Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.

BACKGROUND: EGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database. PATIENTS AND METHODS: Of 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients. RESULTS: EGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61-0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02-2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49-0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96-2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53-0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients. CONCLUSION: EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

[Mycobacterial pulmonary infection due to Mycobacterium simiae]. / Mycobactériose pulmonaire à Mycobacterium simiae.

INTRODUCTION: Mycobacterium simiae pulmonary infections remain exceptional in France. CASE REPORT: We report a case of M. simiae lung infection and a 10-year follow-up in a non-immunocompromised host. CONCLUSION: This case emphasizes the difficulties of choosing the appropriate drugs and their side effects in the absence of any existing gold standard.

Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases.

AIM: To describe the main characteristics and the treatment of cryptococcosis in patients with sarcoidosis. DESIGN: Multicenter study including all patients notified at the French National Reference Center for Invasive Mycoses and Antifungals. METHODS: Retrospective chart review. Each case was compared with two controls without opportunistic infections. RESULTS: Eighteen cases of cryptococcosis complicating sarcoidosis were analyzed (13 men and 5 women). With 2749 cases of cryptococcosis registered in France during the inclusion period of this study, sarcoidosis accounted for 0.6% of all the cryptococcosis patients and for 2.9% of the cryptococcosis HIV-seronegative patients. Cryptococcosis and sarcoidosis were diagnosed concomitantly in four cases; while sarcoidosis was previously known in 14/18 patients, including 12 patients (67%) treated with steroids. The median rate of CD4 T cells was 145 per mm(3) (range: 55-1300) and not related to steroid treatment. Thirteen patients had cryptococcal meningitis (72%), three osteoarticular (17%) and four disseminated infections (22%). Sixteen patients (89%) presented a complete response to antifungal therapy. After a mean follow-up of 6 years, no death was attributable to cryptococcosis. Extra-thoracic sarcoidosis and steroids were independent risk factors of cryptococcosis in a logistic regression model adjusted with the sex of the patients. CONCLUSIONS: Cryptococcosis is a significant opportunistic infection during extra-thoracic sarcoidosis, which occurs in one-third of the cases in patients without any treatment; it is not associated to severe CD4 lymphocytopenia and has a good prognosis.

[Polymyalgia rheumatica revealing a lung cancer]. / Une pseudopolyarthrite rhizomélique paranéoplasique révélant un cancer bronchique.

Polymyalgia rheumatica is an inflammatory condition belonging to the connective tissue diseases, which occurs quite frequently in the elderly. Previously, cases have been reported in association with malignant tumours, in a synchronous fashion or prior to the appearance of the cancer. In these cases, the polymyalgia rheumatica is considered to be a paraneoplastic syndrome. We report the cases of a 63-year-old woman and a 58-year-old man with severe proximal girdle pain associated to a high-level of systemic inflammatory markers and a diagnosis of polymyalgia rheumatica was made. In the face of a lack of ineffectiveness of analgesic and anti-inflammatory treatments, an intensive investigation was undertaken which in both cases revealed an adenocarcinoma of the lung. The rheumatic manifestations responded well to chemotherapy targeting the lung tumour. We present here a review of the literature to give prominence to the diagnostic pitfalls that can occur around paraneoplastic polymyalgia rheumatica. The presence of therapeutic resistance at the onset of treatment and other atypical features may suggest the presence of an occult malignancy.

Immunohistochemistry to identify EGFR mutations or ALK rearrangements in patients with lung adenocarcinoma.

BACKGROUND: Immunohistochemistry has been proposed as a specific and sensitive method to identify EGFR mutations or ALK rearrangements in lung tumours. PATIENTS AND METHODS: We assessed EGFR and KRAS by direct sequencing in 154 patients with lung adenocarcinoma. ALK rearrangements were assayed by FISH and RT-PCR. Immunohistochemistry was carried out and evaluated closely following published methods using recommended monoclonal rabbit or mouse antibodies. RESULTS: Thirteen of 36 exon 19 EGFR-mutated tumours (36%)-including 12 of 22 with p.Glu746_Ala750del (55%)-were positive with the 6B6 antibody that was raised against p.Glu746_Ala750del. One hundred eleven of 114 EGFR exon 19 wild-type tumours (97%) were negative with 6B6. Four of 21 exon 21 EGFR-mutated tumours (19%)-including 4 of 17 with p.Leu858Arg (24%)-were positive with the 43B2 antibody that was raised against p.Leu858Arg. One hundred twenty-two of 124 (98%) EGFR exon 21 wild-type tumours were negative with 43B2. Two of four ALK rearrangements-including two of three with ELM4-ALK fusion transcripts-were identified with the 5A4 antibody. Eleven of 13 tumours without ALK rearrangement (85%) were negative with 5A4. CONCLUSIONS: Immunohistochemistry is a specific means for identification of EGFR mutations and ALK rearrangements. It suffers, however, from poor sensitivity.

[Bifocal lung cancer: the same histology?]. / Cancer bronchique bifocal: une même histologie?

Whereas synchronous lung cancer is rare, synchronous small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are exceptional. The authors report the case of a 61-year-old man with synchronous unilateral adenocarcinoma and small cell lung cancer, raising the question as to the need for the histology of all of the lesions in the same lobe or same lung as well as the treatment. The medical history, biology, CT and (18)F-FDG TEP-CT did not support a diagnosis of synchronous lung cancer. The prognosis was poor and only surgery could improve the prognosis. This is a rare case and illustrates the difficulty in the diagnosis of multiple lung cancer and the difficulty in treating synchronous lung cancer with different histologies (SCLC and NSCLC).

[A phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non squamous, non-small cell lung cancer (NSCLC)]. / Protocole IFCT 0803--Étude de phase II évaluant l'association de cétuximab à une radiothérapie et chimiothérapie concomitante par cisplatine et pémétrexed dans le traitement des cancers bronchiques non à petites cellules non épidermoïdes de stade III, inopérables.

BACKGROUND: Cisplatin-based chemotherapy and concurrent radiotherapy are the standard treatments for locally advanced unresectable NSCLC. New therapeutic combinations using molecular targeted drugs are needed. METHODS: Eligible patients with previously untreated stage III non squamous, NSCLC will receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m(2)) and pemetrexed (500 mg/m(2)) on day 1 administered intravenously every 21 days for four cycles; weekly cetuximab will be added from the first week of therapy. The primary objective of this phase II study (IFCT 0803) is to assess the disease control rate at the 16th week, one month after the completion of the treatment. Based on a two-stage Simon approach, a total of 106 patients are required with an interim analysis of the first 34 planned. EXPECTED RESULTS: This trial will provide information on the feasibility, efficacy and tolerability of this new therapeutic combination. Should the primary objective be achieved, a phase III randomised study testing the position of cetuximab could be considered.

[Impact of positron emission tomography on clinical management of potentially resectable non-small-cell lung cancer: a French prospective multicenter study]. / Impact de la tomographie par émission de positons au 18-FDG dans la prise en charge des patients porteurs d'un cancer bronchique non à petites cellules a priori opérable. Etude prospective multicentrique française.

BACKGROUND: Whole-body (18)F-deoxyglucose positron emission tomography (FDG-PET) has the potential to improve the management of non-small-cell lung cancer (NSCLC). We prospectively evaluated the impact of combining FDG-PET with conventional staging methods, including computed tomography (CT), on the staging and management of patients with potentially resectable NSCLC. METHODS: Ninety-four consecutive patients with newly diagnosed/suspected NSCLC were enrolled. Each patient was first staged by using conventional methods, and then by FDG-PET. FDG-PET results were forwarded in a sealed envelope and divulged at the weekly staff meeting on staging and treatment, only after "Decision 1", based on conventional staging, had been reached by consensus; reevaluation taking FDG-PET into account yielded "Decision 2". The validity of these latter decisions was analyzed retrospectively. RESULTS: Eighty-nine patients were eligible. Relative to standard imaging, FDG-PET led to clinical staging changes in 26 (29.2%) patients. The stage was lowered in eight cases (9%) and raised in 18 cases (20.2%). "Decision 2" differed from "Decision 1" in 19 patients, modifying the surgical procedure in four cases, indicating other investigations to confirm FDG-PET evidence of metastases in 12 cases, or modifying the medical treatment in three cases. These modifications were retrospectively justified in 9/19 cases, and consisted of 2/4 modifications of the surgical procedure (one hilar and one adrenal metastasis not confirmed histologically), 4/12 further investigations (axillary and liver biopsies, mediastinoscopy, occult colon cancer) and three indications for palliative treatment, in patients who all died within 3 months after FDG-PET. CONCLUSIONS: Based on FDG-PET, management was modified in 19/89 (21.3%) patients, but these changes were justified in only 9/89 patients (10.1%). FDG-PET can detect asymptomatic local and distant metastases and improves the preoperative assessment of NSCLC, thereby avoiding unnecessary surgery. However, histological verification is required because of the risk of false-positive results.

[Pulmonary fibrosis and arterial hypertension revealing a chronic pulmonary schistosomiasis. An unusual diagnosis in Europe]. / Fibrose et hypertension artérielle pulmonaires révélant un poumon bilharzien chronique. Un diagnostic inhabituel en Europe.

We report on the case of a Senegalese woman who was hospitalised in Paris for dyspnea on exertion, revealing pulmonary fibrosis and arterial hypertension. With no evident etiology of this fibrosis, a surgical pulmonary biopsy was performed and revealed granulomatosis due to schistosomiasis. Diagnosis of chronic pulmonary schistosomiasis was obtained. The manifestations of the chronic pulmonary schistosomiasis include miliary and pulmonary arterial hypertension. Certain forms can lead to fibrosis as our case study illustrates and pose diagnostic problems outside parasitic endemic areas. Beside cases of acute schistosomiasis observed in tourists, the possibility of chronic forms of the disease in migrant originating from endemic areas should be recognised in industrialised countries.

[What is the role of FDG-PET in thoracic oncology in 2010?]. / Quelle place en oncologie thoracique pour la tomographie par émission de positons au 18FDG (TEP-FDG) en 2010 ?

18F-Fluorodeoxyglucose-Positron Emission Tomography (FGD-PET) has been considered to have a major impact on the management of lung malignancies since the beginning of this century. Its value has been demonstrated by many publications, meta-analysis and European/American/Japanese recommendations. PET combined with computed tomography has provided useful information regarding the diagnosis and staging of lung cancer and allows for the delivery of adaptive radiotherapy. In its more common uses, PET has been shown to be cost-effective. With the widespread use of new radiotracers, PET will play an increasing role in the evaluation of response to treatment.

[Role of chest physician in the management of patient with thoracic trauma]. / Place du pneumologue dans la prise en charge d'un traumatisé du thorax.

Thoracic traumas are frequent and potentially fatal, because of the associated neurological and abdominal lesions. They are observed in car crashes, combat environments and urban terrorist bombings. The mechanisms of the traumatic injury are complex and account for the diversity of the lesions. The management of a chest trauma patient is a model of multidisciplinary collaboration where the chest physician can make a significant contribution.

[Second-line therapy in patients with malignant pleural mesothelioma. A French retrospective study (2005-2006)]. / Traitement de seconde ligne dans le mésothéliome pleural malin. Étude rétrospective française (2005-2006).

BACKGROUND: The role of second-line chemotherapy (SLC) has still not been established in malignant pleural mesothelioma (MPM) but SLC is increasingly used because many patients are still fit at the time of the progression of the disease. METHODS: In this retrospective study, the authors reviewed their experience with SLC in pemetrexed-pretreated patients with MPM at two French thoracic oncology units (institut Gustave-Roussy, Villejuif, and hôpital d'Instruction des Armées Percy, Clamart). RESULTS: Between January 2005 and December 2006, 84 consecutive patients with progressing MPM after pemetrexed chemotherapy were enrolled. Forty-four patients received an SLC. There were 30 men and 14 women. The median age was 58 years (range: 34 to 76 years). Most patients had a performance status (PS) less than or equal to 1 (82%) and an epithelial histological subtype (91 %). The median time to progression (TTP) after first-line chemotherapy was 6.1 months. The SLC was a pemetrexed therapy in 21 patients and a new regime in 20 patients (gemcitabine alone or with oxaliplatin). The other three patients were enrolled in a phase I study. According to the Recist criteria, a partial response was observed in four patients and the disease was stabilised in six patients after SLC. The median TTP after SLC was 3.8 months. The median survival was 12.2 months (range: 2 to 72 months). Four of these 44 patients then received third-line (4.8 %) and two received fourth-line therapy (2.4 %). CONCLUSIONS: This experience indicates the feasibility of administering SLC in patients with MPM who are healthy at the time of the progression of the disease. The optimal treatment has not been defined to date and prospective trials are needed.

[Pulmonary malignant melanoma: primary or metastatic?]. / Mélanome malin pulmonaire: primitif ou métastase ?

Primary pulmonary malignant melanoma is rare (0.01% of pulmonary cancers); only 25 cases are published in the literature. The diagnosis of primary pulmonary malignant melanoma is controversial, the pathogenesis is unknown and a pulmonary metastasis from a mucocutaneous melanoma is the main differential diagnosis. The diagnosis is based on the strict application of the Jensen criteria published in 1967. We report the case of an asymptomatic 82-year-old man presenting with a fortuitously discovered primary pulmonary malignant melanoma according to the Jensen criteria and treated by lobectomy (cT1N0M0). Surgery seems to be the gold standard treatment on account of the poor sensitivity of melanoma to chemotherapy and radiotherapy. Surgical resection and the absence of nodal involvement suggest a good prognosis even though the small number of cases does not produce useful statistical data. This observation raises the question of (18)FDG CT-PET in this situation, particularly of the whole body, by extrapolation from the recommendations in mucocutaneous melanoma. The lack of increased uptake on (18)FDG CT-PET could be a new paraclinical diagnostic criterion to add to the clinical criteria of Jensen. This report is the first, which shows the results of (18)FDG CT-PET (standard and whole-body) under this situation.

[PET-CT for evaluation of the solitary pulmonary nodule: an update]. / TEP-TDM pour l'exploration du nodule pulmonaire solitaire: acquis et perspectives.

INTRODUCTION: Positron emission tomography (PET) with 18F-FDG has become an important tool for the characterization of solitary pulmonary nodules (SPN). BACKGROUND: The results of the main meta-analyses show that the sensitivity and specificity of 18F-FDG PET for determining malignancy of SPN are close to 95% and 80% respectively. The limits of the technology are now well known. False negative results are mainly due to certain histological types with low metabolic activity (such as bronchiolo-alveolar carcinoma and typical carcinoid), or small size (nodules less than 8 mm). False positives are mainly represented by granulomatous and infectious processes. VIEWPOINTS: A gain in accuracy occurred with the advent of hybrid PET/CT machines that combine the functional data from 18FDG-PET and the morphological data of computed tomography. Improved imaging protocols (eg. injection of iodinated contrast media) could further enhance the performance of PET-CT. Further improvements will rely on respiratory synchronization protocols and on the advent of new PET tracers. CONCLUSION: 18F-FDG PET-CT should be performed for any nodule over 8 mm in size when the pre-test probability of malignancy is not deemed negligible.

[Pleuro-pulmonary manifestations disclosing hepatic amoebiasis]. / Manifestations pleuropulmonaires révélatrices de l'amibiase hépatique.

During a mission in ex-Yugoslavia between 2001 and 2004, three French soldiers were sent home because of right pneumopathy, right pleurisy after appendicectomy, haemoptysis and liver haematoma, respectively. They previously were stationed in Africa and/or South America. The initial diagnosis was quickly modified: pleuropulmonary manifestations of amoebic hepatic abscess in two cases, and pleuropulmonary amoebiasis in the last case. The outcome was favourable with standard anti-amoebic treatment. The reports illustrate the possibility of hepatic amoebiasis with local pleuropulmonary manifestations and an exceptional case of pleuropulmonary amoebiasis with hepatobronchial fistula. The authors report this experience because it demonstrates that amoebiasis in European countries remains an often forgotten diagnosis. Although known for a long time in developing countries, amoebiasis in the military or in tourists should be systematically considered.

[Erlotinib and nonsmall cell lung cancer with brain metastases: a case study with a complete and prolonged response over 17 months]. / Erlotinib et métastases cérébrales d'un cancer bronchique non à petites cellules : une réponse complète et prolongée de 17 mois.

The prognosis of stage IV nonsmall cell lung cancer, in particular with brain metastases, is extremely poor. The impact of targeted therapy, in particular erlotinib, on patient survival has still not been determined. The authors report the case of a patient diagnosed with nonsmall cell lung cancer with bone and brain metastases. The patient presented a complete cerebral response for 17 months with erlotinib prescribed as a third line therapy.