J. Cadranel

Primary pulmonary lymphoma

Three distinct entities are now covered by the definition of primary pulmonary clonal lymphoid proliferation. The aim of this review is to describe the pathophysiological, diagnostic, prognostic and therapeutic aspects of these three entities. Low-grade pulmonary B-cell lymphoma is the most frequent form of primary pulmonary clonal lymphoid proliferation. It arises from mucosa-associated lymphoid tissue. It is usually indolent and appears in the form of a chronic alveolar opacity. The prognosis is excellent, but treatment is controversial (simple monitoring, surgery or single-agent chemotherapy). High-grade pulmonary B-cell lymphoma is far rarer and usually occurs in individuals with an underlying disorder (e.g. immunodeficiency). The prognosis is poor and therapeutic options depend on the underlying disorder. The inclusion of lymphomatoid granulomatosis in the definition of primary pulmonary lymphomas is controversial. The clonal nature of the proliferation is very rarely demonstrated and extrapulmonary involvement is frequent (upper airways, skin, kidneys, central nervous system, etc.). The prognosis is extremely variable, with some authors reporting complete remission with steroids and cyclophosphamide and others reporting failure of combination chemotherapy.

Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network

BACKGROUND There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.

Upregulation of bronchioloalveolar carcinoma-derived C-X-C chemokines by tumor infiltrating inflammatory cells.

AbstractObjective and design: The presence of increased numbers of tumor-infiltrating neutrophils is associated with poorer outcome in patients with adenocarcinoma of the bronchioloalveolar (BAC) subtype. We evaluated the role of inflammatory environment on C-X-C chemokine tumor production. Materials: Bronchoalveolar lavage from 31 consecutive patients with adenocarcinoma of the BAC subtype as well as tumor and normal pulmonary tissue samples. A549 BAC cell line. Peripheral blood mononuclear cells (PBMC), polymorphonuclear neutrophils (PMN) and alveolar macrophages (AM). Methods: Elisa measurements and immunohistochemical studies of ENA-78, IL-8, IL-1β and TNF-α. RNA isolation, reverse transcription, and PCR amplification of ENA-78 and IL-8. Results: C-X-C peptides were expressed by tumor cells of all the tumor specimens tested. ENA-78 and IL-8 were also expressed by AM. To better understand the regulation of the C-X-C production, BAC cell line was cultured alone or with inflammatory cells. PBMC upregulated both tumor ENA-78 and IL-8 mRNA expression and protein release whereas AM only upregulated ENA-78 mRNA expression and protein release; PMN had no effect. Anti-human IL-1β antibodies (ab) inhibited the A549 ENA-78 and IL-8 production stimulated by PBMC-CM. Anti-human TNF-α ab inhibited A549 ENA-78 production stimulated by AM-CM. IL-1β and TNF-α were expressed in vivo by inflammatory cells, although TNF-α was also expressed by tumor cells. Conclusions: This work emphasizes the role of the host inflammatory response in promoting tumor growth in vivo.

Acute hepatitis C: analysis of a 126-case prospective, multicenter cohort

Objectives To analyze the data (epidemiology, mode of transmission, course, and outcome) of a large series of patients with acute hepatitis C (AHC) in France. Methods Prospective multicenter register, observational study. Results A cohort of 126 patients with AHC was prospectively enrolled between 1999 and 2007. Fifteen (12%) were HIV coinfected. Suspected modes of hepatitis C virus transmission were drug use (38%), sexual contact (21%), nosocomial transmission (18%), and occupational exposure (12%). For 40% of the patients, AHC was revealed by jaundice. Spontaneous viral clearance occurred in 40% of the 72 patients observed for 3 months without treatment. Only jaundice and nosocomial/occupational transmission were predictive of spontaneous viral clearance. Ninety patients were treated with standard or pegylated interferon-&agr; alone (58%) or in combination with ribavirin (42%), for 24 weeks or less in 90%. In intention-to-treat, a sustained viral response was obtained in 58 of 78 (74%) hepatitis C virus monoinfected patients [19 of 22 (86%) with 24 weeks of pegylated interferon-&agr; alone], but only six of 12 (50%) of HIV coinfected patients. Conclusion AHC remains rare, and drug and sexual transmission are predominant. A 3-month follow-up after diagnosis avoids treatment for four out of 10 patients. Antiviral treatment is highly effective, 24 weeks of pegylated interferon-&agr; alone being a good option.

Infections aspergillaires broncho-pulmonaires du sujet non immunodéprimé

Resume La definition des infections aspergillaires broncho-pulmonaires chez les patients non immunodeprimes reste vague et de nombreuses entites cliniques, radiologiques et anatomo-pathologiques ont ete decrites avec une varietes de denominations, i.e. aspergillome simple, aspergillome complexe, aspergillose semi-invasive, aspergillose pulmonaire chronique necrosante, aspergillose chronique cavitaire, fibrosante ou pleurale, tracheobronchite aspergillaire pseudo-membraneuse et aspergillose invasive. Neanmoins, ces entites partagent des caracteristiques communes, suggerant qu’elles appartiennent au meme groupe d’infections aspergillaires : 1- alteration locale ou systemique des defenses anti-infectieuses (alcool, tabac, diabete) ; 2- maladie broncho-pulmonaire sous-jacente responsable ou non de cavites pleurales ou broncho-pulmonaires residuelles (tuberculose active ou sequelles tuberculeuses, dilatation des bronches, sarcoidose, BPCO) ; 3 utilisation frequente d’une corticotherapie prolongee orale ou systemique a faible dose ; 4- absence de ou faible invasion vasculaire, presence d’une reaction granulomateuse et faible tendance metastatique. A l’exception de l’aspergillose invasive, il n’y a pas de recommandations sur le traitement des infections aspergillaires broncho-pulmonaires du patient non immunodeprime. L’embolisation bronchique peut stopper une hemoptysie dans certains cas. La chirurgie qui s’accompagne d’une morbi-mortalite elevee, est generalement impossible du fait de l’alteration de la fonction respiratoire ou de la severite des co-morbidites. Beaucoup de cas cliniques ou de petites etudes retrospectives ont rapporte l’efficacite de nombreux agents anti-fongiques. Les triazoles per os, i.e. l’itraconazole et, en particulier, le voriconazole apparaissent appropries pour le traitement des infections aspergillaires broncho-pulmonaires du patient non immuno-deprime.

Clinical and molecular features in patients with advanced non-small-cell lung carcinoma refractory to first-line platinum-based chemotherapy

Most of the cases of non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage and are treated with platinum-doublet chemotherapy. However, some patients are refractory to this treatment. The aim of this study was to identify the clinical and molecular characteristics of patients with refractory disease. All consecutive patients between 2003 and 2006, who received a platinum-doublet chemotherapy as first-line treatment for stage IIIb-IV NSCLC, were included. Refractory patients were defined as early progressive disease (PD) at the first evaluation of chemotherapy according to WHO criteria. The clinical, histo-pathological, and molecular characteristics (EGFR: exon 19, 20, 21 and KRAS: exon 2 by PCR sequencing; ALK by immunohistochemistry) and survival of refractory patients with initial PD (r-patients) and controlled disease (c-patients) were compared by univariate analyses. Factors that differed between the two groups (p-value <0.25 in univariate analyses) were entered into multivariate analysis. In this study, 178 patients were included. The first tumor assessment was carried out after a median of three cycles (range 1-4). Forty-six (25.8%) patients were refractory. Clinical presentation was similar between r- and c-patients. The sarcomatoid histological subtype was more common in r-patients than c-patients (10.9% vs. 1.5%, respectively; p=0.057). The proportion of EGFR (5.2% vs. 9.6%, p=0.224) and KRAS mutations (11.1% vs. 5.7%, p=0.357), and the expression of ALK (6.3% vs. 2.5%, p=0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histological subtype was the only factor associated with early PD (OR=7.50; 95%CI: 1.02-55.45; p=0.048). r-Patients had significantly shorter survival than c-patients (median 5 months (IQR 3.2-9.9) vs. 15.4 months (IQR 9.9-22.5), respectively; p<0.0001). In conclusion, patients with early PD under platinum-doublet chemotherapy had shorter survival than c-patients. Sarcomatoid histological subtype was the only independent factor associated with early PD.

Hémorragies intra-alvéolaires de l'adulte d'origine immunitaire.

Resume Introduction Le diagnostic d’hemorragie intra-alveolaire (HIA) est evoque devant l’association d’une hemoptysie, d’une anemie et d’un infiltrat pulmonaire. Le lavage broncho-alveolaire ramene un liquide macroscopiquement hemorragique et/ou riche en siderophages. Le bilan etiologique doit permettre de differencier les HIA d’origine immunitaire des autres, du fait des consequences quant a leur prise en charge therapeutique. Etat des connaissances Les causes immunitaires sont dominees par les vascularites des vaisseaux de petit et moyen calibre (maladie de Wegener, polyangeite microscopique), le lupus et la maladie de Goodpasture. D’autres affections immunitaires sont plus rarement responsables. L’association de l’HIA a une glomerulonephrite aigue, definissant le syndrome pneumo-renal, la presence d’atteinte extra-thoracique suggestive et le bilan immunologique orientent vers une origine immunitaire. Le traitement immunosuppresseur doit etre precoce, associant corticoides et souvent cyclophosphamide intraveineux. Les plasmaphereses sont indiquees dans la maladie de Goodpasture et le lupus mal controle. Les facteurs aggravants (hypervolemie, troubles de l’hemostase) doivent etre recherches et corriges. La mortalite intra-hospitaliere avoisine 20 %. Perspectives et conclusion Les HIA d’origine immunitaire constituent un syndrome dont la rarete justifie la mise en place d’un registre national afin de pouvoir elaborer des strategies diagnostiques et therapeutiques homogenes.

Coexisting pulmonary nodules in operable lung cancer: Prevalence and probability of malignancy

INTRODUCTION Coexistence of pulmonary nodules in operable non small cell lung cancer (NSCLC) may influence the therapeutic indication. The aim of this study was to evaluate prospectively the prevalence and the probability of malignancy of pulmonary nodules in operable lung cancer. METHODS From a prospective database, all surgically treated patients diagnosed with NSCLC from 1998 to 2003 were retrospectively reviewed. Patients presenting pulmonary nodule(s) were identified. RESULTS Two hundred thirty nine patients had a complete resection for a NSCLC and 56 patients (24%) presented altogether 88 nodules on thoracic CT. Twenty-four of these nodules (27%) were malignant, 28 (32%) benign and 36 (41%) of undetermined nature. Five factors associated with nodules malignancy were identified: tumour histology (non-squamous (non-SCC) 44% vs. SCC 7%, p=0.001), localization of the nodules in an upper lobe (vs. other lobe, p=0.004), co localization in the same lobe as the NSCLC (vs. another lobe, p=0.03), nodule size (p=0.05) and shape (speculated vs. non spiculated, p=0.02). From these factors, a probability score was assessed with a malignancy rate in SCC of 0% in nodules presenting ≤ 1 feature, 33% with 2 features and 100% with ≥ 3 features and in non-SCC of 40% with 1 feature, 82% with 2 features and 100% with 3 ≥ features. CONCLUSION Diagnosis of satellite nodules associated with early stage NSCLC is common. We developed a predictive score to estimate the probability of malignancy which may be a precious aid in the management of pulmonary nodules associated to a NSCLC.

Somatostatin receptor scintigraphy screening in advanced hepatocarcinoma: A multi-center French study.

Background: Somatostatin receptor scintigraphy (SRS) has been reported for receptor (SSTR) screening in advanced hepatocarcinoma (aHC) prior to somatostatin analogue treatment. Aims: To evaluate SSTR screening with SRS in aHC patients. Methods: SRS was performed prior treatment, with images at 4, 24, 48 hours. For 7 tumors, SSTR2 subtype was detected immunohistochemically. Results: 70 aHC patients (63 men) aged 65±11 years were included, with alcohol, viral or other causes cirrhosis in 35(50%), 23(33%), 12(17%) cases respectively. CLIP score was 2.7±1.7, with more than 3 nodules in 37(53%) cases. Largest nodule measured 7.6±4.5 cm. Median alpha-fetoprotein was 574 UI/mL. SRS was positive in 25/70 (35.7%) livers and 7/17 (41.2%) metastatic sites. Positive SRS patients differed from others for tumor size (9.2±4 vs. 6.7±4.6 cm, p=0.03), prothrombin time (PT) (75.2±15.2 vs. 61.9±19 %, p=0.005), albumin (34.1±5.9 vs. 30.5±7.2 g/L, p=0.04) and Child-Pugh (6.7±1.8 vs. 7.7±2.3, p=0.04). After multivariate analysis, only PT was associated with positive SRS (p=0.028). Immunohistochemistry was positive for SSTR2s in 6/7 tumors (SRS uptake in 5/6 cases). Conclusions: In advanced hepatocarcinoma, we report SRS uptake in 35.7% of livers and 41.2% of metastatic sites. SRS value in sreening patients for somatostatin analogue treatment remains to be assessed.

2014 update on non-small cell lung cancer (excluding diagnosis)

Lung cancer (LC) is a major public health issue because of its frequency, but especially because of the severity of this disease. The epidemiology has changed with an increased incidence in non-smokers and women. The ATS/ERS/IASLC classification of adenocarcinomas was modified in 2011, and they are now the most frequent histological subtype. More than half the cases of LC are diagnosed at the metastatic stage. Biopsies must provide tissue samples that are quantitatively large enough and of a good enough quality for diagnosis and to search for biomarkers. When the cancer seems to be localized, precise staging must be obtained. Treatment is based on the TNM classification. In localized stages, lobectomy associated with lymph node dissection is the standard therapy. Intraoperative chemotherapy improves survival in case of lymph node infiltration. Stereotactic radiation therapy and radiofrequency can be considered as specific cases. In cases with local progression, treatment is more controversial. In the presence of metastases, the goal is not a cure, but improving survival and quality of life. Numerous advances have been made with personalized treatment, (in particular in relation to the histological type and oncogenic addiction in tumors, access to new drugs, and improved management). Clinical research in thoracic cancer is very active. The fight against tobacco should remain a priority.