Endobronchial tumours in a campaign for early detection of bronchial cancer: Computed tomography versus endoscopy.

OBJECTIVE: To study endobronchial cancers occurring in a population at high risk of bronchial cancer (history of surgically treated bronchial or ENT cancer in complete remission, and symptoms due to smoking) detected by annual volume CT scans and biannual fibroscopy. MATERIAL AND METHODS: Two hundred and sixty-six patients were included in this single centre prospective study; 27 bronchopulmonary cancers were detected. Ten endobronchial cancers (37%) were identified by fibroscopy (nine invasive cancers and one carcinoma in situ) in 10 patients (nine men) (51-78 years old) nine of whom were smokers (dark tobacco: seven). The screening CTs were reappraised by two radiologists. RESULTS: Three cancers out of 10 were detected by CT during the initial reading. The sensitivity of the reappraised CT was 80% with seven false positives. In five cases, the mean period between the first CT scan where the lesion was visible retrospectively, but not described, and the diagnostic fibroscopy was 463 days (213-808 days); two cancers were not visible in the CT scan. Seven curative treatments were undertaken. CONCLUSION: In this population, the sensitivity of the initial reading of the CT scan for detecting endobronchial tumours was 30%, while 80% of the tumours were visible retrospectively, underlining the importance of careful analysis of the proximal bronchial tree.

Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development.

BACKGROUND: In a European multicenter prospective study patients with lung cancer were interviewed for smoking history and biological samples centrally collected. The aim of this study was to compare KRAS mutation analysis with smoking status at the time of diagnosis. METHODS: A nested case-study was performed on 233 non-small cell lung carcinomas. Cases were selected on the basis of progressive disease or disease-free post surgery based on specific criteria. KRAS mutation analysis was performed with the point-EXACCT method. RESULTS: KRAS mutations were found in 39 adenocarcinomas and 1 squamous cell carcinoma in the 233 NSCLC. The median quitting smoking time (QST) for patients with and without KRAS mutations was 9 years, interquartile range [IQR 16-38] and 3 years, IQR [13-50], respectively (p=0.039). No difference was found for age at initiation of smoking, duration of smoking, average tobacco consumption, and smoking status at the time of diagnosis. CONCLUSION: The QST was longer for patients with KRAS mutations, supporting the notion that the presence of a KRAS mutation is a dominant early effect, supporting its role as a driver oncogen.

Primary lung adenocarcinoma: characteristics by smoking habit and sex.

The incidence of adenocarcinoma is increasing, particularly among females. We sought to assess the role of tobacco consumption in clinical presentation according to sex. In this retrospective study, 848 patients diagnosed between 1997 and 2006 at Grenoble University Hospital (Grenoble, France) were stratified into four groups according to smoking habits. Differences between sexes and two contrasting female profiles emerged. Female current smokers were younger than female never-smokers (median 51 versus 69 yrs; p < 0.001), more often had surgery (62.7% versus 39%; p = 0.01) and had a median (95% CI) estimated survival of 26.2 (18.1-49.2) versus 15.1 (12.8-22.2) months (p = 0.002). Both groups had similar survival when taking treatment into account. Among males, smoking did not influence presentation. Male current smokers were older than female current smokers (median 59 yrs; p < 0.001) and fewer had surgery (48.8%; p = 0.015), although the percentage of stage IIIb-IV disease was similar (53% and 46%; nonsignificant) and they had a poorer estimated survival of 14.3 (13.0-18.5) months (p = 0.0024). Males smoked more than females (median 41 versus 30 pack-yrs; p < 0.001). Quitting smoking delayed age at diagnosis by 11 yrs for females (p = 0.0035) and 8 yrs for males (p < 0.001). Our results support the hypothesis that carcinogenesis differs between males and females, and between female smokers and never-smokers.

CT characteristics of resolving ground-glass opacities in a lung cancer screening programme.

PURPOSE: This study aimed at evaluating the computed tomography (CT) characteristics of resolving localized ground-glass opacities (GGOs) in a screening programme for lung cancer. MATERIAL AND METHODS: 280 patients at high-risk for lung cancer (221 men, 59 women; mean age, 58.6 years), divided into four groups (lung cancer history (n = 83), head and neck cancer history (n = 63), symptomatic (n = 88) and asymptomatic (n = 46) cigarette smokers), were included in a prospective trial with annual low-dose CT for lung cancer screening. We retrospectively reviewed all localized GGOs, analyzed the CT characteristics on initial CT scans and changes during follow-up (median 29.1 months). Variables associated with resolution of GGOs were tested using chi-square or Mann-Whitney tests. RESULTS: A total of 75 GGOs were detected in 37 patients; 54.7% were present at baseline and 45.3% appeared on annual CT. During follow-up, 56.2% persisted and 43.8% disappeared. The resolving localized GGOs were significantly more often lobular GGOs (p = 0.006), polygonal in shape (p = 0.02), mixed (p = 0.003) and larger (p < 0.0001) than non-resolving localized GGOs. CONCLUSION: Localized GGOs are frequent and many disappeared on follow-up. CT characteristics of resolving GGOs show significant differences compared to persistent ones. This study emphasizes the importance of short-term CT follow-up in subjects with localized GGOs.

Imaging of a case of extramedullary solitary plasmacytoma of the trachea.

We describe a case of extramedullary tracheal plasmacytoma that was incidentally discovered in a 73-year-old man on a PET scan performed for assessing the extent of colon cancer. CT scan showed the tumor; multiplanar reformation coupled with virtual bronchoscopy allowed proper treatment planning. The tracheal tumor was resected during rigid bronchoscopy. Relevant investigations excluded multiple myeloma. Follow-up CT showed persistent thickening of the tracheal wall, but there has been no recurrence after one-year followup.

Sumoylation of ING2 regulates the transcription mediated by Sin3A.

ING2 (inhibitor of growth 2) is a candidate tumor-suppressor gene involved in cell cycle control, apoptosis and senescence. Although the functions of ING2 within the chromatin remodeling complex Sin3A/histone deacetylase (HDAC) and in the p53 pathway have been described, how ING2 itself is regulated remains unknown. In this study we report for the first time that ING2 can be sumoylated by small ubiquitin-like modifier 1 (SUMO1) on lysine 195 both in vitro and in vivo. Strikingly, ING2 sumoylation enhances its association with Sin3a. We provide evidences that ING2 can bind to the promoter of genes to mediate their expression and that sumoylation of ING2 is required for this binding to some of these genes. Among them, we identified the gene TMEM71 (transmembrane protein 71), whose expression is regulated by ING2 sumoylation. ING2 must be sumoylated to bind to the promoter of TMEM71 and to recruit the Sin3A chromatin-modifying complex to this promoter, in order to regulate TMEM71 transcription. Hence, sumoylation of ING2 enhances its binding to the Sin3A/HDAC complex and is required to regulate gene transcriptions.

The transcription factor E2F1 and the SR protein SC35 control the ratio of pro-angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo.

The transcription factor E2F1 has a crucial role in the control of cell growth and has been shown to regulate neoangiogenesis in a p53-dependent manner through inhibition of activity of the VEGF-A (vascular endothelial growth factor) promoter. Besides being regulated by transcription, VEGF-A is also highly regulated by pre-mRNA alternative splicing, resulting in the expression of several VEGF isoforms with either pro-(VEGF(xxx)) or anti-(VEGF(xxx)b) angiogenic properties. Recently, we identified the SR (Ser-Rich/Arg) protein SC35, a splicing factor, as a new transcriptional target of E2F1. Here, we show that E2F1 downregulates the activity of the VEGF-A promoter in tumour cells independently of p53, leading to a strong decrease in VEGF(xxx) mRNA levels. We further show that, strikingly, E2F1 alters the ratio of pro-VEGF(xxx) versus anti-VEGF(xxx)b angiogenic isoforms, favouring the antiangiogenic isoforms, by a mechanism involving the induction of SC35 expression. Finally, using lung tumour xenografts in nude mice, we provide evidence that E2F1 and SC35 proteins increase the VEGF(165)b/VEGF ratio and decrease tumour neovascularization in vivo. Overall, these findings highlight E2F1 and SC35 as two regulators of the VEGF(xxx)/VEGF(xxx)b angiogenic switch in human cancer cells, a role that could be crucial during tumour progression, as well as in tumour response to antiangiogenic therapies.

Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers.

Cancer cells frequently express genes normally active in male germ cells. ATAD2 is one of them encoding a conserved factor harbouring an AAA type ATPase domain and a bromodomain. We show here that ATAD2 is highly expressed in testis as well as in many cancers of different origins and that its high expression is a strong predictor of rapid mortality in lung and breast cancers. These observations suggest that ATAD2 acts on upstream and basic cellular processes to enhance oncogenesis in a variety of unrelated cell types. Accordingly, our functional studies show that ATAD2 controls chromatin dynamics, genome transcriptional activities and apoptotic cell response. We could also highlight some of the important intrinsic properties of its two regulatory domains, including a functional cross-talk between the AAA ATPase domain and the bromodomain. Altogether, these data indicate that ATAD2 overexpression in somatic cells, by acting on basic properties of chromatin, may contribute to malignant transformation.

[Vaccination practices following the end of compulsory BCG vaccination. A cross-sectional survey of general practitioners and pediatricians]. / Pratiques vaccinales déclarées suite à la levée de l'obligation de vaccination généralisée par le BCG. Enquête auprès des médecins généralistes et des pédiatres.

BACKGROUND: Tuberculosis prevention has been based on generalized BCG vaccination in France since 1949. The aim of this cross-sectional survey was to assess the impact of the change in BCG administration (in January 2006) and the end of compulsory vaccination (in July 2007). METHOD: A self-administered postal questionnaire was sent to a random sample of 2248 physicians practicing in 6 departments in the Rhône-Alpes region in 2008. RESULTS: Overall, 923 questionnaires were analyzed. The median age of the respondents was 52 years, 67 % were male, 93 % were general practitioners, and 91 % practiced in private practice offices. The median number of BCG vaccines administered on a quarterly basis was 5 (interquartile range [IQR], 3-10) before January 2006, one (IQR, 0-3) between January 2006 and July 2007, and zero (IQR, 0-1) after July 2007 (P<0.001). The rate of BCG vaccination was significantly lower for male physicians, physicians older than 50 years, general practitioners, practitioners working in private offices, and for some departments. Thirty-nine percent of the physicians were informed of the national program against tuberculosis 2007-2009, and 41 % wished to be trained in the practice of intradermal vaccination. CONCLUSION: This survey suggests that the withdrawal of Monovax and the lifting of generalized vaccination requirements were followed by a substantial decrease in the number of BCG vaccinations. The intradermal route constitutes an obstacle for BCG vaccination that might be overcome by specific training.

EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration.

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.

[Pathogenesis and treatment of vascular calcification in CKD]. / Invecchiamento cardiovascolare nel soggetto uremico: nuove acquisizioni.

Increased vascular calcification is a major cause of cardiovascular events in patients with chronic kidney disease (CKD). It is the result of an active ossification process counteracted by ''bone'' proteins such as osteopontin, alkaline phosphatase, osteoprotegerin, and osteocalcin. Chronic kidney disease - mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that occurs in CKD. In addition to abnormalities in the serum calcium and phosphate profile, CKD-MBD is characterized by abnormalities of bone turnover, mineralization, volume and growth as well as vascular calcification. Considering that the presence and extent of vascular calcification in CKD portend a poor prognosis, many efforts have been made to shed light on this complicated phenomenon to prevent vascular calcium deposition and its progression. Indeed, careful control of calcium load, serum phosphate and parathyroid hormone along with the use of calcium-free phosphate binders and vitamin D receptor activators represent a new therapeutic armamentarium to improve quality of life and reduce mortality in CKD.

Outcomes and survival after laparoscopic gastrectomy for adenocarcinoma. Analysis on 65 patients operated on by conventional or robot-assisted minimal access procedures.

AIMS: Despite laparoscopic surgery for gastric cancer has gained worldwide acceptance, long term results and survival are seldom reported. This study was designed to assess long term outcomes after laparoscopic gastrectomy with D2 dissection. The short term results of conventional and robot-assisted minimally invasive procedures were also examined. PATIENTS AND METHODS: The charts of 65 patients who underwent laparoscopic surgery for non-metastatic adenocarcinoma were reviewed retrospectively. This series included 35 patients with early gastric cancer (EGC) and 30 with advanced gastric cancer (AGC). A 4/5 laparoscopic subtotal gastrectomy (LSG) with D2 nodal clearance was the procedure of choice for distal cancers. Laparoscopic total gastrectomy (LTG) with modified D1 lymphadenectomy was performed for mid-proximal EGC. RESULTS: Sixty gastrectomies were carried out laparoscopically, 56 LSG and 4 LTG. Conversion to laparotomy was required in 5 patients with distal cancer. No intraoperative complication was registered. Morbidity included 2 duodenal leaks that healed conservatively. Two postoperative deaths were registered. An average number 31.3+/-8.8 lymph nodes were collected. The mean hospital stay was 10 days (range 7-24). The mean follow up was 30 months (range 2-86) and the cumulative overall 5 year survival rate was 78%. Survival at 5 years for EGC was 94% and survival at 4 years for AGC was 53% (57% for non-converted patients). CONCLUSIONS: Laparoscopic gastrectomy for cancer represents a valid alternative to open surgery with minimal morbidity and acceptable long term survival. Considering the risk of preoperative under diagnoses a D2 lymphadenectomy is suggested also for EGC. This study validated the effectiveness of minimally invasive technique in the management of gastric cancer.

E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35.

The transcription factor E2F1 has a key function during S phase progression and apoptosis. It has been well-demonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Alternative splicing of pre-mRNAs also has an important function in the regulation of apoptosis. In this study, we identify the splicing factor SC35, a member of the Ser-Rich Arg (SR) proteins family, as a new transcriptional target of E2F1. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. Taken together, these results demonstrate that E2F1 controls pre-mRNA processing events to induce apoptosis and identify the SC35 SR protein as a key direct E2F1-target in this setting.

[Early diagnosis of bronchial carcinoma after head and neck cancer]. / Diagnostic précoce du cancer bronchique après cancer "tête et cou"

BACKGROUND: Patients with a previous history of cancer of the upper respiratory and digestive tracts (URDT) frequently develop a bronchial carcinoma (synchronous or metachronous) that may affect their survival. OBJECTIVE: To determine the prevalence of bronchial carcinoma at an early stage in a population of patients treated for cancer of the URDT. MATERIALS AND METHODS: This was a single centre prospective study (2002-2006). Patients in remission following treatment of cancers of the buccal cavity, pharynx (stages I -II) and larynx (stages I - III), were examined by a spiral CT scan and fibreoptic bronchoscopy (white light and autofluorescence), with biopsies, and cytology of the bronchial aspirate. RESULTS: 60 patients (55 men) were included. Two peripheral bronchial carcinomas were detected by scanning and two more (proximal) by endoscopy. All 4 bronchial tumours were squamous carcinomas (stage IA). Three patients had surgery, the fourth declined intervention. CONCLUSION: Our study confirms the high prevalence (6.7%) of bronchial carcinoma in patients with a past history of cancer of the URDT. It emphasises the complimentary roles of spiral scanning and bronchoscopy in early diagnosis. It is still too early to evaluate the impact of these investigations on the survival of the patients.

Lung carcinomas with a basaloid pattern: a study of 90 cases focusing on their poor prognosis.

Lung carcinoma with a basaloid pattern (BC) is classified as either a basaloid variant of squamous cell carcinoma (SCC) or as variant of large cell carcinoma (LCC) depending on the presence of a squamous component. In a previous study of 37 cases, the present authors showed that BC presented with a shorter median and overall survival. In order to confirm its clinical significance in a larger series, 90 BC, including 46 basaloid variants of LCC and 44 basaloid variants of SCC, were compared with 1,328 other nonsmall cell lung carcinoma (NSCLC) with regard to clinical features and survival. The survival of basaloid variants of LCC and SCC was comparable. Median and overall survival were significantly lower for BC than for NSCLC in stage I-II patients, with a median survival of 29 and 49 months, respectively, and 5-yr survival rates of 27 and 44% for BC and NSCLC. When disease-specific survival was considered, BC had a shorter survival than both NSCLC and SCC. Basaloid pattern confers a poor prognosis in nonsmall cell lung carcinoma, especially in stage I-II patients, suggesting that lung carcinoma with a basaloid pattern is not only a variant of squamous cell carcinoma or large cell carcinoma, but is a unique entity with a significantly poor prognosis.

Robot-assisted laparoscopic gastrectomy with D2 dissection for adenocarcinoma: initial experience with 17 patients.

Robot-assisted gastrectomy has been practised so far in very few centres in the world. The aims of this study were to assess the feasibility of robot-assisted gastrectomy for adenocarcinoma with D2 lymph nodal dissection and to analyze our preliminary results. Between January 2006 and August 2008, as many as 17 patients (11 females, 6 males) underwent laparoscopic robot-assisted surgery for non-metastatic adenocarcinoma of the stomach by a 3-armed da Vinci(®) Robotic Surgical System. The mean age of patients was 65.9 years. This series included eight patients with early gastric cancer (EGC) and nine with advanced gastric cancer (AGC). A 4/5 laparoscopic subtotal gastrectomy (LSG) with D2 nodal clearance was the procedure of choice for 16 distal cancers. Laparoscopic total gastrectomy (LTG) with D2 lymphadenectomy was performed for one AGC of the middle third of the stomach. No intraoperative complication was registered. Conversion to laparotomy was required in two patients with distal cancer. The mean operating time (excluding converted patients) was 352 min (348 for LSG). Morbidity consisted in one pancreatic leak that healed conservatively. One death occurred postoperatively for haemorragic stroke. On average, 25.5 ± 4 lymph nodes were collected (range 10-40). The resection margin was 6.4 ± 0.6 cm (range 4.2-8), and the margin was tumour free in all the specimens. The mean hospital stay of totally laparoscopic subtotal gastrectomy was 10 ± 1.2 days (range 8-13). The mean follow-up was 14 months (range 1-29) and three patients with AGC showed recurrence after LSG and died of disease. Robotics in gastrectomy for cancer is a feasible and safe procedure, yielding adequate D2 nodal clearance with respect of oncologic principles. Robotic techniques can represent a remarkable tool to improve laparoscopic surgeon's ability and precision in small surgical fields, i.e. during D2 dissection. This study demonstrated the feasibility of robot-assisted gastrectomy for cancer although further studies are required to validate our preliminary results, especially as far as patients' benefits are concerned.

Unusual cystic presentation of pulmonary nodular amyloidosis associated with MALT-type lymphoma.

The case reported herein consists of nodular pulmonary amyloidosis presenting with unusual cystic radiological features which reveal a pulmonary localisation of an extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The present case is the first to report a radiological presentation of nodular pulmonary amyloidosis in the absence of Sjögren's syndrome. Although transthoracic fine-needle biopsy was helpful for the diagnostic of amyloidosis, final diagnosis of associated MALT-type lymphoma required an open lung biopsy. This emphasises the importance of performing surgical investigations in pulmonary nodular amyloidosis in order to depict the presence of underlying lung tumours or lymphoproliferative disorders.