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Abstract Background PARP inhibitors (PARPi) are used in the treatment of ovarian, breast, pancreatic, and prostate cancers. Pneumonitis has been identified as a potential side effect, with a higher meta-analysis-assessed risk for olaparib versus other PARPi. Olaparib-induced interstitial lung disease (O-ILD) was first described within the Japanese population, with few information available for Caucasian patients. Methods We performed a retrospective study by pooling data from the French and Belgian pharmacovigilance databases from 2018 to 2022. Patients with O-ILD were included following a central review by: 1) pharmacologists using the French drug causality assessment method; 2) senior pneumologists or radiologists, using the Fleischner Society’s recommendations. Results Five patients were identified and analysed. All were females, with ovarian or breast cancer. Median age at O-ILD diagnosis was 71 (38–72) years old, with no smoking history. Median delay between treatment initiation and symptom occurrence was 12 (6–33) weeks. Pneumonitis severity assessed using the Common Terminology Criteria for Adverse Events V5 was Grade 3 (n = 4) or 2 (n = 1). CT-scan review (n = 3) described hypersensitivity pneumonitis reaction as a common pattern. Bronchioalveolar lavage (n = 4) revealed lymphocytic alveolitis. Treatments relied on olaparib discontinuation (n = 5) and glucocorticoid intake (n = 4), with no fatal issue. Safe re-challenge with PARPi occurred in two patients. Forty additional O-ILD cases were identified in the WHO VigiBase database, including one fatal case. Conclusions PARPi-ILD is a rare but potentially life-threatening disease, presenting as a hypersensitivity pneumonitis pattern within 3 months of PARPi initiation. Treatment primarily relies on medication discontinuation. Re-challenging with another PARPi could be considered. Clinical trial number CEPRO #2023–010.

BackgroundImmune checkpoint inhibitors (ICIs) have considerably improved patient outcomes in various cancer types, but their efficacy remains poorly predictable among patients. The intestinal microbiome, whose balance and composition can be significantly altered by antibiotic use, has recently emerged as a factor that may modulate ICI efficacy. The objective of this systematic review and meta-analysis is to investigate the impact of antibiotics on the clinical outcomes of cancer patients treated with ICIs.MethodsPubMed and major oncology conference proceedings were systematically searched to identify all studies reporting associations between antibiotic use and at least one of the following endpoints: Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR) and Progressive Disease (PD) Rate. Pooled Hazard Ratios (HRs) for OS and PFS, and pooled Odds Ratios (ORs) for ORR and PD were calculated. Subgroup analyses on survival outcomes were also performed to investigate the potential differential effect of antibiotics according to cancer types and antibiotic exposure time windows.Results107 articles reporting data for 123 independent cohorts were included, representing a total of 41,663 patients among whom 11,785 (28%) received antibiotics around ICI initiation. The pooled HRs for OS and PFS were respectively of 1.61 [95% Confidence Interval (CI) 1.48-1.76] and 1.45 [95% CI 1.32-1.60], confirming that antibiotic use was significantly associated with shorter survival. This negative association was observed consistently across all cancer types for OS and depending on the cancer type for PFS. The loss of survival was particularly strong when antibiotics were received shortly before or after ICI initiation. The pooled ORs for ORR and PD were respectively of 0.59 [95% CI 0.47-0.76] and 1.86 [95% CI 1.41-2.46], suggesting that antibiotic use was significantly associated with worse treatment-related outcomes.ConclusionAs it is not ethically feasible to conduct interventional, randomized, controlled trials in which antibiotics would be administered to cancer patients treated with ICIs to demonstrate their deleterious impact versus control, prospective observational studies and interventional trials involving microbiome modifiers are crucially needed to uncover the role of microbiome and improve patient outcomes. Such studies will reduce the existing publication bias by allowing analyses on more homogeneous populations, especially in terms of treatments received, which is not possible at this stage given the current state of the field. In the meantime, antibiotic prescription should be cautiously considered in cancer patients receiving ICIs.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42019145675.

Background The IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC).Methods In a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131).Results Forty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8–41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3–5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity.Conclusions Neoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.

Abstract Background The phase I trial of the humanized anti-CD26 monoclonal antibody YS110 for CD26-expressing tumors was conducted recently. The present study identifies a potential prognostic biomarker for CD26-targeted therapy based on the phase I data. Methods Box and Whisker plot analysis, Scatter plot analysis, Peason product moment correlation/Spearman’s rank-difference correlation, Bar graph analysis, and Receiver Operating Characteristics (ROC) were used to examine the correlation between sCD26 titer variation with YS110 administration and tumor volume change, RECIST criteria evaluation and progression free survival (PFS). Mechanism for serum sCD26 titer variation was confirmed by in vitro experimentation. Results Serum sCD26/DPP4 titer was reduced following YS110 administration and gradually recovered until the next infusion. Serum sCD26/DPP4 titer before the next infusion was sustained at lower levels in Stable Disease (SD) cases compared to Progressive Disease cases. ROC analysis defined the cut-off level of serum sCD26/DPP4 titer variation at day 29 pre/post for the clinical outcome of SD as tumor response or PFS. In vitro experimentation confirmed that YS110 addition reduced sCD26 production from CD26-expressing tumor and non-tumor cells. Conclusions Our study indicates that serum sCD26/DPP4 titer variation in the early phase of YS110 treatment is a predictive biomarker for evaluating therapeutic efficacy.

Abstract Background Choroidal metastases are the most common eye metastatic site. The prevalence of choroidal metastases in NSCLC patients has been reported to vary from 0.2 to 7% in historical series. Although previously reported, little is known about choroidal metastasis in Epidermal Growth Factor Receptor (EGFR)-mutant Non-small cell lung cancer (NSCLC). This study sought to describe the prevalence of choroidal metastases among patients with EGFR-mutated NSCLC and their characteristics, and to estimate their impact on prognosis. Methods We conducted a single-center retrospective study including all consecutive metastatic EGFR-mutant NSCLC patients, from Sept. 2015 to Oct. 2018. The EGFR-mutant NSCLC patients were identified via the Department of Genetics’ files. Patients who exhibited choroidal metastases were compared to patients without choroidal metastases. Kaplan-Meier analysis and log-rank test were conducted to assess median overall survival (OS) from diagnosis for the two groups. The study was approved by the IRB as CEPRO number #2020–010. Results Prevalence of choroidal metastases in EGFR-mutated NSCLCs was 8.4% (7/83). Five were women, and four current or former smokers. Molecular analysis showed three tumors with exon 19 deletion, three with L858R mutation, and one with complex exon 21 mutation. The choroidal metastases were symptomatic in six/seven patients. Visual disturbances decreased in all but one symptomatic cases upon EGFR TKI, and the choroidal response was maintained over time. Median follow-up was 42.2 mo (95%CI [37.2–47.1]). Median OS in the choroidal metastasis group was 23.4 mo (95%CI [0.1–51.4]) versus 27.9 mo (95%CI [16.9–38.9]) in the non-choroidal metastasis group (p = 0.32). In the choroidal metastasis group, 2-year and 5-year OS were 47.6 and 0%, respectively, versus 55.8 and 26.3% in the non-choroidal metastasis subset. Conclusions Choroidal metastases in NSCLC EGFR-mutant patients are rare but should be systematically suspected in case of visual disturbance. TKIs are efficient for treating visual symptoms. Whether choroidal metastases confer a worse prognosis remains unclear owing to the third-generation EGFR TKI osimertinib first-line registration.

Background Computed tomography (CT) screening has improved lung cancer survival, yet increasingly detects small lung lesions. Thus, the number of transthoracic lung biopsies (TTLB) for small nodules is expected to rise significantly. The aim of the present study was to evaluate the diagnostic accuracy and safety of CT-guided TTLB for nodules ≤20 mm versus nodules >20 mm. Study design and methods Data for CT-guided TTLBs from 474 consecutive patients were prospectively collected over a 3-year period (198 lesions ≤20 mm and 276 lesions >20 mm) in a teaching hospital and analysed in terms of diagnostic performance and complications. Results There were more conclusive biopsies in the >20 mm lesion group (n=236, 85.5%) than in ≤20 mm lesion group (n=140, 70.7%; p20 mm lesions. Pneumothorax requiring drainage was significantly more common for ≤20 mm lesions, compared to TTLB of larger lesions (9.6% versus 4.3%; p=0.02). Prolonged hospital stay due to pneumothorax occurred in 27 (17.4%) TTLBs of ≤20 mm lesions and 15 (7%) TTLBs of >20 mm lesions (p=0.002). There were no deaths. The only variable significantly associated with diagnostic failure in the ≤20 mm lesion group was the radiologist's experience. Interpretation TTLBs for lesions ≤20 mm were associated with slightly lower diagnostic performance, whereas the higher rate of major complications was still inferior to that extrapolated from United States insurance databases.

Due to occupational asbestosis exposure, the incidence of malignant pleural mesothelioma (MPM) has continuously increased over the last 30 years, with a plateau anticipated around the year 2030 in Western countries. Molecular MPM carcinogenesis involves alterations of NF2, RASSF1, LATS2WT1, p16, as well as BAP-1tumor-suppressor genes, which usually regulate apoptosis, cell invasion, motility, cell division, chromatin remodeling, as well as control of DNA repair. In few selected patients, debulking surgery consisting of pleurectomy-decortication is carried out, resulting in unsatisfactory long-term results. For about 15 years, first-line chemotherapy has been primarily based on a doublet of pemetrexed and cisplatin. Adding the monoclonal antibody bevacizumab (Avastin ® ), which targets vascular endothelial growth factor (VEGF), has been shown to improve overall survival (OS) by nearly 19 months. The emergence of immune check-point inhibitors (ICIs) in MPM treatment has recently been associated with substantial survival improvements in both second- and first-line settings. Similarly to non-small-cell lung cancer (NSCLC) patients, on-going trials are presently exploring the chemotherapy-ICI combination in MPM management, and depending on their results, this combination could represent a further major advance in this previously orphan disease. The current article reviews recent clinical trial results, as well as future clinical developments in this moving field.

Background Whereas first-line bronchial artery embolisation (BAE) is considered standard of care for the management of severe haemoptysis, it is unknown whether this approach is warranted for non-severe haemoptysis.Research question To assess the efficacy on bleeding control and the safety of first-line BAE in non-severe haemoptysis of mild abundance.Study design and methods This multicentre, randomised controlled open-label trial enrolled adult patients without major comorbid condition and having mild haemoptysis (onset

Abstract Background RASSF1A, a tumor suppressor gene, is frequently inactivated in lung cancer leading to a YAP-dependent epithelial-mesenchymal transition (EMT). Such effects are partly due to the inactivation of the anti-migratory RhoB GTPase via the inhibitory phosphorylation of GEF-H1, the GDP/GTP exchange factor for RhoB. However, the kinase responsible for RhoB/GEF-H1 inactivation in RASSF1A-depleted cells remained unknown. Methods NDR1/2 inactivation by siRNA or shRNA effects on epithelial-mesenchymal transition, invasion, xenograft formation and growth in SCID−/− Beige mice, apoptosis, proliferation, cytokinesis, YAP/TAZ activation were investigated upon RASSF1A loss in human bronchial epithelial cells (HBEC). Results We demonstrate here that depletion of the YAP-kinases NDR1/2 reverts migration and metastatic properties upon RASSF1A loss in HBEC. We show that NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation. We further report that the RASSF1A/NDR2/GEF-H1/RhoB/YAP axis is involved in proper cytokinesis in human bronchial cells, since chromosome proper segregation are NDR-dependent upon RASSF1A or GEF-H1 loss in HBEC. Conclusion To summarize, our data support a model in which, upon RASSF1A silencing, NDR2 gets activated, phosphorylates and inactivates GEF-H1, leading to RhoB inactivation. This cascade induced by RASSF1A loss in bronchial cells is responsible for metastasis properties, YAP activation and cytokinesis defects.

Abstract Background Sporadic lymphangioleiomyomatosis (LAM) is a rare form of diffuse parenchymal lung disease. PD-1 blocking antibodies constitute an essential treatment option for advanced non-small-cell lung cancer (NSCLC). The effect of immune checkpoint inhibitors in lymphangioleiomyomatosis patients with non-small cell lung cancer is unknown: concomitant symptomatic interstitial lung disease or the use of immunosuppressors was a key exclusion criterion in the original studies of immune checkpoint inhibitors, especially regarding the risk of interstitial lung disease exacerbation. Case presentation A 48-year-old female, active smoker (36 pack-years), diagnosed with sporadic LAM since 2004 suffered from metastatic adenocarcinoma of the lung. Third-line therapy with nivolumab was started in 2015, with a major partial response. Due to pulmonary function alterations, sirolimus was also reinitiated in 2017 in conjunction with nivolumab, without any undesirable effects and a major partial response continuing up to May 2018. Conclusions This case highlights the safe and effective use of nivolumab for managing metastatic lung adenocarcinoma that occurred in a patient with sporadic LAM. In the current case, immunotherapy proved highly successful in managing the NSCLC tumor that occurred upon LAM follow-up, with both a significantly prolonged partial response and acceptable safety profile.

IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O2, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma.

The emerging tumor-on-chip (ToC) approaches allow to address biomedical questions out of reach with classical cell culture techniques: in biomimetic 3D hydrogels they partially reconstitute ex vivo the complexity of the tumor microenvironment and the cellular dynamics involving multiple cell types (cancer cells, immune cells, fibroblasts, etc.). However, a clear bottleneck is the extraction and interpretation of the rich biological information contained, sometime hidden, in the cell co-culture videos. In this work, we develop and apply novel video analysis algorithms to automatically measure the cytotoxic effects on human cancer cells (lung and breast) induced either by doxorubicin chemotherapy drug or by autologous tumor-infiltrating cytotoxic T lymphocytes (CTL). A live fluorescent dye (red) is used to selectively pre-stain the cancer cells before co-cultures and a live fluorescent reporter for caspase activity (green) is used to monitor apoptotic cell death. The here described open-source computational method, named STAMP (spatiotemporal apoptosis mapper), extracts the temporal kinetics and the spatial maps of cancer death, by localizing and tracking cancer cells in the red channel, and by counting the red to green transition signals, over 2-3 days. The robustness and versatility of the method is demonstrated by its application to different cell models and co-culture combinations. Noteworthy, this approach reveals the strong contribution of primary cancer-associated fibroblasts (CAFs) to breast cancer chemo-resistance, proving to be a powerful strategy to investigate intercellular cross-talks and drug resistance mechanisms. Moreover, we defined a new parameter, the 'potential of death induction', which is computed in time and in space to quantify the impact of dying cells on neighbor cells. We found that, contrary to natural death, cancer death induced by chemotherapy or by CTL is transmissible, in that it promotes the death of nearby cancer cells, suggesting the release of diffusible factors which amplify the initial cytotoxic stimulus.

There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.

BackgroundThe optimal treatment for patients with severe coronavirus-19 disease (COVID-19) and hyper-inflammation remains debated.Material and methodsA cohort study was designed to evaluate whether a therapeutic algorithm using steroids with or without interleukin-1 antagonist (anakinra) could prevent death/invasive ventilation. Patients with a ≥5-day evolution since symptoms onset, with hyper-inflammation (CRP≥50mg/L), requiring 3-5 L/min oxygen, received methylprednisolone alone. Patients needing ≥6 L/min received methylprednisolone + subcutaneous anakinra daily either frontline or in case clinical deterioration upon corticosteroids alone. Death rate and death or intensive care unit (ICU) invasive ventilation rate at Day 15, with Odds Ratio (OR) and 95% CIs, were determined according to logistic regression and propensity scores. A Bayesian analysis estimated the treatment effects.ResultsOf 108 consecutive patients, 70 patients received glucocorticoids alone. The control group comprised 63 patients receiving standard of care. In the corticosteroid±stanakinra group (n = 108), death rate was 20.4%, versus 30.2% in the controls, indicating a 30% relative decrease in death risk and a number of 10 patients to treat to avoid a death (p = 0.15). Using propensity scores a per-protocol analysis showed an OR for COVID-19-related death of 0.9 (95%CI [0.80-1.01], p = 0.067). On Bayesian analysis, the posterior probability of any mortality benefit with corticosteroids+/-anakinra was 87.5%, with a 7.8% probability of treatment-related harm. Pre-existing diabetes exacerbation occurred in 29 of 108 patients (26.9%).ConclusionIn COVID-19 non-ICU inpatients at the cytokine release phase, corticosteroids with or without anakinra were associated with a 30% decrease of death risk on Day 15.

Abstract Background By allowing intercellular communication between cells, tunneling nanotubes (TNTs) could play critical role in cancer progression. If TNT formation is known to require cytoskeleton remodeling, key mechanism controlling their formation remains poorly understood. Methods The cells of human bronchial (HBEC-3, A549) or mesothelial (H2452, H28) lines are transfected with different siRNAs (inactive, anti-RASSF1A, anti-GEFH1 and / or anti-Rab11). At 48 h post-transfection, i) the number and length of the nanotubes per cell are quantified, ii) the organelles, previously labeled with specific tracers, exchanged via these structures are monitored in real time between cells cultured in 2D or 3D and in normoxia, hypoxia or in serum deprivation condition. Results We report that RASSF1A, a key-regulator of cytoskeleton encoded by a tumor-suppressor gene on 3p chromosome, is involved in TNTs formation in bronchial and pleural cells since controlling proper activity of RhoB guanine nucleotide exchange factor, GEF-H1. Indeed, the GEF-H1 inactivation induced by RASSF1A silencing, leads to Rab11 accumulation and subsequent exosome releasing, which in turn contribute to TNTs formation. Finally, we provide evidence involving TNT formation in bronchial carcinogenesis, by reporting that hypoxia or nutriment privation, two almost universal conditions in human cancers, fail to prevent TNTs induced by the oncogenic RASSF1A loss of expression. Conclusions This finding suggests for the first time that loss of RASSF1A expression could be a potential biomarker for TNTs formation, such TNTs facilitating intercellular communication favoring multistep progression of bronchial epithelial cells toward overt malignancy.

Abstract Background Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). Methods Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. Results Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. Conclusions This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.

This two-step study evaluated the cost-effectiveness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for presurgery staging of non-small cell lung cancer (NSCLC) in France (EVIEPEB; ClinicalTrial.gov identifier NCT00960271). Step 1 consisted of a high-benchmark EBUS-TBNA-training program in participating hospital centers. Step 2 was a prospective, national, multicenter study on patients with confirmed or suspected NSCLC and an indication for mediastinal staging with at least one lymph node > 1 cm in diameter. Patients with negative or uninformative EBUS-TBNA and positron-emission tomography-positive or -negative nodes, respectively, underwent either mediastinoscopy or surgery. Direct costs related to final diagnosis of node status were prospectively recorded. Sixteen of 22 participating centers were certified by the EBUS-TBNA-training program and enrolled 163 patients in Step 2. EBUS-TBNA was informative for 149 (91%) patients (75 malignant, 74 non-malignant) and uninformative for 14 (9%). Mediastinoscopy was avoided for 80% of the patients. With a 52% malignant-node rate, EBUS-TBNA positive- and negative-predictive values, respectively, were 100% and 90%. EBUS-TBNA was cost-effective, with expected savings of €1,450 per patient, and would have remained cost-effective even if all EBUS-TBNAs had been performed under general anesthesia or the cost of the procedure had been 30% higher (expected cost-saving of €994 and €1,427 per patient, respectively). After EBUS-TBNA training and certification of participating centers, the results of this prospective multicenter study confirmed EBUS-TBNA cost-effectiveness for NSCLC staging.

Summary: A major challenge in cancer research is the complexity of the tumor microenvironment, which includes the host immunological setting. Inspired by the emerging technology of organ-on-chip, we achieved 3D co-cultures in microfluidic devices (integrating four cell populations: cancer, immune, endothelial, and fibroblasts) to reconstitute ex vivo a human tumor ecosystem (HER2+ breast cancer). We visualized and quantified the complex dynamics of this tumor-on-chip, in the absence or in the presence of the drug trastuzumab (Herceptin), a targeted antibody therapy directed against the HER2 receptor. We uncovered the capacity of the drug trastuzumab to specifically promote long cancer-immune interactions (>50 min), recapitulating an anti-tumoral ADCC (antibody-dependent cell-mediated cytotoxicity) immune response. Cancer-associated fibroblasts (CAFs) antagonized the effects of trastuzumab. These observations constitute a proof of concept that tumors-on-chip are powerful platforms to study ex vivo immunocompetent tumor microenvironments, to characterize ecosystem-level drug responses, and to dissect the roles of stromal components. : Inspired by the emerging technology of tumor-on-chip, Nguyen et al. reconstituted ex vivo a human tumor microenvironment (HER2+ breast cancer), characterized the ecosystem-level responses to the drug trastuzumab (Herceptin), and dissected the roles of stromal components (immune cells and fibroblasts), demonstrating the power of immunocompetent tumors-on-chip for preclinical drug studies. Keywords: tumor microenvironment, organ-on-chip, tumor-on-chip, trastuzumab, HER2+ breast cancer, cancer-associated fibroblasts, live cell imaging, microfluidics, pre-clinical models, immunotherapy

The aim of this article is to summarise the published data on prognostic and predictive biomarkers for early-stage non-small cell lung cancer (NSCLC), and discuss how to integrate them into clinical trials. Large phase III trials have been published in resected NSCLC with biomarkers identifying subsets of patients benefitting from perioperative chemotherapy. Initial findings of predictive implications for the DNA repair protein, ERCC1, were not confirmed in a larger series of patients due to the versatility of the commercially available monoclonal ERCC1 antibody. Prediction of survival by RRM1 tumour expression was not confirmed in a prospective phase III trial in 275 patients with stage IV disease, precluding its use in early-stage NSCLC. BRCA1 mRNA tumour content also failed to predict platinum resistance in 287 stage IV NSCLC patients included in a phase II trial, and the results of a similar trial in early-stage patients are still pending. Of the several cDNA gene expression studies in early-stage NSCLC with non-overlapping prognostic signatures, few have been replicated in independent cohorts for prognostic value, and none received external validation for predictive value. Therefore, use of biomarkers predicting chemotherapy efficacy still needs additional validation before becoming routine practice in oncogene-driven pan-negative NSCLC patients.

BACKGROUND: QuantiFERON®-TB Gold in-Tube (QFT) assay is a recently developed test to assess latent tuberculosis infection in contagious tuberculosis (TB) contact subjects. To assess the QFT assay in recently exposed contacts of active tuberculosis patients in a French area with low TB incidence but high Bacille Calmette-Guerin coverage, and evaluate progression rates to TB disease. METHODOLOGY/PRINCIPAL FINDINGS: Between January 2007 and December 2009, 687 contacts of culture-confirmed tuberculosis cases underwent the QFT assay, with tuberculin skin test (TST) in 473, and a 34 months mean follow-up. Of 687 contacts, 148 were QFT positive, while 526 were negative and 13 indeterminate. QFT was positive in 35% of individuals with TST ≥ 10 mm, 47.5% with TST ≥ 15 mm or phlyctenular, but in 21% of cases in which two-step TST (M0 and M3) remained negative. Conversely, QFT was negative in 69% of cases with two-step TST showing conversion from negative to positive. All indeterminate QFT were associated with TST induration