Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer.

Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow-up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma.

Co-registered spectrally encoded confocal microscopy and optical frequency domain imaging system.

Spectrally encoded confocal microscopy and optical frequency domain imaging are two non-contact optical imaging technologies that provide images of tissue cellular and architectural morphology, which are both used for histopathological diagnosis. Although spectrally encoded confocal microscopy has better transverse resolution than optical frequency domain imaging, optical frequency domain imaging can penetrate deeper into tissues, which potentially enables the visualization of different morphologic features. We have developed a co-registered spectrally encoded confocal microscopy and optical frequency domain imaging system and have obtained preliminary images from human oesophageal biopsy samples to compare the capabilities of these imaging techniques for diagnosing oesophageal pathology.

Polymorphisms of inflammatory and metalloproteinase genes, Helicobacter pylori infection and the risk of oesophageal adenocarcinoma.

Helicobacter pylori (HP) infection appears protective against oesophageal adenocarcinoma (EA) risk. Matrix metalloproteinases (MMPs) are released in the presence of HP infection. In MMP2 wild-type individuals, HP was significantly protective of EA risk (adjusted odds ratio: 0.29; 95% confidence interval=0.1-0.7). Matrix metalloproteinases may modulate the EA-HP relationship.

Long-term effects of photodynamic therapy on fluorescence spectroscopy in the human esophagus.

Clinical interest in laser-induced fluorescence (LIF) spectroscopy and photodynamic therapy (PDT) is growing rapidly and may ultimately lead to close parallel use of these techniques. However, variations in LIF due to photosensitizer retention as well as tissue damage and healing processes may interfere with autofluorescence-based diagnostic methods. We have investigated the compatibility of these two techniques by quantifying PDT-induced changes in LIF in the human esophagus. Fluorescence spectra were collected endoscopically at excitation wavelengths (lambda ex) of 337, 400 and 410 nm in 32 patients. Measurements were performed immediately before and after PDT treatment with porfimer sodium and during follow-up procedures. In the months following PDT regions of reepithelialized squamous showed reduced autofluorescence in comparison with untreated squamous regions (P = 0.0007). Photosensitizer fluorescence was undetectable with lambda ex = 337 nm during follow-up procedures, whereas for lambda ex = 400 and 410 nm porfimer sodium fluorescence was noted for nearly a year after treatment. Therefore, residual photosensitizer fluorescence is likely to affect certain LIF-based diagnostic techniques during a period when patients are at high risk for tumor recurrence. Modification of LIF systems and/or the use of alternative photosensitizers may be required to optimize the detection of lesions in the post-PDT patient. Given the potential of LIF as a method for surveillance following cancer therapy, further investigation of the compatibility of specific LIF approaches with cancer pharmaceuticals may be warranted.

Diagnosis of specialized intestinal metaplasia by optical coherence tomography.

BACKGROUND AND AIMS: Optical coherence tomography (OCT) is an imaging technique that produces high-resolution cross-sectional images in vivo. The aim of this study was to establish the sensitivity and specificity of OCT for diagnosing specialized intestinal metaplasia (SIM). METHODS: OCT was used to image the stomach and esophagus of 121 patients. A total of 288 biopsy-correlated OCT images were acquired. OCT criteria for SIM were formulated by analyzing 75 images of SIM. The SIM image criteria were retrospectively tested by applying them to images of gastric, squamous, SIM, and cardiac epithelium. The criteria were then tested prospectively to determine the sensitivity and specificity of OCT for diagnosing SIM. RESULTS: OCT images of SIM are characterized by (1) absence of the layered structure of normal squamous epithelium and the vertical "pit and crypt" morphology of gastric mucosa, (2) disorganized architecture with inhomogeneous tissue contrast and an irregular mucosal surface, and (3) presence of submucosal glands. These criteria were 100% sensitive and 93% specific for SIM when applied retrospectively and 97% sensitive and 92% specific when tested prospectively. CONCLUSIONS: OCT is highly sensitive and specific for SIM and may aid in the diagnosis and surveillance of this preneoplastic lesion.

Optical coherence tomography in the gastrointestinal tract.

Optical coherence tomography (OCT) is a high-resolution, cross-sectional optical imaging technique that allows in situ imaging of tissue by measuring back-reflected light. OCT provides images in real time with a resolution approaching that of conventional histopathology, but without the need for tissue removal. OCT imaging can be performed endoscopically to visualize gastrointestinal tissue using a fiberoptic catheter passed through the instrument channel of a conventional endoscope. The resolution of OCT allows visualization of the different layers of gastrointestinal epithelium and the differentiation of Barrett's epithelium from normal gastric and squamous mucosa. OCT has also been used to image esophageal adenocarcinoma and colonic polyps. Recent developments include Doppler OCT, spectroscopic OCT, and ultrahigh-resolution OCT, which can visualize nuclei within single cells. Although still in its infancy as a clinical tool, OCT currently provides high-resolution images over the same imaging depth as conventional mucosal biopsy, and may prove to be a useful and minimally invasive technique for evaluating gastrointestinal tissue, particularly for early neoplastic changes.

High-resolution imaging of the human esophagus and stomach in vivo using optical coherence tomography.

BACKGROUND: Optical coherence tomography is a new, high spatial-resolution, cross-sectional imaging technique. We investigated the ability of optical coherence tomography to provide detailed images of subsurface structures in the upper gastrointestinal (GI) tract. METHODS: Optical coherence tomography was performed during routine upper GI endoscopy on 32 patients including 20 patients with Barrett's esophagus. An endoscopic mucosal biopsy was obtained immediately after imaging and was used for histopathologic correlation. RESULTS: Optical coherence tomography provided clear delineation of layers of the normal human esophagus extending from the epithelium to the longitudinal muscularis propria. Gastric mucosa was differentiated from esophageal mucosa, Barrett's esophagus was differentiated from normal esophageal mucosa, and esophageal adenocarcinoma was distinguished from normal esophagus and Barrett's esophagus. CONCLUSIONS: Optical coherence tomography allows visualization of the subsurface architectural morphology of the upper GI tract. The diagnostic information provided by this new imaging modality suggests that it may be a useful adjunct to endoscopy.

Burn wound assessment in porcine skin using indocyanine green fluorescence.

BACKGROUND: An accurate assessment of deep dermal burns within the first week after burn is still an unresolved clinical problem. Infrared-excited fluorescence of indocyanine green was examined as a method of early determination of burn depth. METHODS: Burns of varying depths were placed on the paraspinal region, flank, and abdomen of swine using a heated brass block. Fluorescence images of the burns were recorded 1, 24, 48, and 72 hours later. RESULTS: The ratio of fluorescence in 64 burn wounds relative to adjacent normal tissue identified wounds that healed and did not heal within 21 days with an accuracy of 100%, after accounting for the age of the burn. Higher fluorescence ratios were observed in newly placed burns relative to older burns having comparable depths. CONCLUSION: Deep partial-thickness burns were differentiated from deep dermal full-thickness burns in a porcine skin burn model independent of body location. Diagnosis was possible between 1 and 72 hours after injury.

Mucosal exposure to light during routine endoscopy.

BACKGROUND: The spectral irradiance delivered by a variety of gastrointestinal endoscopes was measured as a function of wavelength and used to estimate the amount of light delivered to the mucosal surface during routine endoscopic procedures. METHODS: Spectral irradiances from seven different endoscopes were measured using a commercial spectroradiometer calibrated against a National Institute of Standards and Technology traceable source. RESULTS: The largest maximum irradiance was 8.0 W/cm2 obtained from an endoscope used in transillumination mode. In the typical viewing mode, the largest maximum irradiance measured was 1.6 W/cm2. The majority of the light energy delivered by these gastrointestinal endoscopes was in the visible wavelength region (400 to 700 nm). DISCUSSION: The measurements revealed surprisingly high light exposures in the visible wavelength range. In fact, the estimated tissue exposures can exceed by 40-fold the standards established for skin exposure to light set forth by the American National Standards Institute. Because gastrointestinal endoscopy is widely viewed to be safe, it is probable that the gastrointestinal tract has significant tolerance to light exposure.

Measurement of tissue absorption coefficients by use of interferometric photothermal spectroscopy.

We describe a spectroscopic technique called interferometric photothermal spectroscopy (IPTS) that can measure the absorption coefficient of pulsed laser radiation in nonscattering tissue samples. The technique is suitable for measuring effective absorption coefficients from 10(3) to 10(5) cm(-1). IPTS is particularly attractive because it requires minimal disturbance of the sample. These features indicate potential use for in vivo measurements of tissue absorption coefficients. To validate the technique, the absorption coefficient of pulsed Q-switched Er:YSGG (2.79-microm) radiation in pure water was measured to be 5200 (+/-500) cm(-1) when IPTS was used, in agreement with other published values. IPTS was also used to measure the absorption coefficient of pulsed ArF excimer laser radiation (193 nm) in bovine corneal stroma (in vitro), giving a value of 1.9 (+/-0.4) x 10(4) cm(-1).

Colonic polyp differentiation using time-resolved autofluorescence spectroscopy.

BACKGROUND: Steady-state autofluorescence spectroscopy has been examined previously as a technique for distinguishing polyp types during colonoscopy. Although time-resolved methods have shown promise for tissue diagnosis in vitro, they have never been applied endoscopically. The aim of this study was to examine the feasibility of performing time-resolved autofluorescence spectroscopy in vivo and to determine the diagnostic accuracy of the technique as applied to colonic dysplasia. METHODS: A time-resolved spectrometer was used to measure the spectrally resolved transient decay of laser-induced autofluorescence emission from colonic tissue in vivo. RESULTS: Seventeen patients with 24 polyps (13 adenomatous, 11 non-adenomatous) were studied. The autofluorescence decay from adenomas was faster than that from non-adenomas. The measured decay time provided a means of distinguishing adenomas from non-adenomas with a sensitivity of 85%, a specificity of 91%, a positive predictive value of 92%, and a negative predictive value of 83%. CONCLUSIONS: Time-resolved autofluorescence spectroscopy is a promising optical diagnostic technique for determining polyp types in vivo.

Comparison of pulsed CO2 laser ablation at 10.6 microm and 9.5 microm.

BACKGROUND AND OBJECTIVE: The pulsed CO2 laser has received attention because of its successful application to dermatologic surgery and burn debridement surgery. Despite impressive results, tissue removal using pulsed CO2 laser irradiation has not been optimized. We examined the ablation processes by performing mass removal and thermal injury experiments at wavelengths where tissue water is the primary absorber (10.6 microm), and where water and collagen have comparable absorption (9.5 microm). STUDY DESIGN/MATERIALS AND METHODS: Samples of porcine reticular dermis were irradiated with 180-ns laser pulses at either wavelength. Tissue removal was measured using a digital balance. Thermal injury was assessed using a microscope with a calibrated reticle after hematoxylin and eosin staining. RESULTS: Tissue removal using 10.6-microm radiation resulted in a heat of ablation of 3,740 J/g, an ablation threshold of 1.15 J/cm2, and a zone of thermal injury of 53 microm. By contrast, tissue removal using 9.5-microm radiation resulted in a heat of ablation of 3,330 J/g, an ablation threshold of 1.47 J/cm2, and a zone of thermal injury of 34 microm. The differences in ablation threshold and thermal injury were statistically significant. CONCLUSION: Pulsed CO2 laser irradiation at 9.5 microm removes tissue more efficiently and with a smaller zone of thermal injury than at 10.6 microm.

Carbon dioxide laser ablation with immediate autografting in a full-thickness porcine burn model.

OBJECTIVE: To compare the long-term clinical and histologic outcome of immediate autografting of full-thickness burn wounds ablated with a high-power continuous-wave CO2 laser to sharply débrided wounds in a porcine model. SUMMARY BACKGROUND DATA: Continuous-wave CO2 lasers have performed poorly as tools for burn excision because the large amount of thermal damage to viable subeschar tissues precluded successful autografting. However, a new technique, in which a high-power laser is rapidly scanned over the eschar, results in eschar vaporization without significant damage to underlying viable tissues, allowing successful immediate autografting. METHODS: Full-thickness paravertebral burn wounds measuring 36 cm2 were created on 11 farm swine. Wounds were ablated to adipose tissue 48 hours later using either a surgical blade or a 150-Watt continuous-wave CO2 laser deflected by an x-y galvanometric scanner that translated the beam over the tissue surface, removing 200 microm of tissue per scan. Both sites were immediately autografted and serially evaluated clinically and histologically for 180 days. RESULTS: The laser-treated sites were nearly bloodless. The mean residual thermal damage was 0.18+/-0.05 mm. The mean graft take was 96+/-11% in manual sites and 93+/-8% in laser sites. On postoperative day 7, the thickness of granulation tissue at the graft-wound bed interface was greater in laser-debrided sites. By postoperative day 180, the manual and laser sites were histologically identical. Vancouver scar assessment revealed no differences in scarring at postoperative day 180. CONCLUSIONS: Long-term scarring, based on Vancouver scar assessments and histologic evaluation, was equivalent at 6 months in laser-ablated and sharply excised sites. Should this technology become practical, the potential clinical implications include a reduction in surgical blood loss without sacrifice of immediate engraftment rates or long-term outcome.

Initial experience with a real-time video processor for enhancing endoscopic image contrast.

BACKGROUND: An initial experience using a digital video processor to enhance contrast in endoscopic images in real-time is described. METHODS: Endoscopic images were examined with a system using locally adaptive processing to balance variations in illumination and sharpen fine features in real-time. For comparison, indigo carmine dye, a popular exogenous contrast agent, was applied to one patient. RESULTS: In general, contrast-enhanced images appeared to contain more mucosal detail, with reduced glare and features in shadowed areas revealed. When used in conjunction with indigo carmine, the enlarged crypt openings in an aberrant crypt focus were visible, the first such detection in vivo without the use of magnifying endoscopy. CONCLUSIONS: Real-time video contrast enhancement during endoscopic procedures appears to provide excellent mucosal detail and improve contrast in a clinically useful manner.

Influence of light delivery on photodynamic synovectomy in an antigen-induced arthritis model for rheumatoid arthritis.

BACKGROUND AND OBJECTIVE: Minimally invasive synovectomy techniques have been unsuccessful due to lack of selectivity. The purpose of this study was to evaluate the potential of photodynamic therapy to destroy diseased synovium in an antigen-induced arthritis model. STUDY DESIGN/MATERIALS AND METHODS: Three sets of experiments evaluated the biodistribution and treatment effects of Photofrin (PF) in rabbits with bilateral knee antigen-induced arthritis. The first set of experiments evaluated the biodistribution of PF in articular tissues of 30 rabbits from 6-72 hours after systemic injection of 2 mg/kg. In the second series of experiments, light was delivered to the knee joint via cleaved optical fibers, whereas for the third, light was delivered via a 600 microm diffusion tip fiber. Tissues were harvested at 2 and 4 weeks posttreatment. RESULTS: The biodistribution experiments demonstrated maximal uptake in inflamed synovium at 48 hours and a lack of uptake in normal tissues. With bare cleaved fibers, necrosis was observed in one specimen at 2 weeks and was absent in all specimens at 4 weeks. In the third experiment, synovial necrosis was observed in 3 of 7 specimens at 2 weeks and 3 of 8 at 4 weeks. No damage to articular cartilage or periarticular tissues was seen with either mode of light delivery. CONCLUSION: These studies indicate that selective destruction of synovium can be achieved with PF and suggest that optimization of light delivery techniques will play an important role in development of this new technique.

Biodistribution of indocyanine green in a porcine burn model: light and fluorescence microscopy.

BACKGROUND: Infrared-excited fluorescence of intravenously administered indocyanine green (ICG) is being used as a method of early determination of burn depth. METHODS: Fluorescence microscopy and tissue fluorescence were recorded in a porcine burn model and correlated to burn severity and age. RESULTS: Recently placed superficial burns show significant fluorescence compared with adjacent normal tissue as a result of a strong inflammatory reaction in the superficial dermis with minimal vascular occlusion. The magnitude of the inflammatory reaction decreases with time. For deeper burns, vascular occlusion prevents transport of ICG into the burn and the intensity of ICG fluorescence in burn eschar is negligible. CONCLUSION: The intensity of ICG fluorescence measured at the surface of the wound for burns of similar age was shown to decrease exponentially with the depth of the burn. The enhanced fluorescence of partial-thickness burns is attributable to increased permeability, and the decreased signal associated with deeper injuries is attributable to vascular occlusion. These results suggest that it is possible to differentiate burns that will heal spontaneously with minimal granulation from those that will not by measuring the intensity of ICG fluorescence.

Effects of a rapidly scanned carbon dioxide laser on porcine dermis.

This study systematically examined the effect of varying continuous-wave carbon dioxide laser scanning parameters on the resultant tissue effects. The effects of varying scanning speed, laser power, and laser beam diameter were assessed. Residual thermal damage at the center of the crater was approximately 120 microm independent of dwell time and laser irradiance. However, thermal damage zones along the sides of the ablation crater increased as laser dwell times exceeded 50 msec. This study demonstrates that under appropriate conditions a scanned continuous-wave carbon dioxide laser can ablate tissue with a zone of residual thermal injury less than 200 microm, making it useful for cutaneous surgery and the debridement of burn wounds before skin grafting is performed.

Thermodynamic response of soft biological tissues to pulsed infrared-laser irradiation.

The physical mechanisms that achieve tissue removal through the delivery of short pulses of high-intensity infrared laser radiation, in a process known as laser ablation, remain obscure. The thermodynamic response of biological tissue to pulsed infrared laser irradiation was investigated by measuring and analyzing the stress transients generated by Q-sw Er:YSGG (lambda = 2.79 microns) and TEA CO2 (lambda = 10.6 microns) laser irradiation of porcine dermis using thin-film piezoelectric transducers. For radiant exposures that do not produce material removal, the stress transients are consistent with thermal expansion of the tissue samples. The temporal structure of the stress transients generated at the threshold radiant exposure for ablation indicates that the onset of material removal is delayed with respect to irradiation. Once material removal is achieved, the magnitude of the peak compressive stress and its variation with radiant exposure are consistent with a model that considers this process as an explosive event occurring after the laser pulse. This mechanism is different from ArF- and KrF-excimer laser ablation where absorption of ultraviolet radiation by the collagenous tissue matrix leads to tissue decomposition during irradiation and results in material removal via rapid surface vaporization. It appears that under the conditions examined in this study, explosive boiling of tissue water is the process that mediates the ablation event. This study provides evidence that the dynamics and mechanism of tissue ablation processes can be altered by targeting tissue water rather than the tissue structural matrix.