Expression of retinoid receptor genes and proteins in non-small-cell lung cancer.

BACKGROUND: Retinoids can suppress carcinogenesis in high-risk non-neoplastic bronchial lesions and can reduce the risk of second primary non-small-cell lung cancer (NSCLC). The effects of retinoids are mediated by nuclear receptors, i.e., the retinoic acid receptors (RARalpha, RARbeta, and RARgamma) and the retinoid X receptors (RXRalpha, RXRbeta, and RXRgamma). We investigated whether abnormalities in the in vivo expression of retinoid receptors are observed in NSCLC. METHODS: Expression of retinoid receptors in paired specimens of normal and cancerous tissues from the lungs of 76 patients with NSCLC was studied by use of antiretinoid receptor antibodies (except those against RXRgamma) and immunohistochemistry. RAR messenger RNAs were analyzed by use of in situ hybridization and by reverse transcription-polymerase chain reaction (RT-PCR). Samples were also studied for loss of heterozygosity (LOH) at chromosome 3p24. All P values are two-sided. RESULTS: All studied receptors were expressed in normal lung cells and in high- risk non-neoplastic lesions. In tumor cells, overexpression of RXRalpha and RARalpha was frequently observed. In contrast, RXRbeta expression decreased in 18% of the tumor specimens. Furthermore, there was a marked decrease in the expression of RARbeta in 63% of the tumors (P<.0001). Decreased expression of RARgamma was observed by RT-PCR in 41% of the tumors (P<.0001). LOH at 3p24 was observed in 41% of the tumor specimens from informative patients and in 20% of the non-neoplastic lesions. CONCLUSIONS: Expression of RARalpha and RXRalpha is either normal or elevated in NSCLC. In contrast, a large percentage of tumors show a marked decrease in the expression of RARbeta, RARgamma, and RXRbeta as well as a high frequency of LOH at 3p24, which was also observed in non-neoplastic lesions. These data suggest that altered retinoid receptor expression may play a role in lung carcinogenesis.

The role of platelet-derived growth factor production by tumor-associated macrophages in tumor stroma formation in lung cancer.

Lung cancer is the most common cause of death by cancer in developed countries. Since a tumor cannot develop without the parallel expansion of a tumor stroma, a better understanding of its formation could lead to new therapeutical approaches. In this respect, since platelet-derived growth-factor (PDGF) is a chemotactic and growth factor for mesenchymal and endothelial cells, lung tumors of patients undergoing surgery for non-small cell lung cancer were evaluated for their replication rate using iododeoxyuridine incorporation, and for the expression of PDGF genes and the presence of PDGF A and B chains and of PDGF receptor alpha and beta subunits. This observation demonstrates that: (a) tumor cells and stroma mesenchymal cells, but not tumor-associated macrophages, display a high replication rate; (b) 1 of 3 tumors are characterized by cancer cells expressing the genes for PDGF A and/or B chains, while 1 of 2 tumors are composed of tumor cells presenting PDGF receptors alpha and beta subunits on their surface, and in only 1 of 6 tumors, tumor cells coexpress PDGF and its receptor; (c) in almost all tumors, tumor-associated macrophages express PDGF A and/or B chain genes; (d) mesenchymal cells, as well as endothelial cells, do not express PDGF A and B chain genes but do express PDGF receptor alpha and beta subunits; and (e) an ongoing active process was suggested in the periphery of the tumor by the simultaneous strong expression of PDGF A and B chain genes by tumor-associated macrophages and the high replication rate of mesenchymal and endothelial cells in the same area. Thus, PDGF is likely to have a limited autocrine role in tumor cell replication but is a potential player, in a paracrine fashion, in tumor stroma development.

Predictive survival markers in patients with surgically resected non-small cell lung carcinoma.

Among patients with resected non-small cell lung carcinoma, about 50% will present a tumor recurrence. Thus, it would be of major importance to be able to predict and try to prevent these relapses by an active chemotherapy and/or radiotherapy. In an attempt to answer this question, the tumors of 227 patients with a surgically resected non-small cell lung carcinoma were evaluated as follows: tumors were classified as squamous cell carcinoma (n = 132) or adenocarcinoma (n = 95), and tumor differentiation was evaluated for each type. Then, all tumors were classified in respect to their pathological TNM staging (WHO) and screened by immunohistochemistry for the detection of the expression of the following antigens: Bcl-2, A+B+H blood group antigens, c-erb-b2, p53, and Pan-Ras antigens. Furthermore, adenocarcinomas were screened for the presence of point mutations in Ki-Ras codons 1-31. Finally, the patient blood group was defined, and patient survival was analyzed using nonparametric tests and proportional hazard Cox models. Using Kaplan-Meier survival curves, disease pathological TNM staging was shown to be a strong predictive factor of survival for both squamous cell carcinoma and adenocarcinoma. Patients with squamous cell carcinoma experienced fewer relapses than those with adenocarcinoma (42% versus 63%; P = 0.0002) and had a significantly better survival. All evaluated antigens were more often present in squamous cell carcinoma than in adenocarcinoma except for Pan-Ras (three times more frequent in adenocarcinoma). In patients with squamous cell carcinoma, only tumor staging had a significant prognosis value (P = 0.01). In patients with lung adenocarcinoma, a well-differentiated tumor (P = 0.009) as well as a positive Bcl-2 staining (P = 0.009) and an A+B+H antigen tumor staining (P = 0.024) were associated with a better survival. In contrast, patients with a stage I or II disease and a p53-positive tumor staining and patients with the O blood group (P = 0.01) had a shorter survival. Interestingly, no relation with patient survival was related to c-erb-b2 and Pan-Ras staining. Finally, 12 point mutations were found out of 81 tumors (15%) evaluated for Ki-Ras codons 1-31; they involved codon 12 but also 8, 14, and 15 without any relationship to survival. In respect to lung adenocarcinoma, using Cox proportional hazard models stratified on tumor staging, the following markers were shown to be related to survival: (a) Independent markers of longer survival (ie., high histological degree of tumor differentiation and positive Bcl-2 and A+B+H blood group antigen expression by tumor cells); and (b) Independent markers of shorter survival (i.e., O blood group for all patients and p53 tumor staining in patients with stage I and II diseases). This study suggests that, in patients who undergo surgery for lung adenocarcinoma, the presence or absence of these criteria could be used to define a subset of patients who may benefit from a more specific follow-up.

[Resection of lung neoplasm in patients aged 70 years and over. Apropos of a series of 193 resections]. / L'exérèse du néoplasme bronchique chez les sujets de 70 ans et plus. A propos d'une série de 193 exérèses.

Lung cancer in the elderly is an active cancer. Due to the poor tolerance of radiotherapy and chemotherapy, and the ever increasing life expectancy of patients over the age of 70 years, surgery remains the treatment of choice for these lesions. We report a series of 193 patients over the age of 70 years, the high postoperative mortality of 19% during the first month was counterbalanced by a 5-year survival of more than 20%. The criteria of operability must be rigorous and based on objective elements, especially lung function and the patient's good psychological state.

[Pulmonary metastasis of a dermatofibrosarcoma]. / Métastase pulmonaire d'un dermatofibrosarcome.

Progressive and recurrent dermatofibrosarcoma, described by Darier and Ferrand in 1924, is a fibrous skin tumour with essentially local malignancy. The authors report a case with pulmonary metastasis, a rare event as only 13 cases of visceral metastases have been reported in the literature. The clinical course of this case was favourable (follow-up of 5 years), in contrast with the usually pejorative nature of metastatic disease (death after several months to one year following the discovery of the first metastasis).

[Value of limited resections in the surgical treatment of lung cancers]. / Valeur des exérèses limitées dans le traitement chirurgical des cancers bronchiques.

From 1969 to 1990, 88 limited lung resections were performed for the treatment of malignant lung tumours. These operations consisted of 73 typical resections (29 segmentectomies, 15 bisegmentectomies, 23 middle lobectomies, 6 lingulectomies) and 15 atypical resections. In 15 cases, they were completed by lymph node dissection. These operations were performed in patients with a mean age of 55.8 years (range: 24 to 76). The ventilatory functional status contraindicated wider resection in only 7 cases. The immediate postoperative mortality (7 cases, i.e. 8%) and the postoperative complications observed in 29.6% of cases were higher than those observed after wide resections, but do not constitute a specific argument in the indication for partial resection. Histological examination of the operative specimens revealed 80 primary lung cancers (42 squamous carcinomas, 28 adenocarcinomas, 8 anaplastic and unclassifiable tumours, 1 bronchiolo-alveolar tumour and 1 malignant carcinoid tumour). The primary nature of the tumour could not be definitely confirmed in the other 8 patients (history of head and neck neoplasm in 7 cases and bladder carcinoma in 1 case). The survival according to TNM stage, histological nature of the tumour, positivity of the resection margins and intraoperative tumour effraction was identical to that associated with lobectomies.

[False empyema after artificial pneumothorax. An original entity: type B non Hodgkin malignant lymphoma]. / Faux empyème de nécessité après collapsothérapie. Une entité originale: le lymphome malin non hodgkinien de type B.

Malignant lymphoma developing in the lung after therapeutic pneumothorax is a rare condition in Europe. The authors report one case admitted after a 40-year history of pyothorax resulting from artificial pneumothorax for treatment of pulmonary tuberculosis. The diagnosis at admission was an infection of the chronic pyothorax associated with a lung mass. Histology confirmed the presence of non-hodgkin lymphoma B in the lung mass associated with Epstein-Barr virus. After surgery, chimiotherapy was not effective. Diagnosis before surgery could optimize the medical management. The long-term outcome is pejorative in most cases.

[Treatment of deep wounds with loss of tissue. Value of a 3 percent boric acid solution]. / Traitement des plaies profondes avec perte de substance. Intérêt d'une solution d'acide borique à 3 p. 100.

Following the finding of dramatic improvement in a deep wound with loss of substance treated with a 3 percent boric acid solution, 31 patients hospitalized in a surgical intensive care unit and holding such a wound initially unimproved by classical treatments were subjected, in 1987-88, to a short-time use of this solution. A case-control study retrospectively performed with 12 of the patients demonstrated that after wound granulation was obtained they returned to a normal care unit about three times more rapidly than patients receiving conventional antiseptics (means: 20 and 55 days respectively). This reduction in intensive care duration of stay for these 12 patients saved approximately 2 millions francs. Thus, the 3 percent boric acid solution may be considered an efficient alternative in the treatment of deep wounds with loss of substance, but it is delicate to handle because of toxicity.

[Analgesia after thoracotomy by extrapleural administration of continuous bupivacaine]. / Analgésie après thoracotomie par administration extrapleurale de bupivacaïne à débit continu.

This study was aimed to assess the efficiency and the side effects of a continuous administration of bupivacaine into the paravertebral space. Twenty patients, ranked ASA 2 or 3, with a mean age of 57.9 years, and having had a posterolateral thoracotomy for resection of lung tissue, were randomly assigned to one of two groups, B or C. At the end of the surgical procedure, a 22 gauge catheter was inserted into the paravertebral extrapleural space, at T4 levels As soon as pain occurred during recovery (T0), the patients were given two-hourly intravenous boluses of buprenorphine. The patients in group B were also given, through the paravertebral catheter, a 20 ml bolus of 0.25% bupivacaine, followed by a continuous steady rate infusion (10 ml.h-1). Group C patients were given normal saline in the same way. All patients could improve their analgesia with 0.05 ml boluses of buprenorphine given by an auto-analgesia pump (Pharmacia). The following parameters were assessed during the 72 h which followed the first injection: pain with a visual analogic scale, quality of sedation (5 grades), heart and breathing rate, systolic and diastolic blood pressure, arterial blood gases. In group B, plasma bupivacaine concentrations were measured throughout the infusion, and for an 8-hour period after its end. The statistical analysis included 15 patients only, as the catheter had moved into the chest cavity in the other 5. Analgesia was qualified to be adequate by all patients, but there was no statistically significant difference in the amounts of self-administered buprenorphine between groups B and C.(ABSTRACT TRUNCATED AT 250 WORDS)

[Antibioprophylaxis in pulmonary surgery: a randomized trial with cefamandole versus placebo]. / Antibioprophylaxie en chirurgie pulmonaire: étude randomisée céfamandole versus placebo.

A prospective double-blind study was designed to assess the efficacy of antibiotic prophylaxis in lung surgery. It included 114 patients undergoing lung surgery for primary or secondary malignant tumours randomly assigned to two groups. Group A patients (n = 59) were given cefamandole intravenously every four hours, three times, starting from induction of anaesthesia. The dose was determined according to the patient's weight: 1.5 g for patients weighing less than 60 kg, 2.5 g for those weighing between 60 and 80 kg, and 3 g for those above 80 kg. Group B patients (n = 55) were given a placebo at the same times. Nineteen other patients were excluded because either the tumour was found to be infected, or the patient had to be mechanically ventilated postoperatively, or an exploratory thoracotomy only was carried out, or they were allergic to beta-lactam antibiotics. The efficacy of antibiotic prophylaxis was assessed by recording the incidence of postoperative infections, the length of the patient's stay in hospital, and the need to use an antibiotic treatment. Patients, their sputum and wound were examined every day, and their temperature recorded. The white blood cell count and chest X-ray was carried out every day for the first week. All the drain and catheter tips were cultured, as well as sputum and blood (every three days). In case of infection, samples were obtained and cultured. Both groups of patients were similar with regard to age, risk factors (smoking habit, diabetes mellitus), and type of surgery (segmentectomy, lobectomy, pneumonectomy). There were 9 postoperative infections in group A, and 22 in group B (p = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

[Surgical treatment of flail chest by sliding staples]. / Traitement chirurgical de l'instabilité pariétale thoracique, par l'attelle-agrafe à glissières (AAG).

The authors have compared the results obtained in two series of patients with flail chests treated by internal fixation. In the first series of 36 patients, Judet rib staples were used. The average time of artificial ventilation was 5.8 days. In the second series of 43 patients, gliding staples were used. The average time of artificial ventilation was only 2.6 days, a significant reduction. Thanks to this new technique, the indications for artificial ventilation in the treatment of flail chests have been reduced from 47 per cent to 33 per cent. The technique of fixation has also been used in seven cases of operative treatment of funnel chests. In five other cases it has been used to reinforce plastic mesh inserted after extensive resection for malignant tumour.

[Clinical and bacteriologic course of wounds as a function of various protocols of local antisepsis]. / Evolution clinique et bactériologique des plaies en fonction de différents protocoles d'antisepsie locale.

Antiseptics are drugs, and they must be prescribed by physicians. A correct use allows a favourable evolution of the wounds, and could avoid some amputations. The authors have realized a randomized study, to compare the reliability of a sequence using Eosine and an antiseptic (Chlorhexidine or polyvinylpyrolidone (PVP) iodine) to a more usual sequence using chlorhexidine of PVP iodine alone according with the initial pH of the wound. After fifteen days, if no clinical and bacteriological improvement occurred, the Dakin solution was used. The clinical and bacteriological survey has showed that the sequence with Eosine produced significantly more failures and that there was no significant difference between Chlorhexidine and PVP iodine. The use of the Dakin solution 15 days after inefficacy of the antisepsis previously used allowed a cicatrisation of the wound in about six days. There was no demonstrable resistance of microorganisms to the previously used antiseptics.

[Surgical pulmonary biopsy in diffuse interstitial pneumopathies]. / La biopsie pulmonaire chirurgicale dans les pneumopathies interstitielles diffuses.

On the basis of 81 cases of surgical lung biopsy performed in the course of diffuse interstitial lung disease, the authors report the yield and the tolerance which they observed with this technique in comparison with data from the literature. Like other authors, they obtained an excellent histological yield, as only one case was uninterpretable in this present series. However, they emphasise the "final yield", which consists of a precise aetiological diagnosis, i.e. the exclusion of the diagnosis of diffuse interstitial fibrosis. The analysis of the tolerance of the procedure revealed a higher morbidity and mortality than those generally reported in the literature.

[Lung transplantation: indications, techniques and results]. / La transplantation pulmonaire: indications, techniques et résultats.

Lung transplantation is proposed for young patients with a severe disease that can be expected to be fatal within less than two or three years. The main indications are chronic respiratory failure induced by chronic obstructive lung disease, cystic fibrosis or pulmonary fibrosis, and severe primary or secondary (Eisenmenger syndrome) pulmonary hypertension. The type of transplantation, determined after an exhaustive work-up ruling out all contraindications, is generally a single lung transplantation if there is no bronchial infection or two-lung transplantation or heart-lung transplantation in case of bronchiectasis or pulmonary artery hypertension. Survival at 1, 3 and 5 years is 72, 57 and 43% respectively. Transplantation improves exercise capacity, quality of life and lung function. It normalizes hematosis in case of chronic respiratory failure and pulmonary hemodynamics in case of pulmonary hypertension. The risk of complications, dominated by infections and rejections, requires careful clinical, functional and endoscopic follow-up. Bacterial infections are frequent during the first weeks. The frequency of opportunistic infections can be reduced by anti-infectious prophylaxis strategies. The rejection can occur as an acute episode, frequent during the first 100 days, or is sometimes asymptomatic. Chronic rejection or obliterating bronchiolitis is the main mid-term complication after lung transplantation and is responsible for the low long-term survival rate with recurrent secondary infections due to frequent bronchial colonization with Pseudomonas aeruginosa. Improved prognosis of lung transplantation requires the development of new immunosuppressive agents with lower risk of infection and chronic rejection observed with current treatments.

[Surgery of microcellular bronchial cancer: retrospective multicenter study apropos of 110 cases]. / La chirurgie du cancer bronchique microcellulaire: étude multicentrique rétrospective à propos de 110 cas.

The results of a multicentric retrospective study of 110 cases of small cell bronchial cancer are reported. In 57 of these patients the histological diagnosis was unknown before surgery. Among the remaining 53 patients, 22 were operated upon immediately and 31 after chemo-and/or radiotherapy (12 full responders, 10 partial responders, 5 no change and 4 in relapse). Operative data were as follows: 100 excisions and 10 exploratory thoracotomies; 19 perioperative complications, including 12 deaths; excision considered complete in 78 cases; pericardial involvement in 14 cases; invasion of the hilar lymph nodes in 57 cases, of the mediastinal lymph nodes in 39 cases; positive bronchial section in 16 cases. Overall median survival was 13.8 months for all patients and 18.3 months (perioperative deaths excluded) for patients whose tumour had been excised. At the moment, 46 patients have relapsed with recurrence at the initial site of malignancy alone in 6 cases (13%) and both at this site and at one or several metastatic sites in 10 cases (21.7%). Nineteen patients have survived for more than 2 years. An analysis of the subgroups in this population showed that the longest survivals were obtained in patients who had undergone preoperative chemotherapy.