Localized amyloidosis and Alzheimer's disease: the rationale for weekly long-term low dose amyloid-based fractionated radiotherapy.

Amyloidosis, a plasma cell dyschrasia, is characterized by accumulation in the intercellular spaces of fibrillar proteins with a typical beta-sheet pattern. Vascular-cerebral amyloidosis is the hallmark of Alzheimer's disease and spongiform encephalopathy (Creutzfeldt-Jacob and the like). Current treatment of primary systemic amyloidosis is neither free from complications nor - in some presentations - a mortality rate. Localized tracheo-bronchial amyloidosis (TBA) has been successfully treated with high energy beams of radiation (20 Gy in 10×200 cGy in two weeks). The CT response to radiation takes several months after completion of treatment. As 20 Gy in two weeks are followed by inflammatory reactions, this dosage cannot be suggested in the treatment of amyloidotic radiosensitive organs (e.g. kidneys, liver), or in the hypothetical treatment of Alzheimer's disease. On the basis of the following points: 1) plasma cells in amyloid deposits are not numerous; 2) plasma cells are radioresistant, both in vitro and in vivo (radiotherapy of solitary plasmocytoma); 3) the effects of radiotherapy (20 Gy/2 w) on TBA localizations cannot be exclusively due to plasma cell killing, this study postulates a biophysical mechanism of radiation-induced H-bond breaks in the beta-sheet structure of amyloid, together with depolymerization of glucosaminoglycans, very radiosensitive molecules invariably associated with amyloid fibrils. As both biophysical effects are DNA-independent, the adoption of a definite time/dose ratio (e.g. 20 Gy/2 w) loses much of its importance. Therefore an innovative alternative might be a weekly long-term low-dose fractionated radiotherapy, matching the very slow response of amyloid to radiation. Before being applied to Alzheimer's disease, the proposed radiotherapy (RT) schedule should be tried in TBA patients to compare the new results of long-term fractionated RT with the old results of 20 Gy/2 w. Should long-term fractionated RT prove equally (or almost equally) effective, but certainly much less toxic than 20 Gy/2 w, its application to Alzheimer patients might become an effective and safe treatment, provided clinical and objective control by means of current imaging techniques (MRI, PET) can be assured.

Extremely low-frequency pulsed magnetic fields and multiple sclerosis: effects on neurotransmission alone or also on immunomodulation? Building a working hypothesis.

This paper outlines the current state of knowledge on the pathology and treatment of multiple sclerosis (MS) and critically analyses the vast clinical experience of Sandyk in the use of pulsed magnetic fields of 5 Hz at 7.5 pT to treat many symptoms of MS. A complete regression of symptoms, or at least a major improvement, is sometimes so rapid as to suggest that ELF fields exert a greater effect on axonal and synaptic neurotransmission than on the processes leading to demyelination. Pulsed magnetic fields of 50-100 Hz and a few mT (whose flux intensity is 10(9) times greater than that of the fields used by Sandyk) have been seen to induce profound morphological changes (the Marinozzi effect) in the plasma membrane of several cell types, including Raji human lymphoblastoid cells. These observations underlie the author's hypothesis on the possible use of such fields in the treatment of MS. Indeed, these fields should induce the functional arrest of the cells (B- and T-lymphocytes, macrophages, microglia, dendritic cells) of the MS plaque, thereby providing an "electromagnetic immunomodulatory boost" to the effects of drug therapy. To test this working hypothesis, it is suggested that preliminary experimental research be carried out to ascertain: 1) the Marinozzi effect in vivo; 2) the Marinozzi effect on microglia and dendritic cells; and 3) the duration of the membrane changes and their relaxation rate. ELF magnetic fields in the picotesla and millitesla ranges are aimed at improving neurotransmission and correcting local immune pathology, respectively. Both types of field might find application in the treatment of MS patients who no longer respond to or tolerate currently used drugs.

Evidence of interlinks between bioelectromagnetics and biomechanics: from biophysics to medical physics.

A vast literature on electromagnetic and mechanical bioeffects at the bone and soft tissue level, as well as at the cellular level (osteoblasts, osteoclasts, keratinocytes, fibroblasts, chondrocytes, nerve cells, endothelial and muscle cells) has been reviewed and analysed in order to show the evident connections between both types of physical energies. Moreover, an intimate link between the two is suggested by transduction phenomena (electromagnetic-acoustic transduction and its reverse) occurring in living matter, as a sound biophysical literature has demonstrated. However, electromagnetic and mechanical signals are not always interchangeable, depending on their respective intensity. Calculations are reported in order to show in which cases (read: for which values of electric field in V/m and of mechanical pressure in Pa) a given electromagnetic or mechanical bioeffect is only due to the directly impinging energy or even to the indirect transductional energy. The relevance of the treated item for the applications of medical physics to regenerative medicine is stressed.

Red radioluminescence and radiochemiluminescence: premises for a photodynamic tumour therapy with X-rays and haematoporphyrin derivatives. A working hypothesis.

In a 1989 paper the author put forward the hypothesis of homogeneously illuminating the interior of the human body with red light by means of X-rays, with a view to extending the possibilities of photodynamic therapy with haematoporphyrin derivatives (HPD). In the present paper, two possible mechanisms for the production of red light by tissues irradiated with X-rays are put forward: a physical mechanism (red radioluminescence) and a physical-chemical mechanism (red radiochemiluminescence). Reactive oxygen metabolites produced in the radiolysis of water, singlet oxygen and lipid peroxidation of biomembranes are the key players in this interesting process. However, before any clinical application can be proposed for integrated tumour therapy (photodynamic therapy with X-rays instead of laser light and haematoporphyrin derivatives), quantitative analyses and experimental research will be required.

[Equivalent dose and efficient dose in risk assessment of stochastic effects in diagnostic radiology]. / Dose equivalente e dose efficace nella stima del rischio di effetti stocastici nella pratica radiodiagnostica.

INTRODUCTION: Purpose. The equivalent dose absorbed during a radiological examination and the resulting effective dose correlate with the probability of late stochastic effects, of which the ICRP 60 has determined the nominal coefficients normalized to 1 Sv. We have normalized the risk coefficients to 1 mSv for better simulation of working conditions. We propose a simple method for estimating the radiological stochastic risk by correctly using both the equivalent dose and the effective dose concepts. MATERIAL AND METHODS: The effective dose depends on the irradiated body volume; thus, we calculated the stochastic risk in three hypothetical radiological examinations. The equivalent dose in the volume irradiated by the main beam was assumed to be 10 mSv and homogeneous; the equivalent dose in adjacent volumes was assumed to decrease by two different dose gradients. In our models, the sum of the equivalent dose absorbed by various tissues multiplied by the different weight-tissue values gives three effective dose values. Finally, the stochastic risk is estimated by multiplying the effective dose values by the nominal risk coefficient determined by ICRP 60. RESULTS: The effective dose is highest when the volume irradiated by the main beam is largest and the dose gradient in adjacent volumes is slowest. With a slow gradient, the effective dose is 10 mSv for total body examinations, 6.25 mSv for abdominopelvic examinations and 1.4 mSv for head and neck examinations. With a fast gradient, the effective dose is 10 mSv, 5.99 mSv and 1.10 mSv, respectively. The lethal tumor probability over the entire life-span is 65/10(6) for head and neck examinations, 300/10(6) for abdominopelvic examinations and 500/10(6) for total body examinations. CONCLUSIONS: The risk of stochastic effects in diagnostic radiology is low, inasmuch as it is projected over the entire life-span of the subject. Nevertheless, it must not be overlooked. Our calculation method aims to explain the correct use of equivalent dose and effective dose concepts, particularly relative to that great majority of radiological examinations which involve limited body volumes. In these cases it is important to estimate correctly the dose gradient from the examined volume towards the adjacent volumes. Close collaboration between physicist and radiologist is therefore essential, as their respective specialist tasks must necessarily be integrated.

Halo ring supporting the Brown-Roberts-Wells stereotactic frame for fractionated radiotherapy.

The authors describe a new instrumentation for repositioning of the Brown-Roberts-Wells (BRW) stereotaxic system, useful for precise fractionated radiotherapy. A lucite ring is fixed to the patient's skull with four screws. Another ring, partially open, is then firmly connected co-axially to the lower part of the first one with four spacer-bars. The fixture permits an exact repositioning of the B.R.W. stereotaxic system, placing the target point in the linear accelerator isocenter. The preliminary technical results obtained in five children are reported and the fixture performance, advantages, and perspectives are discussed.

[SARO: a system for irradiating small intracranial tumors under the guidance of magnetic resonance imaging]. / SARO: sistema per la irradiazione dei piccoli tumori endocranici sulla guida delle immagini con risonanza magnetica.

An MR-based system for the accurate irradiation of small intracranial tumors, not less than 5 cm in diameter, is described. The system uses a home-made device (a support base with millimeter scales) and a series of thin individual wood moulds. A full size-enlargement of the central sagittal and of the tumor-containing transverse MR sections is the first operative step. On these enlarged sections the intracranial isocentre, the entry position of the orthogonal laser beams and the flexion-extension degree of the patient's head are chosen. Subsequently, from the sagittal full-size section the fronto-naso-labial outline is cut-out and accurately transferred on to a thin wood plank, which is finally cut with a fine saw. On the plank two orthogonal lines are drawn, crossing at the target-volume centre and matching with both laser beams during the treatment set-up. The millimeter scale on the support base allows the accurate lateral displacements of the treatment couch, when eccentric tumors most be irradiated. By this system, called with the Italian acronym SARO, the patient needs neither to be shaved, nor to be marked on his head skin. No special shell is necessary any more. Though intrinsically simple, the system needs skillful accuracy during all its procedure steps in order to reach the desired reliability when treating small intracranial tumors (not less than 5 cm in diameter).

Intraluminal high dose rate brachytherapy combined with external radiotherapy in the treatment of oesophageal cancer.

Twenty eight patients with previously untreated oesophageal carcinoma without distant metastases were divided into two groups: Group A consisted of 18 pts. treated with conventional external radiotherapy only. Another group of 10 pts. (Group B) received treatment with external beam irradiation with further high dose rate intraluminal brachytherapy up to a dose of 4-12 Gy delivered in 2-3 sessions of 4 Gy (one session a week). All pts. were evaluated clinically, radiologically and endoscopically every 3 months. At the end of treatment there was a marked difference in relief of dysphagia (39% in Group A vs. 90% in Group B), local control (56.7% in Group A vs. 100% in Group B) and time to progression of dysphagia (20.8 weeks in Group A vs. 67.7 weeks in Group B). No marked difference was observed in overall survival. The complication rate was low in both groups and major complications were observed in pts. treated with external radiotherapy alone (two fistulas). The association of external beam and intraluminal radiotherapy can give a better local control of the disease, improving the quality of life.