Endoscopic visible light spectroscopy: a new, minimally invasive technique to diagnose chronic GI ischemia.

BACKGROUND: The diagnosis of chronic GI ischemia (CGI) remains a clinical challenge. Currently, there is no single simple test with high sensitivity available. Visible light spectroscopy (VLS) is a new technique that noninvasively measures mucosal oxygen saturation during endoscopy. OBJECTIVE: To determine the diagnostic accuracy of VLS for the detection of ischemia in a large cohort of patients. DESIGN: Prospective study, with adherence to the Standards for Reporting of Diagnostic Accuracy. SETTING: Tertiary referral center. PATIENTS: Consecutive patients referred for evaluation of possible CGI. INTERVENTIONS: Patients underwent VLS along with the standard workup consisting of evaluation of symptoms, GI tonometry, and abdominal CT or magnetic resonance angiography. MAIN OUTCOME MEASUREMENTS: VLS measurements and the diagnosis of CGI as established with the standard workup. RESULTS: In 16 months, 121 patients were included: 80 in a training data set and 41 patients in a validation data set. CGI was diagnosed in 89 patients (74%). VLS cutoff values were determined based on the diagnosis of CGI and applied in the validation data set, and the results were compared with the criterion standard, resulting in a sensitivity and specificity of VLS of 90% and 60%, respectively. Repeated VLS measurements showed improvement in 80% of CGI patients after successful treatment. LIMITATIONS: Single-center study; only 43% of patients had repeated VLS measurements after treatment. CONCLUSIONS: VLS during upper endoscopy is a promising easy-to-perform and minimally invasive technique to detect mucosal hypoxemia in patients clinically suspected of having CGI, showing excellent correlation with the established ischemia workup.

Intraoperative ischemia of the distal end of colon anastomoses as detected with visible light spectroscopy causes reduction of anastomotic strength.

BACKGROUND: To explore new methods for intraoperative evaluation of tissue oxygenation, we evaluated the use of visible light spectroscopy as a predictor of anastomotic strength in an experimental model with ischemic murine colon anastomoses. MATERIALS AND METHODS: Male rats (n = 34) were divided into 2 groups (ischemia and nonischemia). In the ischemia group the arteries of the distal colon were ligated until tissue oxygen saturation (StO2) dropped below 55%. A segment of the proximal part of the colon was resected until a well-perfused area was reached and an anastomosis was performed. In the nonischemia group, resection of a segment of descending colon and a colon anastomosis was performed. The animals were sacrificed on the 3rd or 7th postoperative d. The anastomosis was tested for bursting pressure and breaking strength. RESULTS: After ligation of the relevant mesenteric arteries, StO2 of the distal part of the colon decreased (54.6% SD 6.4% versus 71.2% SD 7.4%, P

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.

Design of a visible-light spectroscopy clinical tissue oximeter.

We develop a clinical visible-light spectroscopy (VLS) tissue oximeter. Unlike currently approved near-infrared spectroscopy (NIRS) or pulse oximetry (SpO2%), VLS relies on locally absorbed, shallow-penetrating visible light (475 to 625 nm) for the monitoring of microvascular hemoglobin oxygen saturation (StO2%), allowing incorporation into therapeutic catheters and probes. A range of probes is developed, including noncontact wands, invasive catheters, and penetrating needles with injection ports. Data are collected from: 1. probes, standards, and reference solutions to optimize each component; 2. ex vivo hemoglobin solutions analyzed for StO2% and pO2 during deoxygenation; and 3. human subject skin and mucosal tissue surfaces. Results show that differential VLS allows extraction of features and minimization of scattering effects, in vitro VLS oximetry reproduces the expected sigmoid hemoglobin binding curve, and in vivo VLS spectroscopy of human tissue allows for real-time monitoring (e.g., gastrointestinal mucosal saturation 69+/-4%, n=804; gastrointestinal tumor saturation 45+/-23%, n=14; and p<0.0001), with reproducible values and small standard deviations (SDs) in normal tissues. FDA approved VLS systems began shipping earlier this year. We conclude that VLS is suitable for the real-time collection of spectroscopic and oximetric data from human tissues, and that a VLS oximeter has application to the monitoring of localized subsurface hemoglobin oxygen saturation in the microvascular tissue spaces of human subjects.

Optical detection of tumors in vivo by visible light tissue oximetry.

Endoscopy is a standard procedure for identifying tumors in patients suspected of having gastrointestinal (G.I.) cancer. The early detection of G.I. neoplasms during endoscopy is currently made by a subjective visual inspection that relies to a high degree on the experience of the examiner. This process can be difficult and unreliable, as tumor lesions may be visually indistinguishable from benign inflammatory conditions and the surrounding mucosa. In this study, we evaluated the ability of local ischemia detection using visible light spectroscopy (VLS) to differentiate neoplastic from normal tissue based on capillary tissue oxygenation during endoscopy. Real-time data were collected (i) from human subjects (N = 34) monitored at various sites during endoscopy (enteric mucosa, malignant, and abnormal tissue such as polyps) and (ii) murine animal subjects with human tumor xenografts. Tissue oximetry in human subjects during endoscopy revealed a tissue oxygenation (StO2%, mean +/- SD) of 46 +/- 22% in tumors, which was significantly lower than for normal mucosal oxygenation (72 +/- 4%; P < or = 0.0001). No difference in tissue oxygenation was observed between normal and non-tumor abnormal tissues (P = N.S.). Similarly, VLS tissue oximetry for murine tumors revealed a mean local tumor oxygenation of 45% in LNCaP, 50% in M21, and 24% in SCCVII tumors, all significantly lower than normal muscle tissue (74%, P < 0.001). These results were further substantiated by positive controls, where a rapid real-time drop in tumor oxygenation was measured during local ischemia induced by clamping or epinephrine. We conclude that VLS tissue oximetry can distinguish neoplastic tissue from normal tissue with a high specificity (though a low sensitivity), potentially aiding the endoscopic detection of gastrointestinal tumors.

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.

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.

The future of cancer imaging.

Conventional (anatomical, structural) imaging is insensitive to the presence of cancer, often failing to yield the very information needed for accurate diagnosis and staging, for proper treatment selection and monitoring or for effective follow-up after treatment. This, fortunately, is changing. Newer techniques, already in clinical testing, are rapidly pushing clinical imaging in the same direction as the rest of medicine: away from simple detection of the gross structural end-effects of disease, and toward a patient-specific approach based on physiologic, histologic, antigenic, molecular, and (ultimately) genetic markers of disease. By 2010, unimodal, nonspecific, and insensitive radiological images may look as primitive to us as the first Roentgen radiographs. In some cases, these new scans will be so seamlessly integrated into therapeutic treatment that they may not even be thought of as imaging per se. This chapter looks forward to see how imaging for oncology may look in the coming decade, focusing upon near-term trends and techniques by selecting those already demonstrated in vivo in at least animals or which are now under human study, and thus which have moved far enough that they have already begun to impact patient care, or are likely to begin do so in the near future.