Neoadjuvant chemotherapy: a new criterion for selection of candidate patients for surgery of low tumour burden metastases from malignant melanoma?

BACKGROUND: Surgery of limited metastatic lesions from malignant melanoma can achieve long-term remission and better survival than chemotherapy. Existing criteria for selection of candidate patients for this surgery do not seem sufficient to avoid useless excisions. OBJECTIVES: To test use of neoadjuvant chemotherapy as a new criterion in this setting. METHODS: All patients who underwent thoracic surgery for one or two lung metastases from melanoma during 1999-2007 were included in the study. Demographic and medical data were collected and analysed. Several possible prognostic factors were evaluated based on the overall survival curves. RESULTS: Thirteen patients were included in this retrospective study. All but two patients had no evidence of disease after surgery. Ten patients received neoadjuvant chemotherapy. Six responded (absence of progression) and four had progressive disease. Response to chemotherapy and no evidence of disease after surgery were predictive of long-term survival. CONCLUSIONS: Neoadjuvant chemotherapy can be considered as a new criterion for better selection of candidate patients for lung metastasis surgical resection. This would also avoid useless surgical procedures in rapidly progressive disease and give information on the chemosensibility of the metastatic disease. This study needs further confirmation, particularly with chemotherapy regimens that have demonstrated better objective responses.

[When should respiratory physicians consider lung transplantation for their patients? Inscription criteria for the national waiting list]. / Quand le pneumologue doit-il envisager la greffe pulmonaire pour un de ses patients?

INTRODUCTION: Placing a patient on the national lung transplant waiting list remains a difficult matter, and is more a question of timing than selection of the candidate according to disease-specific criteria. BACKGROUND: The listing criteria for cystic fibrosis are FEV1 less than 30% of the predicted value, hypoxaemia with a PaO2 less than 55 mm Hg and hypercapnia with a PaCO2 over 50 mm Hg. The rate of decline of FEV1, increasing antibiotic requirements and life threatening complications can all accelerate the listing procedure. For primary pulmonary hypertension the criteria are persistent dyspnoea, NYHA grade III or IVA, despite epoprostenol treatment and a 6 minute walk test of less than 250 metres. Sarcoidosis, lymphangioleiomyomatosis, histiocytosis X and connective tissue diseases are rare indications for which the listing criteria are similar to those for the more usual respiratory diseases. VIEWPOINTS: Further therapeutic advances, increased numbers of available organs and changes in the allocation rules will necessitate periodical updates of these selection and listing criteria. CONCLUSION: The optimal time for placing lung transplantation patients who have been referred early in the course of their disease on the waiting list will be determined by clinical experience and individual patient follow-up.

Liposarcoma of the pleural cavity. An exceptional tumour.

Primitive liposarcomas of the pleura are exceptional tumours. We report a new case of primitive liposarcoma of the pleura revealed by chest pains in a 50 year old man. Computed tomography showed a large fat density mass in the left pleural cavity. Surgical resection was performed, completed with adjuvant radiotherapy. Few reports are available in the literary world. We present our case, review previously reported cases and discuss treatment.

[Massive haemoptysis: management and treatment. What is the role of surgery?]. / L'hémoptysie massive: prise en charge et traitement. Quelle est la place de la chirurgie?

OBJECTIVE: To define the role of interventional radiology and surgery respectively, in the treatment of massive haemoptysis. GENERAL CONSIDERATIONS: For the management of massive haemoptysis in non-terminal pathologies an intensive care facility and a multi-disciplinary team are necessary. It is of paramount importance to identify rapidly the pulmonary or bronchial source of the bleeding. CT scanning and bronchoscopy are essential to localise the bleeding and determine its cause. Initial management. An attempt to control the initial bleeding to allow localisation of its origin and determine the treatment. TREATMENT: Bronchial or systemic embolisation and surgery are the only effective medium and long-term treatments. Embolisation achieves excellent results in bleeding from bronchial or parietal systemic arteries prior to surgery and may be the only technique possible in the presence of major co-morbidity. Surgery is necessary in the case of failure, in certain specific conditions, and in the case pulmonary artery haemorrhage from a proximal lesion. Various surgical techniques are available depending on the type of lesion encountered and the facilities for post-operative care. Emergency surgery carries a high risk and deferred surgery gives better results. CONCLUSION: The management of massive haemoptysis should be multi-disciplinary. Intensive care, respiratory and radiological diagnosis, Surgical management and interventional radiology should be combined to improve the prognosis of this grave condition. Pulmonary arterial haemorrhage from a necrotic tumour constitutes a surgical emergency and should be operated on without delay.

Detection of circulating cells expressing chromogranin A gene transcripts in patients with lung neuroendocrine carcinoma.

High grade lung neuroendocrine carcinomas, like small and large cell neuroendocrine carcinomas, pose therapeutic problems. Most initially respond to chemotherapeutic agents, but early relapses are frequent and are resistant to the presently available treatments. Our study reports for the first time the development and evaluation of a test for detecting the presence of circulating tumour cells by measuring chromogranin A gene transcripts with reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blotting. The test is specific and sensitive (detection of 10 cancer cells/ml blood), and only minimally invasive. Positivity is statistically correlated to high grade neuroendocrine carcinomas and to a poor prognosis with a 3-fold higher lethal risk. The test now needs to be assessed for its usefulness as a tool in the initial staging procedures and follow-up by comparison with the recent immunoradiometric assay (RIA) for detection of chromogranin A in the serum.

New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.

A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.

Expression of NGF receptors in normal and pathological human thymus.

The expression of NGF receptors was investigated in normal human thymus and in thymic hyperplasias, thymomas and thymic carcinomas. By RT-PCR, we detected TrkAI transcripts encoding for the high-affinity NGF receptor. Western blot analysis showed the presence of both TrkA and p75NGFR proteins. In normal thymuses, epithelial subcapsular and medullar cells were TrkA immunoreactive. Interdigitated medullar cells were stained for both TrkA and p75NGFR. While epithelial cells of normal thymuses or benign thymomas exhibited a TrkA positive-p75NGFR negative phenotype, a switch to a TrkA negative-p75NGFR positive phenotype was observed in malignant epithelial cell tumours and was associated with cell proliferation-associated MIB1 expression. Our results argue for a local role of NGF and its receptors on thymic stromal cells both in normal and neoplastic conditions.

Delayed up-regulation of alpha-adrenoceptor populations in particular regions of the rat brain after stimulation of the nucleus locus coeruleus.

We previously showed that electrical stimulation of the nucleus locus coeruleus resulted 4 weeks later in greatly improved performance in the acquisition and extinction of a food-reinforced operant task. To ascertain whether adrenergic receptors of particular brain regions were involved in this long term behavioral modification, we studied the characteristics of alpha 1, and alpha 2 and beta-binding sites after stimulation of the locus coeruleus. In the first experiment these characteristics were studied, 4 weeks after treatment, in cortex, hippocampus, hypothalamus and the brainstem. Neither the number, nor the affinity of beta-receptors ([125I]iodocyanopindolol binding sites) was modified in any brain region. A significant increase in the number of alpha 1-receptors ([3H]prazosin binding sites) was observed in the cortex (62%). The number of alpha 2-receptors, ([3H]yohimbine binding sites), was significantly increased in cortex (99%), hippocampus (33%) and hypothalamus (113%). No significant alteration of the alpha 1, alpha 2 and beta-adrenoceptors was observed in the brainstem. To investigate the time course of these adrenoceptor changes, the characteristics of alpha 1, alpha 2 and beta-adrenoceptors were studied 2 weeks after stimulation using the same ligands and in the same brain regions. The only significant modifications observed were an increase of the alpha 2-adrenoceptors in the cortex (19.4%) and in the hypothalamus (54%). Furthermore, in both experiments, the increase in the number of alpha 1 and alpha 2-receptors was associated with a significant decrease in affinity. These results are discussed in relation to our previous behavioral and pharmacological findings.

Interference of sodium with [3H]-nitrendipine binding to cardiac membranes.

Interference of sodium with [3H]-nitrendipine binding was studied on membrane homogenates from guinea-pig skeletal muscle, cerebral cortex and left cardiac ventricle. [3H]-nitrendipine binding on homogenates from cerebral cortex and skeletal muscle was unaffected by Na+ (35 and 140 mEql(-1]. On the other hand, for the myocardial receptors, addition of Na+ resulted in an increase in IC50 of nitrendipine. Simultaneously, for the myocardial preparations, saturation curves showed a decrease in [3H]-nitrendipine affinity and an increase in the number of binding sites.

The beta-adrenoceptor of pig coronary arteries: determination of beta 1 and beta 2 subtypes by radioligand binding.

beta-Adrenoceptors of pig coronary arteries were investigated by the use of a new ligand, 125iodocyanopindolol (ICYP) in binding studies. Inhibition of ICYP binding by betaxolol (a selective beta 1-antagonist), zinterol (a selective beta 2-agonist) and ICI 118551 (a selective beta 2-blocking drug) resulted in non-linear Scatchard plots, suggesting that both beta-adrenoceptor subtypes are present in pig coronary arteries. Computer analysis of the data gave a beta 1:beta 2-adrenoceptor ratio of approximately 65:35.

Beta-adrenoceptors of the human myocardium: determination of beta 1 and beta 2 subtypes by radioligand binding.

beta-Adrenoceptors of the human myocardium were investigated with binding studies using 125iodocyanopindolol (ICYP) as ligand. Inhibition of ICYP-binding by betaxolol (a selective beta 1-antagonist) and ICI 118551 (a selective beta 2-blocking drug) resulted in non-linear Scatchard-plots suggesting that both beta-adrenoceptor subtypes are present in human left atrium and left ventricle. Computer analysis of the data gave a beta 1/beta 2-adrenoceptor ratio of approximately 65:35 both for left atrium and for left ventricle.

Comparison of pharmacological and binding assays for ten beta-adrenoceptor blocking agents and two beta-adrenoceptor agonists.

1 The inhibition constants evaluated by binding assays for ten beta-adrenoceptor blocking agents and two beta-adrenoceptor agonists, were compared with the pA2 and pD2 values determined in vitro and in vivo. 2 There was only a limited correlation between beta 1 or beta 2 selectivities observed with the different methods. 3 Selectivity is generally less pronounced in binding assays than for in vivo and in vitro experiments.

Studies on some para-substituted clonidine derivatives that exhibit an alpha-adrenoceptor stimulant activity.

1 alpha-Adrenoceptor stimulant activity was determined for noradrenaline (NA), clonidine and a series of para-substituted derivatives of clonidine on rat aortic strips, a rat brain synaptosome preparation, and anaesthetized pithed rats. The effects on the blood pressure of intraventricular (i.c.v.) injections of para-aminoclonidine were also determined in anaesthetized rats. 2 Para-substituted derivatives of clonidine (amino-, diethylamino-, ethylamino-, acetamido-, bromoacetamido-, N-chloroethyl-N-methyl-amino and N-beta-chloroethyl-N-methylaminomethyl-) retain alpha-adrenoceptor stimulant activity. 3 pD2 values determined on rat aortic strips were 11.2, 7.67 and 9.05 respectively for para-aminoclonidine, clonidine and noradrenaline. The Ki values of these agents, determined on a rat brain synaptosomal preparation with a radioreceptor assay using [3H]-clonidine as ligand, were 1.3, 8.0 and 23 nM respectively for para-aminoclonidine, clonidine and NA. When given by i.c.v. injection in rats, para-aminoclonidine lowered the blood pressure. 4 N-beta-chloroethyl-N-methylaminomethylclonidine is an alkylating agent with an unusual agonist activity. It elicits contractions of the rat aorta that persist despite repeated washing. 5 alpha-Adrenoceptor affinities are discussed in relation to their structural features.

Anti-anginal arylalkylamines and sodium channels: [3H]-batrachotoxinin-A 20-alpha-benzoate and [3H]-tetracaine binding.

[3H]-batrachotoxinin-A 20-alpha-benzoate ([3H]-BTX-B) and [3H]-tetracaine are useful ligands for the study of sodium channels. Inhibition of their binding by various anti-anginal drugs was tested on a rat synaptosomal preparation and on a heart membrane preparation. Diphenylalkylamines and structurally related drugs inhibited [3H]-BTX-B binding in both the synaptosomal preparation and heart membrane preparation. They were almost inactive on [3H]-tetracaine binding. These results suggest that activity of arylalkylamines could be mediated by an interaction on the sodium channel.

[3H]-tetracaine binding on rat synaptosomes and sodium channels.

[3H]-tetracaine binding was studied in a rat synaptosomal preparation. [3H]-tetracaine bound to a single class of binding sites with a mean KD of 188 +/- 28 nM and a mean maximal binding capacity of 13 +/- 0.7 pmol mg-1 protein. [3H]-tetracaine binding was inhibited by tetracaine, procaine and by beta-adrenoceptor blocking agents which possess local anaesthetic properties. [3H]-tetracaine binding was not modified by neurotoxins interacting specifically with the sodium channels.

A potent new beta2-adrenoceptor blocking agent.

1 (t-Butyl-amino-3-ol-2-propyl) oximino-9 fluorene is a new beta2-adrenoceptor blocking agent with a pA2 of 9.23+/-0.25 on isolated trachea. 2 It provokes hypertension in normotensive rats and does not prevent arterial hypertension in SHR rats, although it does prevent the renin secretion normally induced by isoprenaline infusion.

Facilitation of learning consecutive to electrical stimulation of the locus coeruleus: cognitive alteration or stress-reduction?

This chapter summarizes behavioral and neurochemical data on the delayed effect of locus coeruleus stimulation on learning capabilities in the rat. The initial observation showed that electrical stimulation of the locus coeruleus of a 15-day-old-rat improved the early stages of acquisition and extinction of a food-reinforced task performed 4 weeks later. Neurochemical lesion of the dorsal noradrenergic bundle performed 10 days before the stimulation did not attenuate the behavioral effect, whereas the lesion of the locus coeruleus proper suppressed the subsequent behavioral improvement. More recently we showed that the increase of adrenocorticotrophin release consecutive to a moderate stressful situation was significantly lower in previously stimulated rats than in implanted non-stimulated animals. Furthermore, we demonstrated that the neurochemical lesion of the locus coeruleus increased neophobia in the open-field as well as in a specific exploration task. Taken together these data strongly suggest that the long-term improvement in acquisition and extinction of locus coeruleus-stimulated rats results mainly from an attenuated stress reaction when these animals are confronted with a new environment (beginning of acquisition) or a new situation (beginning of extinction). Finally, we were interested in investigating the possibility of some long-term neurochemical modifications that could be related to the observed behavioral effects. The most significant modification observed concerned certain subpopulations of adrenoceptors in specific brain regions. By using specific ligands of the beta-, alpha 1- and alpha 2-adrenoceptors, we studied the long-term effect (4 weeks) of the locus coeruleus stimulation on the kinetic characteristics of these three sub-types of receptors in four brain areas (the cortex, hippocampus, hypothalamus and brainstem). No significant alteration in the density of beta binding sites was observed in any of the four structures analyzed; likewise locus coeruleus stimulation did not modify the density or affinity of the beta-, alpha 1- and alpha 2-receptors in the brainstem. The density of alpha 1- and alpha 2-receptors was significantly increased in the cortex whereas in the hippocampus only the density of the alpha 2-receptors was increased. Finally, a very large increase of the density of alpha 2-adrenoceptors was observed in the hypothalamus (113%). In each case the increase in receptor density was also associated with a decreased affinity. A behavioral counterpart of these changes in the kinetic properties of the alpha 2-receptors has been observed by using a pharmacological approach.(ABSTRACT TRUNCATED AT 400 WORDS)

Intermediate-term results after en bloc double-lung transplantation with bronchial arterial revascularization. Bordeaux Lung and Heart-Lung Transplant Group.

OBJECTIVE: Between May 1990 and January 1994, 18 patients underwent en bloc double-lung transplantation with tracheal anastomosis and bronchial arterial revascularization. Because at that time it was already suggested that chronic ischemia could be a contributing factor in occurrence of obliterative bronchiolitis, the purpose of this study was to evaluate, with a follow-up ranging from 22 to 69 months, the midterm effects of bronchial arterial revascularization on development of obliterative bronchiolitis. RESULTS: Results were assessed according to tracheal healing, functional results, rejection, infection, and incidence of obliterative bronchiolitis. There were no intraoperative deaths or reexplorations for bleeding related to bronchial arterial revascularization, but there were three hospital deaths and five late deaths, two of them related to obliterative bronchiolitis. According to the criteria previously defined, tracheal healing was assessed as grade I, IIa, or IIb in 17 patients and grade IIIa in only one patient. Early angiography (postoperative days 20 to 40) demonstrated a patent graft in 11 of the 14 patients in whom follow-up information was obtained. Ten patients are currently alive with a 43-month mean follow-up. Among the 15 patients surviving more than 1 year, functional results have been excellent except in five in whom obliterative bronchiolitis has developed and who had an early or late graft thrombosis. Furthermore, those patients had a significantly higher incidence of late acute rejection (p < 0.02), cytomegalovirus disease (p < 0.006), and bronchitis episodes (p < 0.0008) than patients free from obliterative bronchiolitis. CONCLUSION: We conclude that besides its immediate beneficial effect on tracheal healing, long-lasting revascularization was, at least in this small series, associated with an absence of obliterative bronchiolitis, thus suggesting but not yet proving the possible role of chronic ischemia in this multifactorial disease.

Tuberculosis in transplanted lungs.

Over a 4-year period in four of 61 patients (6.5%) who survived lung transplantation, pulmonary tuberculosis developed at a mean of 7.5 months (range 3 to 13 months) after operation. Clinical and radiologic features were atypical. Definitive bacteriologic diagnosis, which was established on bronchial, sputum, and pleural fluid samples, may be delayed by the concomitant presence of other infective organisms and the necessity for repeated sampling. All patients were treated successfully with antituberculous chemotherapy, but one patient also required lobectomy. At a mean follow-up of 2.25 years (range, 1 to 3 years), three patients are free of active disease, and one patient had a recurrence at 2 years. Tuberculosis in transplanted lungs is an uncommon but serious infection that may elude diagnosis but respond well to treatment.

L-dopa and streptozotocin-induced diabetic nephropathy in rats.

The purpose of the present study was to determine whether the physiological dopamine prodrug, L-dopa, could suppress streptozotocin-induced diabetic glomerular hyperfiltration, and thus prevent further evolution of the diabetic nephropathy. Male Wistar rats treated with streptozotocin (60 mg/kg, intravenously) rapidly developed hyperglycemia which was stabilized (congruent to 4 g/L) by a daily insulin injection. Within two weeks, a significant increase in glomerular filtration rate (GFR) and a rise in the filtration fraction were observed as described in the early stage of diabetic nephropathy. Increase in both GFR and in the filtration fraction were normalized by treating the rats with L-dopa (10 mg/kg, subcutaneously, twice a day for one week). The effects of L-dopa were linked to endorenal DA synthesis and to DA-1 receptor stimulation since both carbidopa and SCH 23390 suppressed them.