Induction chemotherapy in head and neck cancer patients followed by concomitant docetaxel-based radiochemotherapy.

Concurrent chemoradiotherapy has become the standard of care for patients with inoperable squamous cell head and neck carcinoma. More recently, induction chemotherapy has been adopted as an approach in the management of these patients. We report the results of a phase II trial associating induction chemotherapy and concomitant chemoradiotherapy in a series of patients with inoperable squamous cell head and neck cancer. Twenty-nine patients with advanced squamous cell carcinoma ineligible for surgery were enrolled. Induction chemotherapy with docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 21 days was administered for two cycles. Radiotherapy followed the induction phase. During radiotherapy, docetaxel was administered weekly at the dose of 33 mg/m(2) . Primary end point of the study was feasibility of treatment. Six (18%) patients failed to conclude the treatment schedule. Although response rates in evaluable patients were very high (disease control rate >90%), toxicities were a matter of concern. The reported treatment schedule proved infeasible. However, some modifications in ancillary therapies aimed at exploiting its efficacy could make it practicable.

Ethanol does not increase the hepatotoxicity of cocaine in primary rat hepatocyte culture.

Rat hepatocytes were utilized to investigate the role of cocaine metabolism and the contribution of ethylcocaine formation to cocaine-induced liver damage. Hepatocytes were prepared from rats pretreated with saline, phenobarbital or ethanol and exposed to cocaine, ethanol, or their combination. Hepatotoxicity was assessed by lactate dehydrogenase (LDH) leakage and was correlated with cocaine metabolism which was assessed quantitatively using HPLC. Only phenobarbital-pretreatment produced increases in LDH leakage from cultures exposed to cocaine. This increase in LDH release occurred simultaneous to a decrease in benzoylecognine formation and a marked increase in norcocaine generation. Exposing cultures to ethanol alone did not result in LDH leakage from hepatocytes. Furthermore, including ethanol in cultures treated with cocaine did not enhance the LDH leakage produced by cocaine alone. This study confirms quantitatively that cocaine-induced hepatotoxicity is mediated through cocaine oxidative events and is enhanced by microsomal induction produced by phenobarbital. The finding that ethylcocaine formation was maximal in the ethanol-pretreatment group where no toxicity was observed suggests that ethylcocaine is not the agent responsible for the hepatotoxicity observed in this study.

Developmental immunotoxicity of cocaine and ethanol in postnatal Lewis rats.

The immunomodulatory effect of cocaine (COC), ethanol (EtOH) and their combination was investigated in the developing immune system of postnatal Lewis rats. To simulate the route of exposure during lactation, newborn rats were orally treated with either saline, 20 mg COC/kg, and 0.6 g EtOH/kg or the coadministration of COC and EtOH from day 1 to 21 of life. Rat pups were sacrificed thirty minutes following the last treatment. Total lymphocytes and spleen/body weight ratios were decreased in animals exposed to COC. These immunotoxic effects were not enhanced by the coadministration of EtOH. However, pups exposed to both drugs had significantly decreased levels of serum immunoglobulin M (IgM) when compared to saline-treated rats. Plasma and tissue distribution studies revealed that the combination treatment group had a higher COC content in the brain and spleen as well as an increase in the metabolites benzoylecognine (BE) and norcocaine (NC) in the spleen. Ethylcocaine (EC) formation was not demonstrated in this model.

Role of ethanol exposure on cocaine metabolism in rat hepatocytes.

Cocaine remains a widely abused illicit substance in our society. Cocaine hepatotoxicity has been linked to cocaine metabolism. Cocaine can undergo hydrolytic inactivation via plasma and hepatic esterases or it can be N-oxidized by cytochrome P-450 and FAD-containing monooxygenases. Ethanol is frequently used in combination with cocaine. The presence of ethanol can affect the metabolism of other agents, depending on the dose and duration of exposure. In this investigation, hepatocytes isolated from male Sprague-Dawley rats were utilized to study the effect of ethanol exposure on cocaine metabolism. Hepatocytes were isolated using a two-step collagenase perfusion system. Hepatocytes (2 x 10(6) cells ml(-1)) were exposed to cocaine, ethanol or the combination of cocaine and ethanol for a 2-h period in a shaking water-bath at 30 oscillations per minute maintained at 37 degrees C. Sodium fluoride (NaF) was added to aliquots of cells which were removed from the incubation following 30, 60 and 120 min. The cells were homogenized on ice and immediately extracted for the quantification of cocaine, benzoylecognine, norcocaine and ethylcocaine by HPLC. Quantitative analysis revealed that there was a time-dependent increase in the disappearance of cocaine from hepatocytes. The rate of cocaine disappearance was not changed when ethanol was included in incubations containing cocaine. However, in the presence of ethanol there was a difference in the quantities of cocaine metabolites produced. When ethanol was included in incubations containing cocaine, the formation of norcocaine and benzoylecognine was less than that formed in hepatocytes exposed to cocaine alone. Additionally, when hepatocytes were exposed to cocaine in combination with ethanol, the formation of ethylcocaine was linear with time. This study revealed that in the presence of ethanol, cocaine qualitative metabolism is altered.

The effect of ethanol exposure on cocaine toxicity in rat hepatocytes.

The use of ethanol is common among the cocaine-abusing population. Both of these agents have been associated with hepatotoxicity. This investigation employed an in vitro model to study cocaine and ethanol interactions in the liver. Hepatocytes (2 x 10(6) cells/ml) isolated from male Sprague-Dawley rats were exposed to saline, cocaine, ethanol or the combination of cocaine and ethanol. Cell membrane damage in hepatocytes was assessed by the uptake of 0.4% trypan blue and the leakage of the enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) into the incubation media. An increase in trypan blue uptake was observed following exposure to 5 mm cocaine as early as 30 min of incubation. Hepatocytes were unaffected by treatment with 25 and 50 mm ethanol for the 2-hr time period studied. Including ethanol in incubations containing 1 or 5 mm cocaine did not result in any additional toxicity when compared with hepatocytes treated with cocaine alone. However, AST leakage from hepatocytes exposed to cocaine in combination with ethanol was decreased when compared with hepatocytes treated with cocaine alone. These findings suggest that exposing hepatocytes simultaneously to cocaine in combination with ethanol, under the conditions of this experiment, does not enhance the hepatocellular toxicity produced by cocaine alone.

Severe coronary artery disease after radiation therapy of the chest and mediastinum: clinical presentation and treatment.

OBJECTIVE: To define the clinical and angiographic features and the therapeutic problems in patients with coronary artery disease after therapeutic irradiation of the chest. DESIGN: An observational retrospective study. SETTING: The cardiac catheterisation laboratory, university medical school. PATIENTS: 15 subjects (8 men and 7 women, aged 25-56 years, mean 44) examined in the cardiac catheterisation laboratory, who had significant coronary artery disease years after having radiation treatment to the chest and anterior mediastinum. In the early stages of the study angiography was performed because of typical symptoms of ischaemic heart disease. Later on it was performed because of a high index of suspicion in people with signs of extensive radiation heart damage. MAIN OUTCOME MEASURES: Clinical and electrocardiographic evidence of ischaemic heart disease; echocardiographic signs of pericardial, myocardial or valvar involvement; angiographic evidence of coronary arterial stenosis, with special attention to the ostia; haemodynamic and angiographic signs of pericardial, myocardial, and valvar disease. Survival and symptomatic and functional status were ascertained after medical or surgical treatment. RESULTS: The patients were relatively young and had no risk factors. Seven patients had no signs or symptoms of ischaemic heart disease. Ten patients had ostial stenosis, which was associated with extensive involvement of other cardiac structures in nine of them. Seven required surgical treatment for coronary artery disease. Two died, one at surgery and the other one six months later. Five patients had complications associated with irradiation. CONCLUSIONS: Coronary arterial disease can be reasonably ascribed to the effects of chest irradiation when the patients are young and free from risk factors, especially if the obstructions are ostial and there is important damage to other cardiac structures. In patients with damage to other cardiac structures angina and infarction are often absent and coronary angiography seems to be mandatory. Patients often require surgical treatment and postoperative complications are common.

Associated cardiac lesions in patients with radiation-induced complete heart block.

We investigated the clinical, electrophysiological, haemodynamic and angiographic aspects of four patients (two men and two women, aged 31-46 years) who developed complete heart block 13-20 years after therapeutic irradiation of the chest for Hodgkin's disease. The initial cardiac symptom was syncope in three, effort intolerance in one. The electrocardiogram recorded third-degree atrioventricular block in three patients, right bundle branch block and posterior fascicular block in one. The electrophysiological study, performed in three cases, showed that the block was infranodal in two. Three patients had significant coronary arterial stenoses, that involved the ostia in two. All patients had mild-to-moderate aortic and mitral regurgitation. One patient had haemodynamic signs of constriction. Another patient had recurrent pericardial effusions. All had echocardiographic evidence of a thickened pericardium. Cardiac involvement can be extensive in patient with radiation-induced heart block. Because coronary artery disease can be particularly severe, coronary angiography appears to be warranted in such patients.

[Cardiopathy due to therapeutic irradiation of the thorax. The diagnostic criteria]. / La cardiopatia da irradiazione terapeutica del torace. Criteri diagnostici.

Between January 1, 1985 and June 30, 1992, 37 patients (25 women and 12 men, aged 13-65 years) who had undergone a radiation treatment to the anterior chest and mediastinum, were admitted to our Institution for cardiac evaluation, which included left and right heart catheterisation in all, but 3 patients. Seventeen had signs or symptoms of ischaemic heart disease, in 8 a pericardial disease was suspected, 5 had a complete heart block, 4 were in congestive heart failure caused by valvular dysfunction, and 3 had a dilated, hypokinetic left ventricle. Diagnostic criteria in these patients were as follows. Stenoses of the coronary ostia were always considered to be caused by radiation damage, in the absence of coronary risk factors. Obstructions of other coronary segments were taken to be of X-ray origin only when accompanied by damage to other cardiac structures. Pericardial lesions were always reckoned to be of X-ray origin in the absence of other recognisable causes. The same held true for aortic stenosis or insufficiency of any degree and for mitral insufficiency > or = 3+. Cases of complete heart block were diagnosed according to Slama's criteria. A restrictive cardiomyopathy was recognised only in patients operated on for pericardiectomy, in whom clinical or haemodynamic signs of "constriction" persisted after the operation, or extensive subendocardial fibrosis was found at biopsy. According to the above-mentioned criteria, it was established that radiation therapy was the cause of the cardiac problems in 19 cases: 4 with ischaemic symptoms, 8 with pericardial disease, 4 with complete atrioventricular block, and 3 with valvular disease and congestive heart failure. Coronary ostial lesions were found in all patients with angina, and in 8 of the 14 patients without angina (in 1 the coronary arteries were not investigated), and were critical in 4. Eleven patients were operated on. A myocardial revascularisation was performed in 7 cases, a pericardiectomy in 6, a valve replacement or repair was done in 4. A combined procedure was performed in 4 instances. A pacemaker was implanted in 3 cases, 2 patients had a pericardial drainage, and 3 patients continued their medical treatment. Of the 11 operated patients, 1 died at surgery, in refractory cardiac failure, from what was suspected to be a restrictive disease (normal preoperative left ventricular volume and ejection fraction, extensive myocardial fibrosis at autopsy).(ABSTRACT TRUNCATED AT 400 WORDS)

The interaction of platinum antitumour drugs with mouse liver mitochondria.

A study was undertaken to determine if cis-DDP and its second generation derivatives produced effects on mouse liver mitochondria, and if any of the observed effects could be correlated with the nephrotoxicity of the drugs. Although changes were observed in mitochondrial morphology, enzyme activity, Ca2+ influx, terbium binding and surface potential, no specific effect was correlated with nephrotoxicity. cis-DDP produced marked changes in mitochondrial morphology; electron probe analysis showed binding of the drug to the mitochondria. Inhibition of complex I and II activity of the respiratory chain and an ionic-strength-dependent effect on Tb3+ (a Ca2+ analogue) fluorescence were observed. The non-nephrotoxic derivatives, CHIP and tetraplatin, also produced significant changes in morphology. Treatment with these derivatives also produced decreases in mitochondrial enzyme activity, but the effect on terbium binding had an ionic-strength dependence which was inverse to that observed with cis-DDP. The tetravalent compounds also had a notable effect on mitochondrial surface potential. Carboplatin had an effect on morphology and Ca2+ influx and it inhibited the respiratory enzymes, although in a manner different from that observed with cis-DDP. Carboplatin had a minimal effect on terbium binding. It is evident that if the platinum drugs enter a cell to exert their action at the nuclear level, they will also depress mitochondrial function. The observed effects did not correlate with nephrotoxicity but, since all four compounds significantly altered mitochondrial structure and function, they may be related to the cytotoxicity of the drug.

[Rapid onset aortic stenosis and clinical course in adults. Clinico-hemodynamic correlations]. / Stenosi aortica a rapida insorgenza ed evoluzione nell'adulto. Correlazioni clinico-emodinamiche.

In 8 patients aged 41-66 years, a second left heart catheterisation done 27-98 months after the first study, demonstrated a pressure gradient across the aortic valve, that had not previously existed, or had been trivial. No significant change of the cardiac output had occurred. All but 1 patient were hypertensive. The etiology was rheumatic in 4, degenerative in 4. Electrocardiographic, radiographic, and echocardiographic evolution could not separate the patients with a gradient greater than or equal to 70 mmHg from those whose gradient was less than or equal to 40 mmHg. The intensity of the aortic component of the second heart sound, however, decreased in all former patients, and in only 1 of the latter. Aortic valvular stenosis can arise and rapidly develop in adult patients. Concomitant rheumatic mitral valve disease, coronary artery disease and hypertension can mask and/or modify symptoms, signs and laboratory findings. Changes of the aortic component of the second sound may suggest its occurrence.

[ Bacterial endocarditis of the pulmonary valve damaged by thoracic radiotherapy (in Hodgkin's disease)]. / Endocardite batterica su valvola polmonare danneggiata da radioterapia toracica (per morbo di Hodgkin).

It is well known that radiation therapy to the anterior mediastinum may induce lesions of all cardiac structures. The pericardium is most frequently involved, but atrioventricular conduction disorders, cardiomyopathy, coronary stenosis may also be produced. Aortic, mitral and tricuspid lesions have been described. However, clinical evidence of pulmonic valve involvement has not been reported. Only at necropsy has fibrotic thickening of the pulmonic cusps occasionally been found. We report a case of infective endocarditis of the pulmonic valve in a 53-year-old patient who had undergone thoracic radiation therapy for Hodgkin's disease 31 years previously. Four years prior to the endocarditis he had also been submitted to myocardial revascularisation for critical lesions of the left main and right coronary ostia, and to aortic valve replacement because of stenosis and insufficiency. At that time, the pulmonic valve was fibrotic on echo examination. It is noteworthy that, of all the cardiac valves, the infective process involved only the pulmonic one, which is seldom the target of an infection. To our knowledge this is the first case of bacterial endocarditis of a heart valve that had been previously damaged by radiation therapy.

The interaction of platinum and anthrapyrazole antitumor drugs with mouse thymocytes studied by terbium fluorescence.

The fluorescent lanthanide, terbium has been employed to study the effect of a series of platinum and anthracycline drugs and an anthrapyrazole (oxanthrazole) on terbium binding to mouse thymocytes. It was observed that terbium fluorescence intensity was markedly decreased by two platinum drugs (cis-dichlorodiammine platinum(II) (cis-DDP) and cis-dichloro-trans-dihydroxybis(isopropylammine) platinum(IV) (CHIP)) and an anthrapyrazole (oxanthrazole), but that the lipophylic derivative cis-diammine-1,1-cyclobutanedicarboxylate platinum(II) had a small but significant effect and the anthracyclines (at low concentrations) had no effect. The calcium channel blocker, verapamil also had no effect. The effect of cis-DDP was markedly dependent on ionic strength in contradistinction to CHIP. The decreases in phosphorescence decay produced by cis-DDP also showed a marked dependence on ionic strength. It is proposed that cis-DDP interacts with the membrane primarily by a charge effect, but that CHIP may produce a conformational change in the membrane. These data are interesting, since the lipophylic platinum drugs (CHIP and CBDCA) also increased significantly the amount of bound intracellular calcium, but all the drugs decreased mitogen-stimulated calcium uptake into mouse thymocytes.