Chemoradiotherapy efficacy is predicted by intra-tumour CD8+/FoxP3+ double positive T cell density in locally advanced N2 non-small-cell lung carcinoma.

BACKGROUND: Radiotherapy is a standard of care for locally advanced stage III N2 non-small-cell lung carcinoma (NSCLC) combined with surgery/chemotherapy. Radiotherapy is hypothesised to induce tumour immunogenic cell death, to release neoantigen resulting in intra-tumoural immune infiltration and abscopal effect. Conversely, it has not been demonstrated if immune cells are necessary to drive radiotherapy efficacy and predict patient's survival. PATIENTS AND METHODS: We retrospectively analysed tumour samples and clinical data from 113 patients, 89 resected (PORT) and 24 non-resected (DRC) N2-NSCLC treated with chemotherapy and radiotherapy (same radiotherapy department from 2002 to 2015). The immune environment was characterised with in situ multiplex staining (CD8, FoxP3, PD-L1 and cytokeratin) and correlated with clinical data and survival. RESULTS: High density of CD8+ T cells was associated with OS (p = 0.04, HR = 1.93 [0.99-3.78]) and DFS (p = 0.003, HR = 2.42 [1.31-4.47]) in the PORT. High density of CD8+/FoxP3+ double positive cells was associated with OS (p = 0.01, HR = 1.97 [1.11-3.48]) in the whole population, with OS (p = 0.05, HR = 1.92 [0.98-3.74]) and PFS (p = 0.03, HR = 1.83 [1.03-3.23]) in the PORT without reaching significance for the DRC. Intermediate PD-L1 expression in tumour cells (TPS = 1-49%) was associated with a higher survival in the PORT. CONCLUSIONS: Intra-tumoural CD8+ T cell and particularly CD8+/FoxP3+ double positive T cell densities predict survival in stage III N2-NSCLC suggesting the need for a pre-existing intra-tumour immunity to mediate the action of radiotherapy. Density of CD8+/FoxP3+ cells was the best predictor of patient's survival in multivariate analysis and could represent a biomarker of radiotherapy efficacy.

[IHC, FISH, CISH, NGS in non-small cell lung cancer: What changes in the biomarker era?] / IHC, FISH, CISH, NGS dans les cancers bronchiques non à petites cellules : quelles évolutions dans l'ère des biomarqueurs ?

Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards. These medications are conditioned to the expression of biomarkers that require specific tools in routine to measure them. We will detail in this chapter several techniques of anatomopathology, cytogenetics and molecular biology necessary for the detection of biomarkers in lung cancers, and their applications in thoracic oncology in 2018.

[Malignant pleural mesothelioma: The role of surgery]. / Mésothéliome pleural malin : place de la chirurgie.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease, whose incidence is increasing. Asbestos is the primary causal agent. STATE OF KNOWLEDGE: Knowledge about MPM has evolved. Thoracoscopy is essential for diagnosis of MPM. It allows performing pleural biopsies, to study the extent of the disease and to relieve dyspnea. The pathological diagnosis is also better codified with immunohistochemistry and with analysis by expert of Mesopath group. Curative surgical treatments are pleurectomy decortication and extended pneumonectomy in combination with chemotherapy and/or radiotherapy. Those heavy treatments improve survival in highly selected patients. For the other patients, supportive measures will be considered to reduce pain and dyspnea. PROSPECT: Radical surgical treatment is only offered in therapeutic trials or multimodal treatment. Its place is not formally established. New therapies associated to surgical treatment are being studied. CONCLUSIONS: Surgical management of MPM has to be operated in specialized teams where the survival benefit and quality of life is discussed case by case.

[Biomarkers predictive of PD1/PD-L1 immunotherapy in non-small cell lung cancer]. / Biomarqueurs prédictifs de l'immunothérapie anti-PD1/PD-L1 dans le cancer broncho-pulmonaire non à petites cellules.

Immune checkpoint inhibitors (ICI), targeting the PD1/PD-L1 axis has shown their efficacy in lung cancer but only in a restricted population of patients, thus it is mandatory to identify biomarkers predicting the clinical benefit. In this article we will describe and analyzed biomarkers already published, from protein, to RNA and at last DNA markers, discussing each markers feasibility and interest. In the future, combined analysis of several markers will probably be proposed, particularly with the increasing complexity of therapy schema with molecules association.

[Analysis of immune microenvironment by multiplex immunohistochemistry in locally advanced non-small cell lung cancer: Principles and perspectives]. / Analyse du microenvironnement immunitaire par immunohistochimie multiplex dans le cancer bronchopulmonaire non à petites cellules localement évolué : principes et perspectives.

Recent therapeutic advances in non-small cell lung cancer allow a better understanding of the interactions between the tumour and its direct immune environment. The identification of new immune biomarkers integrating both cell subpopulations and their interactions is a real issue in oncology. New techniques of tissue analysis, particularly multiplex immunohistochemistry, consisting of a labelling of several antigens of interest by immunofluorescence on the same slide, provide a better understanding of the tumour environment. Integration of these modalities of analysis to the therapeutic decision is promising, because it allows an increased characterization of each tumour, particularly interesting with radiotherapy and immunotherapy. This article describes the potential of these assays in locally advanced non-small cell lung cancer.

Dedifferentiated primary mediastinal liposarcoma mimicking a thymic tumor.

Mediastinal tumors are heterogeneous and the diagnosis depends on their location in the mediastinum. The most frequent tumors are germinal tumor, lymphoma and thymoma. The clinical and radiological aspects are often not sufficient to orient the diagnosis and biopsy is necessary to confirmed it. Here, we present a rare case of an anterior mediastinal mass incidentally detected in a 63 years old man during assessment for asthma. The lesion was presumptively diagnosed as a thymic epithelial tumor based on location and radiological characteristics. Surgical biopsy revealed a primary dedifferentiated mediastinal liposarcoma with multiple lung metastases.

Late costal osteomyelitis with a cutaneous fistula after flame burns: a case report.

Chest wall defects are an unusual complication of burn injury, generally seen after high-voltage electrical burns. Here we report the case of a 57-year-old man who developed costal chondritis and osteomyelitis 23 months after flame injury, which covered 50% of the total body surface area. Management included the resection of two ribs and coverage with an omental flap, overlaid by a split-thickness skin graft during the same surgical procedure. Declaration of interest: The authors have no conflict of interest to declare.

Solitary fibrous tumor of the pleura: Can computed tomography features help predict malignancy? A series of 56 patients with histopathological correlates.

OBJECTIVE: To identify computed tomography (CT) predictors of malignancy, from a retrospective study of preoperative CT scans of patients with solitary fibrous tumors (SFT) of the pleura. PATIENTS AND METHODS: The CT scans of 56 patients with histopathologically confirmed SFT (33 women and 23 men; mean age, 60years) who underwent surgery between December 2004 and November 2012 were retrospectively analyzed by three radiologists working in consensus, blinded to the final histological diagnosis. RESULTS: SFT was asymptomatic and incidentally discovered in 22 patients (45.8%). Resection specimen analysis (R0 resection in all cases) revealed that 23 tumors (41%) were malignant. The CT features, which significantly differed between malignant and benign SFTs were tumor size (P=0.002) with a discriminative threshold value of 10cm, tumor heterogeneity before (P=0.02) and after (P=0.03) intravenous administration of iodinated contrast material, presence of intratumoral hydric attenuation areas (P=0.01), pleural effusion (P=0.01), measurable intratumoral vessels (P=0.02), hypervascularization with visible intratumoral vessels and/or marked enhancement (P=0.001). Presence of intratumoral calcifications (P=0.2) and maximum post-contrast enhancement value (P=0.6) were not significantly different between the two groups. CONCLUSION: A size greater than or equal to 10cm, hypervascularization, attenuation heterogeneity and association with pleural effusion are individual variables that suggest malignant SFT on CT.

Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer.

BACKGROUND: Cisplatin-resistant non-small cell lung cancer (NSCLC) cells are often characterized by alterations in vitamin B-related metabolic processes, including the overexpression and hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and the downregulation of pyridoxal kinase (PDXK), correlating with elevated apoptosis resistance. Low PDXK expression is an established negative prognostic factor in NSCLC. PATIENTS AND METHODS: We determined by immunohistochemistry the expression of PARP1 and the level of its product, poly(ADP-ribose) (PAR), in two independent cohorts of patients with resected NSCLC. RESULTS: Intratumoral high levels (above median) of PAR (but not PARP1 protein levels) had a negative prognostic impact in both the training (92 stage I subjects) and validation (133 stage I and II subjects) cohorts, as determined by univariate and multivariate analyses. The simultaneous assessment of PAR and PDXK protein levels improved risk stratification. CONCLUSION: NSCLC patients with high intratumoral PARP1 activity (i.e. elevated PAR levels above median) and low PDXK expression (below median) had a dismal prognosis, while patients with low PARP1 activity and high PDXK expression had a favorable outcome. Altogether, these results underscore the clinical potential and possible therapeutic relevance of these biomarkers.

[Management of malignant pericardial effusion in lung cancer]. / Prise en charge des péricardites secondaires à un cancer broncho-pulmonaire.

Acute pericarditis associated with lung cancer is a relatively frequent complication but is usually not symptomatic unless it causes tamponade. The clinical presentation is classically with dyspnea, thoracic pain, signs of right cardiac failure then left cardiac failure and syncope but it is often a difficult diagnosis in a patient with multi-symptomatic disease. The diagnosis is based on cardiac echography. Toxicity due to radiotherapy or more rarely an infectious etiology must be considered. Clinically significant effusions must be drained because of the high rate of recurrence after a simple aspiration. Drainage is formally indicated when, at echocardiography, the effusion exceeds 20mm in diastole, in cases of tamponade or in cases of compromised hemodynamic status. The formation of a pericardial window at thoracotomy prevents recurrences. Based on old, retrospective, very heterogeneous case series the prognosis, is generally considered to be poor with a median survival which does not exceed 100 days and a one year survival generally lower than 10%. Prognosis is better where diagnosis occurs at an earlier stage allowing regular follow-up and surgical intervention in a non-emergency setting.

Mediastinal recurrence from ovarian cystadenocarcinoma presenting as pleuro-pericardial cyst.

A 56 year-old woman (treated for ovarian cystadenocarcinoma 9-yrs before) presented a slowly increasing dyspnea. CT-scan revealed a mediastinal cyst with typical radiological pattern compatible with benign pleuro-pericardial cyst. The cyst was removed via right thoracoscopy. Surprisingly, the pathology were indicative of cystic mediastinal recurrence from ovarian adenocarcinoma.

Systematic lymph node dissection in lung metastasectomy of renal cell carcinoma: an 18 years of experience.

BACKGROUND: Pulmonary metastasectomy of renal cell carcinomas (RCC) remains controversial. Thoracic lymph node involvement (LNI) is a known prognostic factor. The aim of our analysis is to evaluate whether patients with LNI, and particularly N2 patients, should be excluded from surgical treatment. METHODS: We retrospectively reviewed data from 122 patients who underwent operations at two French thoracic surgery departments between 1993 and 2011 for RCC lung metastases. RESULTS: The population consisted of 38 women and 84 men; the average age at time of metastasectomy was 63.3 years (min: 43, max: 82). LNI was identified as a prognostic factor using univariate and multivariate analysis (median survival: 107 months vs. 37 months, P = 0.003; HR = 0.384 (0.179; 0.825), P = 0.01, respectively). Although differences in survival between metastases at the hilar and mediastinal locations were not significant (median survival: 74 months vs. 32 months, respectively, P = 0.75), length of survival time was associated with disease-free interval less than 12 months (median survival: 23 months vs. 94 months, P < 0.0001; HR = 3.081 (1.193; 7.957), P = 0.02). CONCLUSION: Although LNI has an adverse effect on survival; long-term survival can be achieved in pN+ patients. Consequently, these patients should not be excluded from surgery. Systematic lymphadenectomy should be performed to obtain more accurate staging and to determine appropriate adjuvant treatment.

Thoracic endometriosis syndrome: CT and MRI features.

Thoracic endometriosis is considered to be rare, but is the most frequent form of extra-abdominopelvic endometriosis. Thoracic endometriosis syndrome affects women of reproductive age. Diagnosis is mainly based on clinical findings, which can include catamenial pneumothorax and haemothorax, non-catamenial endometriosis-related pneumothorax, catamenial haemoptysis, lung nodules, and isolated catamenial chest pain. Symptoms are typically cyclical and recurrent, with a right-sided predominance. Computed tomography (CT) is the first-line imaging method, but is poorly specific; therefore, its main role is to rule out other pulmonary diseases. However, in women with a typical clinical history, some key CT findings may help to confirm this often under-diagnosed syndrome. MRI can also assist with the diagnosis, by showing signal changes typical of haemorrhage within diaphragmatic or pleural lesions.

Pneumorachis after cocaine sniffing.

Air in the epidural space is called pneumorachis. The usual mechanism of pneumorachis is air diffusion from the mediastinal tissue layers through the inter-vertebral foramen. Alternatively, air can diffuse directly after spine traumas (e.g., blunt deceleration with vertebral dislocation) or medical procedures. Several mechanisms could explain pneumomediastinum and pneumorachis after cocaine sniffing. Passive apnea and/or cough that occur after sniffing can cause intra alveolar hyper-pressure, which is responsible for alveolar rupture and air diffusion. Another mechanism is alveolar wall fragility and rupture induced by repeated cocaine sniffing, in turn causing air diffusion to the mediastinum, sub-cutaneous tissues and the epidural space. The diagnosis is usually made on Chest tomography scan. Management consists in close monitoring in the intensive care unit to detect aggravation of pneumomediastinum and pneumorachis, which would require surgical management. Supplemental nasal oxygen can be given to accelerate nitrogen washout. We present a case of a 28 years old male who presented to the emergency department for chest pain directly after sniffing cocaine. A computed tomography scan of the chest showed pneumomediastinum, pneumorachis and sub-cutaneous emphysema. The patient was admitted for 24 h: after that delay, surveillance chest tomodensitometry showed stability, and he could be discharged without further treatment.

[Multidisciplinary approach of ventilated necrotizing pneumonia]. / Prise en charge multidisciplinaire des pneumopathies nécrosantes ventilées.

Pneumonia may be complicated by necrosis and destruction of lung tissue due to factors related to both pathogen and host as well as to their interactions. Lung necrosis may lead to two main entities sharing common features, but also several clinical and pathological differences: lung abscesses and necrotizing pneumonia. Necrotizing pneumonia is characterized by diffuse, possibly bilateral, lung parenchyma inflammation with multiple cavitations and necrosis. Necrotizing pneumonia is usually associated with severe sepsis and acute respiratory failure. Adequate antibiotics, mechanical ventilation, pleural drainage, and prolonged supportive care are mandatory. Adult patients with necrotizing pneumonia may require surgery. In our practice, indications for surgery are: (1) uncontrolled sepsis in spite of medical therapy and chest drainage; (2) major air leaks responsible for ventilation difficulties with serious hypoxemia/hypercapnia; and (3) hemodynamic disturbances by compression of vena cava and/or right heart cavities by tumor-like forms. Surgical treatment should be adapted to each case. Despite serious morbidity, massive parenchyma damage and prolonged hospitalization, long-term outcome following necrotizing pneumonia seems good when multidisciplinary care management is used in these patients with unusual but severe respiratory infectious disease.

FADD protein release mirrors the development and aggressiveness of human non-small cell lung cancer.

BACKGROUND: The need to unfold the underlying mechanisms of lung cancer aggressiveness, the deadliest cancer in the world, is of prime importance. Because Fas-associated death domain protein (FADD) is the key adaptor molecule transmitting the apoptotic signal delivered by death receptors, we studied the presence and correlation of intra- and extracellular FADD protein with development and aggressiveness of non-small cell lung cancer (NSCLC). METHODS: Fifty NSCLC patients were enrolled in this prospective study. Intracellular FADD was detected in patients' tissue by immunohistochemistry. Tumours and distant non-tumoural lung biopsies were cultured through trans-well membrane in order to analyse extracellular FADD. Correlation between different clinical/histological parameters with level/localisation of FADD protein has been investigated. RESULTS: Fas-associated death domain protein could be specifically downregulated in tumoural cells and FADD loss correlated with the presence of extracellular FADD. Indeed, human NSCLC released FADD protein, and tumoural samples released significantly more FADD than non-tumoural (NT) tissue (P=0.000003). The release of FADD by both tumoural and NT tissue increased significantly with the cancer stage, and was correlated with both early and late steps of the metastasis process. CONCLUSION: The release of FADD by human NSCLC could be a new marker of poor prognosis as it correlates positively with both tumour progression and aggressiveness.

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.

[Effect of tinzaparin on survival in non-small-cell lung cancer after surgery. TILT: tinzaparin in lung tumours]. / Effet de la tinzaparine sur la mortalité du cancer bronchique non à petites cellules opéré.

BACKGROUND: Experimental and clinical findings suggest that low molecular-weight heparins may improve overall survival in patients with cancer. The evidence is still limited and additional studies are needed to confirm these preliminary findings. METHODS: Patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer will be included in a prospective, controlled, randomized, multicenter open trial. Patients in the control group will receive usual postoperative care including chemotherapy when indicated. Patients in the experimental group will receive tinzaparin given subcutaneously as a daily 100 IU/kg dose for 90 days along with usual postoperative care. Patients will be followed-up for three to eight years. Main end-point is the overall survival. Five hundred and fifty patients are needed to demonstrate a 10% absolute increase in survival in the experimental group. EXPECTED RESULTS: A 10% absolute increase in the survival rate is expected in the patients receiving tinzaparin.