Review of Dber Program at Lampf - October 17-18, 1977

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REVIEW OF DBER PROGRAM AT LANPF TENTAT IV E AGENDA All meetings i n Laboratory Office Building, Room A - 234 on the LAl4PF site. ckup a t Los Alamos Airport "Overview of LANPF Practical Applications and Identification of DBER Programs" Tour of LAWF Taxi pickups a s vcqui rcd

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Section I I Biomedical Instrumentat ion Section 1 1 1 Muonic X-Ray Analysis Section I V Proton Computed Tomography Stct ion VPi on B i onud i ca 1 Program Appendix 1 Experiments at Biomed Channel Appendix 1 I Selected Reprints

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The Los AIamos Meson Physics Facility (LAMPF) provides unique high-intensity beams of protons, muons, and pi-mesons. Several o f these beams, together with some technological advances realized in developing this facility, are be evaluated for use in the detection and treatment o f disease and for appl to environmental problems. The DEER program at LAMPF commenced in 1972. program is conducted by the Practical Applications Group (MP-3) and invo research in three main areas: development and evaluation o f biomedical mentation, new materials analysis techniques, a n d the pi meson biomedical program. The instrumentation development effort (Section I I) has been focused mainly on the application of hyperthermia in cancer therapy and new diagnostic posslbilities for the detection o f cancer. Localized heating techniques have been used on various animal and human tumors. in cattle has been developed and is now in the commerical sector f o r marketing. A similar approach may prove useful f o r some forms o f human eye disease. Instrumentation developed at LAHPF for detecting tumors i s being tested at several normal tissue in temperature and electric potential. A device for treating the "cancer-eye" condition These techniques are based on indications that tumors differ from The materials analysis program involves the use o f muons (Section 1 1 1 ) and protons (Section IV) generated by the LAMPF accelerator. arising from implanting negative muons in a sample has been used to determine the elemental composition of a number of biologically interesting samples. technique is non-destructive, requires low dose, and can be used to selectively interrogate the interior of b u l k specimens. Low-2 elements pose no problem in contrast to m o s t conventional techniques. Experiments have indicated that the x-ray spectrum i s also sensitive to the chemical environment in which the muon stops; this should have significance for a number of biological and environmental procedures. Protons are being used to determine the three-dimensional density distribution of objects i n a manner analogous to that employed in CAT-scanning resolution can be achieved with much less dose than with x rays. The muonic x-ray spectrum The advantage of using protons is that a given spatial and density The primary objective of the LAMPF pion biomedical program i s to evaluate the use of negative pions in cancer therapy. The physical, radiobiological, and

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clinical experiments specifically required for this evaluation are performed by LAHPF and University of New Mexico personnel under a grant from the National channel about 60% of operations tiv. of a fundamental nature not designated in the N C I grant and includes pion radiobiology, selected dosimetry and microdosimetry experiments with pion beams, evaluation of new dosimetry techniques, determination of pion W-values and visualization studies. Huch of this research i s performed b y users from institutions other than these users and some limited in-house research. These activities currently require use o f the biomedical The remaining time i s assigned to research The 3 B E R supports the development and operation o f the channel for In ensuing sections of t h i s report progress i n these areas is described. References are located at the end of each section. include selected reprints and a list of experiments on the pion biomedical channel. Appendices to the report

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I1.BI OHED I CAL I NSTRUHENTAT I ON The des I gn , construct ion and operat ion phases o f LAHPF have resu 1ted i n the creation of a significant technology base, both i n terms o f personnel and hardware. This resource has been directed toward the solution of several non-accelerator-related problems i n the biomedical sphere. The specific technology applied includes radio-frequency techniques, electronic feedback, and monitoring of low-level signals in noisy environments. B. Locallzed Tissue Hyperthermia The results of a number of investigations during the past 25 years show that mallgnant cells are quite often more sensitive to moderate levels of hyperthermia than their normal counterparts. This information has ledto i'nte rest in techniques for generating localized thermal fields in tissue for the treatment of cancer, both as the sole modality and i n combination with radi a - t ion therapy or chemotherapy. Some investigators have reported a synergistic effect from combinations o f (low LET) radiation treatments and hyperthermia. The Practical Applications Group a t LAHPF began investigating the utility of localized radio frequency current fields (LCF) for this application during the summer o f 1972. (See attached reprint, c.I nstr., 10, Jan-Feb 1976). In this approach, electrodes are placed on (or into) the tissue to create the desired radio frequency current field pattern,with highly localized hyperthermia being the goal. One or more thermistors (mounted i n hypodermic needles) a r e placed into the tissue to be heated; one o f these thermistors i s used to control the temperature i n the tissue via electronic feedback t o the rf source. I n this manner, temperature (at the control location) can be regulated during the autumn of 1972 t o " t r e a t " transplanted sarcomas on mice obtained from LASL's H-Division. Almost all the tumors regressed after treatments a t 45°C for 20 t o 30 minutes. In the spring of 1973, a collaboration was arranged with the University of New Mexico Medical School (Dept. of Surgery and Animal Resource Faci 1ity)to test the LCF hyperthermia technique i n the treatment o f spontaneous animal tumors. Arrangements were made with local veterinarians for referral ; most o f the cases referred were i n an advanced state of disease. This work continued through 1974, with the majority of the animals (cats and dogs) ex peri - encing regression of tumor with attendant (apparent) palliation and improvenient This hyperthermia method was used In

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period of 1 t o 2 years following treatment. at UNM-HS with equipment loans from LASL to test the effectiveness of combined radiation and hyperthermia on similar animal tumors. LAMPF-designed equlpmcnt was also used to test the effectiveness of whole-body hyperthermia in the treatment of advanced canine and feline tumors. This work, while very limited, sparked interest in a whole-body hyperthermia cancer therapy program for humans that i s still active at the Albuquerque VA Hospital under direction of the Dept. o f Surgery a t the UNH Medical School. The localized hyperthermia technique is also being investigated a t the UNM Cancer Research and Treatment Center in the experimental treatment of selected human tumors. LAMPF is active with technical input and instruments in this UNM-CRTC clinical effort. LAMPF LCF hyperthermia instrumentation is also currently on loan for A minority of the animals were free of tumor for a follow-up A modified program i s continuing In the earlier program, the very active hyperthermia program at the University o f Arizona in as well as programs that are just being initiated at the Tufts University School (Boston) and Washington University Medlcal School (St. Louis). Results of the L C F animal treatments in 1973-74 raised the question of the applicability of this technique to a disease called "cancer-eye" which has long been almost at epidemic proportions in Hereford cattle. these tumors are squamous cell carcinoma which occur on the globe or in the lid. A smaller proportion are papillomas or "plaques", both considered to be precursors to the malignant tumor. Portable LCF treatment equipment was constructed, and arrangements were made through the New Mexico Herefrbrd Association and the USDA Extension Service (NHSU) to test the techniques on two Hereford operations in northern experiment was complete by kr ch, 1977. considerably during the ten-month experiment. LCF treatment unit that could be powered from a vehicle cigarette lighter (or portable battery) and used by ranch workers. treated (0.2 to 2 cm diameter), approximately 90% remission can be expected with The first animals were treated d u r i n g June, 1976 and the pilot Equipment and technique were refined The final result was a portable When tumors of moderate size are Cancer-eye (or s i i n i lar) treatment equipment has been loaned to a number Of universities and one private research institution for the investigation of

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veterinary and human applications. Included in this group are: University of Arizona (Ext. Service) New Mexico State University (Ext. Service) Oklahoma State university (College o f Vet. Med.) McGee Eye Instltute, Oklahoma C i t y (Poss. human applications) University o f New Mexico, Cancer Research t Treatment Center (Now in use in human tumor treatment) Colorado State University (College of Vet Med.) (See attached reports: LA-6714-HS a n d LASL Mini-Review 877-14) D. Thermal Hodification of Corneal Structure Experimental results reported by Stringer and Parr (Nature, %4965, p. 1307, Dec. 26, 1964) indicated that collagen in the human cornea exhibited a critical shrinkage temperature (58-60°C) that was lower t h a n the shrinkage temperature for collagen In other structures. This information led to the development (at the University of Florida, Gainsville) of a technique called thermokeratoplasty; i.e., the appllcation o f heat to the cornea to alter curvature. This technique has involved the application of a preheated metal probe (90 to 130'C) to the cornea for durations o f approximately one second. A condition that has been treated with this method is keratoconus, i.e. "cone-shaped cornea". m i l e sane clinical success has been reported, there have also been reports o f excessive damage to the superficial portion of the cornea, and, in other cases, only transient changes in shape which may be due to insufficient heating of the deeper stromal collagen. distribution across the cornea (higher temperatures on the surface) which result from conduction heating. Each o f these problems m a y be due to the temperature LAMPF Is developing a technique which should reverse the temperature gradient In the cornea so t h a t the important superficial tissue (Bowman's membrane) can be spared while applying sufficient temperature levels to stroma to cause long-term shrinkage. An r f source (2 HHz) with servo control o f the rf amp1 itude appl ied to the cornea, and precise electronic timing of the duration h of the "treatment" has been constructed by LAHPF and loaned to HcGee Eye Institute .-: in Oklahoma City for animal tests. Corneal probes have also been loaned, with d updated versions being constructed and tested at CAMPF on animal eyes procured from a meat-packing plant in Albuquerque. 0 The basic technique involves passing r f currents through the cornea with an electrode that is placed into good electrical and thermal contact with the

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inthe cornea. The electrode is simultaneously cooled t o remove heat from the surface o f the cornea by conduction. energy by rf current, and cooling of the surface by conduction, i t should be possible to achieve a more desirable temperature distribution in the cornea. Initial measurements of the temperature distribution are being made a t LASL I n dissected animal eyes. t o be sufficiently well designed, they will be loaned t o HcGee for further evaluation on living animals. Eventual success of this experiment could lead t o treatment o f keratoconus (and similar corneal 'Ishape" disorders) without With the appropriate electrode, energy i s deposited almost uniformly By this combination of deposition of Once these data arc complete, and probes are considered E. Bio electric Potentials in Cancer Diagnosis There have been reports(It2)that negative dc electric potentials are usually associated with malignant tumors in laboratory animals and i n humans. l n one clinical e ~ peri ment, ' ~ ) malignant tumors i n the female genital tract were identified by the presence of this electric potential. LAMPF is collaborating with the University of New Mexico Cancer Reseerch and Treatment Center in a pilot program to investigate the relationship between these potentials and the presence o f breast cancer. 1977. To date seven subjects have had differential breast potentials recorded. No cases of breast cancer have been measured yet; the seven subjects i n c l u d e (r "norma1s" and cases o f cancer o f the skin, lung and pancreas. Six of the subjects M had differential potentials that were typically in the one to five milli volt 6 range. One case, with possible recurrent lung cancer, exhibited a relatively The first measurements o f large reading o f 18-20 milli volts. breast cancer, must be taken in this experiment before even tentative conclusions can be reached. Much more data, particularly on proven d1. Design ofa portable device for long-term monitoring o f The Practical Applications Group has also been involved i n the differential breast skin temperature for use i n breast cancer diagnosis. ERDA was issued a patent on this circuit (#3,960,138 -- 6/1/76). The device i s under test at the University of Arizona

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Hedical School i n Tucson. It appears that the device faithfully records the data, but the relevancy o f the data for tumor detection has not been definitely established. 2. Two electrosurgical devices have been developed at LAMPF. One of has been used to cut and seal branch arteries during arterial transplant surgery. The other device i s a bipo1ar electrosurgical blade, which eliminates the need for the conventional llpatient-plate" remote electrode normally used in electrosurglcal procedures. The bi-polar blade confines r f current flow to a very small volume of tissue with improved safety and reduced ECG noise. ERDA has applied fora patent (Application Serial Elo. 601113) on this device. 3. Circuitry has been developed fsr the removal o f electro4. ERDA has been issued a patent (84,016,886) on the LCF tissue heating technique and is applying for a patent on a load-sensitive oscillator circuit developed for use i n the cancer-eye treatment electropotentials and their possible significance." Research, l2, pp. 325-329 (1972). Journal o f Surgical Journal o f Surqical Research, -9, pp. 517-520 (1969). 3. Langman, L. and Burr, H.S., "A technique to aid in the detection of malignancy o f the female genital tract.'' American Journal of Obstetrics and Electro-Surgery," Anesthesia and Analgesia ..... Current Rcscarches, 52, No. 2,

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When a negative muon stops in matter it is attracted to an atomic nucleus and cascades dawn through muonic atom energy levels emitting x rays. T h e relative yields of muonic x-rays emitted when muons stop i n a sample of material provide information about elemental and chemical properties of the material. The total …