Patients with atherosclerotic peripheral arterial disease have a high risk of lung cancer: Systematic review and meta-analysis of literature.

PURPOSE: Lung cancer and atherosclerosis share common risk factors. Literature data suggest that the prevalence of lung malignancy in patients with peripheral arterial disease (PAD) is higher than in the general population. Our goal was to determine, through a systematic literature review, the prevalence of lung cancer in patients with PAD. METHODS: We consulted available publications in the Cochrane library, MEDLINE, PUBMED, EMBASE, and ClinicalTrials.gov. We included all articles, written in English or French, published between 1990 and 2020 reporting the prevalence of lung cancer in patients with PAD (atherosclerotic aortic aneurysm or peripheral occlusive diseases). Patients with coronary artery disease, cardiac valvulopathy or carotid stenosis were not included. We did not include case reports. We performed a critical analysis of each article. Data were collected from two independent readers. A fixed effect model meta-analysis allowed to estimate a summary prevalence rate. RESULTS: We identified 303 articles, and selected 19 articles according to selection criteria. A total of 16849 patients were included (mean age 68.3 years, 75.1% of males). Aortic aneurysms were found in 29% of patients and atherosclerotic occlusive disease in 66% of patients. Lung cancer was identified in 538 patients, representing a prevalence of 3%. DISCUSSION: Lung cancer is found in 3% of patients with atherosclerotic PAD. This prevalence is higher than that found in lung cancer screening programs performed in the general population of smokers and former smokers. These patients should be screened for lung cancer. Their selection may dramatically increase the benefit of lung cancer screening.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

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.

Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer.

Background: Various programed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed and used in clinical trials in association with different drugs. In order to harmonize and make PD-L1 testing in non-small-cell lung cancer (NSCLC) widely available, we conducted a multicenter study comparing PD-L1 standardized assays and laboratory-developed tests (LDTs). Methods: IHC with five anti-PD-L1 monoclonal antibodies (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers using Dako Autostainer Link 48 (3 centers), Leica Bond (2 centers) or Ventana BenchMark Ultra (2 centers) platforms. For each matching platform, 22C3, 28-8 and SP263 assays were performed. For nonmatching platforms and other antibodies, LDTs were developed in each center. A total of 35 stainings were performed for each case across different platforms and antibodies. PD-L1 staining was assessed in tumor cells and immune cells by seven trained thoracic pathologists. For statistical analysis, 1%, 50% and 1%, 5%, 10% expression thresholds were used for tumor cells and immune cells, respectively. Results: 28-8, 22C3 and SP263 assays were highly concordant for tumor cells staining across the five Dako or Ventana platforms. Among 27 LDTs developed in 7 centers on Dako, Ventana and Leica platforms, 14 (51.8%) demonstrated similar concordance when compared with reference assays for tumor cell staining. Clone SP263 achieved the highest concordance rate across all platforms. Lower concordance was observed for immune cells staining when using a four categories scale. Conclusion: 28-8, 22C3 and SP263 assays had close analytical performance for tumor cell staining across seven centers. Some LDTs on Dako, Ventana and Leica platforms achieved similar concordance, but caution is warranted for their validation. These LDTs will be further validated in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.

Anaplastic Kaposi's sarcoma: 5 cases of a rare and aggressive type of Kaposi's sarcoma.

BACKGROUND: Anaplastic Kaposi's sarcoma (KS) is a rare form of KS characterized clinically by the development of a tumour mass with unusual local aggressiveness and histologically by a specific architecture and cytological morphology. A very small number of limited series in endemic countries have established characteristics common to these anaplastic forms of KS. We present five patients with an anaplastic form in a context of KS ongoing for several years in a non-endemic country. MATERIALS AND METHODS: We collected 5 cases of anaplastic KS followed in our department over a period of 20years. We describe the main developmental, clinical, virological and histological features. RESULTS: The cases involved 4 men and 1 woman whose mean age at diagnosis of anaplastic KD was 70years, with an average time of 25years between initial diagnosis of KD and anaplastic transformation. Our patients were all treated with chemotherapy and/or radiotherapy (RT) prior to diagnosis of anaplastic transformation. All patients had a tumour mass of the lower limbs developing in classically indolent KS with associated chronic lymphoedema. Progression was very aggressive locally with deep invasion of the soft tissues as well as osteoarticular involvement, without visceral dissemination. At present, three patients are dead, one patient is showing partial response, and one patient is in locoregional progression. Diagnosis of the disease was based on histopathological findings. The tumour cells were undifferentiated, pseudo-cohesive, and chiefly organized in sheets. The mitotic count was high (27 mitoses per 10 fields at high magnification). Necrosis was constant. DISCUSSION: To our knowledge, this is the first series describing anaplastic Kaposi's sarcoma in a non-endemic country. The severity of the prognosis, despite the absence of visceral dissemination, is related to the local aggressiveness of anaplastic KS and to its resistance to radiotherapy and chemotherapy, with amputation being required in certain cases.

The HIV-1 viral synapse signals human foreskin keratinocytes to secrete thymic stromal lymphopoietin facilitating HIV-1 foreskin entry.

The complexity of signal transduction resulting from the contact of human immunodeficiency virus type 1 (HIV-1)-infected cells and mucosal cells has hampered our comprehension of HIV-1 mucosal entry. Such process is driven efficiently only by viral synapse contacts, whereas cell-free HIV-1 remains poorly infectious. Using CD4+ T-cells expressing only HIV-1 envelope inoculated on human adult foreskin tissues, we designed methodologies to identify the signals transduced in foreskin keratinocytes following HIV-1-envelope-dependent viral synapse formation. We find that the viral synapse activates the MyD88-independent TLR-4-nuclear factor (NfκB) signaling pathway in keratinocytes and the subsequent secretion of cytokines including thymic stromal lymphopoietin (TSLP), a cytokine linking innate and T-helper type 2-adaptive immune responses. Moreover, the viral synapse upregulates the non-coding microRNA miR-375, known to control TSLP, and transfection of keratinocytes with anti-miR-375 blocks significantly TSLP secretion. Thus, the secretion of TSLP by keratinocytes is induced by the viral synapse in a miR-375 controlled manner. At the tissue level, these signals translate into the epidermal redistribution of Langerhans cells and formation of conjugates with T-cells, recapitulating the initial events observed in human foreskin infection by HIV-1. These results open new possibilities for designing strategies to block mucosal HIV-1 transmission, the major pathway by which HIV-1 spreads worldwide.

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.

The immune microenvironment: a major player in human cancers.

Cancer is a major public health issue and figures among the leading causes of death in the world. Cancer development is a long process, involving the mutation, amplification or deletion of genes and chromosomal rearrangements. The transformed cells change morphologically, enlarge, become invasive and finally detach from the primary tumor to metastasize in other organs through the blood and/or lymph. During this process, the tumor cells interact with their microenvironment, which is complex and composed of stromal and immune cells that penetrate the tumor site via blood vessels and lymphoid capillaries. All subsets of immune cells can be found in tumors, but their respective density, functionality and organization vary from one type of tumor to another. Whereas inflammatory cells play a protumoral role, there is a large body of evidence of effector memory T cells controlling tumor invasion and metastasis. Thus, high densities of memory Th1/CD8 cytotoxic T cells in the primary tumors correlate with good prognosis in most tumor types. Tertiary lymphoid structures, which contain mature dendritic cells (DC) in a T cell zone, proliferating B cells and follicular DC, are found in the tumor stroma and they correlate with intratumoral Th1/CD8 T cell and B cell infiltration. Eventually, tumors undergo genetic and epigenetic modifications that allow them to escape being controlled by the immune system. This comprehensive review describes the immune contexture of human primary and metastatic tumors, how it impacts on patient outcomes and how it could be used as a predictive biomarker and guide immunotherapies.

High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial.

The dosage of soluble programmed cell death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed in a prospective patient cohort. We evaluated the clinical impact of sPD-L1 level measured at the time of diagnosis for newly diagnosed diffuse large B-cell lymphoma (DLBCL). Soluble PD-L1 was measured in the plasma of 288 patients enrolled in a multicenter, randomized phase III trial that compared R-high-dose chemotherapy with R-CHOP. The median follow-up was 41.4 months. A cutoff of 1.52 ng/ml of PD-L1 level was determined and related to overall survival (OS). Patients with elevated sPD-L1 experienced a poorer prognosis with a 3-year OS of 76% versus 89% (P<0.001). Considering clinical characteristics, the multivariate analysis retained this biomarker besides bone marrow involvement and abnormal lymphocyte-monocyte score as independently related to poor outcome. sPD-L1 was detectable in the plasma and not in the serum, found elevated in patients at diagnosis compared with healthy subjects and its level dropped back to normal value after CR. The intention-to-treat analysis showed that elevated sPD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). Plasma PD-L1 protein is a potent predicting biomarker in DLBCL and may indicate usefulness of alternative therapeutic strategies using PD-1 axis inhibitors.

Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study.

BACKGROUND: The optimal treatment of large-cell neuroendocrine carcinoma (LCNEC) of the lung remains unclear. Here, our primary objective was to assess the efficacy of cisplatin-etoposide doublet chemotherapy in advanced LCNEC. Accuracy of the pathological diagnosis and treatment toxicity were assessed as secondary objectives. PATIENTS AND METHODS: Prospective, multicentre, single-arm, phase II study with a centralised review of treatment-response and pathological data. Patients had untreated performance status (PS) 0/1 stage IV/IIIB LCNEC and received cisplatin (80 mg/m22 d1) and etoposide (100 mg/m22 d1-3) every 21 days. RESULTS: Eighteen centres included 42 patients (mean age, 59 ± 9 years; 69% men; median of four cycles/patient). At least one grade-3/4 toxicity occurred in 59% of patients (neutropaenia, thrombocytopaenia, and anaemia in 32%, 17%, and 12%, respectively). The median progression-free survival (PFS) and overall survival (OS) were 5.2 months (95% confidence interval, CI, 3.1-6.6) and 7.7 months (95% CI, 6.0-9.6), respectively. The centralised pathologist review reclassified 11 of 40 (27.5%) patients: 9 as small-cell lung cancer, 1 as undifferentiated non-small-cell lung cancer, and 1 as atypical carcinoid. Survival data were not significantly changed by excluding the reclassified patients. CONCLUSIONS: The pathological diagnosis of LCNEC is difficult. The outcomes of advanced LCNEC treated with cisplatin-etoposide doublets are poor, similar to those of patients with advanced small-cell lung carcinoma (SCLC).

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.

Adult celiac disease with severe or partial villous atrophy: a comparative study.

BACKGROUND AND AIMS: While severe villous atrophy (SVA) is the most typical histological feature in adult celiac disease (ACD), partial villous atrophy (PVA) is now also frequently found. So far, the impact of the severity of villous atrophy on the clinical presentation of ACD has been scarcely investigated. We aimed to compare the clinical, biological and immune features and outcomes in ACD patients presenting with PVA at diagnosis versus patients with SVA. PATIENTS AND METHODS: Medical files of 48 patients with ACD diagnosed between 1992 and 2003 were retrospectively studied. The diagnosis was based on the presence of intestinal villous atrophy, with increases in intraepithelial lymphocytes and circulating celiac specific antibodies. Villous atrophy was classified as severe (subtotal and total) or partial. Symptoms, biological signs of malabsorption, immune markers, bone mineral density at diagnosis and response to gluten-free diet were recorded. RESULTS: At diagnosis, ten patients (four M/six F) had PVA and 38 patients (five M/33 F) had SVA, with a median age of 54 and 33 years, respectively (p<0.05). Positivity for specific antibodies, HLA typing and frequency of autoimmune disease at diagnosis were similar in both PVA and SVA patients, as was their response to gluten-free diet. Diarrhea, malabsorption syndrome and osteopenia were independent of the degree of villous atrophy. CONCLUSION: PVA was observed in 21% of patients with ACD. Except for their older age at diagnosis, patients with PVA presented with similar clinical, biological and immune characteristics and outcomes as did patients with SVA.

Non-Hodgkin's lymphomas with Burkitt-like cells are associated with c-Myc amplification and poor prognosis.

Out of 344 patients with newly diagnosed non-Hodgkin's lymphoma (NHL), this study identified 16 patients presenting Burkitt-like cells (BLCs) after cytological and/or histological review. Conventional cytogenetic analysis showed at diagnosis complex chromosomal abnormalities in 13 cases and a normal karyotype in three cases. However, neither t(8;14)(q24;q32) nor the variants t(2;8)(p12;q24) or t(8;22)(q24;q11) was detected. FISH studies showed c-MYC amplification in all cases with four to more than seven copies in 10 - 77% metaphase or inter-phase cells. This study did not observe any gene fusion signal for c-MYC/IgH excluding a t(8;14) translocation and partial tri or polysomy of chromosome 8. It also excluded in that cases a break apart for the c-MYC locus. This study also never detected IgL/c-MYC, IgK/c-MYC or X-c-MYC. The BLCs were present whatever the lymphoma sub-type: follicular lymphoma (FL) was diagnosed in six out of 16 patients, mantle cell lymphoma (MCL) in four out of 16 patients, marginal zone lymphoma (MZL) in two out of 16 patients and diffuse large B-cell lymphomas (DLBCL) in three out of 16 patients. One additional patient presented a T-cell lymphoma. The clinical course was aggressive with a poor prognosis, as death occurred in nine patients, within 6 months after diagnosis for eight of them. These data could suggest a sub-group of NHL patients (15 B-NHL, 1 T-NHL) have been identified with a poor prognosis characterized by the association of Burkitt-like cells and c-MYC amplification without t(8;14)(q24;q32) or its variants. The possibility that this profile may represent a distinct morphologic NHL sub-set remains to be determined on a large cohort of patients.