KR20200044294A - Methods for poviding information about metastasis of the lymph and devices for poviding information about metastasis of the lymph using the same - Google Patents

Abstract

Provided are a method for providing information on metastasis of lymph nodes and a device for providing information using the same. The method for providing information on metastasis of lymph nodes comprises the steps of: measuring the level of at least one clinical parameter of the elasticity of lymph nodes to adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes for a biological sample including the lymph nodes separated from a subject and the adipose tissue around the lymph nodes; and evaluating metastasis of the lymph nodes to the subject based on the measured level of the clinical parameter.

Description

METHODS FOR POVIDING INFORMATION ABOUT METASTASIS OF THE LYMPH AND DEVICES FOR POVIDING INFORMATION ABOUT METASTASIS OF THE LYMPH USING THE SAME}

The present invention relates to a method and a device for providing information regarding the metastasis of a lymph node, and more specifically, to the metastasis of a lymph node, configured to evaluate whether the lymph node is metastatic based on the level of clinical parameters for a biological sample isolated from an individual. It relates to a method for providing information and a device using the same.

Axillary lymph node metastasis is an important factor in determining the prognosis of breast cancer. To determine whether axillary lymph node metastasis is present, the use of a sentinel lymph node biopsy (SLNB) is currently used as a standard method.

Surveillance lymph nodes are the axillary lymph nodes in which the metastasis of cancer cells from the tumors in the breast through the lymphatic vessels occurs first. Therefore, it is possible to predict whether the entire axillary lymph node is metastatic, depending on whether the metastatic lymph node is metastatic.

For this reason, the pathological evaluation of a surveillance lymph node biopsy performed during breast cancer surgery can determine whether full axillary lymph node resection should be performed during breast cancer surgery, thereby avoiding further surgery. In addition, avoiding unnecessary axillary lymph node dissection can contribute to reducing the occurrence of side effects, such as lymphedema, seroma, and the like.

However, surveillance lymph node biopsies performed during surgery should be performed by a skilled pathologist, and as expensive equipment may be required, there is a disadvantage that may cause an increase in long operation time and cost.

For this reason, development of a new method for easily and simply predicting axillary lymph node metastasis is continuously required.

The technology that is the background of the invention was created to facilitate understanding of the invention. It should not be understood that the items described in the background of the invention are recognized as prior art.

Shear wave elastography (SWE) is an ultrasound technique that quantitatively calculates the elasticity parameters of a target lesion, resulting in standard stiffness, minimum stiffness, maximum stiffness, elasticity standard deviation and adjacent tissue. It can provide a value such as the elasticity ratio of the breast lesions. Particularly, in the case of malignant tumors or metastasized lymph nodes, the cell density is higher than that of the surrounding normal tissues or benign tumors, so the stiffness is high when measured by SWE. Using these SWE characteristics, it is possible to diagnose cancer lesions in vivo.

Therefore, the inventors of the present invention paid attention to SWE as a method to compensate for the shortcomings of the surveillance lymph node biopsy and to more easily determine whether the monitoring lymph node metastases.

Furthermore, the inventors of the present invention were expected to be able to predict whether the metastasis of the axillary lymph nodes was predicted through various clinical parameters measured by SWE.

In particular, for biological samples such as surveillance lymph nodes isolated from individuals compared to evaluating lesions in vivo by SWE, ex vivo stiffness and clinical parameters such as elastic modulus for adjacent adipose tissue were measured in vivo. A more accurate value can be obtained when the clinical parameter is measured at.

As a result, the inventors of the present invention, when analyzing axillary lymph nodes isolated from individuals in vitro, have metastasized axillary lymph nodes larger in size than normal axillary lymph nodes, and are the parameters of SWE, the average stiffness, minimum stiffness, and maximum stiffness. , It was confirmed that the elasticity standard deviation and the elasticity ratio of breast lesions to adjacent tissues were high.

Furthermore, the inventors of the present invention provide a nomogram configured to predict the metastasis of lymph nodes based on the level of clinical parameters measured in vitro, such as the size of the lymph nodes, the stiffness of the lymph nodes and the elasticity to surrounding adipose tissue. Further developed.

Specifically, the nomogram was designed to calculate the metastatic score based on the level of clinical parameters, and to probabilistically evaluate the metastasis of lymph nodes to the individual based on the calculated score.

The inventors of the present invention considered that the developed nomogram could be easily predicted without the pathological examination of the presence or absence of metastasis of the surveillance lymph nodes removed during surgery. To prove this, it was confirmed that the application of the nomogram developed to predict the presence or absence of monitoring lymph node metastasis in a new group of breast cancer patients provides a reliable diagnostic evaluation of whether or not lymph node metastasis is a high AUC value.

Taken together, the problem to be solved by the present invention is to measure the size of the lymph nodes, the average stiffness of the lymph nodes and the elasticity of the lymph nodes to adipose tissue, for the monitoring lymph nodes, which are biological samples isolated from the individual, and based on these three clinical parameters. It provides an easy and simple method to evaluate the metastatic status of lymph nodes for each individual using a nomogram.

Another problem to be solved by the present invention is for a biological sample comprising lymph nodes and adipose tissue surrounding a lymph node separated from an individual, a receiver configured to receive a level of clinical parameters, and an individual based on the level of clinical parameters It is to provide a device for providing information regarding the metastasis of a lymph node, including parameters configured to evaluate whether the lymph node is metastatic.

The problems of the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to solve the problems as described above, there is provided a method for providing information regarding metastasis of lymph nodes according to an embodiment of the present invention. At this time, the method for providing information of the present invention, for a biological sample including lymph nodes and adipose tissue surrounding the lymph nodes separated from the individual, the elasticity ratio of the lymph nodes to the adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes It comprises the steps of measuring the level of the three clinical parameters consisting of and evaluating the lymph node metastasis to the individual based on the level of the measured clinical parameters.

According to a feature of the present invention, the evaluating step comprises: entering a level of clinical parameters into a nomogram configured to calculate a lymph node metastatic score based on the level of clinical parameters, and entering the clinical parameter level entered using the nomogram. The method may include calculating a lymph node metastatic score based on the result, and evaluating whether the lymph node is metastatic based on the calculated lymph node metastatic score.

According to another feature of the invention, the clinical parameters may include the elastic modulus of the lymph nodes to adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes. Further, calculating the lymph node metastatic score may include calculating a total lymph node metastatic score by summing the lymph node metastatic scores for each clinical parameter using a nomogram. In addition, evaluating whether the lymph node is metastatic based on the lymph node metastatic score may include evaluating whether the lymph node is metastatic based on the total lymph node metastatic score.

According to another feature of the present invention, the method for providing information of the present invention may include converting the total lymph node metastatic score to metastatic probability using a nomogram, performed after the step of calculating the total lymph node metastatic score. have. In addition, evaluating whether the lymph node is metastatic based on the lymph node metastatic score may include a step of probabilistically evaluating whether the lymph node is metastatic based on the metastatic probability.

According to another feature of the invention, the clinical parameters may include the elastic modulus of the lymph nodes to the adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes. In addition, the evaluating step may include calculating a metastatic probability based on the level of the clinical parameter, and statistically evaluating whether the lymph node is metastatic to the individual based on the metastatic probability.

According to another feature of the invention, the metastatic probability can be calculated by the following equation (1).

[Equation 1]

1/1 + e (-A)), A = -4.9621 + (0.1461 크기 the size of the lymph node) + 0.0347 ⅹ the stiffness of the lymph node) + 0.5686 탄성 elastic modulus of the lymph node to the adipose tissue)

According to another feature of the present invention, the lymph node is a sentinel lymph node, and the level of clinical parameters can be measured by ultrasound and a shear wave elastography (SWE) method based thereon. Furthermore, the evaluating step may include evaluating whether the patient has axillary lymph node metastasis based on the level of clinical parameters.

According to another feature of the invention, the clinical parameters may include the size of the monitoring lymph nodes. Further, the evaluating step may include evaluating that the individual has metastatic axillary lymph nodes when the size of the monitoring lymph nodes is 7.5 mm or more.

According to another feature of the invention, the clinical parameters may include stiffness of the monitoring lymph nodes. The evaluating step may include evaluating that the subject has metastatic axillary lymph nodes when the stiffness of the monitoring lymph nodes is 10 kPa or more.

According to another feature of the present invention, the clinical parameter may include the elastic modulus of the surveillance lymph node relative to the surrounding adipose tissue of the monitoring lymph node, and the evaluating step may be performed when the individual has metastatic armpit lymph nodes when the elastic modulus of the monitoring lymph node is 1.5 or more. And evaluating as having.

In order to solve the problems as described above, a device for providing information regarding metastaticity of lymph nodes according to an embodiment of the present invention is provided. The information providing device of the present invention receives a level of three clinical parameters: lymph node elasticity, lymph node size, and lymph node stiffness to adipose tissue, for a biological sample comprising lymph nodes and adipose tissue surrounding the lymph node isolated from the individual. And a processor configured to communicate with the receiver. At this time, the processor is configured to evaluate whether the patient has metastatic lymph nodes based on the level of clinical parameters.

According to a feature of the present invention, the processor may be configured to calculate a lymph node metastatic score based on the clinical parameter level using a nomogram, and to evaluate whether the lymph node is metastatic based on the calculated lymph node metastatic score. According to another feature of the invention, the clinical parameters may include the elastic modulus of the lymph nodes to adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes. Furthermore, the processor may be further configured to calculate the total lymph node metastasis score by summing the lymph node metastatic scores for each of the clinical parameters using the nomogram, and to evaluate whether the lymph nodes are metastatic based on the total lymph node metastatic score. According to another feature of the present invention, the processor may be configured to convert the total lymph node metastatic score to a metastatic probability using a nomogram, and to probabilityly evaluate whether the lymph node is metastatic based on the metastatic probability.

According to another feature of the invention, the clinical parameters include the elastic modulus of the lymph nodes to the adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes, and the processor calculates the metastatic probability based on the level of the clinical parameters, and based on the metastatic probability It can be configured to probabilistically assess the metastasis of lymph nodes to an individual.

According to another feature of the invention, the metastatic probability can be calculated by the following equation (1).

[Equation 1]

1/1 + e (-A)), A = -4.9621 + (0.1461 크기 the size of the lymph node) + 0.0347 ⅹ the stiffness of the lymph node) + 0.5686 탄성 elastic modulus of the lymph node to the adipose tissue)

According to another feature of the invention, the level of the phase parameter can be measured by ultrasound and the SWE method based thereon. Furthermore, the processor can be further configured to evaluate whether the patient has axillary lymph node metastasis based on the level of clinical parameters.

According to another feature of the invention, the clinical parameters may include the size of the monitoring lymph nodes. Furthermore, the processor may be configured to evaluate that the subject has metastatic axillary lymph nodes when the size of the monitoring lymph nodes is 7.5 mm or more.

According to another feature of the invention, clinical parameters may include stiffness of the monitoring lymph nodes. Furthermore, the processor can be configured to evaluate that the subject has metastatic axillary lymph nodes when the stiffness of the monitoring lymph nodes is greater than 10 kPa.

According to another feature of the invention, the clinical parameter may include the elastic modulus of the monitoring lymph node relative to the surrounding adipose tissue of the monitoring lymph node. Further, the processor may be configured to evaluate that the individual has metastatic axillary lymph nodes when the elastic modulus of the monitoring lymph nodes is 1.5 or more.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are only intended to illustrate the present invention by way of example, and the scope of the present invention should not be construed as being limited by these examples.

The present invention has an effect of providing information on armpit lymph node metastasis, which may be an important factor in prognosis of breast cancer. More specifically, as the present invention can provide information on whether the monitoring lymph node is metastatic, the medical staff can more easily determine whether the axillary lymph node is excised.

In addition, the present invention can contribute to reducing the occurrence of side effects, such as lymphedema, serous edema, by reducing unnecessary axillary lymph node dissection.

In particular, the present invention has the effect of overcoming the problems of the conventional lymph node metastasis prediction system, such as surveillance lymph node biopsy, by using SWE. More specifically, the present invention should be performed by an experienced pathologist, and can overcome the shortcomings of surveillance lymph node biopsy, which can lead to an increase in long operating time and cost as expensive equipment may be required. It works.

In addition, the present invention uses a biological sample, such as a surveillance lymph node isolated from an individual, that is, a method using a clinical parameter measured in vivo (i n vivo ) by using an ex vivo measured clinical parameter level. There is an effect that can provide a prediction result of whether the metastasis of a lymph node is more reproducible.

Furthermore, the present invention has an effect capable of providing clinically accurate information than a method using clinical parameters measured in vivo.

On the other hand, the present invention is based on a nomogram configured to predict the metastasis of lymph nodes based on the level of clinical parameters measured in vitro, such as the size of the lymph nodes, the stiffness of the lymph nodes, and the elastic modulus for surrounding adipose tissue. There is an effect that can provide information about.

More specifically, the present invention calculates metastatic scores based on the level of clinical parameters, and provides a nomogram designed to stochastically evaluate the metastasis of lymph nodes to an individual based on the calculated scores. It has the effect of providing a reliable diagnostic evaluation for axillary lymph node metastasis.

Furthermore, the present invention can provide a method for providing information on the metastasis of the lymph nodes of the present invention and a system for predicting lymph node metastasis based on a device using the same, so that medical staff can accurately and quickly determine axillary lymph node incision for an individual regardless of skill level. You can.

The effects according to the present invention are not limited by the contents exemplified above, and more various effects are included in the present specification.

FIG. 1 exemplarily shows a system for predicting lymph node metastasis based on a method and device for providing information on metastasis of a lymph node according to an embodiment of the present invention.
FIG. 2A exemplarily shows a configuration of a device for providing information regarding metastasis of lymph nodes according to an embodiment of the present invention.
Figure 2b is an exemplary input-output of a device for providing information about the metastasis of lymph nodes according to an embodiment of the present invention.
FIG. 3 exemplarily shows a procedure of a method for providing information on metastasis of lymph nodes according to an embodiment of the present invention.
4 exemplarily shows a nomogram used in various embodiments of the present invention.
Figure 5 shows the change in the level of clinical parameters depending on whether the monitoring lymph node metastasis.
6A and 6B show evaluation results of a nomogram used in various embodiments of the present invention.

Advantages and features of the present invention, and methods for achieving them will be clarified with reference to embodiments described below in detail together with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various different forms, and only the present embodiments allow the disclosure of the present invention to be complete, and common knowledge in the art to which the present invention pertains. It is provided to completely inform the person having the scope of the invention, and the present invention is only defined by the scope of the claims.

The shapes, sizes, ratios, angles, numbers, etc. disclosed in the drawings for describing the embodiments of the present invention are exemplary and the present invention is not limited to the illustrated matters. In addition, in the description of the present invention, when it is determined that detailed descriptions of related known technologies may unnecessarily obscure the subject matter of the present invention, detailed descriptions thereof will be omitted. When 'include', 'have', 'consist of', etc. mentioned in this specification are used, other parts may be added unless '~ man' is used. When a component is expressed as a singular number, the plural number is included unless otherwise specified.

In analyzing the components, it is interpreted as including the error range even if there is no explicit description.

Each of the features of the various embodiments of the present invention may be partially or totally combined with or combined with each other, and technically various interlocking and driving may be possible as those skilled in the art can fully understand, and each of the embodiments may be independently implemented with respect to each other. It can also be implemented together in an association relationship.

For clarity of interpretation of the present specification, hereinafter, terms used in the specification will be defined.

As used herein, the term “individual” may refer to a subject who wishes to evaluate whether lymph node metastasis has occurred. On the other hand, in the present specification, the individual is an individual who has developed breast cancer clinically, and may be an object to predict metastasis of the axillary lymph nodes. However, it is not limited thereto.

As used herein, the term “biological sample” may refer to a sample isolated from the individual in order to assess in vitro whether the patient has lymph node metastasis. More specifically, a biological sample within the present specification may include lymph nodes isolated from an individual and adipose tissue surrounding the lymph nodes. However, the biological sample is not limited thereto, and a variety of samples may be used as the biological sample, as long as the lymph node metastasis can be evaluated by measuring clinical parameters. For example, the biological sample may be cancerous tissue present in the lymph node.

 As used herein, the term “clinical parameter” may mean a clinical variable associated with metastasis of lymph nodes. More specifically, the clinical parameter may be a clinical variable associated with metastasis of the sentinel lymph node, which can provide information about axillary lymph node resection.

For example, the clinical parameter is a level of a parameter measured for a biological sample including lymph nodes and surrounding adipose tissue of the lymph node, and may be at least one of a lymph node elastic modulus, a lymph node size, and a lymph node stiffness to the adipose tissue. . More specifically, metastatic lymph nodes may have a higher cell density than non-metastatic lymph nodes (or surrounding adipose tissue). Accordingly, metastatic lymph nodes may have a relatively large size, high stiffness, and high elastic modulus compared to non-metastatic lymph nodes. Accordingly, the level of the clinical parameter as described above may provide information regarding metastasis of the lymph node.

Meanwhile, the lymph nodes disclosed in the specification of the present invention may be surveillance lymph nodes. More specifically, the clinical parameter of the present invention may be at least one of elastic modulus of adipose tissue of the monitoring lymph node, size of the monitoring lymph node, and stiffness of the monitoring lymph node. Preferably, the clinical parameters of the present invention may include all modulus of elasticity of the monitoring lymph nodes to adipose tissue, size of the monitoring lymph nodes, and stiffness of the monitoring lymph nodes.

Meanwhile, the level of the clinical parameter of the present invention may be measured by a shear wave elastography (SWE) or magnetic resonance elastography (MRE) method. Preferably, the level of clinical parameters of the present invention can be measured by SWE. For example, surveillance lymph nodes isolated from individuals identified as breast cancer can be measured in vitro by the level of clinical parameters by the SWE method.

The term “nomogram” used in the present specification may mean a model constructed to receive and output a level of clinical parameter with a probability of predicting lymph node metastasis to an individual based on the level.

More specifically, the nomogram disclosed herein uses the level of clinical parameters such as the elasticity of the lymph nodes to the adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes as variables to correlate the level of these parameters with the lymph node metastasis. And can be configured to stochastically predict lymph node metastasis.

For example, the nomogram calculates a lymph node metastasis score based on each of the levels of clinical parameters of the monitoring lymph node's elasticity to adipose tissue, the size of the monitoring lymph node, and the stiffness of the monitoring lymph node, and summing each lymph node metastasis score The total lymph node metastatic score may be calculated, and the total lymph node metastatic score may be converted to a lymph node metastatic probability, and finally, an individual may be configured to stochastically calculate whether the patient has metastasis to a monitored lymph node.

On the other hand, the nomogram of the present invention, 'input nomogram' configured to receive the level of clinical parameters such as the elasticity of the lymph nodes to the adipose tissue, the size of the lymph nodes and the stiffness of the lymph nodes, and the lymph node metastatic score based on the clinical parameters and It may be composed of an 'output nomogram' configured to calculate and output the lymph node metastatic probability. However, the configuration of the nomogram of the present invention is not limited thereto.

Hereinafter, with reference to FIGS. 1, 2A, and 2B, a device for providing information on metastasis of lymph nodes according to an embodiment of the present invention and a lymph node metastasis prediction system using the same will be described in detail.

FIG. 1 exemplarily shows a system for predicting lymph node metastasis based on a method and device for providing information on metastasis of a lymph node according to an embodiment of the present invention. FIG. 2A exemplarily shows a configuration of a device for providing information regarding metastasis of lymph nodes according to an embodiment of the present invention. Figure 2b is an exemplary input-output of a device for providing information about the metastasis of lymph nodes according to an embodiment of the present invention.

First, referring to FIG. 1, the lymph node metastasis prediction system 1000 according to an embodiment of the present invention is obtained from a device 100 for providing information about metastasis of a lymph node, an elasticity measurement apparatus 200 and an individual It consists of lymph nodes (300).

More specifically, in the lymph node metastasis prediction system 1000, the device 100 for providing information about the metastasis of the lymph nodes, the lymph node 300 separated from the individual, for example, the elasticity measurement device 200 for the monitoring lymph nodes 200 It can be configured to receive a level of various clinical parameters measured by. At this time, the elasticity measuring device 200 may be an ultrasonic device capable of performing the SWE mode, but is not limited thereto. Meanwhile, the device 100 for providing information regarding the metastasis of the lymph node may be further configured to evaluate whether the lymph node is metastatic based on the level of the clinical parameter of the lymph node 300 of the individual measured in vitro.

For example, the device 100 for providing information about the metastasis of the lymph nodes calculates the lymph node metastasis scores based on the size of the lymph nodes, the average stiffness, and the elasticity of the lymph nodes to surrounding adipose tissue, and based on this, the armpit lymph nodes It can be configured to calculate the metastatic probability and output it.

Accordingly, the medical staff, on the basis of the probabilistic information about the lymph node metastasis output by the device 100 for providing information about the metastasis of the lymph node, that is, the metastatic probability of the lymph node, confirms the metastatic lymph node axilla for the individual, and the armpit lymph node It is easy to decide whether or not to perform an incision.

More specifically, referring to FIG. 2A, the device 100 for providing information regarding the metastasis of lymph nodes includes a receiving unit 110, an input unit 120, an output unit 130, a storage unit 140, and a processor 150. Includes.

Specifically, the receiving unit 110 to receive the level of at least one clinical parameter of the elasticity of the lymph node to the adipose tissue, the size of the lymph node and the stiffness of the lymph node, measured for the lymph node 300 from the elasticity measuring device 200 Can be configured.

The input unit 120 is not limited, such as a keyboard, mouse, and touch screen panel. The input unit 120 may set the device 100 for providing information about the metastasis of the lymph nodes, and may instruct the operation of the device 100 for providing information about the metastasis of the lymph nodes. On the other hand, the input unit 120 may be further configured to directly receive the level of clinical parameters such as the elasticity of the lymph nodes, the size of the lymph nodes, and the stiffness of the lymph nodes with respect to the adipose tissue previously measured for the lymph nodes 300.

The output unit 130 may be configured to display the level of the clinical parameter of at least one of the elastic modulus of the lymph node to the adipose tissue, the size of the lymph node, and the stiffness of the lymph node, received by the receiving unit 110. Furthermore, the output unit 130 may display a lymph node metastatic score, a lymph node metastatic probability, and the like calculated by the processor 150. That is, the output unit 130 may display information associated with lymph node metastasis predicted by the processor 150 on a display.

On the other hand, in various embodiments of the present invention, the device 100 for providing information regarding the metastasis of lymph nodes, the input unit 120 and the output unit 130 may be provided as a touch screen panel. That is, the device 100 for providing information regarding the metastasis of the lymph nodes may be configured to allow input-output simultaneously. For example, referring to FIG. 2B, the medical staff may directly input the level of clinical parameters for the lymph node 300 measured from the outside through the input monogram 122, and will be described later through the output monogram 132. Information associated with lymph node metastasis predicted by processor 150 may be identified.

The storage unit 140 stores the level of clinical parameters for the lymph node 300 received through the receiving unit 110, and instructs the device 100 for providing information regarding the metastasis of the lymph node set through the input unit 120. It can be configured to store. Furthermore, the storage 140 may be further configured to store the level of clinical parameters previously measured for the lymph node 300, input to the input 120. In addition, the storage 140 may be configured to store information associated with the lymph node metastatic score, lymph node metastatic probability, and lymph node metastasis calculated by the processor 150 to be described later. However, the present invention is not limited to the above, and the storage unit 140 may store various information determined by the processor 150.

The processor 150 may be a component for providing accurate prediction results of the device 100 for providing information about metastasis of lymph nodes. At this time, the processor 150 is configured to calculate the lymph node metastasis score using a nomogram configured to calculate the lymph node metastatic score based on the level of the clinical parameter, and to evaluate whether the lymph node metastasis is based on the calculated lymph node metastatic score. Can be.

According to one embodiment of the present invention, the processor 150 calculates a total lymph node metastatic score by summing the lymph node metastatic scores for each of the clinical parameters using a nomogram, and metastatic lymph nodes based on the total lymph node metastatic score. It can be further configured to evaluate whether or not.

According to another embodiment of the present invention, the processor 150 may be further envisioned to convert a total lymph node metastatic score into a metastatic probability using a nomogram, and to probabilistically evaluate whether the lymph node is metastatic based on the metastatic probability. You can.

According to another embodiment of the present invention, the processor 150 may be further configured to determine whether metastatic axillary lymph nodes are based on the level of clinical parameters. For example, the processor 150 may be configured to evaluate that when the size of the monitoring lymph node is 7.5 mm or more, the metastatic probability for the axillary lymph node is higher than that of an individual having a lymph node having a size of the monitoring lymph node of less than 7.5 mm. Furthermore, the processor 150 may be configured to evaluate that when the stiffness of the monitoring lymph node is 10 kPa or more, the metastatic probability of the axillary lymph node is higher than that of an individual having a lymph node having the stiffness of the monitoring lymph node of less than 10 kPa. Further, further, the processor 150 may be configured to evaluate that the metastatic probability of the axillary lymph node is higher than that of an individual having the elastic modulus of less than 1.5 when the elastic modulus of the monitoring lymph node to surrounding fat tissue of the monitoring lymph node is 1.5 or more.

As such, the processor 150 may provide medical personnel with information related to lymph node metastasis, particularly armpit lymph node metastasis, so that medical personnel can more easily determine whether the subject has an axillary lymph node incision.

Hereinafter, with reference to FIG. 3, a method of providing information on metastatic properties of lymph nodes according to an embodiment of the present invention will be described in detail. FIG. 3 exemplarily shows a procedure of a method for providing information on metastasis of lymph nodes according to an embodiment of the present invention.

Referring to FIG. 3, a method of providing information on metastaticity of a lymph node according to an embodiment of the present invention is first performed on a biological sample including a lymph node separated from an individual and adipose tissue surrounding the lymph node, and the elastic modulus of the lymph node with respect to adipose tissue , The level of the clinical parameter of at least one of the size of the lymph node and the stiffness of the lymph node is measured (S310), and the level of the clinical parameter is input to a nomogram configured to calculate a lymph node metastatic score based on the level of the clinical parameter (S320). ). Then, using the nomogram, the lymph node metastatic score is calculated based on the input clinical parameter level (S330), and finally, the metastatic status of the lymph node is evaluated based on the lymph node metastatic score (S340).

More specifically, in the measuring step (S310), at least one of the elastic modulus for the lymph node, the size of the lymph node, and the stiffness of the lymph node may be measured by using an ultrasound-based elasticity measuring device capable of performing the SWE mode.

According to a feature of the present invention, in the measuring step (S310), a monitoring lymph node is used as a biological sample, and thus the elastic modulus, the size of the lymph node and the stiffness of the lymph node can be measured.

Next, in the step of inputting the level of the clinical parameter (S320), the level of the clinical parameter of at least one of the elastic modulus for the lymph node, the size of the lymph node, and the stiffness of the lymph node obtained in the measuring step (S310) described above is nomo. It can be entered in grams. At this time, the nomogram may be a model constructed to receive a level of clinical parameters and to predict and output whether the patient has lymph node metastasis based on the probability.

On the other hand, according to the feature of the present invention, in the step of inputting the level of the clinical parameter (S320), the level of the clinical parameter of at least one of the elastic modulus, the size of the lymph node, and the stiffness of the lymph node through the input nomogram is measured. Can be entered.

Next, in the step of calculating the lymph node metastatic score (S330), the lymph node metastatic score for each level of the input clinical parameter is calculated by the nomogram.

According to a feature of the present invention, in the step of calculating the lymph node metastatic score (S330), the lymph node metastatic score for each of the clinical parameters may be summed to calculate the total lymph node metastatic score.

Meanwhile, according to another feature of the present invention, after the step of calculating the lymph node metastatic score (S330), a step of converting the total lymph node metastatic score to a metastatic probability using a nomogram may be further performed.

More specifically, in the step of converting to probability, the probability of lymph node metastasis is transformed by a nomogram constructed to estimate the correlation between the level of each clinical parameter (lymph node metastasis score) and lymph node metastasis, and to predict lymph node metastasis stochastically. Can be.

According to a feature of the present invention, the metastatic probability of lymph node in the step of converting to probability may be calculated based on raw data of the level of clinical parameters by the following [Equation 1].

[Equation 1]

1/1 + e (-A)), A = -4.9621 + (0.146146 lymph node size) + 0.0347ⅹ lymph node stiffness) + 0.5686ⅹ elasticity of lymph nodes to adipose tissue)

That is, based on the size of the lymph node (mm), the stiffness of the lymph node (kPa), and the elastic modulus of the lymph node, a probability for lymph node metastasis can be calculated.

Finally, in the step of evaluating the metastasis of the lymph nodes (S340), whether the lymph node metastasis to the individual can be evaluated based on the lymph node metastatic score for each of the clinical parameters calculated in the step (S330) of calculating the lymph node metastatic score. have.

According to a feature of the present invention, in the step (S340) of evaluating whether a lymph node is metastatic, based on the total lymph node metastatic score, whether the patient has metastatic lymph nodes can be evaluated.

According to another feature of the present invention, in the step (S340) of evaluating whether the lymph node is metastatic, the step of probabilistically evaluating whether the lymph node is metastatic based on the metastatic probability calculated by the above-described nomogram may be further performed. have.

On the other hand, the method for providing information on the metastasis of lymph nodes of the present invention is not limited thereto. For example, according to another embodiment of the present invention, the method for providing information regarding the metastasis of the lymph nodes of the present invention is based on the level of clinical parameters measured in vitro for lymph nodes isolated from individuals without the use of nomograms. It can be configured to provide information about metastasis.

More specifically, according to another embodiment of the present invention, the method for providing information of the present invention, when the size of the monitored lymph node is determined to be 7.5 mm or more, metastatic to the axillary lymph node than an individual having a lymph node having a size of the monitored lymph node of less than 7.5 mm It can be configured to evaluate as having a high probability. Furthermore, the method for providing information of the present invention may be configured to evaluate that when the stiffness of the monitoring lymph node is 10 kPa or more, the metastatic probability of the axillary lymph node is higher than that of an individual having a lymph node having the stiffness of the monitoring lymph node of less than 10 kPa. In addition, the method for providing information of the present invention is configured to evaluate that when the elasticity modulus of the monitoring lymph node with respect to the surrounding adipose tissue of the monitoring lymph node is 1.5 or more, the metastatic probability of axillary lymph nodes is higher than that of the individual having the elastic modulus of less than 1.5. You can.

According to the above procedure, a method for providing information regarding a treatment response according to an embodiment of the present invention may provide information on lymph node metastasis, particularly armpit lymph node metastasis. Accordingly, the medical staff can more easily determine whether the subject has an axillary lymph node incision.

Hereinafter, the configuration of the nomogram used in various embodiments of the present invention will be described in more detail. 4 exemplarily shows a nomogram used in various embodiments of the present invention.

Referring to FIG. 4, the nomogram 400 includes a lymph node metastatic score axis 410, a lymph node size axis 420, an average stiffness axis 430, an elastic modulus axis 440, a total lymph node metastatic score axis 450, and Lymph node metastatic probability axis 460.

More specifically, each level of clinical parameters appearing on the lymph node size axis 420, the average stiffness axis 430, and the elastic modulus axis 440 may be converted and displayed on the lymph node metastatic score axis 410. Furthermore, scores for each of the clinical parameters can be summed and displayed on the total lymph node metastatic score axis 450. Finally, the lymph node metastatic probability transformed according to the total lymph node metastatic score can be displayed on the lymph node metastatic probability axis 460.

Accordingly, the medical staff may determine whether the patient has an axillary lymph node resection based on the lymph node metastatic probability of the lymph node output to the lymph node metastatic probability axis 460.

Example 1: Setting of clinical parameters for predicting lymph node metastasis

Hereinafter, clinical parameters used in various embodiments of the present invention will be described in detail with reference to FIG. 5 and Table 1. Figure 5 shows the change in the level of clinical parameters depending on whether the metastasis of the axillary lymph nodes.

At this time, in order to observe changes in clinical parameters related to the presence or absence of metastatic lymph nodes, clinical data on 228 axillary lymph nodes obtained from a total of 55 breast cancer patients was used.

Referring to Table 1 below, according to the presence or absence of metastasis of 228 axillary lymph nodes, lymph node size, average stiffness, and elastic modulus for surrounding adipose tissue are shown.

 [Table 1]

Referring to FIG. 5 (a) and [Table 1], metastasized axillary lymph nodes (Macro) of -2.0 mm or more appear to have a larger lymph node size than non-metastatic lymph nodes (Non meta + Micro) of less than 0.2 mm. (1050 mm vs 7.52 mm). On the other hand, referring to (b) and [Table 1] of FIG. 5, metastasized axillary lymph nodes (Macro) of 2.0 mm or more have an average stiffness of about 2 times that of non-metastatic lymph nodes (Non meta + Micro) of less than 0.2 mm. It appears to be abnormally high. That is, the average stiffness of metastatic surveillance lymph nodes appears to be significantly higher than that of non-metastatic lymph nodes (45.41 vs 17.69 kPa). 5 (c) and [Table 1], 2.0 mm or more of metastasized axillary lymph nodes (Macro), non-metastatic lymph nodes less than 0.2 mm (Non meta + Micro) elastic modulus for adipose tissue is about 3 It appears to be high. In other words, the elastic modulus of metastatic surveillance lymph nodes appears to be significantly higher than that of non-metastatic lymph nodes (4.36 vs 1.57). These results may be associated with the increased cell density of metastatic surveillance lymph nodes compared to non-metastatic surveillance lymph nodes.

Through Example 1 above, it was confirmed that the size of the lymph nodes, the stiffness of the lymph nodes, and the modulus of elasticity of the metastatic monitoring lymph nodes and non-metastatic monitoring lymph nodes appear to show significant differences in vitro.

Accordingly, the size of the lymph nodes measured in vitro, the average stiffness and elastic modulus of the lymph nodes were set as clinical parameters for the prediction of lymph node metastasis, particularly the metastasis of the axillary lymph nodes in various embodiments of the present invention.

Accordingly, the present invention is more reproducible than a method using clinical parameters measured in vivo (i n vivo ), as biological samples such as surveillance lymph nodes isolated from an individual, that is, using clinical parameter levels measured ex vivo It may provide a predicted result of high lymph node metastasis.

Example 2: Evaluation of nomogram used in various examples of the present invention

Hereinafter, evaluation results of the nomogram used in various embodiments of the present invention will be described in detail with reference to FIGS. 6A and 6B. 6A and 6B show evaluation results of a nomogram used in various embodiments of the present invention.

In this evaluation, a nomogram based on a 'Dvelopment cohort' constructed based on clinical parameters measured in vitro for lymph nodes obtained from 55 breast cancer patients and 80 breast cancer patients different from the construct cohort Evaluation of each of the nomograms based on a 'Validation cohort' built on the basis of clinical parameters of 217 surveillance lymph nodes was performed.

More specifically, the clinical and pathological features between the Kuchuk cohort and the validation cohort are shown in Table 2 below.

[Table 2]

Referring to (a) of FIG. 6A, in the construction cohort, the AUC (Area Under the Curve) value of the ROC curve for the nomogram according to various embodiments of the present invention is as high as 0.8559 (95% reliability, 0.783-0.929) Level. In this case, the AUC value may refer to a hit ratio associated with excellent diagnostic ability. That is, the nomogram configured to predict whether or not to metastasize lymph nodes based on the level of clinical parameters for the lymph nodes appears to have excellent diagnostic ability.

Referring to (b) of FIG. 6A, a result of performing internal validation using 200 bootstrap samples for a nomogram according to various embodiments of the present invention in a construction cohort is illustrated. More specifically, the average absolute error of the nomogram in the construction cohort appears to be very low, 0.029. In addition, the calibration plot of the nomogram indicated by the solid line appears to have a value close to that of the logistic calibration indicated by the dotted line. That is, the nomogram of the present invention can more accurately predict the probability of lymph node metastasis based on the level of clinical parameters for the monitoring lymph nodes.

Referring to FIG. 6B (a), in the verification cohort, the AUC value of the ROC curve for the nomogram according to various embodiments of the present invention is shown to be high at 0.791 (95% reliability, 0.668-0.915). That is, the nomogram configured to predict whether or not to metastasize lymph nodes based on the level of clinical parameters for the lymph nodes appears to have excellent diagnostic ability.

Referring to (b) of FIG. 6B, a result of performing internal validation using 200 bootstrap samples with respect to a nomogram according to various embodiments of the present invention in a verification cohort is illustrated. More specifically, the calibration plot of the nomogram indicated by the dotted line appears to have a value close to that of the logistic calibration indicated by the solid line. That is, the nomogram of the present invention can more accurately predict the probability of lymph node metastasis based on the level of clinical parameters for the monitoring lymph nodes.

As a result of the above Example 2, it was confirmed that the nomogram used in various examples of the present invention predicts the lymph node metastasis with an accurate probability, in particular, about the lymph node metastasis of the armpit. Furthermore, according to the results shown to have a high AUC value, it was confirmed that the nomogram of the present invention has excellent diagnostic ability.

According to the results of Examples 1 and 2, the present invention is configured to predict the metastasis of lymph nodes based on the level of clinical parameters measured in vitro, such as the size of the lymph nodes, the stiffness of the lymph nodes, and the elasticity to surrounding adipose tissue. By using the nomogram, there is an effect that can provide accurate information about whether the lymph node metastases.

More specifically, the present invention calculates metastatic scores based on the level of clinical parameters, and provides a nomogram designed to stochastically evaluate the metastasis of lymph nodes to an individual based on the calculated scores. It has the effect of providing a reliable diagnostic evaluation for axillary lymph node metastasis.

Furthermore, the present invention can provide a method for providing information on the metastasis of the lymph nodes of the present invention and a system for predicting lymph node metastasis based on a device using the same, so that medical staff can accurately and quickly determine axillary lymph node incision for an individual regardless of skill level. You can.

Each of the features of the various embodiments of the present invention may be partially or totally combined or combined with each other, and technically various interlocking and driving may be possible as those skilled in the art can fully understand, and each of the embodiments may be implemented independently of each other. And may be feasible together.

The embodiments of the present invention have been described in more detail with reference to the accompanying drawings, but the present invention is not necessarily limited to these embodiments, and may be variously modified without departing from the technical spirit of the present invention. . Therefore, the embodiments disclosed in the present invention are not intended to limit the technical spirit of the present invention, but to explain, and the scope of the technical spirit of the present invention is not limited by these embodiments. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of protection of the present invention should be interpreted by the claims below, and all technical spirits within the scope equivalent thereto should be interpreted as being included in the scope of the present invention.

Claims (20)

For a biological sample comprising lymph nodes isolated from an individual and adipose tissue surrounding the lymph nodes, measuring a level of clinical parameters of at least one of the elastic modulus of the lymph nodes to the adipose tissue, the size of the lymph nodes, and the stiffness of the lymph nodes. ; And
And evaluating whether the patient has lymph node metastasis to the individual based on the measured level of the clinical parameter. According to claim 1,
The evaluation step,
Inputting a level of the clinical parameter into a nomogram configured to calculate a lymph node metastatic score based on the level of the clinical parameter,
Calculating the lymph node metastatic score based on the entered clinical parameter level, using the nomogram, and
Comprising the step of evaluating whether the metastasis of the lymph node based on the calculated lymph node metastasis score, method for providing information about the metastasis of the lymph node According to claim 2,
The clinical parameters,
Elastic modulus of the lymph node to the adipose tissue, size of the lymph node and stiffness of the lymph node,
Calculating the lymph node metastatic score,
Using the nomogram, further comprising the step of summing the lymph node metastatic score for each of the clinical parameters to calculate a total lymph node metastatic score,
The step of evaluating the metastatic status of the lymph node based on the metastatic score of the lymph node,
And evaluating whether the lymph node is metastatic based on the total lymph node metastatic score. According to claim 3,
Performed after the step of calculating the total lymph node metastatic score,
Using the nomogram, further comprising converting the total lymph node metastatic score to metastatic probability,
The step of evaluating the metastatic status of the lymph node based on the metastatic score of the lymph node,
And probabilistically evaluating whether the lymph node is metastatic based on the metastatic probability. According to claim 1,
The clinical parameters,
Elastic modulus of the lymph node to the adipose tissue, size of the lymph node and stiffness of the lymph node,
The evaluation step,
Calculating a metastatic probability based on the level of the clinical parameter, and
And probabilistically evaluating whether the lymph node is metastatic to the individual based on the metastatic probability. The method of claim 5,
The metastatic probability is calculated by the following equation (1), a method for providing information on metastasis of lymph nodes.
[Equation 1]
1/1 + e (-A)), A = -4.9621 + (0.1461 크기 the size of the lymph node) + 0.0347 ⅹ the stiffness of the lymph node) + 0.5686 탄성 elastic modulus of the lymph node to the adipose tissue) According to claim 1,
The lymph node is a sentinel lymph node,
The level of the clinical parameter is measured by at least one of ultrasound, shear wave elastography (SWE) and magnetic resonance elastography (MRE) methods,
The evaluation step,
And evaluating whether the patient has axillary lymph node metastasis to the individual based on the level of the clinical parameter. The method of claim 7,
The clinical parameters,
The size of the monitoring lymph nodes,
The evaluation step,
And when the size of the monitoring lymph node is 7.5 mm or more, evaluating that the individual has metastatic axillary lymph node, the method of providing information about the metastasis of the lymph node. The method of claim 7,
The clinical parameters,
The stiffness of the monitoring lymph nodes,
The evaluation step,
And when the stiffness of the monitoring lymph node is 10 kPa or more, evaluating that the individual has metastatic axillary lymph node, the method of providing information about the metastasis of the lymph node. The method of claim 7,
The clinical parameters,
The elastic modulus of the monitoring lymph node relative to the surrounding adipose tissue of the monitoring lymph node,
The evaluation step,
And if the elastic modulus of the monitoring lymph node is 1.5 or more, evaluating that the individual has metastatic axillary lymph node, a method of providing information regarding metastasis of the lymph node. For a biological sample comprising lymph nodes isolated from an individual and adipose tissue surrounding the lymph nodes, configured to receive a level of clinical parameter of at least one of: the elastic modulus of the lymph node to the adipose tissue, the size of the lymph node and the stiffness of the lymph node Receiver, and
And a processor configured to communicate with the receiver,
The processor,
A device for providing information regarding the metastasis of a lymph node, configured to evaluate whether the patient has metastatic lymph nodes based on the level of the clinical parameter. The method of claim 11,
The processor,
The lymph node metastasis score is calculated using a nomogram configured to calculate a lymph node metastatic score based on the level of the clinical parameter, and the metastasis of the lymph node is configured to evaluate whether the lymph node is metastatic based on the calculated lymph node metastatic score. Device for providing information about. The method of claim 12,
The clinical parameters,
Elastic modulus of the lymph node to the adipose tissue, size of the lymph node and stiffness of the lymph node,
The processor,
Using the nomogram, the lymph node metastasis score for each of the clinical parameters is summed to calculate a total lymph node metastasis score, and further configured to evaluate whether the lymph node is metastatic or not based on the total lymph node metastasis score. Device for providing information about. The method of claim 13,
The processor,
A device for providing information about metastasis of a lymph node, further configured to convert the total lymph node metastatic score to a metastatic probability using the nomogram, and to probabilityly evaluate whether the lymph node is metastatic based on the metastatic probability The method of claim 11,
The clinical parameters,
Elastic modulus of the lymph node to the adipose tissue, size of the lymph node and stiffness of the lymph node,
The processor,
A device for providing information regarding metastasis of a lymph node, further configured to calculate metastatic probability based on the level of the clinical parameter and to probabilistically evaluate whether the lymph node is metastatic to the individual based on the metastatic probability. The method of claim 15,
The metastatic probability is calculated by the following equation (1), a device for providing information about the metastasis of lymph nodes.
[Equation 1]
1/1 + e (-A)), A = -4.9621 + (0.1461 크기 the size of the lymph node) + 0.0347 ⅹ the stiffness of the lymph node) + 0.5686 탄성 elastic modulus of the lymph node to the adipose tissue) The method of claim 11,
The lymph node is a monitoring lymph node,
The level of the clinical parameter is measured by SWE or MRE method,
The processor is further configured to evaluate whether a patient has axillary lymph node metastasis to an individual based on the level of clinical parameters. The method of claim 17,
The clinical parameters,
The size of the monitoring lymph nodes,
The processor,
A device for providing information about metastasis of lymph nodes, further configured to evaluate that the individual has metastatic axillary lymph nodes when the size of the monitoring lymph nodes is 7.5 mm or more. The method of claim 17,
The clinical parameters,
The stiffness of the monitoring lymph nodes,
The processor,
A device for providing information about metastasis of lymph nodes, further configured to evaluate that the individual has metastatic axillary lymph nodes when the stiffness of the monitoring lymph nodes is 10 kPa or more. The method of claim 17,
The elastic modulus of the monitoring lymph node relative to the surrounding adipose tissue of the monitoring lymph node,
The processor,
A device for providing information about metastasis of lymph nodes, further configured to evaluate that the individual has metastatic axillary lymph nodes when the elastic modulus of the monitoring lymph nodes is 1.5 or more.

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