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Platinum/etoposide therapy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a major health problem in the United States and in many other parts of the world. Identification of systemic therapy that can maintain or improve quality of life and prolong survival is essential because locally advanced disease or distant metastasis is found in the majority of these patients. A variety of combination regimens have produced response rates of 20% or greater in stage IV NSCLC patients in cooperative group trials, including studies conducted within the Eastern Cooperative Oncology Group (ECOG). Although no regimen has emerged as clearly superior, the highest 1-year survival rate (25%) in ECOG trials was observed in EP(etoposide/cisplatin)-treated patients. Subsequently, a randomized trial in which EP was compared to etoposide/carboplatin revealed no significant differences in survival or response rate, and toxicity was slightly less with etoposide/carboplatin. Results from recent phase II trials in which stage III NSCLC patients received preoperative EP and concurrent thoracic irradiation have shown response rates of 65-85%, as well as acceptable toxicity and surgical morbidity and mortality. Future stage IV NSCLC trials should include studies of platinum/etoposide plus new agents. Also a study comparing platinum/etoposide versus supportive care should be considered. The objectives of this study would be to compare survival, quality of life, and cost-effectiveness ratio. The results of recent phase II studies in stage III NSCLC patients suggest that preoperative cisplatin/etoposide and concurrent thoracic irradiation should be considered for evaluation in a phase III trial in stage IIIa NSCLC patients and that this regimen should also be evaluated in stage IIIb patients.

Antineoplastic Combined Chemotherapy Protocols

Bone-conducted stimulation in electrocochleography.

The mechanical vibration patterns close to the cochlea in intact skulls of human cadavers have been studied by means of a miniature accelerometer. A Radioear B70A vibrator and a Brüel & Kjaer Mini Shaker have been used, fed with filtered clicks and with short tone bursts. The tone bursts were found to be superior to the clicks with regard to the vibration spectrum. At 500 Hz a considerable distortion was observed in the accelerometer signal, also when using tone bursts. This distortion was presumably due to resonant vibrations in the skull itself, and may be a source of error not only when using stimuli of short duration as in bone-conduction ECoG but also in conventional bone-conduction audiometry. When the vibrations were applied to the exposed bone surface of the mastoid, vibration levels increased by 10-25 dB compared with when soft tissues covered the point of application. This could be of advantage in bone-conduction ECoG performed at ear surgery.

Acoustic Impedance Tests

Electrocochleography used as a clinical hearing test in difficult-to-test children.

Thirty difficult-to-test children have been tested with transtympanic ECoG. When possible, informal hearing tests and/or free-field testing were performed. Children in whom no action potential (AP) could be recorded were submitted to conventional radiography of the inner ear, and vestibular tests. The correlation between free-field test thresholds and AP "thresholds" was good, especially in subjects with relatively good hearing. Response amplitude increased, and latency decreased, with increasing frequency of the stimulus implying that different parts of the basilar membrane are stimulated according to the frequency of the stimulus. Input-output curves of response amplitude and latency were plotted, and three different types were distinguished. ECoG can contribute to the evaluation of peripheral hearing in difficult-to-test children, and vestibular tests should always be performed on a child with suspected deafness or sensorineural hearing loss. Conventional radiography of the inner ear, however, seems to be of little value.

Action Potentials

[Theory of the EEG potential in models of the leptomeninges of the brain. IV. Radial dipoles and their double layers in the depths and on the surface of the brain].

The estimaiton of ECoG-potentials is fulfilled by means of a simple model of the isolated sphere, which is exact enough, as it was proved earlier [1]. A simple limit formula for the qualitative estimation of ECoG-potentials of a source situated in the cerebral cortex is obtained. The EEG as in [2] is obtained using the transformation of the first 20 spheric harmonics. The experimental facts of registration of the evoked potentials of comparatively little subcortical sources were explained theoretically. Numerical results of the model are used to estimate the intensity of the field induced in the brain by two electrodes placed on the scalp.

Brain

Cortical synchronization induced by thermal stimulation of the preoptic area in immobilized rats.

Cortical synchronization characterized by frontal spindles and occipital slow wave activity was induced by bilateral thermal stimulation of 2--4 degrees C of the preoptic area in unanaesthetized immobilized rats. The synchronization was demonstrated by ECoG and its power density spectra. The ECoG of the synchronization was similar to that of slow wave sleep. Switching off the thermal stimulation the original activity was recovered in most of the cases. Frontal spindle activity and slow wave activity recorded over the posterior cortex seemed to be dissociated to some degree. Low frequency stimulation at the points of thermal stimulation resulted in frequency following synchronization. In some cases electrical and thermal stimulation induced gradually developing seizure activity.

Animals

Spectral density analysis of the effects of barbiturates and benzodiazepines on the electrocorticogram of the squirrel monkey.

The effects of pentobarbital and diazepam were compared in a series of tests in squirrel monkeys; the effects of phenobarbital and flurazepam were compared in a second series. Observations were made of gross behavior and on the ECoG; the latter was analyzed by the spectral density technique. The two barbiturates induced sedation,which was occasionally so deep that the monkeys could not be readily aroused. The benzodiazepines induced sedation in some monkeys, but others showed signs of restlessness. The ECoG showed general slowing with the barbiturates, whereas the benzodiazepines produced mixed fast and slow patterns. Spectral density analysis showed that pentobarbital increased activity at frequencies below 40 Hz, with the largest increases occurring below 8 Hz. Phenobarbital increased activity below 8 Hz, but differed from pentobarbital by decreasing activity above 13 Hz. The benzodiazepines increased activity below 8 Hz, decreased it between 8 and 20 Hz, and increased it between 20 and 50 Hz.

Animals

[The effect of low-frequency electric stimulation of the caudate nucleus on the electrical activity of the cortex and on the sleep-wakefulness cycle].

In cats, the effect of low-frequency electric stimulation of the caudate nucleus on electric activity of neo- and archipaleocortex and on wakefulness-sleep cycle, was studied. The data obtained suggest: 1) at threshold and suprathreshold single electric shocks applied to the caudate nucleus they evoked potential occurs more readily in the sensorimotor area of the neocortex than in the dorsal hippocampus. At 2-6/sec stimulation the evoked potentials in the hippocampus are facilitated and become very stable, whereas in the sensorimotor cortex the most obvious responses occur at the 6-8/sec frequency. However, the evoked potentials are variable in the sensorimotor cortex, and at prolonged 8-12/sec stimulation spindle activity soon develops; 2) behavioral correlate of the synchronized activity in the neo- and archipaleocortical structures during low-frequency stimulation of the caudate nucleus, may involve development of drowsiness with the cessation of stimulation, however, both the EEG and behavioral signs of the drowsiness disappear. The onset of drowsiness following withdrawal of the caudate stimulation, is a rare phenomenon only occurring because of an occasional coincidence of the stimulation with the spontaneous onset of natural sleep; 3) low-frequency caudate stimulation entailing the ECoG synchronization does not cause the transition of paradoxical phase into the slow-wave phase of sleep, and as soon as the stimulation ceases its normal structure recovers. However, if the stimulation of the caudate nucleus is repeated several times in one paradoxical phase, this would shorten the subsequent slow-wave phase and accelerate the onset of the next paradoxical phase; 4) prolonged low-frequency stimulation of the caudate nucleus causing the ECoG synchronization results in a considerable change of wakefulness-sleep cycle in the post-stimulation period: a decrease in the total time of slow-wave sleep due to shortening of its different phases, and an increase in the total amount of paradoxical sleep because of the onset of its phases is rendered more frequent. This effect is more obvious in the first half of the 8-hr cycle.

Animals

The effects of 21 or 30% O2 plus umbilical cord occlusion on fetal breathing and behavior.

We have shown previously that continuous fetal breathing can be induced by 100% O2 alone or combined with umbilical cord occlusion (Baier, Hasan, Cates, Hooper, Nowaczyk & Rigatto, 1990). To know whether it could also be induced by lower O2 concentrations plus cord occlusion, we studied 9 chronically instrumented fetal sheep (16 experiments) using our window model. After a baseline cycle [1 low voltage + 1 high voltage electrocortical activity (ECoG) epoch] the fetal lung was distended via an endotracheal tube to about 30 cm H2O. Inspired N2 (control) and 21 or 30% O2 were given for one cycle each. While on 21% or 30% O2 the umbilical cord was occluded (balloon cuff). In 10 out of 16 experiments breathing output (% maximum of integral of EMGdi x f) increased after cord occlusion from 80 +/- 48 (N2) to 2871 +/- 641 (SEM; P < 0.01); in 7 of them breathing became continuous. Arterial PO2 increased from 14 +/- 1 (N2) to 33.5 +/- 5 Torr (occlusion; P < 0.01). In the other 6 experiments breathing output decreased from 319 +/- 116 (N2) to 86 +/- 38 (occlusion; P < 0.01) and arterial PO2 changed from 18 +/- 1 (N2) to 22 +/- 5 Torr (occlusion; P = 0.4). Arterial PCO2 increased similarly after occlusion in both groups, those which did respond with increased breathing (to 46 +/- 2 Torr) and those which did not respond (to 48 +/- 3 Torr; P = 0.6). The percent low voltage ECoG and the behavioral score increased after occlusion in the responder group only.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

[The interhemispheric brain asymmetry of the rabbit in a state of "animal hypnosis"].

By the method of forced immobilization the rabbits were brought into the state of "animal hypnosis" (immobilization reflex), and their ECoG was recorded, which was further processed on the computer. It was found that during hypnosis a functional interhemispheric brain asymmetry was developed in rabbits with activity predominance in the right hemisphere. The "animal hypnosis" is a phasic process: in the ECoG of the rabbit under hypnosis a regular alternation of delta and theta activity takes place. Electrophysiological reconstructions in the rabbit brain during the change of its functional state correlate with the brain thermal reactions, revealed earlier.

Animals

[Degree of homogeneity of the forms of statistical relationship between the EEG and spike currents of neurons].

The correlation between the spike activity and the waves of surface ECoG was studied in the visual and motor cortex of alert non-immobilized rabbits. A comparison was made between the forms of the obtained correlation functions for the cells with different horizontal and vertical distances between them. The analysis revealed the similarity of such functions in neurones of V-VI cortical layers, situated vertically under each other along the microelectrode track. Similar in form statistic connections between the ECoG and the background spike activity were also found, beginning with the depth of 1.000 mc, in the neurones situated at the same horizontal cortical level; however, with the increased distance between the cells the degree of similarity of these connections decreases in a non-linear way. On the basis of the obtained data a conclusion is made that the tangential sizes of the background functional ensembles of the cortical neurones are within the range of 140-300 mc.

Animals

Mechanism of the cerebrocortical vasodilatation during anoxia.

The possible role of cerebrocortical ion homeostasis, NAD/NADH redox state and of cortical oxygen tension was investigated in the initiation of hypoxic cortical vasodilatation. In addition, changes in cerebrocortical extracellular concentrations of Na+, K+, and Cl- during anoxia were studied. The results were as follows. a) The cerebrocortical reflectance decrease, e.g. cerebral vasodilatation, lagged behind the cortical pO2 decrease by 1-2 sec, but preceded the decrease of arterial blood pressure and ECoG as well as the extracellular Na+, K+, Cl- increases by 20-30 sec. Since the cortical pO2 decreased first and the ion changes lagged behind the onset of vasodilatation by 20-30 sec, it is suggested that the CBF increase in hypoxia is mediated via the cortical pO2 decrease. b) A significant NAD reduction was already present after 20 sec. of nitrogen breathing. Since the ECoG and MABP decreased, and K+ activity increased much later than this, it is presumed that the NAD reduction during the first 30-40 sec of anoxia indicates an increased rate of glycolysis, but not mitochondrial hypoxia. c) In the predepolarization phase a 17% K+, 4% Na+, 5% Cl- increase is probably the result of a reduction of the extracellular spaces caused by water movement and by the migration of Na+ and Cl- from the extracellular to the intracellular space. The large K+, Na+, Cl- changes during terminal depolarization can be interpreted as a result of the failure of the membrane bound Na+ -K+ pump and of the altered ion permeability of the cell membranes.

Action Potentials

Intracellular oxygen tension and energy metabolism in the cat brain cortex during haemorrhagic shock.

The changes in intracellular oxygen tension and energy metabolism of the cat brain cortex were studied by surface fluororeflectometry during haemorrhagic shock. The results may be summarized as follows. (a) Intracellular oxygen tension, i.e. the maximum cortical NAD reduction obtained during nitrogen gas inhalation decreased gradually during the hypovolaemic phase of shock and finally, the brain cortex became ischaemic. (b) Partial uncoupling of the cerebrocortical mitochondrial respiration and oxidative phosphorylation appeared in the very early period of bleeding, as indicated by the overshot of the cortical NAD/NADH redox state towards oxidation subsequent to the cessation of nitrogen gas inhalation. Partial uncoupling of mitochondrial respiration and oxidative phosphorylation became more pronounced during the later phases of bleeding, finally, the mitochondrial electron transport stopped. In line with these changes the frequency and the amplitude of ECoG decreased gradually and markedly during the hypovolaemic phase of shock. (c) Microcirculation and energy metabolism of the cat brain cortex were severely and irreversibly damaged during the hypovolaemic phase of shock. This was clearly shown by the fact that in the majority of experiments the nitrogen anoxia after reinfusion failed to bring about changes in the cortical NAD/NADH redox state and the ECoG changes occurred during bleeding did not improve after reinfusion. It is concluded that the early disturbances of cerebrocortical energy metabolism play an important role in the development of neural and vascular lesions of the brain that occur during haemorrhagic shock.

Action Potentials

[Role of the median forebrain bundle in organizing the electrical activity of the neocortex].

Bilateral coagulation of the forebrain medial bundle in the lateral hypothalamus enhances the formation of spontaneous spindles and facilitates the recruiting response in the neocortex. This combines with a defect of desynchronizing influences of the posterior hypothalamus and the concurrent dominance of synchronizing effects of the preoptic area (PA). PA stimulation enhances the slow wave and spindle activity in the ECoG of the intact brain. After disruption of PA connections with the bulbar synchronizing apparatus the stimulation effect is manifested only in enhanced spindle activity. It is assumed that in addition to hypnogenic influences which PA shares with the parasolitary apparatus, it maintains a definite level of cortical reactivity after the onset of sleep. Elimination of the orbito-frontal cortex, as well as PA coagulation, does not prevent the appearance of spindles in the ECoG of the preparation with an intersected medial bundle, only limiting them to some extent.

Animals

[Theory of EEG potential in a model of the thin membranes of the brain].

The methods of estimating a momentary value of the epidural potential using several values of EEG, sampled at the same instant, are explored theoretically. The weights of the summation of these EEG-potentials for the case of simple disposition of electrodes, are single-valued by means of elementary consideration of the potential theory and symmetry. The space filters of EEG obtained in such a way, were analysed on the basis of the model of thin integuments of the brains. The systems of 4--8 electrodes on the scalp are proposed for the estimation of mono- and bipolar ECoG's, which are less sensitive to ECoG of the remote cortex than ordinary derivations of EEG.

Cerebral Cortex

Impairment of cerebral blood flow autoregulation after hypertonic urea administration.

The effect of unilateral intracarotid administration of 3 M urea on resting cerebral blood flow, arterial blood pressure, perfusion pressure-cerebral blood flow relation, ECoG and Evans blue permeability was tested in dogs. The injection of urea was without effect on ECoG and enhanced the arterial blood pressure temporarily. Cerebral blood flow measured 10 min after the urea injection was not affected. Extravasation of Evans blue was observed in the urea-perfused hemisphere for about 40 min following the urea administration. Cerebral perfusion pressure-blood flow relation for the urea affected hemisphere studied at the time when blood-brain barrier to protein was restored revealed loss of the normal autoregulatory response, despite that it was preserved in the control hemisphere.

Animals

[Influence of the anterior and posterior hypothalamus on the conditioned reflex activity and delayed responses of lower simians].

In 4 adult monkeys, electrical stimulation of the anterior hypothalamus followed by subsidence in the animal and the ECoG synchronization evoked also an impairment of conditioned reflex activity and a decrease in the test performance during delayed responses. Strong stimulation of the posterior hypothalamus followed by emotional arousal and desynchronization in the ECoG, on the contrary, improved the conditioned reflex activity and increased the level of the test performance. The hypothalamus is then supposed to play a certain role in memory as an emotiogenic structure.

Animals

Prognostic modeling of overall survival in metastatic pancreatic cancer: an inflammation-based tool validated in PANTHEIA-SEOM cohort.

PURPOSE: To develop and internally validate the PANTHEIA-SIRI prognostic model, which integrates log-transformed systemic inflammation response index (SIRI) with clinical predictors, to estimate overall survival (OS) in metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line chemotherapy. METHODS: We used data from the multicenter PANTHEIA-SEOM registry. OS was defined from chemotherapy start. The model was fitted as a Weibull accelerated failure time model in the survival-analysis population with multiple imputation. Predictors were log-transformed baseline SIRI, modeled with restricted cubic splines, ECOG, tumor burden, chemotherapy regimen, and anorexia-cachexia syndrome. Internal validation used a separate, non-overlapping cohort from the same registry; the centers contributing to each cohort are listed in a supplementary annex. TRIPOD was followed. Discrimination was assessed with Harrell&#xb4;s C-index and calibration with IPCW Brier scores and IPA. RESULTS: The derivation cohort comprised 672 patients with SIRI data (593 analyzed for survival) across 22 Spanish hospitals (2015-2025); 80.1% had died after a median OS of 9.9 months. The imputation-pooled derivation C-index was 0.654 (95% CI, 0.627-0.681); optimism-corrected, 0.629. Internal validation used 62 separate patients from the same registry; 96.8% had died after a median OS of 9.2 months. The validation C-index was 0.603 (95% CI, 0.518-0.687). Calibration was adequate at 6 and 12 months. CONCLUSIONS: The PANTHEIA-SIRI model provides individualized OS estimates in mPDAC with routine clinical predictors. Its open-access calculator ( https://pantheia-siri.shinyapps.io/calc/ ) may support prognostic communication, treatment-intensity selection, and supportive-care planning. Routine clinical implementation will require further validation in larger, fully independent cohorts.

Cachexia

Results of a randomized study comparing DTIC with TIC mustard in malignant melanoma.

This prospective randomized Eastern Cooperative Oncology Group (ECOG) study (1071) was designed to compare a new and promising cytotoxic agent TIC Mustard (triazeno imidazole carboxamide mustard, NSC 82196) with DTIC (dimethyl triazeno imidazole carboxamide, NSC 45388) in the treatment of inoperable melanoma. One hundred and seventy-eight patients were randomized to receive either DTIC (150 mg/m2/day X 5) or TIC Mustard (800 mg/m2/day X 5). Of this group 145 patients were evaluable for tumor response at the completion of the study. Objective responses were seen in 15/79 (19.0%) DTIC patients and 4/66 (6.1%) TIC Mustard patients. Adjustment of crude response rates yielded final response rates of 18.2% for DTIC patients and 5.8% for TIC Mustard. These differences were significant at the p less than or equal to .03 level. Median response duration was 15 weeks for the DTIC responders and 4 weeks for the TIC Mustard responders. Responders and nonresponders did not differ significantly in any of the standard prognostic categories. However, responders had a significantly longer median survival (47.5 weeks) compared to that for nonresponders (17.8 weeks). Toxicity was tolerable for either drug and no deaths were ascribed to either. We conclude that TIC Mustard has limited usefulness in the treatment of malignant melanoma and is less effective than DTIC.

Clinical Trials as Topic