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M-14 human tumor cells have been subjected to two regimens of step-down heating (SDH) consisting of a conditioning treatment at 42 degrees C for 1 h or at 44.5 degrees C for 20 min, immediately followed by heating at 40 degrees C. Both conditioning treatments thermosensitize the cells towards the subsequent heating at 40 degrees C; the thermosensitization ratio is 6.4 for cells conditioned at 42 degrees C for 1 h and 32.3 for cells conditioned at 44.5 degrees C for 20 min. The overall protein synthetic activity is reduced to 32.7% or 18.4% of control values following 1 h at 42 degrees C and 20 min at 44.5 degrees C, respectively; this inhibition is followed by a full recovery of the synthetic activity during the subsequent exposure at 40 degrees C. SDH-treated cells synthetize four heat shock proteins, with approximate molecular weights of 28, 64, 70 and 90 kDa. The pattern of HSPs induction observed in SDH-treated cells is similar to that found in cells subjected to single hyperthermic exposures. Cells subjected to the SDH sequence 42 degrees C/1 h-->40 degrees C/4 h develop thermotolerance, as indicated by a reduced sensitivity to further hyperthermic challenges.

To optimize the total and the weekly number of heat treatments to be combined with a conventional radiotherapy course, a study was designed on a 75-year-old woman with 40 cutaneous nodules of metastatic mammary carcinoma. All nodules were individually irradiated by means of orthovoltage radiation to doses of 36 to 44 Gy, given in 20 equal fractions in 4 weeks. The nodules were randomly assigned to receive radiotherapy alone or radiotherapy combined with one or four heat treatments. Eight lesions were left untreated as a control arm of the systemic therapy (endocrine manipulation). Hyperthermia at a minimum temperature of 43 degrees C was applied for 45 min once per week for four times or only once, during a course of radiotherapy. Percent mean diameter of the treated lesions continuously decreased, reaching a minimum of 25-30% of the initial value after 4 months from the beginning of treatment with no difference between the three arms. After this period, tumors treated with radiotherapy alone or radiotherapy plus one heat treatment started to regrow, whereas those treated with radiotherapy plus four heat treatments continued to decrease slowly. The actuarial analysis of freedom from local progression showed a trend of improvement of response duration with four hyperthermic treatments with respect to radiotherapy alone or combined with one hyperthermic treatment.

The effects of lonidamine on membrane electrical properties of Ehrlich ascites tumor cells are investigated. Using a dielectric relaxation technique based on the Maxwell-Wagner effect and elaborated by a 'single-shell' fitting procedure, the data indicate that both membrane conductivity and membrane permittivity increase after treatment of these cells with lonidamine while the conductivity of the cytosol remains unchanged. Changes in membrane proteins and/or lipids are suggested which lead to altered membrane structure and/or function.

The effect of association of 1,3-bis-(2-chloroethyl)-l-nitrosourea (BCNU)- Rhein (RH) and BCNU-Lonidamine (LND) on the clonogenic activity of human glioma cells was evaluated. Both RH and LND modulate the lethal effect of BCNU regardless of the schedule of treatment. The analysis of the interactions, performed with the isbolar method according to Berembaum, demonstrates an additivity of the effects. The possible mechanisms as well as the implications for the design of brain tumor schedule treatment are discussed.

From 1974 to 1987, a total of 199 patients with prostatic carcinoma localized to the pelvis were treated with definitive external beam radiation therapy at the Istituto Medico e di Ricerca Scientifica. The median follow-up for all 126 surviving patients was 60 months. Actuarial 5-(and 10-) year overall survival rates for U.I.C.C. clinical Stage T1-2, T3 and T4 disease were 76.1% (58.5), 66% (42.5), and 27.6%, respectively. The corresponding 5- and 10-) year disease-specific survival rates were 81.7% (73), 72.5% (57.4), and 36.2%. The corresponding values of disease-free survival were 81.3% (76.8), 59.2% (57), and 17%, respectively. In 120 patients with more than 5 years of follow-up, local failure was seen alone in eight patients (6.6%) and associated with distant metastases in 19 patients (15.8%). In 28 patient (23.3%), distant metastases were observed alone. The median survival from the first evidence of metastases was 20 months, with no patient surviving beyond 5 years. The incidence of complications was acceptable. Serious complications, consisting of stenosis of both ureters and sigmoid colon requiring both urinary and intestinal diversion, occurred in two patients (1.3%). This study reveals that external radiotherapy is an efficacious and safe modality for locoregional control of prostate cancer.

Results obtained in a controlled tumor growth depend on the experimental model used, the agent employed (drugs, ionizing radiations, heat), aw well as the administration scheduling and the host environment. Empirical search and treatment optimization are related to a discrete number of agent combinations and fractioning, and system parameters and dependencies are strictly connected to biological assumptions. A simplified model for the evaluation of the rate of change of tumor volume at the time of cytotoxic agent administration is proposed here, as well as a computer program to perform the simulation of tumor growth controlled by therapeutic agents.

The effect of Rhein (RH) and Lonidamine (LND) on the clonogenic activity of cultured human glioma cells has been evaluated. Both these drugs decrease the survival fraction, but their effect is strictly related to the duration of exposure. A brief exposure, i.e. 4 hours, even at the highest drug concentrations does not induce any significant decrease in the survival which, on the contrary, is strongly affected by 24 and 48 hours of exposure. The reason for this behaviour lies in the mechanism of action of these drugs which do not interfere with replicative processes, but selectively affect the energy metabolism of the neoplastic cell. The validity of currently employed screening tests to evaluate the antitumoral activity of non anti-mitotic drugs is also discussed.

In radiotherapy in many clinical cases it is necessary to employ electron beams of small dimensions and/or shielded in order to have shaped fields. It is well known that percentage depth dose and output depend on the energy, on the field dimensions and on the collimation system. In order to evaluate separately the influence of these factors measurements were performed with electron beams of nominal energy from 6 to 14 MeV, of a linear accelerator Philips SL/75. Measurements were performed in standard dimension phantoms and in a small perspex phantom, 3 cm diameter. The values obtained in this small phantom were compared with the ones obtained for the same diameter collimator in order to have information on effect of missing lateral scatter equilibrium. Other measurements for an applicator, open and partially shielded, were performed. The results of these measurements are shown in graphics. Data show that the percentage depth dose ionization curves at fixed energy depend on the collimator linear dimension in particular, when these dimensions are smaller than the range of secondary electrons. However it is evident the difficulty to find a correlation between linear field dimensions and the percentage depth ionization curves. In the clinical practice it is important to take into account this difficulty when employing small or irregular electron fields.

In this paper, preliminary results on the IORT dosimetry performed on the two radiotherapy centers, "Regina Elena National Cancer Institute" and "S. Cuore Catholic University", are presented. The absolute dosimetry has been performed with ion chambers (ENEA chamber and Markus flat chamber) using a water phantom. The relative measurements have been performed with solid state diodes and radiographic films, calibrated on absolute dosimetry system.

Recent international guidelines on hyperthermia (HT) quality assurance have pointed out the necessity of defining standard operative procedures and technical checks to guarantee an accurate performance of HT treatments. In the present paper, experience is described of quality control procedures that are performed in agreement with the more general guidelines concerning thermometry, sensor positioning, phantoms, applicator characterisation, and electromagnetic (EM) radiation leakage. This practical experience comes from the use of equipment for superficial and loco-regional HT working in the range 13.56-915 MHz.

Site- and tumor-specific data obtained from two groups of patients with head and neck and melanoma lesions, respectively, showed that both immediate response and response duration were enhanced by the addition of heat. Two important variables, however, such as tumor volume and "isoeffect thermal dose" appeared to influence local tumor control. The volume effect was less pronounced in the lesions treated with radiotherapy plus heat than in those treated with radiotherapy alone, suggesting that the addition of heat was more damaging to the large than to the small lesions. Furthermore, a striking isoeffect thermal dose-response relationship was shown in head and neck lesions. Those data were collected and used to design a mathematical model relating the probability of local control to clinical and treatment variables. The analysis shows that, by using the same radiation parameters, the probability of local tumor control is a function of both "isoeffect thermal dose" and tumor volume.

Two continuous human glioma derived cell lines, LI and DF, were established in our laboratory. Both cell lines showed cytological features and in vitro behavior similar to those of the respective original neoplasms. These two lines were characterized for their main biological properties including in vitro and in vivo growth rate, clonogenic ability and tumorigenicity in nude mice. The plating efficiencies were generally high both during exponential and stationary growth phases and a high tumorigenicity was observed. All injected nude mice developed tumors. The two lines were tested for chemosensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-Diamminedichloroplatinum II (DDP). Heterogeneity in biological features and in drug sensitivity was observed. Exposure of the two lines to BCNU and DDP showed that the glioblastoma (LI) was less sensitive than the anaplastic astrocytoma (DF). For both lines BCNU was more effective on cells in plateau than in exponential phase, while the killing effect of DDP was not phase-dependent.

On the basis of previous data suggesting the involvement of cardiac histamine in ischemic heart disease (IHD), we evaluated plasma histamine (H) and creatine-kinase isoenzyme (CK-MB) level in cardiac and healthy subjects. 20 patients with acute myocardial infarction (AMI) (10 developing AMI in Hospital, thus making possible the detection of plasma H level before acute event), 10 patients with IHD not developing AMI and 10 presumably healthy subjects were admitted to the study. 15 of all patients with AMI showed a correlated H and CK-MB trend during AMI reaching the highest peak 24 hours after onset of pain. 7 of the patients with IHD who developed AMI in Hospital showed a slightly higher plasma H level, before AMI, than those with IHD who did not develop AMI. A possible role of histamine in the pathogenesis of AMI is discussed.

Total body irradiation (TBI) using high doses (about 10 Gy) with photons in the range between 1 and 10 MV combined with intensive chemotherapy has been used successfully in treatment of acute and chronic leukemia before bone marrow transplantation. One of the principal international guidelines in TBI is to use in vivo dosimetry in order to compare the prescribed dose with that absorbed. The use of in vivo dosimetry is also useful as a retrospective evaluation of any deviation from the prescribed dose greater than +/- 5% for relevant parts of the body, especially in the lung and in other organs at risk. In this paper, Electron Spin Resonance (ESR), using alanine dosimeters, is demonstrated to be a powerful tool for absorbed dose evaluation in TBI by detection of free radicals produced in alanine by ionizing radiation. In this study, we present the results obtained using ESR dosimetry in eleven patients undergoing TBI. The major advantages appear to be: 1. the ESR signal in alanine dosimetry is stable for years without fading: 2. the detection of the ESR signal does not destroy the information and so enables a retrospective judgment of the TBI plan adopted.

The work described here represents an attempt to use mathematical models of single-cell survival for radiotherapy planning. The aim of the study is to develop a procedure in which the distribution of the effects achieved by optimizing physical radiation dose is implemented by taking into account radiobiological terms. An algorithmic model has been developed to evaluate the probability of tumor control and of excessive damage to normal tissue on the basis of the linear-quadratic model of cell survival. In its present preliminary form, the procedure can be used to predict differential isoeffect distributions obtained by varying the total dose and the fraction size of multifraction radiotherapy courses. This approach can also be used to extract from historical clinical results, by maximum-likelihood methods, parameters related to the cellular response to radiation (for instance, alpha and beta of the linear-quadratic model).

The animal proteins in a low-lipid, low-cholesterol diet were substituted with a textured soybean preparation for 127 outpatients with stable type II hyperlipoproteinaemia selected from eight Italian and one Swiss lipid clinics. Eight weeks of the modified diet reduced plasma cholesterol by 23.1% in the 67 participating male patients and by 25.3% in the 60 females. No significant changes in plasma triglycerides, high-density lipoprotein cholesterol, and body weight were recorded. Better reductions in plasma cholesterol occurred in non-familial cases and in very young male patients. The acceptable taste of the soybean preparation used in this study, and its easy handling, indicate that this type of dietary treatment may be suitable for outpatients.

Lonidamine (LND), a powerful antispermatogenic compound, has been shown to impair differentially the energy metabolism of normal and neoplastic cells and to increase significantly the survival of animal bearing experimental tumors. Clinical trials are presently ongoing and preliminary favourable results have been obtained with LND as a single agent or associated with other antineoplastic drugs. In this work the effect of the combination LND plus ADM was investigated on in vitro and in vivo tumors. The in vitro effect was analysed by the colony forming technique and the in vivo antitumor activity was assessed by means of local control parameters, increase in host lifespan and weight reduction of metastasing target organs (liver, kidney, ovary). The results obtained indicate that LND is poorly effective when used alone, while a very high cytotoxicity is observed when it is combined with ADM. Exposure of cells to different time-sequences and schedules of both drugs elicits a different response. In particular a synergistic effect is obtained when ADM precedes LND. These results have been preliminarily confirmed by in vivo studies.

A theoretical study on evolution has been carried out, with the aim of disproving some value judgements essentially represented by the idea that the degree of evolution can increase. Our conclusions are based upon the preliminary statement that efficiency of survival is directly related to regulative ability. On this ground our reasoning led us to conclude that: (i) actual fitness measure units derive from an anthropocentric bias, and they mainly evaluate similarity to man rather than some objective parameter; (ii) a complete and meaningful unit is, at present, impossible to achieve in practice; (iii) since the study of evolution is only descriptive, and since the evolutionary process is time dependent, every ecological dominant living today must be considered as the most fitted to its environment; (iv) the view we can have of evolution is simply a transection, so that many generalized phyletic trees are trivial and it is impossible to claim the persistence today of those "ancestor organisms" upon which such trees are constructed. Moreover, a functional definition of the term "organism" is given, following criteria drawn from bioenergetics and from biological hierarchization. The concluding step is the assemblage of a slightly heterodox model for evolution.

1) The kinetics of phosphofructokinase and growth rate of submaxillary gland cells of C3H mice of both sexes in presence and in absence of testosterone have been studied. 2) Both enzymes show sigmoidal kinetics, with Hill's coefficient higher for the females. 3) The maximal activity is remarkably more elevated for the males. 4) The testosterone modifies the growth rate and the kinetic properties of the phosphofructokinase and these modifications depend on the sex.

In stereotactic irradiation by external beams there are many problems involved with dosimetry of small fields, three-dimensional representation of dose distribution, radiobiological involvement of tissue response to total dose and fractionation. Dosimetric problems arise by critical dimension of dosimetric chambers and by difficulties of films calibration. The amount of data required for a correct three-dimensional simulation of isodose curves, tumor and anatomical structures require a very speed computer system, sophisticated computer graphic techniques and calculation algorithm. By use the linear quadratic model of cell survival, maps of combined dose and biological effect (isoeffect curves) are also obtained.

281 patients with a total of 463 symptomatic osseous metastases treated for palliation between 1975 and 1985 have been retrospectively analysed. The most frequent primary sites were breast (50.1%) prostate (16.6%) and lung (11%), accounting for more than three fourths of all metastatic areas. Other primaries were represented by bladder, kidney, colorectal, uterus (corpus and cervix) melanoma and thyroid tumors, and by cancer from unknown origin. Palliation was evaluated only on a subjective pain score. Complete response meant complete pain relief, and partial response meant more than 50% and less than complete pain relief in all treated sites. Complete response rates were similar independently from the primary site, except for the adenocarcinomas of the kidney and for non-small cell carcinomas of the lung in which the response tended to be lower. A correlation was also found between the incidence of pain relief and the site of bone metastases, in that a lower response was shown in limb localizations. Also, the number of metastatic sites did not influence the complete response rate. As expected, the response rate in all cases seemed to be dependent on total absorbed dose while, surprisingly, it could not be shown to be affected by the fraction size. A similar trend was shown for the pain recurrence.

A stochastic model is proposed to simulate the phenomenon of acquisition of genetic resistance by a tumor cell population treated with antineoplastic cytotoxic agents. In the model, stochastic differential equations are numerically integrated to simulate the expected response after treatment with two different agents. The model takes into account the initial number of cells, the sequence of the agents, the time intervals between administrations, the birth and death rates of the untreated cells, the probabilities of mutations to resistance, and the induced cell-killing kinetics. Satisfactory demonstration runs of the model indicate that it could represent a useful tool in verifying the results of experimental and clinical chemotherapy courses and planning treatment strategies.