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Neon ion radiotherapy: results of the phase I/II clinical trial.

Neon ion radiotherapy possesses biologic and physical advantages over megavoltage X rays. Biologically, the neon beam reduces the oxygen enhancement ratio and increases relative biological effectiveness. Cells irradiated by neon ions show less variation in cell-cycle related radiosensitivity and decreased repair of radiation injury. The physical behavior of heavy charged particles allows precise delivery of high radiation doses to tumors while minimizing irradiation of normal tissues. In 1979 a Phase I-II clinical trial was started at Lawrence Berkeley Laboratory using neon ions to irradiate patients for whom conventional treatment modalities were ineffective. By the end of 1988 a total of 239 patients had received a minimum neon physical dose of 1000 cGy (median follow-up for survivors 32 months). Compared with historical results, the 5-year actuarial disease-specific survival (DSS5) and local control (LC5) rates suggest that neon treatment improves outcome for several types of tumors: a) advanced or recurrent macroscopic salivary gland carcinomas (DSS5 59%; LC5 61%); b) paranasal sinus tumors (DSS5 69%; LC5 69% for macroscopic disease); c) advanced soft tissue sarcomas (DSS5 56%, LC5 56% for macroscopic disease); d) macroscopic sarcomas of bone (DSS5 45%; LC5 59%); e) locally advanced prostate carcinomas (DSS5 90%; LC5 75%); and f) biliary tract carcinomas (DSS5 28%; LC5 44%). Treatment of malignant gliomas, pancreatic, gastric, esophageal, lung, and advanced or recurrent head and neck cancer has been less successful; results for these tumors appear no better than those achieved with conventional x-ray therapy. These findings suggest that Phase III trials using the neon beam should be implemented for selected malignancies.

Drug Evaluation

Neon flank and illusory contour: interaction between the two processes leads to color filling-in.

Two aspects of neon color spreading, local color spreading (neon flank) and illusory contour, were investigated by dichoptic viewing. Neon flank was not observed under appropriate dichoptic stimulation, suggesting that input to the process for local color spreading is based on monocular configuration. However, illusory contours were formed according to the interocularly combined configuration rather than according to each monocular configuration, suggesting that input to the process responsible for illusory contours should be ocularly-nonselective and binocular, rather than monocular. The possibilities of artifacts such as those arising from interocular rivalry were appropriately eliminated, and thus, it is tentatively concluded that the process underlying local color spreading is monocularly driven, whereas the process underlying illusory contours is binocularly driven. Furthermore, a new demonstration is presented that indicates that interocularly-induced illusory contours 'capture' and extend the monocularly-induced local color spreading, resulting in global color spreading (neon color spreading). These results support our hypotheses that neon color spreading involves two separable processes in the early visual processing, the feature detection process (for local color spreading) and the illusory contour process, and that these two processes interact with each other at later stages of cortical processing. The relation of local color spreading and illusory contours to surface separation is also discussed.

Adult

The relative biological effectiveness of 670 MeV/A neon as a function of depth in water for a tissue model.

Linear energy transfer (LET infinity) spectra of identified charge fragments and primaries, produced by nuclear interactions of 670 MeV/A neon in water, were measured along the unmodulated Bragg curve of the neon beam. The relative biological effectiveness (RBE) values for spermatogonial cell killing, as reported on the basis of weight loss assay of mouse testes irradiated with beams of approximately constant single LET infinity, were summed over the particle LET infinity spectra to obtain an effective RBE for each charged-particle species, as a function of water absorber thickness. The resultant values of effective RBE were combined to obtain an effective RBE for the mixed radiation field. The RBE calculated in this way was compared with experimental RBEs obtained for spermatogonial cell killing in the mixed radiation field produced by neon ions traversing a thick water absorber. Discrepancies of 10-40% were observed between the calculated RBE and the RBE measured in the mixed radiation field. Part of this discrepancy can be attributed to undetected low-Z fragments, whose contribution is not included in the calculation, leading to an overestimated value for the calculated RBE. On the other hand, calculated values 10% greater than the measured RBE are explained as track structure effects due to the higher radial ionization density near neon tracks relative to the ionization density near the silicon tracks used to fit the RBE vs LET infinity data.

Animals

Repair but not potentiation observed in mouse lung irradiated with neon ions.

The lungs of mice were irradiated with 1, 4, or 7 fractions of X rays or neon ions in a 4-cm spread Bragg peak. Lung function as a function of total radiation dose was tested at 7 and 12 months after irradiation by measuring the resting breathing rate in a whole-body plethysmograph. The isoeffect doses increased sequentially with X rays for 1 through 4 to 7 fractions, demonstrating repair of sublethal radiation injury as previously reported. There was also a significant increase of isoeffect dose with neon ions between 1 and 4 fractions but no further increase at 7 fractions. Thus repair instead of potentiation of radiation injury in lung clearly occurred after neon ion irradiation. The effectiveness of neon ions appeared to be closer to that of neutrons with a mean energy of 8 meV than those with a mean energy of 2.3 meV.

Animals

Qualitative study of chromosomal lesions induced by neutrons and neon ions in human lymphocytes at G0 phase.

Chromosomal lesions, mitotic index and cell cycle progression delay induced by neutron (protons 34 MeV on beryllium) and neon (250 MeV/i) particles are studied in human lymphocytes. The cell cycle progression is slightly decreased at a dose of 1 Gy. Mitotic indexes are significantly decreased after irradiation by the different particles, except neon in 52-h cultures. By comparison to chromosome damages caused by gamma-rays, previously published, it is found that the lesions observed here are frequently more complex: the number of breaks is higher per abnormal mitosis and higher per rearrangement on the average. This complexity is higher for neon ions than for neutron beams.

Cell Cycle

[Rationale for using helium-neon laser in medical rehabilitation of patients with atrophy].

High resolution measurements of helium-neon laser spectra have been conducted about 0.64 mm wavelength. The singlet oxygen photo-generation was demonstrated to be responsible for the bioeffects of this spectral interval. Helium-neon radiation with 0.633 mm wavelength was used for medical rehabilitation of 15 patients with muscular atrophy as a result of wearing immobilizing plaster arm-bends on lower extremity fractures. 50-day hypokinesia of a damaged extremity induced differences in functional indices between damaged and healthy extremities in the same patient. This difference was diminishing more rapidly after laser therapy than in the control group though all patients had adequate rehabilitative treatment. Due to the likelihood of hypokinesia- and weightlessness-induced atrophies, helium-neon laser may be recommended for atrophy prophylaxis and treatment in both cases.

Adolescent

Morphological criteria for comparing effects of X-rays and neon ions on mouse small intestine.

Several techniques have been used to assess changes in different parts of mouse small intestine three days after a single dose of either 16.5 Gy X-rays or 11 Gy neon beam. The doses were chosen to be approximately equivalent in terms of their effect on the number of microcolonies present. In qualitative terms, villous damage was seen after both types of radiation exposure: collared crypts, similar to those seen in biopsies taken from patients suffering from coeliac disease, were conspicuous after neon irradiation. In semi quantitative terms the doses used, although estimated from previous work to give biologically equivalent damage, produced a greater drop in microcolony numbers after X-irradiation. This makes all the more important the fact that significantly greater changes were seen after neon irradiation-a greater drop was seen in the number of villous profiles and the number of goblet cells per villus. There was also greater breakdown in the integrity of the villous basement membrane. Different responses after the two types of irradiation are therefore seen in the cryptal and villous compartment. Progress is being made towards identifying and quantitating radiation induced changes in different populations of cells or tissues in the small intestine.

Animals

[The Helium-neon laser effect on skin and oral mucosal tissue].

The biological effects of the helium-neon (He-Ne) laser on skin and oral mucosa were examined for the first time electron microscopically. Canine epidermis, gingiva and sublingual regions were subjected to treatment by the helium-neon laser with varying exposure times. The exposed tissues were excised immediately after radiation and studied with an electron microscope. Depending on the exposure times, ultrastructural alterations were observed such as cytoplasmic vesiculation and vacuolization, mitochondrial changes, dilation of the endoplasmic reticulum, the Golgi cisternae and other endomembranes of the keratinocytes. Furthermore, ultrastructural changes were seen in stromal cells, endothelial cells of the blood and lymphatic vessels, nerves, muscle cells and in the extracellular compartment of the lamina propria. The ultrastructural alterations of different cell and tissue structures following helium-neon laser radiation were compared with the effects induced by other types of lasers. The results are discussed in light of the stimulation of biological cell processes by low-energy lasers.

Animals

Endoscopic enhancement of the healing of high-risk colon anastomoses by low-power helium-neon laser. An experimental study.

Recent studies suggest that helium-neon (He-Ne) lasers at low energy can enhance wound healing in intestinal anastomoses. In this experimental study, we tested the strength and collagen concentration of high-risk anastomoses of the rat colon after endoscopic irradiation by helium-neon laser. Our results show that repeated helium-neon laser irradiation (1.9 J/cm2) increases the bursting strength of the anastomoses by almost 100% on the fourth postoperative day. This effect is not observed by increasing the radiation dose (6.4 J/cm2). Differences in collagen (hydroxyproline) concentration did not reach statistical significance.

Anastomosis, Surgical

Neon colors illuminate reading units.

The effect of syllable-size reading units on neon color was investigated in 6 experiments. The stimuli consisted of 5- or 7-letter words or pseudowords with a syllable break either just before or just after the middle (target) letter. The target letter was overlaid with a plaid of red and green lines that gave it an ambiguous neon color. The letters preceding the target were overlaid with a monochromatic grid (red or green), and the letters following the target were overlaid with the other color. Ss were significantly more likely to judge the target as more similar to the color of other letters within its syllable than colors of letters outside that unit. The effect was shown not to be an artifact of guessing strategy or eye movements. Word structure determined by orthography and morphology affected neon colors, but no effect was found for purely phonological units.

Adult

Illusory depth from moving subjective figures and neon colour spreading.

If a pattern of concentric circles, interrupted so as to produce the perception of a subjective bar extending from the centre to the periphery of the pattern, was slowly rotated in a plane perpendicular to the line of sight, observers reported seeing the bar slanted in depth and moving over complete and stationary concentric circles. When the interrupted concentric circles were completed by red segments--thereby giving rise to a neon colour-spreading effect--observers reported seeing a reddish bar, which sometimes appeared to be slanted in depth, moving behind the plane of the concentric circles. A combination of the two patterns was found to originate a compelling percept of a unitary bar slanted in depth: part of the bar (the subjective half) appeared to be located in front of its inducing elements, whereas the other part (the neon-like half) appeared to continue behind them. When translatory instead of rotary motion was used, the bars did not look slanted in depth: however, the neon bar appeared either behind or in front of the inducing lines, depending on the luminance contrast between the segments and the inducing lines themselves.

Attention

[The action of helium-neon laser radiation on the growth of Mycobacterium tuberculosis].

The growth properties of M. tuberculosis subjected to the action of helium-neon laser radiation was studied. Laser radiation was shown to change the quantitative and qualitative composition of mycobacterial population. Disturbances in the viability of mycobacteria appear as a consequence of changes in the morphological structure of mycobacterial cells. The maximum effect of helium-neon laser radiation was achieved after the irradiation of M. tuberculosis culture on days 2-3 after inoculation. These results made it possible to suggest that the effect of helium-neon laser radiation was most pronounced in cells at the stage of mitosis (the logarithmic stage of growth) with the highest degree of metabolism.

Colony Count, Microbial

[Morphological and functional changes in the rat ovary under exposure to a helium-neon laser].

The authors studied the occurring morphological and functional changes in the ovaries of mature rats after transcutaneous irradiation with helium-neon laser over the hypogastric region. Density of power of 1.5 mW/ml with exposition time of 1 min and dimensions of irradiation of 16.61 ml was used. The results from the study showed that helium-neon laser, used for a period of incomplete estrous cycle (4 days), stimulated estrogen function of ovaries, manifested with prolongation of the stages of proestrus and estrus. The action for a period of two incomplete estrous cycles stimulated the ovarian endocrine function to a lesser degree, but induced dystrophic changes and ovarian hemorrhages. The indicated morphological and functional changes were established up to the third estrous cycle after the finished irradiation with helium-neon laser.

Animals

Electrophysiologic recording and thermodynamic modeling demonstrate that helium-neon laser irradiation does not affect peripheral Adelta- or C-fiber nociceptors.

The effect of helium-neon laser irradiation (632.5 nm) on A delta- and C-fiber sensory afferents was investigated in the rabbit cornea, to determine the physiologic basis for reports that low power (0.1-5 mW) helium-neon (He-Ne) lasers produce acute analgesia and alleviate chronic pain. Multiple and single unit extracellular recordings from nociceptive corneal afferent nerves (C-fiber cold, C-fiber chemical, A delta mechanical and A delta bimodal) were used to study the effects of He-Ne laser radiation upon the electrophysiologic responses to mechanical, thermal, chemical and electrical stimulation of the cornea. Action potentials were analyzed for latency, amplitude, rise time, duration and frequency. Exposure of the neural receptive field and/or nerve bundle to a 4-mm diameter He-Ne laser (0-5 mW; 0-1800 sec) did not alter spontaneous or evoked neural activity. In addition, single unit action potential parameters were not altered by laser irradiation. Modeling of thermal changes produced by He-Ne radiation on corneal nerves indicated that effects predicted for receptor and axonal depths in both skin and cornea were minimal (less than 0.15 degrees C) and unlikely to alter sensory transduction or transmission.

Afferent Pathways

Effects of helium-neon laser irradiation on skin resistance and pain in patients with trigger points in the neck or back.

The purpose of this double-blind study was to ascertain the effects of helium-neon (He-Ne) laser irradiation on skin resistance and pain in patients with trigger points in the neck or low back. This study entailed a partial replication of a previous study by Snyder-Mackler and associates that determined the use of the He-Ne laser increased skin resistance overlying a trigger point. Twenty-four patients were randomly assigned to either a treatment or a control group and received three 20-second applications of laser irradiation or placebo "stimulation," respectively. Pretreatment and posttreatment skin resistance and pain measurements (via visual analog scale) were taken during each session. Results indicated a statistically significant increase in skin resistance (p less than .001) and a decrease in pain (p less than .005) following laser treatment. There was not a significant correlation between skin resistance and pain across subjects. These data substantiate the previous findings of Snyder-Mackler and associates and demonstrate a reduction in pain. Helium-neon laser treatment, therefore, may be an effective adjunct to conventional physical therapy of these patients.

Double-Blind Method

The relative biological effectiveness (RBE) and oxygen enhancement ratio (OER) of neon ions for the EMT6 tumor system.

EMT6 tumors were exposed to neon ions in vivo and in vitro in the plateau and spread-out Bragg peak regions of the beam. The RBE in vivo was 1.7-2.1 in the plateau region and 2.6-2.9 in the Bragg peak; the OER was 2.0 and 1.4, respectively. Neon ions have great potential in the radiotherapy of tumors because of their decreased OER and excellent depth-dose distribution in tissue.

Animals

[Helium-neon laser in the complex treatment of patients with pulmonary tuberculosis].

The paper gives the results of helium-neon laser irradiation of the endobronchus used in the combined treatment of 30 patients with newly-diagnosed pulmonary tuberculosis complicated by nonspecific endobronchitis. Inclusion of endobronchial phototherapy and helium-neon laser radiation in the complex treatment of patients with newly diagnosed pulmonary tuberculosis complicated by nonspecific endobronchitis makes it possible to achieve clinical cure of an inflammatory bronchial process by 35% more frequently and over 2-3 times more rapidly than in its absence and to increase treatment efficiency of the main process; the terms of bacillary excretion decrease by 1 month, on the average, closure of destruction cavities (with an increase in the parameter by 17%) by 1.2 months and hospital treatment by 1.2 months, as compared with the respective parameters obtained by the traditional treatment of the similar patients.

Antitubercular Agents

[Dynamics of morphological changes in the epithelial layer of the respiratory tract after endobronchial treatment of suppurative endobronchitis by helium-neon laser irradiation (experimental study)].

The results of a dynamic examination with the use of an electron microscope of semi- and ultrathin sections of the epithelial lining of the respiratory tract in the experimental dogs under endobronchial treatment of nonspecific endobronchitis with varying doses of low-energy radiation from helium-neon laser are presented. It was proved that the outcomes of regeneration of the bronchial mucosal membrane epithelium under endobronchial treatment of purulent endobronchitis with low-energy radiation of the helium-neon laser much depend both on exposure time (single doses of energy), and multiplicity (cumulative dose of energy), and the period after the laser therapy. The most favourable regeneration takes place under 5-minute (single dose of 4.5 J) radiation with 8 to 9 sessions (cumulative dose of 23.1 +/- 1.5 J). A regeneration most close to the normal condition of the bronchial mucous membrane epithelium is achieved at 2.5-3d months after the onset of the experiment (or a month after the laser therapy).

Animals