Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Patients with breast cancer underwent sentinel lymph node biopsy

Sentinel lymph node detector using photoacoustic signal

Photoacoustic finder

Dooreh Kim, MD

Determining the prognosis of breast cancer relies significantly on axillary staging by sentinel lymph node biopsy (SLNb). The SLNb is generally performed using radioisotopes, blue dyes, or both to improve the false negative rate. However, a gamma probe with radioisotopes involves ionizing radiation, and blue dye detection relies on visual inspection by an operator. To overcome these limitations, the photoacoustic finder (PAF) was developed as a highly sensitive, non-radioactive detector that uses only blue dye and a photoacoustic signal to detect SLNs. To evaluate the PAF, its performance was compared with the standard SLN detection method for breast cancer patients.

-Introduction The presence of lymphatic metastases in breast cancer patients is an important prognostic factor for survival, and accurate staging leads to appropriate adjuvant treatment. Sentinel lymph node biopsy (SLNb) is a standard method used to confirm regional axillary lymphatic metastases in breast cancer patients. Sentinel lymph nodes (SLNs) are a group of initial lymph nodes (LNs) located in proximity to the tumor and connected via lymphatic vessels (LVs), hypothetically the first ones that a primary tumor drains in the regional lymphatic basin. If metastatic tumor cells are not confirmed in the excised SLNs, the incidence of morbidities, such as lymphedema, can be reduced by omitting unnecessary axillary lymph node dissection (ALND). The SLNb procedure is a dual-modal method utilizing a radioactive tracer (e.g., 99mTc) and/or blue dye to identify the SLNs. The radioactive tracer and blue dye are administered before surgery and absorbed by the lymphatic system, and eventually they flow into the SLNs. During the surgical procedures, the SLNs are identified through visual inspection of blue-dyed LVs and radioactivity detection using a gamma probe. The identified SLNs are subsequently excised and sent for pathological examination to assess the potential metastatic tumor.

The dual-modal method enhances the accuracy and efficiency of SLN identification by leveraging the distinct advantages of each method. However, the radioactive isotopes in the SLNb surgery present an inherent radiation exposure risk and necessitate specialized facilities and skilled medical personnel. These factors introduce complexities into the surgical procedure and create obstacles for the implementation of SLNb in local hospitals. Moreover, the administration of radioactive material typically requires cooperation with a nuclear medicine department, which restricts direct usage by the surgeon and may impact surgical scheduling. Lastly, because radioactive isotopes do not provide visual information, the intuitive identification of SLNs is challenging. On the other hand, blue dye visually stains the lymphatic network, enabling the intuitive identification of SLNs without radiation exposure. However, relying on visual inspection of blue-dyed SLNs may introduce inter-physician variability and potential inaccuracies in identifying SLNs, owing to variable lesion characteristics such as the presence of adipose tissue and blood. These limitations make it challenging to see blue dye within LNs, ultimately leading to reduced sensitivity in the SLN detection.

Photoacoustic (PA) imaging or sensing is a non-ionizing technique that utilizes the intrinsic light absorption properties of biological tissue components . To generate PA signals, a nanosecond pulsed laser induces repeated instantaneous thermal expansions within a sample, creating acoustic waves . These acoustic waves are then captured by an ultrasound transducer and analyzed to confirm the presence of specific constituents within the sample. PA sensing technology can detect dye-stained LNs with high sensitivity and provide a real-time quantitative representation. This method can precisely determine the presence or absence of dyed SLNs that may have been indistinguishable through visual inspection. Consequently, it can facilitate SLNb procedures without radioactive materials. In our previous studies, a cutting-edge system known as the photoacoustic finder (PAF) was successfully deviesed. It is remarkably efficacious in detecting SLNs while maintaining a high signal-to-noise ratio (SNR). The PAF combines a solid-state dye (SSD) laser handpiece and a transparent ultrasound transducer (TUT) in a precisely coaxial configuration. This study describes preclinical trials of the PAF, which confirmed its ability to accurately detect blue-dyed SLNs.

This cross-sectional clinical study was conducted ex vivo to validate the feasibility of using the PAF in a clinical setting. The process confirms the signal from excised LNs identified by the dual-modal method and the PAF before sending them to pathology. To determine its detection performance, the effectiveness of PAF is compared to the detection rate of standard SLNb. The results establish the clinical feasibility of using PAF for SLNb, providing a non-radioactive alternative.

-Study design: This study was conducted as a cross-sectional, open-label, single-arm ex vivo study within a single institution to investigate the efficacy of PAF compared to standard dual-modal methods for SLN detection in the treatment of breast cancer. The SLNb procedures followed international guidelines, using both radioisotope and blue dye mapping. SLNs were identified using gamma probe and blue dye visual inspection, then resected and labeled to reconfirm the with gamma probe and blue dye visual inspection. Subsequently, PAF was employed to capture signals from the LNs. To minimize potential errors such as labeling mistakes and LN delivery errors, the PAF system was placed in the operating room. The study enrolled women diagnosed with breast cancer who presented to the Department of Breast Surgery at St. Mary's Hospital, Seoul, The Republic of Korea.

-Sentinel lymphnode biopsy: The SLNb was performed in accordance with established international guidelines, utilizing both radioisotope and blue dye mapping methods. Five surgical oncologists participated in the study, all of whom were experienced in performing standard dual-modal SLNb and understood the clinical protocol. The radioisotope (0.1 mL of 99mTc-phytate) was administered into the subdermal lymphatic flexus under the areola within 30 minutes to 8 hours prior to operation. When the surgery started, the operator confirmed the location of the tumor. Then, a blue dye (indigo carmine, 2-5 ml) was injected peritumorally or periareolarly prior to incision, with subsequent massaging for 1 minute following injection. The axillary nodal basin was closely examined using a handheld gamma probe to detect radioactive signals and visually examined by the naked eye to detect grossly blue-dyed LNs. The identification of SLNs continued until either no further signal was detected by the gamma probe or blue-dyed LNs were no longer found in the nodal basins within the operation field. For this study, SLNs were defined as LNs with a gamma probe signal greater than 10% of the maximum signal value and/or visibly stained with blue dye. Additionally, based on the surgeon's experience, abnormally palpable LNs that were not detected by gamma probe and visual inspection were also excised, and these were labeled as non-SLNs. The SLNs and non-SLNs were further examined by PAF, and subsequently were forwarded to the pathology department for frozen section analysis.

-Sample Size: To determine the required sample size for testing the non-inferiority of PAF and the dual-modal method, the non-inferiority chi-square sample size estimator was utilized, employing a non-inferiority margin of 5%, a significance level (alpha) of 5%, and a power (1-beta) of 80%. Drawing from prior research and based on experimental data from tests, it was assumed that the visual detection rate would be approximately 78% for SLNs and 84% for PAF. Calculations revealed that a total of 157 SLNs would be necessary, corresponding to approximately 1.5 SLNs per patient, thus requiring the enrollment of 115 patients to fulfill the sample size requirements with an anticipated 10% drop-out.

-Static Analysis Methods:

The primary endpoints, which were the SLN detection rates for the gamma probe, visual inspection, and PAF were defined as follows:

Detection rate= (Number of detected SLNs)/(Total number of SLNs) ×100 \[%\]

The secondary endpoints encompassed the results of a non-inferiority analysis conducted using the chi-square test. Additionally, the sensitivity and specificity were assessed through ROC curve analysis as part of the additional endpoints. Regarding primary and secondary endpoints, SLNs were specifically examined, excluding non-SLNs to minimize potential surgeon subjectivity.

The Wilcoxon Mann-Whitney U-Test was performed to determine the cutoff for the PAF, and the statistical significances between 99mTc+/-, blue+/-, and non-injected groups were compared. In a non-inferiority analysis, a chi-square test was performed to compare the risk differences for 99mTc+, blue+, and PAF+ nodes. The independent samples t-test was used for other normal distributions, such as age and BMI. All statistical analyses in this study were conducted using MATLAB R2022a with the Statistics and Machine Learning Toolbox.

A Clinical Feasibility Study of a Photoacoustic Finder

Clinical Utility of Photoacoustic Finder in Sentinel Lymph Node Detection in Breast Cancer - Pilot Study

Provide clinical metrics and PAF signals for individual participant data.

Number of detected SLNs / Number of total resected LNs

Pohang University of Science and Technology

Seoul St. Mary's Hospital

Clinical Assistant Professor

Head and Neck Neoplasms

Those undergoing radiation therapy treatment to their lymph nodes upon diagnosis of head and neck cancer

Photoacoustic Imaging investigate changes of measured PA markers and compare these to radiological assessment of response of lymph node involvement to chemoradiation therapy for head and neck cancer

Photoacoustic Imaging System

Gregory J Czarnota, PhD, MD

In this study, PA imaging will be used to examine the physiological and physical changes in lymph node involvements of head and neck cancer during radiotherapy with or without chemotherapy. Our objective in this pilot study will be to evaluate if PA parameters change within the lymph node involvements during chemoradiation therapy over time. Our hope is to use this information to correlate the changes in measured PA parameters with radiological response.

A trained clinical research coordinator will evaluate and authorize that each screened volunteer is a suitable subject for the study prior to enrolment. Written informed consent will be obtained from each participant prior to any clinical research scans to be performed on the subject. Those subjects who qualify will have their lymph node imaged using a PA imaging system. Up to 50 subjects will be recruited for this study.

Participants will be imaged 5 times over the course of radiotherapy regimen, which span up to 7 weeks. The patients will be assessed with MRI 10 to 12 weeks after the completion of Chemoradiation therapy as per the institution's standard of care. The lymph nodes will be measured by a staff radiologist, and the sizing information will be used to categorize patients into responders or non-responders. This information will be accessed using the patient's electronic medical record. Each patient will be assigned an anonymized accession number to the study that withholds any identifiers. There will be a complete accounting of all missing and excluded data, if any.

Although we do not anticipate any adverse events, all AEs will be documented in the CRF, and will be immediately reported to the REB, the overseeing physician responsible for the patient's care, and the study principal investigators.

Descriptive statistics (arithmetic mean, standard deviation, and coefficient of variation) and tabulation (stem and leaf plots) of study endpoints (absolute values and absolute value/comparator differences) will be used. PA datasets will be tested for normality, using a Shapiro-Wilk test (alpha=0.05). Comparative tests will use an independent t-test (or Mann Whitney test for normality violations) to compare the PA measurements between different breast masses (fibroadenomas, cysts, tumors).

In determining chemoradiation therapy evaluation, the primary endpoint, multiple linear regression models to relate study endpoints to subject characteristics and a logistic regression model will be used to build for multiparametric analysis of multiple PA parameters as a predictive model to pathological response. Descriptive statistics (frequency per scan, frequency per subject) and tabulation will be used to analyze the frequency of system malfunction.

Overall Survival Evaluation, the secondary endpoint, will use linear discriminant analysis to test for sensitivity, specificity and accuracy of the PA parameters as a diagnostic test. Receiver-operating characteristic will be used to test for PA cutoff values and a logistic regression model will be used to build for multiparametric analysis of multiple PA parameters as a predictive model to pathological response.

Pilot Study to Evaluate Photoacoustic Imaging in Head and Neck Cancer

The primary study endpoint will investigate changes of measured PA markers and compare these to radiological assessment of response of lymph node involvement to chemoradiation therapy for head and neck cancer. Changes in PA parameters will be made to a pre-treatment point over the course of treatment.

The secondary study endpoint will correlate changes of measured PA markers to five-year overall survival (OS) of the same patient cohort. The survival status and of the patient cohort will be tracked after the treatment for five years based on the patient information system and follow up surveys if necessary.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Clinical Feasibility Study of a Photoacoustic Finder	NCT06412211	Sentinel Lymph ... Breast Cancer	Photoacoustic f...	19 Years - 74 Years	Seoul St. Mary's Hospital
Pilot Study to Evaluate Photoacoustic Imaging in Head and Neck Cancer	NCT04428515	Head and Neck C...	Photoacoustic I...	-	Sunnybrook Health Sciences Centre
A Clinical Feasibility Study of a Photoacoustic Finder	NCT06412211	Sentinel Lymph ... Breast Cancer	Photoacoustic f...	19 Years - 74 Years	Seoul St. Mary's Hospital

Spots Global Cancer Trial Database for photoacoustic