis of the 91 lesions revealed 44 benign and 47 malignant. For qualitative analysis, benign and malignant lesions differ significantly in enhancement patterns (p < 0.05). Malignant lesions more often showed heterogeneous and centripetal enhancement, whereas benign lesions mainly showed homogeneous and centrifugal enhancement. The detectable rate of peripheral radial or penetrating vessels was significantly higher in malignant lesions than in benign ones (p < 0.001). For quantitative analysis, malignant lesions showed significantly higher (p = 0.031) and faster enhancement (p = 0.025) than benign ones, and its time to peak was significantly shorter (p = 0.002). The areas under the ROC curve for qualitative, quantitative and combined analysis were 0.910 (Az1), 0.768 (Az2) and 0.926(Az3) respectively. The values of Az1 and Az3 were significantly higher than that for Az2 (p = 0.024 and p = 0.008, respectively). But there was no significant difference between the values of Az1 and Az3 (p = 0.625).
Conclusions: The diagnostic performance of qualitative and combined analysis was significantly higher than that for quantitative analysis. Although quantitative analysis has the potential to differentiate benign from malignant lesions, it has not yet improved the final diagnostic accuracy.
Breast HistoScanning: the development of a novel technique to improve tissue characterization during breast ultrasound
Results: In 17 normal testing volumes, 3% of isolated voxels were classified as abnormal. In 15 abnormal testing volumes, the subclassifiers differentiated between malignant and benign tissue. BHS in benign tissue showed <1% abnormal voxels in cyst, hamartoma, papilloma and benign fibrosis. The fibroadenomas differed showing <5% and <24% abnormal voxels. Abnormal voxels in cancers increased with the volume of cancer at pathology.
Conclusions: HistoScanning reliably discriminated normal from abnormal tissue and could distinguish between benign and malignant lesions.
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0You are making the case, but I also had to study each argument carefully.
[1] In DOT the quality of the observation is significantly enhanced by the Hg concentration, but there are too many missed cases based on the predictive value for absence of disease at 65%, supporting the argument that physician skill, dependent on experience, past mentoring, and ability to discern makes this very much an art. However, I am skeptical about the difference between 90 and 92 percent. So the combined method could be introduced for training in US, but it could be dropped later. Of course, the sample size is not large, with a 2:1 ratio of benign to malignant.
[2] An increase in absence of malignant lesion in results without a malignant mass from 25% to 34% would be a substantial gain in accuracy, but I don’t know what effect it would have in driving down the number of biopsies. It could be a quality control measure. If a biopsy is taken and it is read as negative, with a negative scan, it would be the end. If a biopsy is taken, then read as negative, but the scan is positive, there would be rebiopsy to be sure they get the lesion. This is important because of the small amount of tissue removed when it is seen early.
[3] It looks like Az1 may be sufficient, but you would want to see if “no difference” holds up with more accumulated cases.
[4] This is most interesting!
Congratulations once more Dr Dror!Yes Medicine is also an Art,yes there is a big space to ultrasound alone or combined with other techniques.ULtrasounds/echography will continue to grow much more,sorry “big boys”,and no radiation at all!
Dr. Nir,
Thank you for this post
Indeed, I agree with Dr. Bretes’ comment above.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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