Ms. Montana Watnasuvisuth
Beckman Laser Institute
1002 Health Sciences Road East
Irvine, CA 92612-
Phone: 949-824-9265
Fax: 949-824-8413
E-mail: mwatnasu@uci.edu
Number of Human Subjects projects reported: 1
| BLI-91-ER61227 | "A Center of Excellence for Laser Applications in Medicine" |
"A Center of Excellence for Laser Applications in Medicine"
Principal Investigator: Dr. Michael W. Berns, UC Irvine
Project started in: 1991
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 3
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Beckman Laser Institute/UC Irvine
Most recent approval: 10/26/02
IRB approval number: HS 95-563
Explanation of IRB approval:
IRB Pending
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 106
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
Objectives:
Our goal is to develop a simple, rapid, hand-held optical screening device which will yield low resolution tissue functional information that complements and enhances the detailed structural information obtained from x-ray mammography. The functional information obtained from the optical screening device should allow for distinguishing between healthy and diseased tissue by providing a description of the tissue cellular state. Most non-optical imaging technologies measure static physical structure rather than cellular state, so that while images may reflect anatomical details, they reveal nothing about the functionality of the tissue. For example, x-ray mammography often does not distinguish between healthy and dying tissues, even though such functional information may be crucial to accurate diagnosis and effective treatment. The long-term goal is to develop a novel, non-invasive optical diagnostic technique which quantitatively determines near-infrared optical absorption and scattering in breast tissues.
Methodology:
Optical properties can be determined in biological tissues using Frequency-Domain Photon Migration (FDPM) by a single non-invasive measurement. In FDPM, the intensity of light aimed upon a biological material is modulated at high frequencies, and the diffusely reflected or transmitted signal is measured with a phase-sensitive detector. Intensity-modulated light propagates through a turbid medium with a coherent front, forming photon density waves. The wave dispersion is highly dependent on the optical properties of the medium and the measured parameters characterizing the wave dispersion can be used to rapidly determine these properties, namely the medium scattering and absorption parameters.
Prior studies have been conducted on tissue phantoms and have shown that accurate optical properties can be extracted regarding the medium under investigation. Ex vivo studies on bulk human and animal tissues using a "first generation" low-bandwidth (250 MHz) FDPM device have demonstrated the need for in vivo measurements using a high-bandwidth, multi-wavelength instrument. Other studies have been performed on suspensions of cells and subcellular organelles under carefully controlled environmental conditions. These experiments were conducted in order to establish a structural basis for optical properties in simple biological models. They demonstrate varied optical characteristics for different cell types and subcellular components. It is expected that these observations will allow us to gain histo/physiological diagnostic insight from the scattering and absorption parameters derived from FDPM breast tissue measurements. To address this need, Dr. Tromberg's group has developed a high-bandwidth (1 GHz) FDPM device.
Instrumentation: FDPM device
The portable high-bandwidth FDPM instrument employs intensity-modulated diode lasers and conventional steady-state lamps as sources and an avalanche photodiode as the detector. A network analyzer (Hewlett Packard model 8753C), which measures reflection and transmission characteristics of devices and networks, is used to produce an RF signal swept from 300 kHz to 1 GHz superimposed on the direct current of the laser diode (SDL, Inc. model 7420). The network analyzer is driven by a computer (Dell Dimension PC), which uses custom-designed virtual instrument code to render the measurement session convenient and “user-friendly”. Different wavelengths are accessed by serially addressing an RF switch array (Hewlett Packard, model 8768K). Up to 16 unique laser wavelengths within the visible to near-infrared region are used. In some cases, a conventional light source is used to fill the gap between laser wavelengths. Each laser output is directly coupled into optical fibers which are bundled at the probe end and placed in contact with the tissue. The optical power launched into the sample (lasers or conventional sources) averages 10 - 50 mW (comparable to halogen-bulb household flashlights). Backscattered light is either collected by an optical fiber or coupled directly to an optical detector ( avalanche photodiode detector (APD, Hamamatsu, model C5658, 12 V bias) placed in contact with the skin. The time required to perform an FDPM measurement depends on the desired precision and number of sweeps. At present, approximately 30-60 seconds to record data from typical tissues at a given wavelength and position. Several locations judged clinically relevant are probed. Total measurement time ranges from approximately 5 to 90 minutes, depending on the number of sites mapped and style of measurement.
Involvement of Human Subjects:
1. Procedures:
Non-invasive measurements of breast tissue optical properties will be performed on the skin surface using a specially designed FDPM measurement probe which is similar in shape to an ultrasound probe. The FDPM probe is embedded with optic fibers set at a fixed separation. The FDPM probe will be placed on different areas of the breast including areas suspected to have disease and areas appearing to be normal. The diseased location will be identified by clinical palpation. In some cases, optical measurements will be guided by co-registered ultrasound measurements for the purpose of determining lesion size and location. There are two guiding principles as to the use of ultrasound: (1) The ultrasound will ONLY be used in women who have had a breast lesion detected by a physician, and (2) the ultrasound scan will ONLY be performed in the region of the lesion, and will not be used in other areas of the breast. This ultrasound will NOT be available as a medical record for the patient; it is for research purposes only. Some mild tissue compression will be performed within comfort tolerance of the patient during the application of the FDPM probe. When the probe is in position, the laser will be activated and a measurement will be taken. Each measurement will require about 30-60 seconds to record the data and calculate optical properties. The probe will then be turned off and moved to a new position for further measurements. The process will be repeated until an adequate number of measurements are performed (about 10-20). The whole process should take 30 to 90 minutes for the “Non-Invasive” and only 20-40 minutes for the “Cyclics.” This concludes measurements on both “Non-Invasive” and “Cyclic” protocols. In the case any measurements involve lesions, we will perform a standard-of-care ultrasound for the purpose of localizing the region we want to study. This ultrasound is not meant to provide the subject with any clinical information, but rather lesion location information for the investigators. Subjects will be referred to Dr. Butler for consultation should new lesions be revealed by the ultrasound procedure. In the case of repeated measurements (i.e., only the “Non-Invasive” and “Cyclic” protocols), we also would like to perform a measurement on the abdomen and/or arm in order to see if the changes we see in the breast are local or global hemodynamic changes. These additional measurements are not meant to spearhead an additional study, but rather provide additional information as to the nature of changes we see in the breast. No additional risk is anticipated to the subject.
Some subjects studied under these two consents (‘Non-Invasive” & ‘Cyclic’) will have breast diseases. In these situations, we might request specimens from the subject, such as blood, biopsy samples, or urine, if they are available. We will not take any specimens ourselves, but will obtain these samples from the subject’s physicians. Subjects must sign an additional medical release form, separate from the optical study consent, before we may obtain these specimens.
In the case of the “Surgical” protocol, patients will be taken on the day of operation to the operating room as they normally would for their procedure. During the procedure, the skin will be opened using standard surgical techniques. The tissue of concern will be exposed and hemostasis will be obtained. The probe will have been gas sterilized prior to surgery using the following techniques:
1) The probe with attached optical fibers are placed into an air tight sterilizing chamber and preconditioned for 90 minutes at 122 degrees F and 30-35% humidity.
2) The air is then evacuated and replaced by “8812” gas consisting of 12% ethylene oxide and 88% dichlorofluoromethane. The instrument is exposed to this for 105 minutes.
3) Three pulse air washes are performed on the instrument still in the chamber over 120 minutes.
4) The chamber is aerated, a constant flush of air for 8 hours, completing the sterilization procedure. The instrument is then sterile and ready for use.
5) The optical fibers are then attached to the FDPM device leaving the probe end of the instrument sterile.
A self-retaining retractor will be placed in the skin incision for exposure of the breast tissue and the sterile probe will be placed into the incision 10-20 measurements will be taken from surgical patients. The probe is smooth, blunt, and will be placed gently into the incision and will not damage the patient's tissues. The laser will be turned on and measurements will be taken within the incision. The laser will be turned off and the probe moved to a new measurement within the incision. This will be repeated about 10 times taking about 5 to 10 minutes. This extra time will not be charged to the patient.
The tissue will then be excised according to normal procedure and optical properties of the ex vivo tissue will be measured using the probe and then comparing the findings to the macro and microscopic pathologic findings. The ex vivo tissue optical property measurements will be done at the time of surgery immediately after the tissue has been excised and will have no effect on the pathologic examination of the tissue.
The clinical histories and pathology reports will be reviewed to obtain the following information: patient age, menopausal status, hormonal treatment during the last three months, mammography, and histopathologic findings. In addition, out a brief questionnaire surveying medical information applicable to the study will be filled out by each volunteer prior to the study. This data will be correlated with the in vivo invasive and non-invasive optical properties as well as the ex vivo optical properties of the breast tissue. Specific mammographic and ultrasound findings will be correlated to ultrasound data, including size, location, calcification pattern, and other abnormalities. The pathologic findings of interest will include the type of lesion, the presence or absence of malignancy, the tumor size, its location, its cellularity, and areas of necrosis seen with gross, microscopic, and histochemical analysis.
2. Risks:
The optical scan is not expected to cause any pain, burning, or discomfort during or after the exam. There may be risks, however, that are currently unforeseeable. During all measurements, the laser will be turned on only when needed. Although not required for safety, subjects may wear protective eye goggles if requested.The length of surgery and anesthesia time will be slightly longer as a result of this study, and the chance of infection may be minimally increased. However, the patient's face will be behind and opaque sheet to reduce the risk of injury to the eyes and will be monitored very closely during this time and no significant increase in risk is anticipated. No additional risk or discomfort is anticipated. No other instruments will be used to perform breast biopsy other than those used in conventional surgery.
Informed consent for research will be obtained when the patients are scheduled for surgery and a detailed explanation of the study will be given.
3. Privacy/confidentiality/consent:
The collection and submission of medical information from this study will be accomplished with the strictest adherence to professional standards and confidentiality. An identification number for each patient will be kept on file, and all records will be filed in a locked area, accessible only to researchers listed on this protocol, authorized representatives of UCI, and any other officials as required by law. Patients will be identified by initials and corresponding identification number. A locator sheet will be completed for each patient that bears the necessary information needed to contact the patient should new information about the use of the study test articles become known in the future which might adversely affect that patient's well-being.
A report of the results of this study may be published; however, anonymity will be maintained and names will be known only to the investigator and his technical personnel.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Beckman Laser Institute/UC Irvine
Most recent approval: 09/13/02
Explanation of IRB approval:
Pending IRB approval.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
Objectives:
The objective of the proposed clinical study is to determine the efficacy and safety of photodynamic treatment of the endometrium after topically applied 5-Aminolevulinic acid is injected into the uterine cavity using a fixed drug dose and application schedule and variable light dose.
Methodology:
This is an open label study designed to assess the safety and efficacy of topical ALA in Hyskon R and red laser light (635 nm) for Photodynamic therapy (PDT) of the endometrium.
One and one-half milliliters of pH adjusted ALA/HyskonR will be injected into the uterine cavity through a smooth, fine catheter 4-7 hours prior to light application. One ml of fluid is needed to cover the entire cavity of a normal size uterus as demonstrated in hystero-salpingography. This volume covers the walls of the entire uterine cavity without spillage through the fallopian tubes. Up to 12 patients will be enrolled into study during a period of 12 months.
Ionizing Radiation, Radioactive Substances, or Chemical Substances:
Pharmacology of ALA - the product will consist of a solution of 600 mg ALA in 1.5 mL dextran 70 (32% W/V) in dextrose (10% W/V; HyskonR). The crystallized 5-Aminolevulinic acid will be dissolved to 400 mg/mL in HyskonR and titrated with NaOH to pH 6 extemporaneously just before use under sterile conditions.
The light diffuser (L-IUD) is similar in shape and size to a contraceptive intra uterine device. It contains trifurcated transparent plastic tubes that fits the size and shape of the uterine cavity. One laser diffusing fiber is inserted into each tube.
The topical application of the ALA solution will be performed in lithotomy position 4, 5 1/2 or 7 hours prior to light application.
The light intrauterine device will be inserted while the patient is in lithotomy position. The uterine cavity will be illuminated with red light of 635 nm wavelength from a Coherent Medical Model 920 argon pumped dye laser.
Involvement of Human Subjects:
Twelve patients with chronic dysfunctional uterine bleeding who did not respond to conventional treatment and surgical intervention are justified, or patients with stage I cervical cancer who are scheduled for cone (LEEP) biopsy and simple hysterectomy will be asked to enroll into this study.
Risks:
PDT as compared to all other surgical procedures for endometrial ablation is low risk. However, there is a minimal risk of perforating the uterus during insertion of the drug or the light cannula. If this happens the procedure will be terminated and appropriate treatment will be given. All adverse experiences will be recorded in the case report form. Patients may be discontinued from the study prior to its completion for the following reasons:
1) Development of a severe adverse reaction before or during PDT.
2) Patient requests to withdraw from the study.
3) The investigator decides it is the patient's best interest to be withdrawn.
4) Intercurrent illness which may, in the judgment of the investigator, significantly affect assessments of clinical status.
5) Non-compliance.
Safety analysis will be performed on all subjects who receive treatment. Safety will be assessed by compilation of adverse even data including the expected PDT-related symptoms at the treatment site, such as subject discomfort.
Confidentiality:
The collection and submission of medical information from this study will be accomplished with the strictest adherence to professional standards and confidentiality. An identification number for each patient will be kept on file, and all records will be filed in a locked area, accessible only to the study physician and his designated assistants. Patients will be identified by initials and corresponding identification number. A locator sheet will be completed for each patient that bears the necessary information needed to contact the patient should new information about the use of the study test articles become known in the future which might adversely affect their well-being. The FDA may inspect the study and medical records.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Beckman Laser Institute/UC Irvine
Most recent approval: 08/12/02
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 19
Reporting period for number of human subjects:
Fiscal Year 2002
Type(s) of Human Subjects Involvement:
Objective:
The objective of this study is to determine the degree of PWS lightening and the incidence of side effects during treatment with pulsed dye laser in association with CSC (ScleroPLUS) at high incident light dosages.
Methodology:
A port wine stain (PWS) is a vascular malformation found in approximately 0.3% of children. These lesions are generally noted at birth as a faint pink macule which, as the patient ages, thickens and darkens to a red-purple color. Histologically, PWS birthmarks consist of dermal, dilated, capillary-like vessels with no endothelial proliferation.
PWS birthmarks may be located anywhere on the body but are commonly found on the face and neck where they have serious psychological consequences. Patients are often perceived by others as "marked" which may adversely affect personality development. For this reason and because PWS birthmarks are unlikely to involute with time, patients or their families often seek treatment.
Developing acceptable treatment options has been difficult. Early attempts at treatment included cosmetic cover-up, skin grafting, radiation, dermabrasion, cryosurgery, tattooing and electrotherapy but none of these modalities provided cosmetically acceptable results. The development of lasers and their ability to damage PWS blood vessels offered another treatment option. A variety of lasers have been utilized for the treatment of PWS birthmarks but the flashlamp-pumped pulsed dye laser (FLPDL) has offered the best results with the lowest incidence of side effects.
The FLPDL has become the treatment of choice for PWS birthmarks; however, therapeutic challenges remain. Unfortunately, for many lesions, the threshold for epidermal damage following laser therapy is lower than that for permanent blanching of the PWS. As a result, only 10-20% of patients obtain 100% fading of their PWS even after many treatments.
Clinical studies have demonstrated the efficacy and safety of cryogen spray cooling during pulsed laser treatment of PWS birthmarks. This technology allows the use of higher incident laser light dosages and has been demonstrated to improve treatment results. CSC also decreases treatment pain and the duration of post-laser treatment purpura.
Ionizing Radiation, Radioactive Substances, or Chemical Substances:
None
Involvement of Human Subjects:
1. Procedures:
Subjects will be recruited from previously treated and untreated patients at the Beckman Laser Institute seeking removal for PWS birthmarks.
The PWS will be treated with a cryogen spurt of 10-100ms, a delay of 10-60 ms and light doses of 6-15 J/cm2. Patients will have repeat treatments every 8-12 weeks until the completion of the study or such time as they no longer desire treatment with the ScleroPLUS laser. After each treatment patients will be asked to describe the pain as none (0), slight (1), moderate (2) or severe (3). Patients will also be monitored for any adverse effects.
2. Risks:
Possible adverse reactions associated with the proposed laser procedure include:
-scarring
-pigmentary change
-atrophy
-infection
-induration
-pain
-edema
-frostbite
-local skin allergic reaction to the cryogen
A low incidence of mild side effects was reported in clinical trials performed by Candela. This has been confirmed by our own experience with this laser over the past 6 months.
Safety will be evaluated at each visit by asking the patient about any adverse effects and by evaluating the treatment area for scarring, pigmentary change, atrophy or induration. Photographs will be taken at each visit to document treatment efficacy as well as any adverse effects.
3. Privacy/confidentiality/consent:
Informed consent will be sought only after the participating physician explains the full details of the protocol, possible side effects, risks and complications to the subject. Consent will be documented by signing the standard University of California, Irvine form. Explanation will be given of all treatment alternatives with respect to advantages and disadvantages. Complete confidentiality will be maintained by staff physicians, nurses, and technical support personnel. A sequential code number for each patient will be kept in a log book and all records stored in a locked file. The records and results of these studies will not be identified as pertaining to a certain patient without his expressed permission to safeguard the confidentiality of the subject. The data assembled will be used for research purposes only to assess the efficacy of the laser therapy and to develop optimum treatment parameters.