Sandy Mosse

Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer.

Background:Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin.Methods:Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg−1 verteporfin. After 60–90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently.Results:In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm3 at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple’s pancreaticoduodenectomy.Conclusions:Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.

Photodynamic therapy of locally advanced pancreatic cancer (VERTPAC study): final clinical results

We undertook a phase I dose-escalation study of verteporfin photodynamic therapy (PDT) in 15 patients with locally advanced pancreatic cancer. Needle placement and laser delivery were technically successful in all patients. Thirteen patients were treated with a single laser fibre. Three treatments were carried out each at 5, 10 and 20 J/cm2; and 5 treatments (4 patients) at 40 J/cm2. A further 2 patients were treated with 2 or 3 laser fibres at 40 J/cm2. Tumour necrosis was measured on CT (computed tomography) by two radiologists 5 days after treatment. There was a clear dosedependent increase in necrosis with a median area of 20 x 16 mm (range 18 x 16 to 35 x 30 mm) at 40 J/cm2. In the 2 patients treated with multiple fibres, necrosis was 40 x 36 mm and 30 x 28 mm, respectively. There were no early complications in patients treated with a single fibre. Both patients treated with multiple fibres had evidence on CT of inflammatory change occurring anterior to the pancreas but without clinical deterioration. These results suggest that single fibre verteporfin PDT is safe in a clinical setting up to 40J/cm2 and produces a dose-dependent area of pancreatic necrosis.

7071 Endoscopy without air insufflation.

Background: Most gastrointestinal endoscopy is performed with inflation with air to distend the viscus. For some applications and the development of new endoscopic methods airless endoscopy is likely to become important. Little is known about the efficacy and limitations of airless gastrointestinal endoscopy. Methods: A variety of experimental airless endoscopes were constructed. These included: 1. short focal length lens of a) curved shape, b) conical shape were mounted on the tip. 2.Wire cage fronted endoscope. 3. Transparent balloon fronted airless endoscope: balloon filled with a) clear gas, b) clear water. 4.Water immersed endoscope. Lighting was transmitted either through the lens, cage, balloon, water or by mounting the light source coaxially adjacent to the lens or optics. These experimental endoscopies were tested in post mortem and live oesophagus, stomach, small bowel and colon. Results: Reasonably good quality video images were obtained using all these experimental endoscopes in airless endoscopy of the GI tract. Short focal length lenses required careful focussing to optimise image quality. Reflections from the cage were diminished by using a non-reflecting paint. Mucus adherence was occasionally a problem but mucus was often wiped off as the endoscope moved. Movement of the endoscope allowed assessment of whether the mucus was adherent to the lens or tissue. Gas and water filled transparent balloons gave moderately good views but were unreliable and not robust. Tissue laying on the lenses sometimes impaired the view although this was less of a problem in live supported bowel. Practically, it was difficult to maintain water in the GI tract for immersion endoscopy. Curved shape short focal length lenses gave the best images overall. Conclusion: Despite some limitations airless endoscopy was able to give high quality images of the small bowel and oesophagus. Better than expected views could also be obtained in the stomach and large bowel but were limited by the diameter of the viscus. Problems with illumination with internal reflection were encountered and resolved.

3434 Electrostimulation to move endoscopes in the small bowel.

Background: Methods are required for tip propulsion of endoscopes passing through the small bowel and for propelling miniature capsule endoscopes without cables. Aim: To test the hypothesis that electrical stimulation could propel an endoscope by stimulating muscular contraction. Methods: Prototype devices of ovoid shape were constructed with electrodes mounted on the tapered section of the device. When in contact with the bowel wall electrical stimulation was applied causing circular muscle contraction of the adjacent muscle which when applied to the taper of the ovoid resulted in forward propulsion of the device. The device was connected by wires to an electrical generator allowing a range of currents and voltages to be tested. The device was tested in the small bowel (non-striated muscle) and in the oesophagus (transition of striated to non striated muscle) of the anaesthetised pig. Results: In initial tests in the pig oesophagus electrostimulation caused the ovoid to advance rapidly (6 mm/sec) down the oesophagus by inducing circular oesophageal muscle contraction. To our surprise the device moved at the same speed back up the oesophagus when reversed. Testing in the small bowel showed that this device was capable of moving in both directions and was capable of negotiating tight curves which could not be passed by conventional enteroscopes. Measured rates of travel at optimal settings were 3-4.5 mm/sec. The method does not induce peristalsis but works by stimulating local contraction. The current of 10 milliamps required for optimal movement seems to be below the threshold current that is reported as being perceived as painful in the human bowel although this remains to be demonstrated in man. The animals showed no ill effects and no effect on the cardiac cycle was noted during stimulation. A hearing aid type battery could supply power to keep this device moving in the small bowel for several hours. Conclusion: Electrostimulation might be used to move endoscopes in the small bowel.

In vivo sampling of Verteporfin uptake in pancreas cancer xenograft models: comparison of surface, oral and interstitial measurements

Photodynamic therapy (PDT) mediated with Verteporfin is being investigated as a pancreatic cancer treatment in the cases for non-surgical candidates. Tissue response to PDT is based on a number of parameters including photosensitizer (PS) dose, light dose and time interval between light application and PS injection. In this study, PS uptake and distribution in animal leg muscle, oral cavity tissues, pancreas and tumor was measured in vivo using light-induced fluorescence spectroscopy (LIFS) via an Aurora Optics Inc. PDT fluorescence dosimeter. An orthotopic pancreatic cancer model (AsPC-1) was implanted in SCID mice and treated with the PS. Probe measurements were made using a surface probe and an interstitial needle probe before and up to one hour after intravenous tail vein injection of the PS. The study demonstrated that it is possible to correlate in-vivo LIFS measurements of the PS uptake in the pancreas with measurements taken from the oral cavity indicating that light dosimetry of PDT of the pancreas can be ascertained from the LIFS measurements in the oral cavity. These results emphasize the importance of light dosimetry in improving the therapeutic outcome of PDT through light dose adaptation to the relative in situ tissue PS concentration.

Fibre-optic pressure and temperature measurements using phase-resolved low-coherence interferometry (Conference Presentation)

Percutaneous coronary interventions are widely performed minimally invasive procedures used to treat narrowing (stenosis) of arteries in the heart. Differential blood pressure measurements across a stenosis are invaluable to estimate the prognostic benefit of performing angioplasty and stenting via calculation of the fractional flow reserve. Achieving stable measurements from within pressure microcatheters and guidewires that are compatible with stenosed vessels, and which can be fabricated with low cost manufacturing methods, remains an important challenge. We have developed all-optical pressure and temperature sensors with a single optical fibre and sensing element. This approach provides simultaneous temperature and pressure measurements in a highly miniaturised device, with a simple construction method using low cost materials. Polymeric structures including membranes and domes are applied to the distal ends of single mode optical fibres. Temperature and pressure changes induce time-varying displacements of these structures, which are monitored using phase-resolved low-coherence interferometry. Phase measurements are acquired at 250 Hz with a sensitivity of approximately 0.2 rad/°C for temperature measurements between 20 and 45°C, and approximately 0.08 rad/mmHg for pressure between 760 and 1060 mmHg. In vivo studies in arteries and hearts of sheep and swine indicate that the sensors have sufficient sensitivity and speed for measurement of physiological pressure waveforms in clinical settings. We will discuss the integration of these sensors within medical devices, and the potential for providing additional physiological parameters with the same devices.

3D printed micro-scale fiber optic probe for intravascular pressure sensing

Small form-factor invasive pressure sensors are widely used in minimally invasive surgery, for example to guide decision making in coronary stenting procedures. Current fiber-optic sensors can have high manufacturing complexities and costs, which severely constrains their adoption outside of niche fields. A particular challenge is the ability to rapidly prototype and iterate upon sensor designs to optimize performance for different applications and medical devices. Here, we present a new sensor fabrication method, which involves two-photon polymerization printing and integration of the printed structure onto the end-face of a single-mode optical fiber. The active elements of the sensor were a pressure-sensitive diaphragm and an intermediate temperature-sensitive spacer that was insensitive to changes in external pressure. Deflection of the diaphragm and thermal expansion the spacer relative to the fiber end-face were monitored using phase-resolved low coherence interferometry. A pressure sensitivity of 0.031 rad/mmHg across the range of 760 to 1060 mmHg (absolute pressure), and a temperature sensitivity of 1.2 mrad/°C across the range 20 to 45°C were observed. This method will enable the fabrication of a wide range of fiber-optic sensors with pressure and temperature sensitivities suitable for guiding minimally invasive surgery.

3486 A new device for endoscopic submucosal resection.

Background: There is a need for better control of endoscopic submucosal resection which is a minimally invasive method for removing small tumors, cancers or areas of dysplasia from gut mucosa or submucosa. It might also have an application in the treatment of Barratt s esophagus. Snare electrodiathermy injury patterns are often deeper than appreciated and saline injection though protective can be unpredictable. It is currently limited by difficulty in controlling the depth of the cut and by a consequent high risk of perforation. Our aim was to develop endoscopic devices which facilitate endoscopic submucosal resection to predetermined depths and decrease the risk of perforation. Methods : A device was constructed which could be mounted on the tip of an endoscope and arranged so that none of the functions were impaired and the field of endoscopic view was unimpaired in 3 out of 4 quadrants. The device featured a cavity into which tissue could be sucked. By adjusting the floating floor the depth of a tissue sucked into the cavity could be altered and different size resection capsules were constructed to fit the size of the tumor to be resected.Various methods of cutting of tissue were studied in combination with this instrument. Snare diathermy was designed to open in a rim of this cavity. (Shearing and blade cutting were also studied). The device was designed to be used in combination with endoscopic ultrasound and to incorporate a probe ultrasound transducer and allow real-time imaging of the tissue as the tumour is resected to a predetermined depth to ensure complete removal and avoid perforation. This device was tested on submucosal tumors created in postmortem stomach, oesophagus, colon. (Preliminary studies were performed in survival studies in pig.) Results : Artificial tumors were created by submucosal injection of saline, glues(including cyanoacrylate) and mucosa raised with elastic bands. The device successfully resected artificially produced submucosal and mucosal tumors at varying depths according to the adjustment of the floor of the suction cavity. When the device was used to remove small submucosal tumors created in post-mortem stomach perforation occurred 8/10 with the cavity depth set at 8mm, and 1/10 with the depth set at 5mm (p

3334 Hydrogels and other lubricants in endoscopy.

Background: Lubrication is commonly used in endoscopy despite little data on efficacy. Hydrogels are polymers, which when bonded to surfaces and wetted, become very effective lubricants. Hydrogels are biocompatible and could make very effective endoscopic lubricants. Aims: To measure the static and dynamic coefficient of friction of freshly excised porcine colonic tissue, using different lubricants including hydrogels, on the shaft of a colonoscope. Methods: The shaft of the endoscope was curved to form rails held in place by a wooden jig. A toboggan of known weight was constructed with colonic tissue stretched on the underside to run on the rails. The jig was tilted using a rotary table and control unit which allowed accurate measurements of the angles at which the toboggan started to move and the angle required to keep the toboggan moving using water, KY jelly, silicone spray and spray oil lubricants. Hydrogel measurements were made using hydrogel coated urinary catheters as the rails. Coefficient of friction was calculated for the different lubricants. Results: The static and dynamic coefficient of friction were difficult to measure for the lubricants other than hydrogels due to their viscosity resulting in very slow movements. The values for KY, silicone and oil were generally less than water, though not significantly. The static coefficient of friction was reduced by a factor of 6 for hydrogels and by a factor of 10 for dynamic coefficient of friction over all other lubricants. These results were significant(p

3495 Esophageal dilatation-how hard do you push?

Background: Little is known about the forces exerted during esophageal dilatation. The complications of which are discomfort and perforation, and relate to the forces applied to the dilator. We aimed to measure these forces. Methods: A device was designed and tested which measured the forces exerted on 13mm and 18 mm diameter thermoelastic Celestin bougies. The device took the form of a hinged split cylinder which can grip the dilator and measure forces imparted by the endoscopists hand. The split cylinders incorporated strain gauges that measure push and pull forces. The device was calibrated and used to measure the forces applied to the dilator during 17, over the guide-wire dilatations. The device was optically isolated and tested by the hospital s medical equipment department. Results: 12 dilatations were for esophageal malignancy, 2 for dysphagia post Nissen fundoplication and 3 for peptic strictures. Peak forces varied from 0.4-3.8Kg force(mean 1.73Kg force) for dilating malignancy,0.8-1.3Kg force(mean 1.05Kg force) post Nissen fundoplication and 0.7-1.4Kg force(mean 1.1Kg force) for peptic strictures. Mean peak force for the 13 and 18mm dilator was 1.46 and 1.61Kg force respectively. The degree of dysphagia did not correlate with the size of dilator used or force required for dilatation. There were no complications and of the 12 patients questioned post procedure, all reported some improvement in their dysphagia. Conclusions: This device was successfully used to measure accurately forces imparted to the bougie during esophageal dilatation. Clinical diagnosis did not seem to significantly affect the force required for dilatation in this series, but the forces required varied widely with individual patients. Further assessment could be helpful in defining safe forces to use and as an aid in teaching.