Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration.

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.

Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions.

Smoking prevention will decrease lung cancer incidence in time. However, early detection would improve lung cancer prognosis in subjects at risk provided that specific markers could be identified. We previously reported that retinoic acid receptor (RAR) and retinoid X receptor (RXR) expression was altered in lung tumors. RAR-beta gene status could be derived from corresponding allelotyping and immunohistochemistry data. We now report the continued study on lung cancer precursor lesions. Fluorescence PCR-based assays were used for allelotyping at the RAR/RXR loci of: (a) 66 lung precursor lesions found at the free resection margins of 41 patients undergoing surgery for lung cancer (+ 31 paired tumors); and (b) bronchial cells also found at the free resection margins from 16 current and 8 never smokers operated on for noncancerous diseases. Three microsatellites located at 3p14-21 and 9p21 were also used for interwork comparison. Immunohistochemistry was additionally performed to evaluate P53 and RAR-beta expression in precursor lesions. Chi2 tests showed significant differences (P < 0.05) when comparing the results obtained from never smokers, smokers, squamous metaplasia, dysplasia + in situ carcinoma, and tumors. Microsatellite changes occurred frequently in all samples, but without specificity for any group (P < 0.08-0.52). They were globally correlated with tobacco exposure (P < 0.04), for which the RAR-gamma marker appeared as a preferential target (P < 0.004). Few reparation error phenotypes were observed, mostly at the RXR-alpha and RXR-gamma markers for which combined changes were also linearly increasing from never smokers to dysplasia + in situ carcinoma (P < 0.05 and P < 0.03). RAR-beta marker losses also increased from the first to the last group studied (P < 0.01), with a concomitant decrease in RAR-beta protein expression and correlated p53 increased immunoreactivity (P < 0.02). Losses at 3p14, 3p21, and P16 were frequent, but no significant differences between groups could be found. Unexpectedly, high constitutive homozygosity was observed near the RAR-alpha locus in squamous cell lung cancer cases. RARs/RXRs form homodimers or heterodimers involved in ligand binding. Their added alterations could result in a state of functional vitamin A deficiency in the affected bronchial cells. Further deletion events drawn from a limited repertoire of specific regions such as 3p14-21 and 9p21 could subsequently drive the deficient cells to invasive carcinoma.

Synchronous roentgenographically occult lung carcinoma in patients with resectable primary lung cancer.

OBJECTIVE: To assess the prevalence of synchronous roentgenographically occult lung carcinoma (ROLC) in patients with resectable roentgenographically visible lung cancer (RVLC). METHODS: Patients undergoing surgery for RVLC in the same University Hospital were prospectively evaluated before surgery by fluorescence bronchoscopy under local anesthesia to detect synchronous ROLC. All abnormal areas, with the exception of the RVLC, had biopsies made. RESULTS: From June 1996 to January 1999, 43 patients (male/female ratio: 1.7/1.0) were evaluated before lobectomy (n = 34) or pneumonectomy (n = 10) for 44 primary RVLC. There were 10 T1N0, 19 T2N0, 1 T1N1, 9 T2N1, 1 T3N0, 3 T1N2, and 1 T3N1 lesions. The histologic type was mainly squamous carcinoma (n = 21) and adenocarcinoma (n = 14). All but two patients were smokers or ex-smokers (mean +/- SD, 48 +/- 28 pack-years). A total of 177 endobronchial biopsies were performed (4.1 +/- 2.5); 8 were too small to be informative, 43 showed non-preneoplastic alterations, and 50 were normal. There were 7 basal cell hyperplasias, 56 metaplasias, 9 dysplasias, and 4 carcinomas in situ (CIS). All the dysplasias and CIS lesions were observed in eight subjects. The synchronous CIS were treated by surgery (n = 1) or localized therapeutic modalities (n = 3). CONCLUSIONS: The high prevalence of synchronous early lung cancers (9.3%) as well as metaplasia and dysplasia in this series of patients with resectable RVLC suggests that fluorescence bronchoscopy may be a useful adjunct in the preoperative evaluation of lung cancer.

Detection of bronchial preneoplastic lesions and early lung cancer with fluorescence bronchoscopy: a study about its ambulatory feasibility under local anaesthesis.

BACKGROUND: Autofluorescence bronchoscopy (AB) enhances the bronchoscopist's ability to diagnose bronchial preneoplastic lesions and early cancer. We undertook a study to assess its feasibility and performance under local anaesthesia on a real ambulatory mode. METHODS: Thirty-four consecutive patients at very high risk for lung cancer were prospectively studied by AB under local anaesthesia, without any sedation. Lidocaine doses, time, oxygen saturation, peak expiratory flow (PEF) and the number of cough episodes were measured. Continuous assessment of the respiratory sensation was obtained with a visual analog scale. A total of 172 biopsies were performed in abnormal and normal areas. RESULTS: The procedure was long-lasting (mean +/- SD: 26.6 +/- 6.0 min), required high total doses of Lidocaine (660 +/- 107 mg) without any significant side effect, and was associated with significant decreases in O2 saturation from 98.5 +/- 1.4 to 96.1 +/- 2.5% and in PEF from 380 +/- 96 to 310 +/- 78 l/min. However, the cough counts were moderate and the majority of patients reported no respiratory discomfort. 62 hyperplasia, metaplasia, dysplasia and carcinoma in situ (CIS) were detected and the relative sensitivity of AB +/- white-light bronchoscopy (WLB) versus WLB alone was 3.75 for intraepithelial lesions corresponding to moderate dysplasia or worse. CONCLUSIONS: AB, a procedure that increases our ability to recognize preneoplastic lesions and early lung cancer, can be performed under local anaesthesia, without systemic sedation in patients at very high risk for lung cancer.

Maintenance chemotherapy for small cell lung cancer: a critical review of the literature.

Maintenance chemotherapy after induction therapy is a controversial topic in small cell lung cancer. We carried out a critical review of the literature on this topic. Since 1980, 13 randomized trials have been published. One shows a statistically significant difference in survival in favor of maintenance, five obtain some survival advantages in subgroups of patients, one shows a significantly shorter survival with maintenance and in six studies, there is no difference between both arms. A quantitative overview or meta-analysis was unpracticable because of the lack of data for calculation of the odds ratio in the publications and because of the heterogeneity of the studies' designs. A qualitative overview was carried out using two scales: the Chalmers scores and the European Lung Cancer Working Party (ELCWP) score. Correlation between both scores was excellent. There was no significant difference in quality scores with both methods between negative trials and those who showed some survival advantage for survival. The overall quality of the publications was not good, with important methodological aspects missing, such as a clear definition of the primary objective or an a priori estimate of the sample size necessary to conduct the trial. We concluded that maintenance chemotherapy could have some indications and that good quality trials, as reflected by very high quality scores, need to be carried out in the future.

A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis.

PURPOSE: Cisplatin (CDDP) and etoposide (VP16) are considered major standard cytotoxic drugs for small cell lung cancer (SCLC). The present systematic review had as its objective the evaluation of their role, as components of chemotherapy regimens, on survival. METHODS: Published randomised clinical trials (from 1980 to 1998) were selected comparing, in SCLC patients, chemotherapy regimens, given as first-line therapy. One arm (the experimental arm) had to include CDDP and/or VP16, while another had to omit the same drug(s). Trials quality was assessed by two published scores (Chalmers and European Lung Cancer Working Party (ELCWP)). For each individual trial, the hazard ratio (HR) of the survival distributions was estimated on the basis of reported statistics or, if not available, by extracting, from the survival graphical representations, the data required to construct the difference between expected and observed numbers of events as calculated in the log-rank statistic. A combined hazard ratio was obtained by the Peto method (a value < 1 meaning a benefit for CDDP and/or VP16). RESULTS: Thirty-six trials eligible for our systematic review were identified, classified into four groups (I-IV): group I, 1 trial testing a CDDP-based regimen (without VP16) against another arm not including either CDDP or VP16; group II, 17 trials testing a VP16-based regimen (without CDDP) against a regimen without VP16 and CDDP; group III, nine trials comparing a regimen including CDDP and VP16 with a regimen using neither drug; and, finally, group IV, nine trials comparing a regimen based on both drugs with a regimen based on VP16 only. Overall, Chalmers and ELCWP scores correlated well (r(S) = 0.76, P < 0. 001) and had respective median scores of 50.3 and 63.7%. The number of eligible patients did not have a significant impact on the scores as well as the trials group, the trial positivity (a positive trial defined as showing itself a statistically significant survival benefit for the experimental regimen), overall or in categories, and the year of publication. Combined hazard ratios with 95% confidence intervals were: 0.70 (0.41-1.21) for group I, 0.72 (0.67-0.78) for II, 0.57 (0.51-0.64) for III, and 0.74 (0.66-0.83) for IV, showing a survival benefit in favour of regimens including etoposide alone or in combination with cisplatin, justifying with high significance levels the use of each of these drugs. Overall survival benefits could also be shown for regimens including CDDP (HR = 0.61; confidence interval (CI), 0.57-0.66), as well as for those including VP16 (HR = 0. 65; CI, 0.61-0.69). Robustness of these results has to be confirmed with appropriate randomised trials.

Expression of thrombospondin in non-small cell lung cancer.

OBJECTIVE: Initially considered as an inhibitor of angiogenesis, the role of thrombospondin is currently controversial. The primary purpose of our study was to determine the expression of thrombospondin (TSP) in invasive lung tumours. The secondary objectives were to investigate its relationship with other factors related to angiogenesis and to assess their clinicopathological significance. MATERIALS AND METHODS: From January 1993 to September 1998, we collected non-small cell lung cancer (NSCLC) and normal nearby-matched tissues from surgical specimens of 64 patients. Using these specimens, we assessed the expression of TSP by immunohistochemistry with monoclonal antibody to human TSP (clone 11.4). This expression was also correlated with other factors directly or indirectly related to angiogenesis:p53, Ki-67 as proliferation factor and microvessel count determined with anti-CD-31 antibody. RESULTS: The resected tumours (stages I-IIIB) consisted of 30 adenocarcinomas, 24 squamous cell carcinomas, 5 bronchioalveolar carcinomas, 4 adenosquamous carcinomas and 1undifferentiated NSCLC. The mean values of TSP expression in neoplastic and normal related tissues were 63.08% and 86.57 %, respectively. This difference was statistically significant (p = 0.02). There was a higher level of variability of TSP expression between tumours than between normal tissues. The expression of TSP in NSCLC was statistically correlated to the expression of TSP in normal matched tissues (coefficient correLation rate = 0.31, p<0.01). The median expression of p53, Ki-67 and microvessel count in tumours was 45.00%, 38.80% and 8.33%, respectively. The correlations between TSP and the other biological variables and between these latter variables themselves were not statistically significant. No statistically significant difference was observed in survival according to TSP expression. CONCLUSION: TSP appeared to be decreased in NSCLC in comparison with normal matched tissue. The TSP expression was not correlated with the other studied variables and was not associated with a significant difference in survival.

Phase II and III studies with new drugs for non-small cell lung cancer: a systematic review of the literature with a methodology quality assessment.

We carried out a systematic review of new drugs active in non-small cell lung carcinoma (NSCLC). Fifty five phase II and III trials were reviewed (vinorelbine (19 trials), paclitaxel (15), gemcitabine (11), docetaxel (6), topotecan (2) or irinotecan (2)). The first four ones could be considered as active drugs when given as single agent. More information is required for the camptothecin derivatives. Four phase III randomised studies were available, all concerning vinorelbine. They showed that in combination with cisplatin, vinorelbine improved the response rate and perhaps survival, in comparison to vinorelbine alone and that vinorelbine was better than 5 fluorouracil and vindesine. A quantitative overview was impracticable, because of too few randomised trials. A qualitative overview was carried out using the European Lung Cancer Working Party score. The overall median quality score was 65.3%. There was no statistically significant difference between the drugs, but there was a positive correlation between the score and the number of patients. There was also an improvement of the quality score in favour of the randomised trials. Some important methodological aspects were often missing in the articles. In conclusion, gemcitabine, vinorelbine, paclitaxel and docetaxel are active against NSCLC but more good-quality data are required to define their exact role in the routine.

[Critical review of the randomized trials assessing the role of adjuvant thoracic irradiation and chemotherapy in the treatment of limited-stage small cell lung cancer]. / Revue critique des études randomisées évaluant le rôle de la radiothérapie thoracique adjuvante à la chimiothérapie dans le traitement du cancer bronchique à petites cellules au stade limité.

The role of chest irradiation in the treatment of small cell lung cancer remains controversial. Two meta-analyses have shown a significant improvement of survival when this therapy is associated to chemotherapy but the controlled studies individually lead to contradictory conclusions. We have performed qualitative and quantitative evaluation of the literature on this topic in order to try to clarify this problem. On 15 published trials, 8 only give sufficient data allowing a meta-analysis. This does not show that chest irradiation improves statistically significantly survival in comparison to chemotherapy alone (odds ratio = 0.82; 95% CI: 0.63-1.07). The qualitative evaluation has been performed with the Chalmers and ELCWP scales. The scores obtained by both methods are highly correlated. There is no significant difference between the scores obtained by studies showing a survival improvement with irradiation or by negative studies. Very few trials report important criteria like definition of the primary end-point or the a priori estimate of the population size, attesting important methodological deficiencies. In conclusion, the quantitative aggregation of studies seems difficult to interpret because of the non optimal quality of the studies.

[Maintenance chemotherapy in the treatment of small cell lung cancer: the advocate's view]. / La chimiothérapie d'entretien dans le traitement du cancer bronchique à petites cellules: le point de vue partisan.

The role of maintenance chemotherapy in the treatment of small cell lung cancer remains controversial. We have collected the arguments in favor of that approach by performing a quantitative and qualitative overview of the studies published on this topic in the French and English literatures since 1980. On the thirteen prospective randomized trials reported, six demonstrated a significant survival advantage in favor of maintenance, no difference was observed in 6 and 1 study had a significant survival advantage for no maintenance. Due to the heterogeneity of the study designs and to the lack of published data, no meta-analysis could be performed. A qualitative overview of the different trials showed that the quality scores of the positive trials was similar to the negative ones, allowing us to conclude that they could be considered at the same level. No negative trial with a similar design can be opposed to each particular positive trial that is thus not conterbalanced. Moreover the trials not in favor of maintenance could be falsely negative by a lack of power, the publications mentioning no statistical consideration. There are thus a series of arguments in favor of maintenance chemotherapy for small-cell lung cancer, which require to be confirmed by randomised trials of adequate quality.

[Current topics in pulmonary oncology]. / Actualités en cancérologie pulmonaire.

Thoracic oncology practice is changing with the end of the century. New diagnostic tools like photodetection allow to diagnose at a white light undetectable level. Preneoplastic lesions or very early cancers that can be locally treated by photochemotherapy, cryotherapy or brachytherapy. The natural history of lung cancer will also be better known. Concerning advanced disease, cisplatin chemotherapy improves survival of patients with stage III non-small cell lung cancer in combination with surgery or chest irradiation and of those with stage IV in comparison with best supportive care alone. New approaches in small cell lung cancer seem promising like accelerated chemotherapy, early chest radiotherapy and maintenance treatment. Moreover, a series of new active cytotoxic agents has been recently identified. The complexity of these modalities makes more and more necessary a integrated pluridisciplinary approach of the lung cancer patient.

[Diagnosis and treatment of early-stage bronchial cancer: current status]. / Diagnostic et traitement du cancer bronchique au stade précoce: état de la question.

Lung cancer is the cancer with the largest mortality in Belgium. Nowadays, the most potent risk factor for lung cancer, tobacco smoking, is increasing, principally in teenagers. It is therefore necessary to intervene more efficiently in the natural history of the disease. This aim can be achieve by the early detection and the local treatment of small size lung cancer and in situ carcinoma. Interestingly, pulmonary preneoplastic lung lesions have been identified and characterized in the central airways as well as in the peripheral lung parenchyma. These preneoplastic lesions can evolve to invasive cancer or regress after tobacco smoking cessation or chemoprevention treatment. A new autofluorescence based endoscopy technique is described, that allows to detect preneoplastic pulmonary lesions and radio-occult lung cancer. These small sized lesions can be cured with endoscopic local treatment such as photodynamic therapy.

Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinoma.

The MaTu interval (MN)/carbonic anhydrase (CA) IX tumour-associated antigen is a protein that is normally expressed in the gut and belongs to the carbonic anhydrase enzyme family (CA IX). It has been detected in tumour cell lines and in some solid tumours including cervical, oesophageal and clear cell renal carcinoma. This study determined MN/CA IX expression in 65 primary non-small cell lung cancer resected with curative intent and in 38 bronchial preneoplastic lesions, carcinoma in situ or microinvasive carcinoma as well as in normal bronchial tissue. The presence of MN/CA IX was detected using immunohistochemistry and Western blot analysis, whenever frozen material was available. Immunostaining was positive in 52/65 (80%) of the tumour samples. The staining was more often focal than diffuse. The percentage of stained cells in positive tumours was highly variable, ranging 1-85%. The pattern of immunostaining was predominantly cytoplasmic with a membranous reinforcement (87%). The intensity was mainly strong (69%). The presence of the protein in the tumour was confirmed by Western blot analysis in the eight samples tested. All the morphologically normal epithelia, except in close vicinity of tumours in some cases, as well as the preneoplastic bronchial lesions (basal cell hyperplasia, metaplasia and dysplasia) were immunonegative for MN/CA IX expression. In contrast, carcinoma in situ and microinvasive epithelioma showed the presence of MN-immunopositive tumoural cells in 5/7 and 4/5 of the samples, respectively. These data suggest that MN/CA IX is a useful marker for the differentiation between preneoplastic lesions and bronchial non-small cell lung cancer in the lung.

Disseminated angiosarcoma presenting as a hemophagocytic syndrome in a renal allograft recipient.

A case of angiosarcoma arising in the setting of transplantation is reported. This rare and malignant tumor of the endothelial system is seldom observed in allograft recipients, with only seven cases having been previously reported. What is interesting about the present observation is that the tumor is thought to have developed in the vicinity of a Dacron graft and that it showed prominent erythrophagocyte-like activity. This activity was associated with a particular clinical syndrome that shared some attributes with infection-associated hemophagocytic syndrome.