The Cole Relaxation Frequency as a Parameter to Identify Cancer in Lung Tissue: Preliminary Animal and Ex Vivo Patient Studies

Abstract

Background Lung cancer is the world’s leading cause of cancer deaths, and diagnosis remains challenging. Lung cancer starts as small nodules; early and accurate diagnosis allows timely surgical resection of malignant nodules while avoiding unnecessary surgery in patients with benign nodules. Objective The Cole relaxation frequency (CRF) is a derived electrical bioimpedance signature, which may be utilized to distinguish cancerous tissues from normal tissues. Methods Human testing ex vivo was conducted with NoduleScan in freshly resected lung tissue from 30 volunteer patients undergoing resection for nonsmall cell lung cancer. The CRF of the tumor and the distant normal lung tissue relative to the tumor were compared to histopathology specimens to establish a potential algorithm for point-of-care diagnosis. For animal testing in vivo, 20 mice were implanted with xenograft human lung cancer tumor cells injected subcutaneously into the right flank of each mouse. Spectral impedance measurements were taken on the tumors on live animals transcutaneously and on the tumors after euthanasia. These CRF measurements were compared to healthy mouse lung tissue. For porcine lung testing ex vivo, porcine lungs were received with the trachea. After removal of the vocal box, a ventilator was attached to pressurize the lung and simulate breathing. At different locations of the lobes, the lung's surface was cut to produce a pocket that could accommodate tumors obtained from in vivo animal testing. The tumors were placed in the subsurface of the lung, and the electrode was placed on top of the lung surface directly over the tumor but with lung tissue between the tumor and the electrode. Spectral impedance measurements were taken when the lungs were in the deflated state, inflated state, and also during the inflation-deflation process to simulate breathing. Results Among 60 specimens evaluated in 30 patients, NoduleScan allowed ready discrimination in patients with clear separation of CRF in tumor and distant normal tissue with a high degree of sensitivity (97%) and specificity (87%). In the 25 xenograft small animal model specimens measured, the CRF aligns with the separation observed in the human in vivo measurements. The CRF was successfully measured of tumors implanted into ex vivo porcine lungs, and CRF measurements aligned with previous tests for pressurized and unpressurized lungs. Conclusions As previously shown in breast tissue, CRF in the range of 1kHz-10MHz was able to distinguish nonsmall cell lung cancer versus normal tissue. Further, as evidenced by in vivo small animal studies, perfused tumors have the same CRF signature as shown in breast tissue and human ex vivo testing. Inflation and deflation of the lung have no effect on the CRF signature. With additional development, CRF derived from spectral impedance measurements may permit point-of-care diagnosis guiding surgical resection.

Bioimpedance Based Biomarker for the Detection of Precancerous and Cancerous Lesions of the Pancreas: Feasibility Animal Study

“…All tests were performed in multiple locations of the pancreases using a custom-built bioelectrical impedance measurement device and tetrapolar electrodes (Figure 1). The tetrapolar configuration is comprised of 4 electrodes including a source electrode (for the generation of the stimulating high-frequency signal), a drain electrode (for the measurement of the current through a precision 50 Ohm shunt resistor), and two pick up electrodes placed between the source and the drain (for the measurement of the voltage drop across the tissue) [32]. The device performed a bioelectrical impedance measurement of the samples over a…”

“…In this paper, the authors propose a feasibility study for the use of a novel bioimpedance based biomarker -the Cole Relaxation Frequency (CRF) -to detect PC. We have previously shown CRF to quantitatively detect cancer in breast, skin, and lung tissues [30][31][32][33]. The aim of this pilot study is to determine if the CRF based biomarker can detect PC and also discern pancreatitis from PC in the genetically modified KPC and KC mouse models, acute pancreatitis mouse model and wild type controls.…”

“…The algorithm extracts the CRF that is used as an impedance spectroscopy biomarker to detect cancer. NovaScan has established proof-of-concept technologies to detect cancer in breast [30,42], skin [31], and lung [32,33] tissues. Moreover, for each tissue kind, NovaScan has developed customized prototype devices that have been tested and validated ex vivo [30][31][32][33].…”

“…NovaScan has established proof-of-concept technologies to detect cancer in breast [30,42], skin [31], and lung [32,33] tissues. Moreover, for each tissue kind, NovaScan has developed customized prototype devices that have been tested and validated ex vivo [30][31][32][33]. We based the feasibility of the current work on these previous studies and on the work by Subramanian et al, which illustrated cell architecture derangement across tumor formation, further explaining the physical foundation of CRF deviations observed for cancer [43].…”