Ms. Anne E. Rosse
Beckman Laser Institute
1002 Health Sciences Road E.
Irvine, CA 92612
Phone: 714-824-4111
Fax: 714-824-8413
Email: aerosse@uci.edu
Projects are approved by an IRB located at: Beckman Laser Institute/UC Irvine.
The approving IRB operates under a Multiple Project Assurance (MPA) recognized by DOE or by the Department of Health and Human Services (HHS).
MPA number of the IRB: M-1305
Number of Human Subjects Projects reported: 1
Project Identifier: UCI-91-ER61227
Project Title:
A center of excellence for the medical application of lasers
Principal Investigator:
Dr. Michael W. Berns
Principal Investigator's Institution: UC Irvine
Project started in: 1991
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Project involves use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 5
Protocol/Subproject # 1
Protocol/Subproject Identifier: HS 94-200
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 31, 1996
IRB Approval Number: HS 94-200
Number of Human Subjects who participated in this project/protocol during
07/31/95 - 07/31/96: 0
Type of Human Subjects Involvement:
Objectives
The objective of the study is to obtain data, on dose-ranging as well as clinical efficacy and safety, on the use of dynamic cooling during pulsed laser treatment of Port Wine Stain (PWS) malformations.
Methodology
This is a single center, open study to explore dose response relationships of dynamic cooling at varying cryogen spurt durations during pulsed laser exposure, and to determine safety and efficacy in treated patients having PWS. Subjects will be recruited from an on-site population of approximately 250 previously laser-treated or previously untreated patients at the Beckman Laser Institute and Medical Clinic, University of California, Irvine. There are no limitations in terms of skin distribution of the PWS. Successive patient groups will be given longer durations of the cryogen spurt (range 0-20 milliseconds) and within each group, escalating light doses (range 5-10 J/cm2). On each patient, test sites will be compared and evaluated for efficacy and safety of the test doses. Eighteen circular sites will be treated with different cryogen spurt regimes: six sites will be treated without dynamic cooling; six adjacent sites will be treated immediately after a 10 millisecond cryogen spurt; and six adjacent sites will be treated immediately after a 20 millisecond cryogen spurt.
Efficacy will be determined by cryogen spurt duration/light doses necessary to produce clinically significant blanching without adverse effects of treated PWS sites compared to uncooled sites and untreated control sites.
Involvement of Human Subjects
Treatment Visit Patients will be allocated a sequential identification number and assigned to treatment. It should be noted after such assignment, all subjects including drop outs must be accounted for and fully documented through withdrawal or study completion.
In each subject, eighteen test sites on the PWS will be chosen for clinical study. All sites will be circular in shape, 5 mm in diameter and identified by a skin marker. Six sites (numbered 1,4,7,10,13,16) will be selected for irradiation without dynamic cooling. Six adjacent sites (numbered 2,5,8,11,14,17) will be selected for identical light doses of irradiation immediately after a 10 millisecond cryogen spurt. Six adjacent sites (numbered 3,6,9,12,15,18) will be selected for identical light doses of irradiation immediately after a 20 millisecond cryogen spurt. Before laser irradiation all numbered sites will be photographed under standardized conditions for film, light source and exposure. Incremental dosages of light (range 5-10 J/cm2, in increments of 1 J/cm2) will be applied ranging from the lowest in sites 1,2 and 3 to the highest in sites 15,16 and 17. A surgical drape will be used to define the study sites and to protect the remaining skin from exposure. Subjects will wear protective eye glasses to shield their eyes during the light treatment.
Risks/Discomfort/Inconveniences
Possible adverse effects are as follows:
- hypertrophic scarring
- changes in the normal skin pigmentation or color
- atrophy
- induration
- frostbite
- local skin allergic reaction to the cryogen
Previous studies cited above using the flashlamp-pumped pulsed dye laser for the treatment of PWS have reported an incidence of adverse effects of less than 2%. Flashlamp-pumped pulsed dye laser treatment is likened to "a rubber band snapping against the skin." We have found the treatment to be well tolerated by adult patients. No local or general anesthetics are required. Prolonged skin exposure to the cryogen can cause frostbite. However, the proposed application of a 0-20 millisecond aerosol cryogen spurt is not expected to cause frostbite and, therefore, does not constitute a significant risk to subjects participating in this study.
The possibility of a local skin allergic reaction to the cryogen does exist and participating subjects will be followed closely. Skin allergic reactions will be assessed on a five point scale:
SCORE SKIN ALLERGIC RESPONSE
1 No reaction; identical to surrounding non-irradiated skin
2 Minimal perceptible erythema; blotchy areas of faint erythema
confined to the irradiated site
3 More pronounced, even bright, erythema without edema
4 Marked erythema with edema
5 Violaceous erythema with vesiculation
Adverse Effects Reporting
Safety will also be evaluated at each visit by searching for any adverse effects such as hypertrophic scarring, changes in the normal skin pigmentation, atrophy or induration. Additional photographs will be taken during the course of the study of any adverse effects.
Adverse effects monitoring will consist of those symptoms, complaints, or effects reported by subjects or investigators. Subjects will be asked about their symptoms, complaints, or adverse effects at each evaluation visit, and the information recorded on the Adverse Experiences form. Any severe or unexpected adverse experiences, any increase in the frequency of adverse experiences or death that may occur in this study will be reported immediately to the Institutional Review Board together with an evaluation as to whether or not the adverse experience is in any way related to the treatment. The initial report will be made by telephone and will be followed by a complete written report within five working days. The structure of the described protocol, close clinical supervision and an awareness of the potential adverse reactions provide a significant margin of safety for this investigation. Vital signs monitoring will take place only at baseline.
Informed Consent Procedures
Informed consent will be obtained from all subjects. The principal investigator will explain the full details of the protocol, experimental procedure, possible side effects, risks, and complications of the treatment to each participant before informed consent is sought and documented on the standard University of California, Irvine consent form. The subject will then be given the opportunity to sign the informed consent form in the presence of the principal investigator and a witness, who will also sign the informed consent. The patient will be informed that he or she may withdraw his consent at any time during the course of the study without prejudice to further care. The patient will be given a copy of the informed consent to keep, and a copy will be placed as a permanent record in the patient's medical chart.
Measures Taken To Protect The Rights/Welfare Of Subjects
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 respective 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. Patients will be identified only by their corresponding code numbers. The records and results of these studies will not be identified as pertaining to a certain patient without his or her 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. Study progress will be monitored through monthly Operations Committee meetings. These provide the opportunity to review subject data and ensure the safety of the subjects in the unlikely event of problem situations.
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 31, 1995
IRB Approval Number: HS 94-214
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 21
Type of Human Subjects Involvement:
Objectives.
The purpose of this study is to assess the fluorescence (red color) produced in uterine tissue by application of a ALA test formulation into the uterus. The fluorescence of uterine tissue will be examined after the planned removal of the uterus on tissue sections.
In this protocol we learned about the conversion of ALA to Protoporphyrin IX by uterine tissue in vivo, and we were able to define the optimal timing for maximal selectivity of PpIX uptake by the endometrial glands. Following this study, we defined a clinical study for PDT as an office procedure for selective endometrial ablation. This study was recently approved by the FDA.
Methodology.
5-aminolevulinic acid (ALA) is a natural compound made by the body that is used in the production of red blood cells. When ALA is applied into the uterus, it is converted by the tissue to a compound that is sensitive to light. Topical ALA and red light have been used experimentally for the "photodynamic treatment" of skin cancers.
Involvement of Human Subjects.
At a defined time before the scheduled hysterectomy, 1 cc of ALA solution will be slowly injected into the uterus through a fine catheter. In some patients, this will be done in the operating room just before surgery; in others, it will be done 24 hours before the operation. After hysterectomy, small tissue samples will be taken from the uterus for fluorescence evaluation by microscopy. The main specimen (99% of the uterus) will be handled in the operating room for further analysis as indicated. Handling of the specimen will not hamper the quality of pathologic evaluation. Information learned from the additional microscopic examination will be reported to the pathologist.
The direct possible risks of intrauterine applications of ALA include:
1. Discomfort while introducing the fine catheter into the entrance of the uterus. 2. Contractions of the uterus after injection of the drug. 3. Allergic reaction to the ALA or the solution containing Hyskon. 4. A prolonged photosensitivity of skin to light that is very unlikely but possible.
Privacy, confidentiality, consent issues for this protocol are in compliance with IRB requirements.
IRB Review:
Type of Review: Expedited
Most Recent Approval: November 16, 1995
IRB Approval Number: HS 95-230
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 6
Type of Human Subjects Involvement:
Objectives.
The goal of this study is to produce an excellent in vitro model that will define specific light and drug parameters. This model could then be used to assist in the development of studies designed for the photodynamic treatment of cervical dysplasia and cancer in the human.
Methodology.
The chick chorioallantoic membrane (CAM) is an established in-vivo experimental model for studying biological processes, such as implantation and the ensuing angiogenesis. The CAM model presents an attractive alternative to whole-animal studies. Extensive experience has been accumulated by our group using the CAM model for a variety of PDT- and laser-related studies.
It has been demonstrated that between 7 and 14 days of embryonic development, the chick chorioallantoic membrane contains pre- and post-capillary vessels. It is possible to view the blood vessels and to examine structural changes in real time, thus simplifying experimental animal procedures. Tumor-bearing CAM systems will enable us to monitor such activities at the micro vessel-tissue interfaces during a period of system differentiation in which agent-induced modifications are pronounced at the cellular level.
Involvement of Human Subjects.
Patients scheduled for colposcopic guided biopsies for cervical intraepithelial neoplasia (CIN) or hysterectomies for cervical cancer will be verbally consented, and a 0.5-1mm sample will be removed from the biopsy (or from the removed uterus in the cases of hysterectomy) for the purpose of this study. The specimens will be seeded on an 8-10 day old chick chorioallantoic membrane (CAM).
The CAM method used is a modification of a previously described technique. Fertilized eggs are washed with 70% alcohol and incubated at 37 C in 60% humidity and rolled over regularly. On day 3-4, a hole is drilled through the egg shell and 2-3 ml of albumin is withdrawn from each egg to create a false air sac. On the following day, part of the CAM is exposed by opening a round window of ~2 cm diameter in the shell which is covered with a Petri dish; the incubation is continued (no rolling over) until day 10 when the CAM is fully developed and ready for experimentation. The specimen will then be seeded on the 8-10 day old CAM by dropping 20 ml of the suspension containing cells into the area defined by a 6 mm sterile ring placed on the CAM near a vessel bifurcation. Tissue proliferate within 3-4 days after implantation and show vascularization and metastases outside the ring.
The PDT drugs are dissolved in an appropriate buffer and administered (1) topically - dropping 20 ml of the drug solution onto the CAM, within the area defined by a Teflon ring placed onto the CAM; (2) intravenously, micro-injection in CAM veins using glass pipettes; or (3) systematically - by yolk sac injection, using conventional needle and syringe techniques to administer relatively large quantities of drugs. For topical application, an egg will be furnished with two Teflon rings (one on the normal CAM and the other surrounding the tumor implant) which will be filled with the drug solution of interest or with the buffer (as a control). For IV or yolk sac application of drug, no rings will be used. The egg will be covered with a blackened petri dish and returned to the incubator.
Because the photosensitizing drugs possess fluorescence, we will be able to determine the uptake of a drug into the CAM. Since egg albumin is transparent to the excitation and emission wavelengths, the CAM system facilitates real-time, in-vivo observation and analysis of microvasculature activities.
At the appropriate time between day 10-15, the eggs will undergo photodynamic treatment. After sufficient time for drug uptake (time to be determined for each drug and each route of administration), the egg will be removed from the incubator and placed in a heating block at 37 C filled with glass beads. The CAM will be irradiated using either an Ar-ion-laser pumped dye or Ti:Saph laser with the laser wavelength matched to the drug absorption peak and light dose ranging from 10-100 J/cm2, delivered during a time within the range of 10 minutes. Control experiments will be performed to determine (1) dark toxicity, with drug and no radiation and (2) the effects of maximal incident light dose alone. Following irradiation, the egg will be re-covered with a blackened petri dish and returned to the incubator to enable observation of vascular and tumor response at selected time points.
Specimens will be obtained from patients who are scheduled to undergo clinically indicated hysterectomy. There will be no connection between the indication for surgery and the participation in this study. There are no additional risks involved.
IRB Review:
Type of Review: Expedited
Most Recent Approval: August 23, 1996
IRB Approval Number: HS 95-330
Number of Human Subjects who participated in this project/protocol during
08/23/95 - 08/23/96: 0
Type of Human Subjects Involvement:
Objectives
Specifying the distribution of laser energy within human skin is the first step toward understanding and capitalizing on a variety of laser-tissue interactions. Whether photothermal, photochemical, or photomechanical in nature, laser-tissue interactions begin with the absorption, scattering, transmission, and reflection of photon energy. The spatial distribution of photon energy within human skin specifies the required laser exposure to be delivered and the extent of subsequent therapeutic action.
Methodology
Optical low coherence reflectometry (OLCR) or white light interferometry are existing techniques whereby the location and relative strength of optically scattering structures can be deduced. Results from OLCR are analogous to ultrasound B-scan except the imaging is performed optically instead of acoustically. However, OCLR is far superior to ultrasound in that the technique is non-contact, has high sensitivity (>140 dB dynamic range) and, most importantly, exceptional spatial resolution (<1 mm) in both the axial and radial directions. In practice, light emitted from a low coherence source is coupled into a two beam fiber optic interferometer and split into sample and reference paths. Light backscattered by the test material is recombined with that retroreflected from the reference to produce interference only for coherent photons that have a time-of-flight difference that matches the reference-target optical delay to within the source coherence length.
Infrared tomography (IRT) uses a fast infrared focal plane array (IR-FPA) camera to detect temperature rises in a substrate, induced by pulsed radiation. The temperature rise, due to the selective optical absorption of pulsed laser light, creates an increase in infrared (blackbody) emission which is measured by a fast IR-FPA. Although the use of IRT has become a topic of great interest in the physical sciences to image subsurface cracks in aircraft fuselage due to metal fatigue, the application of this modality to determine the initial space-dependent temperature increase in absorbing subsurface chromophores in human skin immediately following pulsed laser exposure is novel.
Involvement of Human Subjects
We propose to use OLCR and IRT to measure the absorption, scattering, transmission, and reflection of photon energy within human skin. Discarded skin samples will be collected by Dr. Bruce Achauer, Associate Professor of Plastic Surgery, University of California, Irvine, from patients undergoing elective rhytidoplasty ("face lift") and abdominoplasty ("tummy tuck") surgical procedures. The epidermal and dermal papillary layers will be non-destructively isolated using a standard technique developed in the Department of Dermatology, University of California, Irvine. After isolation, each layer will be slowly heated with a temperature controlled gel pack. The pliable gel pack will allow good contact and insulation of the tissue sample under test. Using OLCR and IRT, the absorption, scattering, transmission, and reflection of photon energy within human skin will be measured. The experimental procedure will be conducted with a number of skin samples so that statistically significant conclusions can be made.
Every effort will be made to obtain skin samples from the appropriate gender and minority/ethnic background representation that reflects the general population distribution seen at the University of California Irvine Medical Center. This protocol is being filed as Exempt Research under Category #4 because the work involves the collection of data from discarded pathological specimens by the investigator in such a manner that the subjects cannot be identified directly or through identifiers linked to the subjects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: August 23, 1996
IRB Approval Number: HS 95-333
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 0
Type of Human Subjects Involvement:
Objectives.
The purpose of this study is to assess the optical properties in uterine tissue by application of a specially-designed intrauterine probe. Routinely, the uterus has to be dilated with a uterine dilator before surgery. The probe will consist of two fibers introduced in the uterine dilator. No other instruments will be used to dilate the cervix other than those used for conventional diagnostic procedures.
Methodology.
Patients scheduled for hysterectomy, dilatation and curettage (D&C), or hysteroscopy will be given an opportunity to participate in in-vivo optical property studies. Optical property measurements will be conducted using a specially-designed FDPM measurement probe consisting of a Hegar dilator with source and detector fibers embedded in the outer walls at fixed separations (defined by the dilator diameter). The probe is inserted into the uterus as follows: (1) the external cervical ostium is grasped with a two teeth tenaculum, (2) a hysterometer is inserted to measure the length of the cervical canal and uterine cavity, (3) the photon migration Hegar probe is inserted through the cervical canal to the same depth as measured previously, (4) once the fundus is reached, confirmation of accurate fiber location is provided using ultrasound imaging (the ultrasound probe is turned off during optical property measurements). FDPM measurements are acquired using our 1 GHz portable instrument which is currently able to record data and calculate optical properties in less than 1 minute.
Involvement of Human Subjects.
The measurement of the optical properties of the uterus will be done at the beginning of the scheduled operation under anesthesia. Routinely, the cervical canal has to be dilated with a uterine dilator before the instrument for D&C or hysteroscopy can be inserted into the uterine cavity. Two fibers placed at opposite sites in specially made channels of the uterine dilator will get in direct contact with the fundus for the measurement of the optical properties. This will add approximately five minutes to the surgical procedure.
No additional risk or discomfort is anticipated. No other instruments will be used to dilate the cervix other than those used for conventional diagnostic procedures.