Enhanced effectiveness of radiochemotherapy with tirapazamine by local application of electric pulses to tumors.

Tumor hypoxia is associated with resistance to radiotherapy and anticancer chemotherapy. However, it can be exploited to therapeutic advantage by concomitantly using hypoxic cytotoxins, such as tirapazamine (TPZ). Tumor electroporation offers the means to further increase tumor hypoxia by temporarily reducing tumor blood flow and therefore increase the cytotoxicity of TPZ. The primary objective of this work was to determine whether electric pulses combined with TPZ and radiotherapy (electroradiochemotherapy) was more efficacious than radiochemotherapy (TPZ + radiation). In these studies using the SCCVII tumor model in C3H mice, electroradiochemotherapy produced up to sixfold more tumor growth delay (TGD) than TPZ + radiation. In these studies, (1) large tumors (280 +/- 15 mm3) responded better to electroradiochemotherapy than small tumors (110 +/- 10 mm3), (2) TGD correlated linearly with tumor volume at the time of electroradiochemotherapy, (3) electric pulses induced a rapid but reversible reduction in O2 saturation, and (4) the electric field was highest near the periphery of the tumor in a 3D computer model. The findings suggested that electroradiochemotherapy gained its therapeutic advantage over TPZ + radiation by enhancing the cytotoxic action of TPZ through reduced tumor oxygenation. The greater antitumor effect achieved in large tumors may be related to tumor morphology and the electric-field distribution. These results suggest that electro-pulsation of large solid tumors may be of benefit to patients treated with radiation in combination with agents that kill hypoxic cells.

Liver tumor gross margin identification and ablation monitoring during liver radiofrequency treatment.

PURPOSE: To determine whether tissue visible light spectroscopy (VLS) used during radiofrequency (RF) ablation of liver tumors could aid in detecting when tissue becomes adequately ablated, locate grossly ablated regions long after temperature and hydration measures would no longer be reliable, and differentiate tumor from normal hepatic tissue based on VLS spectral characteristics. MATERIALS AND METHODS: Studies were performed on human liver in vivo and animal liver ex vivo. In three ex vivo cow livers, RF-induced lesions were created at 80 degrees C. A 28-gauge needle embedded with VLS optical fibers was inserted alongside an RF ablation array, and tissue spectral characteristics were recorded throughout ablation. In one anesthetized sheep in vivo, a VLS needle probe was passed through freshly ablated liver lesions, and ablated region spectral characteristics were recorded during probe transit. In two human subjects, a VLS needle probe was passed through liver tumors in patients undergoing hepatic tumor resection without ablation, and tumor spectral characteristics were recorded during probe transit. RESULTS: In bovine studies, there was significant change in baseline absorbance (P < .0001) as a result of increased light scattering as liver was ablated. Liver exhibited native differential absorbance peaks at 550 nm that disappeared during ablation, suggesting that optical spectroscopy detects markers of tissue altered during ablation. In sheep, liver gross ablation margins were clearly defined with millimeter resolution during needle transit through the region, suggesting that VLS is sensitive to gross margins of ablation, even after the temperature has normalized. In humans, absorbance decreased as the needle passed from normal tissue into tumor and normalized after emerging from the tumor, suggesting that absence of native liver pigment may serve as a marker for the gross margins and presence of tumors of extrahepatic origin. CONCLUSIONS: In human subjects, VLS during RF liver tumor ablation depicted gross hepatic tumor margins in real time; in animal subjects, VLS achieved monitoring of when and where RF ablation endpoints were achieved, even long after the tissue cooled. Real-time in vivo monitoring and treatment feedback may be possible with the use of real-time VLS sensors placed along side of, or embedded into, the RF probe, which can then be used as an adjunct to standard imaging during tumor localization and RF ablation treatment.

Continuous, noninvasive, and localized microvascular tissue oximetry using visible light spectroscopy.

BACKGROUND: The authors evaluated the ability of visible light spectroscopy (VLS) oximetry to detect hypoxemia and ischemia in human and animal subjects. Unlike near-infrared spectroscopy or pulse oximetry (SpO2), VLS tissue oximetry uses shallow-penetrating visible light to measure microvascular hemoglobin oxygen saturation (StO2) in small, thin tissue volumes. METHODS: In pigs, StO2 was measured in muscle and enteric mucosa during normoxia, hypoxemia (SpO2 = 40-96%), and ischemia (occlusion, arrest). In patients, StO2 was measured in skin, muscle, and oral/enteric mucosa during normoxia, hypoxemia (SpO2 = 60-99%), and ischemia (occlusion, compression, ventricular fibrillation). RESULTS: In pigs, normoxic StO2 was 71 +/- 4% (mean +/- SD), without differences between sites, and decreased during hypoxemia (muscle, 11 +/- 6%; P < 0.001) and ischemia (colon, 31 +/- 11%; P < 0.001). In patients, mean normoxic StO2 ranged from 68 to 77% at different sites (733 measures, 111 subjects); for each noninvasive site except skin, variance between subjects was low (e.g., colon, 69% +/- 4%, 40 subjects; buccal, 77% +/- 3%, 21 subjects). During hypoxemia, StO2 correlated with SpO2 (animals, r2 = 0.98; humans, r2 = 0.87). During ischemia, StO2 initially decreased at -1.3 +/- 0.2%/s and decreased to zero in 3-9 min (r2 = 0.94). Ischemia was distinguished from normoxia and hypoxemia by a widened pulse/VLS saturation difference (Delta < 30% during normoxia or hypoxemia vs. Delta > 35% during ischemia). CONCLUSIONS: VLS oximetry provides a continuous, noninvasive, and localized measurement of the StO2, sensitive to hypoxemia, regional, and global ischemia. The reproducible and narrow StO2 normal range for oral/enteric mucosa supports use of this site as an accessible and reliable reference point for the VLS monitoring of systemic flow.