Paul S. Dale

Analysis of biomolecule detection with optofluidic ring resonator sensors

We theoretically and experimentally analyze the biomolecule detection capability of the liquid core optical ring resonator (LCORR) as a label-free bio/chemical sensor. We first establish a simple and general linear relationship between the LCORRs bulk refractive index sensitivity (BRIS) and its response to molecule deposition onto the surface, which enables us to easily characterize the LCORR sensing performance. Then, biosensing experiments are performed with bovine serum albumin (BSA) and LCORRs of various BRISs. The experimental results are in good agreement with the theoretical prediction. Further analysis shows that the LCORR is capable of detecting BSA below 10 pM with sub-picogram/mm2 mass detection limit.

Photoacoustic detection of metastatic melanoma cells in the human circulatory system

Detection of disseminating tumor cells among patients suffering from various types and stages of cancer can function as an early warning system, alerting the physician of the metastatic spread or recurrence of the disease. Early detection of such cells can result in preventative treatment of the disease, while late stage detection can serve as an indicator of the effectiveness of chemotherapeutics. The prognostic value of exposing disseminating tumor cells poses an urgent need for an efficient, accurate screening method for metastatic cells. We propose a system for the detection of metastatic circulating tumor cells based on the thermoelastic properties of melanoma. The method employs photoacoustic excitation coupled with a detection system capable of determining the presence of disseminating cells within the circulatory system in vitro. Detection trials consisting of tissue phantoms and a human melanoma cell line resulted in a detection threshold of the order of ten individual cells, thus validating the effectiveness of the proposed mechanism. Results imply the potential to assay simple blood draws, from healthy and metastatic patients, for the presence of cancerous melanoma providing an unprecedented method for routine cancer screening.

Rapid and Label-Free Detection of Breast Cancer Biomarker CA15-3 in Clinical Human Serum Samples with Optofluidic Ring Resonator Sensors

Sensitive and specific detection of breast cancer biomarker CA15-3 in human serum is an important step toward successful evaluation of clinical treatment and prediction of breast cancer recurrence. In this work, we developed an optofluidic ring resonator (OFRR) sensor and the corresponding sensing protocols for label-free CA15-3 detection without any additional signal amplification steps. Nonspecific serum protein adsorption was minimized with effective surface blocking methods. The sensor performance for CA15-3 detection was first characterized in phosphate-buffered saline (PBS) buffer and in fetal calf serum. Then the potential use of the OFRR as a simple clinical laboratory testing device for breast cancer diagnostics was tested by measuring the CA15-3 level in clinical human serum samples, and the results were compared with those of standard clinical lab tests. It was found that the OFRR was capable of detecting approximately 1 unit/mL CA15-3 in both PBS buffer and diluted serum within approximately 30 min. Our work marks the first demonstration of the optical ring resonator biosensor in real clinical applications that features low cost, simple detection procedures, rapid response time, low sample consumption, and high specificity.

Photoacoustic Detection of Melanoma Micrometastasis in Sentinel Lymph Nodes

Melanoma is the deadliest form of skin cancer and has the fastest growth rate of all cancer types. Proper staging of melanoma is required for clinical management. One method of staging melanoma is performed by taking a sentinel node biopsy, in which the first node in the lymphatic drainage path of the primary lesion is removed and tested for the presence of melanoma cells. Current standard of care typically involves taking fewer than ten histologic sections of the node out of the hundreds of possible sections available in the tissue. We have developed a photoacoustic method that probes the entire intact node. We acquired a lymph node from a healthy canine subject. We cultured a malignant human melanoma cell line HS 936. Approximately 1 x 10(6) cells were separated and injected into the lymph node. We also had a healthy lymph node in which no melanoma cells were implanted. We used a tunable laser system set at 532 nm to irradiate the lymph nodes. Three piezoelectric acoustic detectors were positioned near the lymph node to detect photoacoustic pulses generated within the lymph nodes. We also acquired lymph nodes from pigs and repeated the experiments with increased amplification and improved sensors. We detected photoacoustic responses from a lymph node with as few as 500 melanoma cells injected into the tissue, while normal lymph nodes showed no response. Photoacoustic generation can be used to detect melanoma micrometastasis in sentinel lymph nodes. This detection can be used to guide further histologic study of the node, increasing the accuracy of the sentinel lymph node biopsy.

Metastasis of primary melanoma to two separate lymph node basins: Prognostic significance

AbstractBackground and Methods: Depending on the location of the primary lesion, melanoma patients may develop metastases in more than one regional lymph node basin. To determine whether this is prognostically significant, we reviewed our experience with melanoma patients who had undergone regional lymphadenectomy (RLND) in two separate basins. Results: Of 3,603 patients who underwent RLND between April 1971 and January 1993, 406 underwent procedures in two separate basins; of these, 120 (30%) had metastases in both basins and 124 (30%) had metastases in one basin. When calculated from the first positive RLND, 1-year, 3-year, and 5-year survival rates were 82%, 48%, and 33%, respectively, for patients with dual-basin involvement and 88%, 59%, and 48%, respectively, for patients with single-basin involvement (p=0.0173). Median survival from the first positive RLND was 33.5 months for dual-basin involvement and 56.6 months for single-basin involvement. Univariate analysis demonstrated that Breslow thickness of the primary melanoma, clinical status of the regional lymph nodes, number of positive RLNDs, and tumor burden (total number of positive lymph nodes) were significant indicators of survival. The patients age and gender, the anatomic location and Clark level of the primary melanoma, the disease-free interval before regional metastasis, and the site and timing of RLNDs were not significant by univariate analysis. Multivariate analysis demonstrated significance for Breslow thickness, number of positive RLNDs, and tumor burden. Conclusions: The survival rate of melanoma patients with regional metastases in two lymph node basins is lower than that of patients with an equal tumor burden confined to a single basin. This suggests that primary melanomas metastasizing to more than one lymph node basin may have a higher metastatic potential, or that dual-basin involvement may increase the risk of systemic spread. We advocate lymphatic mapping, sentinel node biopsy, and selective lymphadenectomy as a cost-effective technique with little morbidity to identify and manage occult metastases in patients who have two lymph basins at risk.

Mammography as a Screening Tool for Coronary Artery Disease

BACKGROUND The leading cause of death in women over 40 y old is coronary artery disease (CAD) followed by cancer. This large retrospective study investigates the relationship between mammographic benign arterial calcifications (BAC) and a history of CAD to determine if mammography is a suitable screening tool for CAD. METHODS To determine the incidence of BAC in our general screening population, we prospectively studied 1000 consecutive women undergoing screening mammography. We retrospectively identified a population of women with known CAD who had undergone screening mammography as our study group. These groups were compared according to age and the significance of BAC in each group was statistically evaluated using the Cochran-Mantel-Haenszel test and Cochran-Armitage test for trend. RESULTS We prospectively evaluated the mammograms of 819 women with no history of diabetes or CAD. Eighty-six women had mammographic BAC for a baseline BAC incidence of 10.5%. We identified 395 women with CAD and 193 (49%) of these women had BAC. Vascular calcifications significantly increased with age (P < 0.0001) in both groups. Stratifying by age, women with CAD had a significant increase in BAC compared with women undergoing routine screening (P < 0.0001). The odds ratio of having CAD when BAC are present on screening mammography compared with having CAD when BAC are not present is 6.2 (95% confidence interval estimate 4.3-8.8). CONCLUSIONS This preliminary study indicates that across age groups, the odds of having CAC are approximately 6.2 times greater if BAC are present compared with women without BAC indicating that mammography may be a useful screening tool for CAD.

Detection of circulating melanoma cells in human blood using photoacoustic flowmetry

Detection of circulating tumor cells (CTCs) in human blood and lymph systems has the potential to aid clinical decision making in the treatment of cancer. The presence of CTCs may signify the onset of metastasis, indicate relapse, or may be used to monitor disease progression. A photoacoustic flowmetry system was designed and tested for detecting circulating melanoma cells (CMCs) by exploiting the broadband absorption spectrum of melanin within CMCs. The device was tested on cultured melanoma cells in saline suspension and in a Stage IV melanoma patient. The device showed a detection threshold of a single melanotic melanoma cell from culture. Transient photoacoustic events were detected in a sample derived from a Stage IV melanoma patient that corresponded to particles passing through the laser beam path, indicating the presence of single melanoma cells in the human circulatory system.

Ethical Management of Conflict of Interest: Proposed Standards for Academic Surgical Societies

BACKGROUND A significant increase in industry support of professional medical associations coupled with data suggesting that gifts from industry have significant clinical influence have prompted calls from the Institute of Medicine and physician leaders to identify and manage conflicts of interest that stem from financial support of professional medical associations by industry. STUDY DESIGN A joint task force of members appointed by the Association for Academic Surgery and the Society of University Surgeons was convened in July 2009. Recommendations were developed regarding management of all potential conflicts of interest that can arise within the context of an academic surgical society, with specific focus on relationships with industry. Task force members reached consensus around each recommendation and the guidelines were subsequently adopted by the Executive Councils of both societies. RESULTS The committee identified 4 primary areas of need for transparent and definitive management of conflict of interest: 1) individual society activities, including general budget support, society endorsements, and journal affiliation; 2) individual personnel conflicts such as society leadership and standards for disclosure of conflict; 3) meeting activities including budgetary support, program committee associations, and abstract review process; and 4) foundation support and research and travel awards. The resulting guidelines aim to protect the societies and their membership from undue bias that may undermine the credibility and mission of these associations. CONCLUSIONS Policy guidelines to mitigate conflict of interest are necessary to protect the integrity of the work of academic surgical societies and their fiduciary duty to members and patients. Guidelines created and adopted by the Association for Academic Surgery and Society of University Surgeons form an effective model for academic surgical societies and their members.

Vascular calcifications on screening mammography identify women with increased risk of coronary artery disease and diabetes

BACKGROUND Mammographic breast arterial calcifications (BAC) have been reported in women with diabetes and coronary artery disease (CAD). This prospective study further investigates the clinical significance of BAC, CAD, and diabetes. METHODS Women undergoing screening mammography were prospectively evaluated for mammographic BAC. The association among BAC, CAD, and diabetes was statistically evaluated. RESULTS Of 1,000 consecutive women undergoing screening mammography, 181 had a history of CAD and/or diabetes. Of those women without diabetes or heart disease, 86 of 819 (10.5%) had BAC. One hundred forty women had diabetes, of whom 57 (40.7%) had BAC, and 72 women had CAD, of whom 36 (50%) had BAC. The association among BAC, CAD, and diabetes was highly significant (P <.0001, 95% confidence interval [CI]). The odds ratio of having diabetes or CAD with BAC is 4.3 and 3.6 times greater than the odds of having these diseases without BAC. COMMENTS This large prospective study indicated a significant association between BAC identified on screening mammography and a personal history of CAD and diabetes, indicating that screening mammography may identify women at increased risk for these diseases.

Detection of melanoma cells in vitro using an optical detector of photoacoustic waves.

Circulating tumor cells have been shown to correlate positively with metastatic disease state in patients with advanced cancer. We have demonstrated the ability to detect melanoma cells in a flow system by generating and detecting photoacoustic waves in melanoma cells. This method is similar to flow cytometry, although using photoacoustics rather than fluorescence. Previously, we used piezoelectric films as our acoustic sensors. However, such films have indicated false‐positive signals due to unwanted direct interactions between photons from the high laser fluence in the flow system and the film itself. We have adapted an optical detection scheme that obviates the need for piezoelectric films.