Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.

A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT-0701 MAPS phase 3 trial.

The Hippo pathway effector YAP is dysregulated in malignant pleural mesothelioma (MPM). YAP's target genes include the secreted growth factor amphiregulin (AREG), which is overexpressed in a wide range of epithelial cancers and plays an elusive role in MPM. We assayed the expression of YAP and AREG in MPM pathology samples and that of AREG additionally in plasma samples of patients from the randomized phase 3 IFCT-0701 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) using immunohistochemistry and ELISA assays, respectively. MPM patients frequently presented high levels of tumor AREG (64.3%), a high cytosolic AREG expression being predictive of a better prognosis with longer median overall and progression-free survival. Surprisingly, tumor AREG cytosolic expression was not correlated with secreted plasma AREG. By investigating the AREG metabolism and function in MPM cell lines H2452, H2052, MSTO-211H and H28, in comparison with the T47D ER+ breast cancer cell line used as a positive control, we confirm that AREG is important for cell invasion, growth without anchorage, proliferation and apoptosis in mesothelioma cells. Yet, most of these MPM cell lines failed to correctly execute AREG posttranslational processing by metalloprotease ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and extracell secretion. The favorable prognostic value of high cytosolic AREG expression in MPM patients could therefore be sustained by default AREG posttranslational processing and release. Thus, the determination of mesothelioma cell AREG content could be further investigated as a prognostic marker for MPM patients and used as a stratification factor in future clinical trials.

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial.

BACKGROUND: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation. METHODS: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines. RESULTS: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines. CONCLUSIONS: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.

C4d detection and histological patterns in the diagnosis of antibody-mediated rejection after lung transplantation: a single-centre study.

AIMS: Antibody-mediated rejection (AMR) is an emerging and challenging issue in transplantation. Endothelial deposition of C4d and microvascular inflammation (MI) are reliable markers of AMR in renal and cardiac transplantation, but remain controversial in the lung. Our aim was to assess C4d immunohistochemistry and histological patterns for the diagnosis of lung AMR. METHODS AND RESULTS: We reviewed 158 transbronchial biopsies (TBBs) (n = 85 clinically indicated, and n = 73 surveillance TBBs) from 48 recipients, blinded to clinical and serological data. C4d was scored as 0, 1+ (<10%), 2+ (10-50%) or 3+ (>50%). TBBs were reassessed for MI and acute lung injury (ALI). Donor-specific antibodies (DSAs), acute clinical graft dysfunction and chronic lung allograft graft dysfunction (CLAD) were recorded. C4d3+, C4d2+, C4d1+ and C4d0 occurred respectively in four (2.5%), six (3.8%), 28 (17.7%) and 120 (75.9%) TBBs. MI and ALI were rare but more frequent in C4d1-3+ TBBs than in the absence of C4d. C4d2+ was frequently observed with concomitant infection. Among the surveillance TBBs, only two (2.7%) showed MI. Neither ALI nor C4d3+ was diagnosed on surveillance TBBs. No significant association was found between histopathological findings and DSAs. All four patients with C4d3+ could retrospectively be diagnosed with AMR and developed CLAD. CONCLUSION: Although rare, diffuse C4d deposition appears to be a strong indication of acute clinical AMR in lung transplant patients, whereas intermediate C4d2+ requires more investigations. In stable patients, histopathology and C4d may lack the sensitivity to diagnose subclinical AMR. This emphasises the need for a multidisciplinary evaluation of each suspected AMR case, and the need for complementary diagnostic tools.

Safe and effective use of nivolumab for treating lung adenocarcinoma associated with sporadic lymphangioleiomyomatosis: a rare case report.

BACKGROUND: Sporadic lymphangioleiomyomatosis (LAM) is a rare form of diffuse parenchymal lung disease. PD-1 blocking antibodies constitute an essential treatment option for advanced non-small-cell lung cancer (NSCLC). The effect of immune checkpoint inhibitors in lymphangioleiomyomatosis patients with non-small cell lung cancer is unknown: concomitant symptomatic interstitial lung disease or the use of immunosuppressors was a key exclusion criterion in the original studies of immune checkpoint inhibitors, especially regarding the risk of interstitial lung disease exacerbation. CASE PRESENTATION: A 48-year-old female, active smoker (36 pack-years), diagnosed with sporadic LAM since 2004 suffered from metastatic adenocarcinoma of the lung. Third-line therapy with nivolumab was started in 2015, with a major partial response. Due to pulmonary function alterations, sirolimus was also reinitiated in 2017 in conjunction with nivolumab, without any undesirable effects and a major partial response continuing up to May 2018. CONCLUSIONS: This case highlights the safe and effective use of nivolumab for managing metastatic lung adenocarcinoma that occurred in a patient with sporadic LAM. In the current case, immunotherapy proved highly successful in managing the NSCLC tumor that occurred upon LAM follow-up, with both a significantly prolonged partial response and acceptable safety profile.

[Autochthonous hydatid cyst of the lung]. / Kyste hydatique pulmonaire autochtone.

Cystic echinococcosis, or hydatidosis, also known as hydatid cyst, is a cosmopolitan parasitosis mainly present in breeding areas. This anthropozoonosis is related to the tissue development of an hydatid of an echinococcus tænia, Echinococcus granulosus, found in the digestive tract of canids, at the adult state. In France, this larval cestosis is essentially an import disease developed by patients from endemic areas such as East and North Africa, South America or Asia. However, autochtonous forms, although rare, still persist. Here we describe the case of a 39-year-old non-smoking patient from Paris, admitted in the emergency department for chest pain associated with sweating and chills. The clinical examination found the notion of a right lower lobar pulmonary nodule discovered 20 years ago, on a chest X-ray, but never explored. Thoracic computed tomography shows two large cystic opacities with endocystic flaky images, including one ruptured in the pleura with right pleural effusion. This radiological suspicion of fissured cystic echinococcosis was confirmed by positive hydatidosis serology. The multidisciplinary meeting retained the indication of right basal segmentectomy enlarged to a diaphragmatic patch, associated with treatment by albendazole. The diagnosis was confirmed by parasitological and pathological data. In this article, we will deal with the macroscopic and microscopic features of this rare parasitosis in metropolitan France and we will discuss the elements of management of a fresh resected specimen during macroscopic examination to prevent parasite swarming.

Lung histopathology of non-infectious pulmonary complications after allogeneic haematopoietic stem cell transplantation.

AIMS: Non-infectious pulmonary complications (NIPCs) occur frequently following allogeneic haematopoietic stem cell transplantation (HSCT). As there is no consensus on the description of the related pulmonary pathological lesions, pathologist reports and clinical conclusions are largely inconsistent in routine practice. The aim of our study was to provide an accurate overview of post-allogeneic HSCT NIPCs from a large number of lung biopsies. METHODS AND RESULTS: We reviewed 61 lung biopsies in patients with an NIPC, including 51 surgical lung biopsies, four post-mortem biopsies and six lung explants. We found both bronchiolar (n = 59) and alveolar/interstitial pathologies (n = 27). We describe two types of bronchiolar lesions: bronchiolectasies (n = 37) and fibrous and cellular lesions with luminal narrowing (n = 43). We found a wide spectrum of airway/interstitial pathologies that were labelled using the terminology of the 2013 American Thoracic Society and European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs), including the following: organising pneumonia (OP, n = 8), non-specific interstitial pneumonia (NSIP, n = 9), diffuse alveolar damage (DAD, n = 6), lymphoid interstitial pneumonia (LIP, n = 1) and pleuroparenchymal fibroelastosis (PPFE, n = 2), as well as one instance of associated PPFE and NSIP. CONCLUSIONS: Interstitial pathology was associated with bronchiolar lesions in 41% of the cases reviewed (n = 25). Lung airway and interstitial inflammation was still present in lung explants from patients who underwent lung transplantation for post-allogeneic HSCT end-stage respiratory insufficiency. Herein, we describe a wide spectrum of pathological lung lesions encountered in post-allogeneic HSCT NIPCs.

Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses.

BACKGROUND: Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). METHODS: Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. RESULTS: Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. CONCLUSIONS: This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.

Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case.

BACKGROUND: BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man. CASE PRESENTATION: While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation. CONCLUSION: These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors.

Ex vivo relaxations of pulmonary arteries induced by prostacyclin mimetics are highly dependent of the precontractile agents.

Prostacyclin (PGI2) mimetics (iloprost, treprostinil) are potent vasodilators (primarily via IP-receptor activation) and major therapeutic interventions for pulmonary hypertension (PH). Increased plasma levels of endothelin (ET-1), thromboxane (TxA2) and catecholamines have been demonstrated from patients with PH. In this study, we aimed to compare relaxant effects of iloprost and treprostinil on human (HPA) and rat pulmonary arteries precontracted with either ET-1, thromboxane (U46619) or an α-adrenergic receptor agonist (Norepinephrine, NE or phenylephrine, PE). Treprostinil and iloprost induced vasorelaxation of HPA precontracted with NE, ET-1 or U46619. We obtained greater relaxation response and sensitivity to treprostinil when ET-1 or U46619 were used to induce the precontraction in comparison to NE. In contrast, iloprost showed less relaxation response and sensitivity in HPA precontracted with U46619 versus NE. In the rat, treprostinil and iloprost induced vasorelaxation of pulmonary arteries precontracted with PE and U46619 but minimally with ET-1. However, in rat pulmonary arteries, PE-induced precontractions were comparatively low amplitude. Our study showed that the ex vivo relaxation or sensitivity of pulmonary arteries induced by PGI2 mimetics is highly dependent on both the pre-contraction agent and the species. To best extrapolate to effects on human tissue, our results suggest that U46619 is the appropriate contractile agent for assessing the relaxant effect of PGI2 mimetics in rat pulmonary arteries. Finally we suggest that in PH patients with high plasma concentration of TxA2, treprostinil (not iloprost) would be a preferential treatment. On the other hand, if the ET-1 plasmatic level is high, either treprostinil or iloprost will be effective.

α-Hemolysin, not Panton-Valentine leukocidin, impacts rabbit mortality from severe sepsis with methicillin-resistant Staphylococcus aureus osteomyelitis.

BACKGROUND: Severe sepsis, combining acute osteomyelitis and lung involvement, has been described increasingly in healthy children with the spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). METHODS: Outcomes (mortality, hematogenous spread, lung and bone involvements) of rabbit osteomyelitis caused by CA-MRSA LAC(WT) USA300 and its Panton-Valentine leukocidin (PVL)- and α-hemolysin (Hla)-negative isogenic derivatives (LACΔpvl and LACΔhla, respectively) were compared. RESULTS: Three days after inoculation (D3), all LAC(WT)- and LACΔpvl-, and 72% of LACΔhla-infected rabbits had no hematogenous spread and similar lung and bone bacterial densities. LACΔpvl and LACΔhla caused less severe histological lung lesions than LAC(WT) (P ≤ .01). Between D3 and D9, 10 (53%) LAC(WT)-, 11 (55%) LACΔpvl-, but no LACΔhla-infected rabbits (P < .005) died of severe sepsis with disseminated infection. Unlike deceased animals, most LAC(WT), LACΔpvl, and LACΔhla D14 survivors had no hematogenous spread (P < .001). LAC(WT) (88%) caused more bone abscesses than LACΔpvl (0, P = .001) or LACΔhla (30%, P = .01). CONCLUSION: In this model, both PVL and Hla seemed to be required for early lung involvement via hematogenous spread. Hla, but not PVL, significantly impacted severe sepsis-related mortality. PVL was the predominant factor determining late-stage bone abscesses.

Distinguishing the histological and radiological features of cystic lung disease in Birt-Hogg-Dubé syndrome from those of tobacco-related spontaneous pneumothorax.

AIMS: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominantly inherited genodermatosis that predisposes to cystic lung disease, leading to spontaneous pneumothoraces. This retrospective analysis of five BHD cases (two men, three women) compared lung histology and computed tomography (CT) imaging to a matched cohort of non-BHD patients with spontaneous pneumothoraces (SPN). METHODS AND RESULTS: Lung was sampled during pleurodesis to resect bullae. Recurrent pneumothoraces was seen in two patients. Fourteen sets of histological slides (seven in each group) and 10 CT scans (five in each group) were reviewed. CT scans in BHD showed multiple cysts with a basal predominance and intraparenchymal/peribronchial distribution. On histological examination, BHD lungs showed punch-out cysts with no inflammation, and lacked subpleural fibroelastotic scars and smoking changes. In contrast, all SPN cases showed respiratory bronchiolitis and subpleural fibroelastotic scars. CONCLUSIONS: This study emphasizes the importance of smoking history and topography of the lesions in assessing cystic lung disease. Pathologists need to remain alert to the possibility of BHD in the setting of recurrent pneumothoraces in a non-smoker, in particular in a woman, at any age, and should take part in a multidisciplinary approach to the diagnosis of cystic lung disease to obtain clinical and CT scan details.

Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma.

Given the interest in defining biomarkers of asbestos exposure and to provide insights into asbestos-related and cell-specific mechanisms of neoplasia, the identification of gene alterations in asbestos-related cancers can help to a better understanding of exposure risk. To understand the aetiology of asbestos-induced malignancies and to increase our knowledge of mesothelial carcinogenesis, we compared genetic alterations in relevant cancer genes between lung cancer, induced by asbestos and tobacco smoke, and malignant pleural mesothelioma (MPM), a cancer related to asbestos, but not to tobacco smoke. TP53, KRAS, EGFR and NF2 gene alteration analyses were performed in 100 non-small cell lung cancer (NSCLC) patients, 50 asbestos-exposed and 50 unexposed patients, matched for age, gender, histology and smoking habits. Detailed assessment of asbestos exposure was based on both specific questionnaires and asbestos body quantification in lung tissue. Genetic analyses were also performed in 34 MPM patients. TP53, EGFR and KRAS mutations were found in NSCLC with no link with asbestos exposure. NF2 was only altered in MPM. Significant enhancement of TP53 G:C to T:A transversions was found in NSCLC from asbestos-exposed patients when compared with unexposed patients (P = 0.037). Interestingly, TP53 polymorphisms in intron 7 (rs12947788 and rs12951053) were more frequently identified in asbestos-exposed NSCLC (P = 0.046) and MPM patients than in unexposed patients (P < 0.001 and P = 0.012, respectively). These results emphasise distinct genetic alterations between asbestos-related thoracic tumours, but identify common potential susceptibility factors, i.e. single nucleotide polymorphisms in intron 7 of TP53. While genetic changes in NSCLC are dominated by the effects of tobacco smoke, the increase of transversions in TP53 gene is consistent with a synergistic effect of asbestos. These results may help to define cell-dependent mechanisms of action of asbestos and identify susceptibility factors to asbestos.

A comparative study of PGI2 mimetics used clinically on the vasorelaxation of human pulmonary arteries and veins, role of the DP-receptor.

Prostacyclin (PGI2) and its mimetics (iloprost, treprostinil, beraprost and MRE-269) are potent vasodilators (via IP-receptor activation) and a major therapeutic intervention for pulmonary hypertension (PH). These PGI2 mimetics have anti-proliferative and potent vasodilator effects on pulmonary vessels. We compared the relaxant effects induced by these recognized IP-agonists in isolated human pulmonary arteries (HPA) and veins (HPV). In addition, using selective antagonists, the possible activation of other prostanoid relaxant receptors (DP, EP4) was investigated. Iloprost and treprostinil were the more potent relaxant agonists when both vessels were analyzed. HPA were significantly more sensitive to iloprost than to treprostinil, pEC50 values: 7.94±0.06 (n=23) and 6.73±0.08 (n=33), respectively. In contrast, in HPV these agonists were equipotent. The relaxations induced by treprostinil were completely or partially inhibited by IP-antagonists in HPA or HPV, respectively. The effects of the IP-agonists were not significantly modified by the EP4 antagonist. Finally, DP-antagonists inhibited the relaxations induced by treprostinil in HPV, suggesting that the DP-receptor plays a role in treprostinil-induced relaxation in the HPV. These data suggest that iloprost and treprostinil should be the most effective clinically available agonists to decrease pulmonary vascular resistance and to prevent oedema formation (by similar decrease in HPA and HPV resistance) in PH patients.

VEGFR2 and CD34 expression associated with longer survival in patients with pleural mesothelioma in the IFCT-GFPC-0701 MAPS phase 3 trial.

OBJECTIVES: VEGF/VEGFR autocrine loop is a hallmark of pleural mesothelioma (PM). We thus assayed the prognostic and predictive values of VEGFR-2 [vascular endothelial growth factor receptor 2 or Flk-1] and CD34, a marker of endothelial cells, in samples from patients accrued in the Mesothelioma Avastin Cisplatin Pemetrexed Study ('MAPS', NCT00651456). MATERIALS AND METHODS: VEGFR2 and CD34 expression were assayed using immunohistochemistry in 333 MAPS patients (74.3%), and their prognostic value was evaluated in terms of overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses, before validation by bootstrap methodology. RESULTS: Positive VEGFR2 or CD34 staining was observed in 234/333 (70.2%) and 322/323 (99.6%) of tested specimens, respectively. VEGFR2 and CD34 staining correlated weakly, yet significantly, with each other (r = 0.36, p < 0.001). High VEGFR2 expression or high CD34 levels were associated with longer OS in PM patients in multivariate analysis (VEGFR2: adjusted [adj.] hazard ratio [HR]: 0.91, 95% confidence interval [CI] [0.88; 0.95], p < 0.001; CD34: adj. HR: 0.86, 95 %CI [0.76; 0.96], p = 0.010), with only high VEGFR2 expression resulting in significantly longer PFS (VEGFR2: adj. HR: 0.96, 95 %CI [0.92; 0.996], p = 0.032). Stability of these results was confirmed using bootstrap procedure. Nevertheless, VEGFR2 expression failed to specifically predict longer survival in bevacizumab-chemotherapy combination trial arm, regardless of whether the VEGFR2 score was combined or not with serum VEGF concentrations. CONCLUSION: VEGFR2 overexpression independently correlated with longer OS or PFS in PM patients, such biomarker deserving prospective evaluation as stratification variable in future clinical trials.

DeltaN TP63 reactivation, epithelial phenotype maintenance, and survival in lung squamous cell carcinoma.

Genes, active during normal development, are frequently reactivated during neoplastic transformation and may be related to progression. One of them, the transcription factor TP63, is crucial for pulmonary epithelial development and a possible target of the recurrent 3q amplifications in lung squamous cell carcinoma (SCC). Here, we explored whether TP63 reactivation could be associated to cancer progression in lung SCC through an epithelial to mesenchymal transition. We studied TP63 amplification and TP63 expression at RNA and protein levels and we analyzed the ΔNTP63/TATP63 ratio that quantifies the proportion of the isoform lacking the transactivation domain/the isoform containing the transactivation domain. We correlated TP63 status to survival and to the expression of epithelial (E-cadherin and plakoglobin) and mesenchymal (N-cadherin, vimentin, TWIST1, and SNAIL) markers. We found that high ΔN/TA TP63 ratio was related to high E-cadherin and plakoglobin mRNA levels (P < 0.05) and that E-cadherin mRNA level was the only marker related to survival. Kaplan-Meier survival curves stratified according to the expression level of E-cadherin showed, as already reported in breast cancer, that patients with low (first quartile) or high (last quartile) E-cadherin expression had a worse survival with respect to patients with intermediate E-cadherin expression. Altogether, our results indicate that a reactivation of ΔNTP63 is linked to the maintenance of epithelial markers and suggest that E-cadherin has a dual role in lung SCC.

Pulmonary carcinoid tumors and asbestos exposure.

OBJECTIVES: The hypothesis that asbestos exposure may have more specific associations with particular histological types of lung cancer remains controversial. The aim of this study was to analyze the relationships between asbestos exposure and pulmonary carcinoid tumors. METHODS: A retrospective case-control study was conducted in 28 cases undergoing surgery for pulmonary carcinoid tumors and aged >40 years and in 56 controls with lung cancer of a different histological type, matched for gender and age, from 1994 to 1999, recruited in two hospitals in the region of Paris. Asbestos exposure was assessed via expertise of a standardized occupational questionnaire and mineralogical analysis of lung tissue, with quantification of asbestos bodies (AB). RESULTS: Definite asbestos exposure was identified in 25% of cases and 14% of controls (ns). Cumulative asbestos exposure was significantly higher in cases than in controls (P < 0.05), and results of the quantification of AB tended to be higher in cases than in controls (24 and 9% had >1000 AB per gram dry lung tissue, respectively, P = 0.09). Mean cumulative smoking was lower in cases than in controls (P < 0.05). CONCLUSIONS: This study argues in favor of a relationship between asbestos exposure and certain pulmonary carcinoid tumors.