Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. RESULTS: We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. CONCLUSIONS: Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.

Paclitaxel-bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel-bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19-82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2-9.6] and 10.8 [IQR: 5.3-19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI-): 7.0 [IQR: 4.2-11.0] versus 5.2 [IQR: 2.9-8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0-1. Only a performance status of 0-1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

Spread Through Air Spaces (STAS) Is an Independent Prognostic Factor in Resected Lung Squamous Cell Carcinoma.

Objective: There is no histoprognostic grading for lung squamous cell carcinoma (LUSC). Different prognostic factors have been described in the recent literature and are not always studied in parallel. Our objective was to search for morphological histopathological prognostic factors in LUSC. Materials and Methods: In this single-center retrospective study of 241 patients, all patients with LUSC who underwent surgical excision over a 12-year period were included. The primary endpoint was 5-year overall survival. Results: STAS was present in 86 (35.7%) patients. The presence of Spread Through Air Spaces (STAS) was correlated with tumor location (p < 0.001), pathological stage (p = 0.039), tumor differentiation (p = 0.029), percentage of necrosis (p = 0.004), presence of vascular and/or lymphatic emboli, budding (p = 0.02), single cell invasion (p = 0.002) and tumor nest size (p = 0.005). The percentage of tumor necrosis was correlated with the overall survival at 5 years: 44.6% of patients were alive when the percentage of necrosis was ≥50%, whereas 68.5% were alive at 5 years when the necrosis was <30% (p < 0.001). When vasculolymphatic emboli were present, the percentage of survival at 5 years was 42.5% compared to 65.5% when they were absent (p = 0.002). The presence of isolated cell invasion was correlated with a lower 5-year survival rate: 51.1% in the case of presence, versus 66% in the case of absence (p = 0.02). In univariate analysis, performance status, pathological stage pT or pN, pleural invasion, histopathological subtype, percentage of tumor necrosis, vasculolymphatic invasion, single-cell invasion, budding and tumor nest size correlated with the percentage of survival at 5 years. On multivariate analysis, only STAS > 3 alveoli (HR, 2.74; 95% CI, 1.18−6.33) was related to overall survival. Conclusion: In conclusion, extensive STAS is an independent factor of poor prognosis in LUSC. STAS is correlated with the presence of other poor prognostic factors such as emboli and pleural invasion and would reflect greater tumor aggressiveness.

Preventive tract embolization with gelatin sponge slurry is safe and considerably reduces pneumothorax after CT-guided lung biopsy with use of large 16-18 coaxial needles.

OBJECTIVE: To evaluate the clinical impact of the tract embolization technique using gelatin sponge slurry after percutaneous CT-guided lung biopsy. METHODS: We retrospectively compared coaxial needle CT-guided lung biopsies performed without embolization (100 patients) and with the tract embolization technique using a mixture of iodine and gelatin sponge slurry (105 patients) between June 2012 and July 2020. Uni- and multivariate analyses were performed between groups to determine risk factors of pneumothorax. RESULTS: Patients with gelatin sponge slurry tract embolization had statistically lower rates of pneumothorax ((17.1% vs 39%, p < 0.001). In univariate analysis, tract embolization (OR = 0.32, CI = 0.17-0.61 p<0.001) and nodule size >2 cm (OR = 0.33 CI = 0.14-0.8 p = 0.013) had a protective effect on pneumothorax. The puncture path lengths > 2-20 mm and >20 mm were risk factors for pneumothorax (OR = 3.35 IC = 1.44-8.21 p = 0.006 and OR = 4.36 CI = 1.98-10.29 p<0.001, respectively). In multivariate regression analysis, tract embolization had a protective effect of pneumothorax (OR = 0.25, CI = 0.12-0.51, p < 0.001). The puncture path lengths > 2-20 mm and >20 mm were risk factors for pneumothorax (p = 0.030 and p = 0.002, respectively). CONCLUSIONS: The tract embolization technique using iodinated gelatin sponge slurry is safe and considerably reduces pneumothorax after percutaneous CT-guided lung biopsy. Our results suggest that it could be use in clinical routine. ADVANCES IN KNOWLEDGE: The systemic use of gelatin sponge slurry is safe and reduces considerably the rate of pneumothorax upon needle removal when CT-guided core biopsies are performed using large 16-18G coaxial needles.

Adjuvant chemotherapy for completely resected IIA-IIIA non-small cell lung cancer: compliance to guidelines, safety and efficacy in real-life practice.

Background: Since randomised clinical trials demonstrated a survival benefit of adjuvant chemotherapy (AC) following curative-intent lung surgery, AC has been implemented as a standard therapeutic strategy for patients with a completely resected IIA-IIIA non-small cell lung cancer (NSCLC). Regarding the moderate benefit of AC and the lack of literature on AC use in real-life practice, we aimed to evaluate compliance to guidelines, AC safety and efficacy in a less selected population. Methods: Between January 2009 and December 2014, we retrospectively analysed 210 patients with theoretical indication of AC following curative-intent lung surgery for a completely resected IIA-IIIA NSCLC. The primary objective of this retrospective study was to evaluate compliance to AC guidelines. Secondary objectives included safety and efficacy of AC in real-life practice. Results: Among 210 patients with a theoretical indication of AC, chemotherapy administration was validated in multidisciplinary team (MDT) for 62.4% of them and 117 patients (55.7%) finally received AC. Patient's clinical conditions were the main reasons advanced in MDT for no respect to AC guidelines. Most of the patients received cisplatin-vinorelbine (86.3%) and AC was initiated within 8 weeks following lung surgery for 73.5% of patients. One-half of patients who received AC experienced side effects leading to either dose-intensity modification or treatment interruption. In real-life practice, AC was found to provide a survival benefit over surgery alone. Factors related to daily-life practice such as delayed AC initiation or incomplete AC planned dose received were not associated with an inferior survival. Conclusions: Although AC use might differ from guidelines in real-life practice, this retrospective study highlights that AC can be used safely and remains efficient among a less selected population. In the context of immunotherapy and targeted therapies development in peri-operative treatment strategies, the place of AC has to be precised in the future.

Histopathological typing in diffuse malignant epithelioid mesothelioma: implication for prognosis and molecular basis.

The prognostic impact of tumour grading, cytological and architectural patterns and stromal features in diffuse pleural malignant epithelioid mesothelioma (MEM) has been partly studied but not correlated to molecular features. We performed a retrospective study on 92 MEM in our department in order to assess the prognostic role of architectural and stromal patterns, especially tumour to stroma ratio. Secondly, based on The Cancer Genome Atlas (TCGA) database, we analysed the differentially expressed genes in prognostic groups of interest. Our results showed that tumour grading, tumour to stroma ratio and predominant pattern were related to overall survival, p≤0.001, p=0.01 and p=0.001, respectively. In univariate analysis, for high grade tumours hazard ratio (HR) was 4.75 (2.47-9.16), for stroma poor tumours HR=0.016, for predominant tubular or tubulopapillary pattern HR=0.044. In multivariate analysis, high grade tumours were related to overall survival [HR=3.09 (1.50-6.35), p=0.002] and predominant tubular or tubulopapillary pattern [HR=0.56 (0.32-0.99), p=0.045]. In TCGA analysis, after grading of diagnostic slides, we showed that KRTDAP and CXRCR1 expression was higher in low grade tumours, unlike PDZD7 and GPR176 expression which was higher in high grade tumours. FAM81B had a higher expression in stroma poor tumours. We did not find any differentially expressed genes in the architectural patterns group. Our work suggests that tumour grading is an important parameter in MEM with an underlying genomic basis. The role of tumour to stroma ratio needs to be investigated and might also have a genomic basis.

Vaccination and Immune Checkpoint Inhibitors: Does Vaccination Increase the Risk of Immune-related Adverse Events? A Systematic Review of Literature.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become part of cancer treatments. Their main side effects are immune-related adverse events (irAEs). So far, there has been no recommendation regarding routine vaccinations during ICIs treatment. Clinicians are aware of the risk of irAEs increases in this specific situation. The aim of this review of literature is to summarize the main studies about vaccination and ICIs interactions. METHODS: A systematic assessment of literature articles was performed by searching in PubMed (MEDLINE), and major oncology meeting following PRISMA guidelines. RESULTS: This review highlights the lack of literature. Indeed, most of the studies published were about influenza vaccination. Vaccination for patients under ICIs causes a humoral response and seems to be associated with an increase rate of seroconversion. Interestingly vaccination may provoke irAEs in ICIs-treated patients. So far, inactivated vaccines have not been contraindicated during ICI treatment. CONCLUSION: Larger prospective studies are needed in order to define a consensus on the use of vaccines under immunotherapy.

Predictive resistance factors in lung cancer patients treated with Nivolumab. Retrospective study.

OBJECTIVES: Immunotherapy is the current treatment in non-small cell lung cancer (NSCLC). 20% of patients treated with immunotherapy have a prolonged response. What about the remaining 80%? How can we explain that some patients get no benefit from immunotherapy? MATERIEL AND METHODS: We retrospectively analyzed predictive factors of primary or secondary resistance to immunotherapy in NSCLC patients from 2 French hospitals between 2015 and 2018. Moreover, we evaluated whether PD1 inhibitor had an impact on the antitumor effects of salvage chemotherapy administered after immunotherapy. We chose to focus on taxanes. RESULTS: Ninety-six patients were included in this cohort, 65(68%) patients were considered as having primary resistance and 31(32%) secondary resistance. Resistant populations did not differ. At immunotherapy initiation, median survival was 4.6 months for primary resistant patients (95%CI-4.6-6.8) and 15.6 months (95%CI-9.8-NA) for secondary resistant patients. The disease control rates with taxane were 15% in pre immunotherapy conditions vs 50% in post immunotherapy. Response rates improved regardless of the status of resistance. CONCLUSION: This study enriches data about immunotherapy in real-life in NSCLC. Prognostic resistance factors still seem complicated to identify. The high rate of taxane responders in post immunotherapy in this retrospective cohort support the use of taxane in therapeutic escape.

Use of adjuvant chemotherapy in resected non-small cell lung cancer in real-life practice: a systematic review of literature.

BACKGROUND: Adjuvant chemotherapy (AC) is recommended since 2004 for patients with a completely resected non-small cell lung cancer (NSCLC). Indeed, several randomized clinical trials have demonstrated an improved survival for patients treated with adjuvant cisplatin-based regimen than surgery alone. In these large clinical trials, patients were well selected and fit to receive AC. As the benefit of AC was estimated at 5.4% of 5-year overall survival (OS), it seems important to evaluate AC use in a less selected population. In particular, elderly patients were underrepresented in large randomized clinical trials. Furthermore, other confounding factors might limit AC efficacy in real-life practice such as the delay of chemotherapy initiation following lung surgery or the number of AC cycles received. Therefore, the aim of this systematic review is to summarize the state of the literature on AC use in current clinical practice. METHODS: A systematic assessment of literature articles and reviews on AC use in real-life practice was performed by searching in several relevant database including Medline, Google Scholar and Cochrane Library following PICOS (i.e., Population, Intervention, Comparison, Outcomes, Study design) eligibility criteria and PRISMA guidelines. Among the 1,957 results obtained with the request formulated on these research database, 56 relevant articles on AC use in non-trial setting were selected and included in the results section. RESULTS: This systematic literature review highlights the lack of literature on AC use in real-life practice as most of these studies were retrospective. Interestingly, a delayed AC-mostly due to postoperative complications-was better than surgery alone. Furthermore, AC was less purposed to elderly patients, despite retrospective studies outlined that this therapeutic option could be benefit in this specific population as for younger patients. In real-life practice, AC was also often incomplete due to adverse events, but dose reduction or omission was not always associated with an inferior survival. In non-trial setting, number of AC cycles delivered, dose reduction or omission is quite similar to randomized clinical trials. DISCUSSION: Nowadays, AC is part of the therapeutic strategy used in completely resected NSCLC. In a population of less selected patients, this systematic literature review shows that AC can be used safely and efficiently, especially in elderly patients. As well, delayed AC seems effective. Finally, the place of immunotherapy and targeted therapies have to be precised in the future as well as biomarkers to better select patients that would response to chemotherapy.

Clinical Relevance of an Amplicon-Based Liquid Biopsy for Detecting ALK and ROS1 Fusion and Resistance Mutations in Patients With Non-Small-Cell Lung Cancer.

PURPOSE: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK /ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes. PATIENTS AND METHODS: Patients with advanced ALK/ROS1-positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes. RESULTS: Of the 128 patients included in the study, 101 were positive for ALK and 27 for ROS1 alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for ALK/ROS1 fusion detection. Higher detection was observed for ALK fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). ALK-resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total ALK-resistance mutations identified occurred after next-generation TKI therapy. ALK G1202R was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. ROS1 G2032R resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex ALK-resistance mutations correlated with poor overall survival (median, 26.9 months v NR for single mutation; P = .003) and progression-free survival to subsequent therapy (median 1.7 v 6.3 months; P = .003). CONCLUSION: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.

Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non-Small Cell Lung Cancer.

PURPOSE: The limited knowledge on the molecular profile of patients with BRAF-mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF-mutant NSCLC. EXPERIMENTAL DESIGN: This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n = 208) were collected from BRAF-TT-naïve patients (n = 47), patients nonprogressive under treatment (n = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA. RESULTS: BRAFV600E ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1. CONCLUSIONS: ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF-mutant NSCLC.

Histopathological subtyping is a prognostic factor in stage IV lung adenocarcinoma.

Lung adenocarcinoma is a heterogeneous tumor made of different architectural patterns. These tumors are classified into subtypes according to the predominant pattern in the primary tumor because the predominant pattern is related to overall survival. The prognostic role of these subtypes in stage IV disease is not well known, and most lung adenocarcinomas are diagnosed at the stage of metastatic disease. We aimed to evaluate the prognostic role of histopathological subtypes in lung adenocarcinoma metastases in a retrospective study of 253 patients with clinical, histopathological and molecular data. The presence of the solid subtype was related to overall survival (p = 0.045); the median overall survival was 6.8 months (95 % confidence interval (95 %CI) 4.4-9.1) when present and 11.1 months (95 %CI 8.6-21.3) when absent. Thyroid transcription factor 1 (TTF-1) immunohistochemistry was related to overall survival (p < 0.001); the median overall survival was 11.2 months (95 %CI 8.4-17.7) when positive and 4 months (95 %CI 2.3-5.7) when negative. On multivariate analysis, the presence of the solid subtype (p = 0.0036, hazard ratio (HR) 1.55, 95 %CI 1.03-2.34), TTF-1 positivity (p = 0.044, HR 0.64, 95 %CI 0.42-0.98), age <60 years at the time of resection (p = 0.017, HR 1.89; 95 %CI 1.12-3.21), performance status <2 (p = 0.017, HR 0.57; 95 %CI 0.36-0.91), treatment by chemotherapy (p = 0.033, HR 0.54, 95 %CI 0.31-0.95), and treatment by tyrosine kinase inhibitor or immunotherapy (p = 0.013, HR 0.36, 95 %CI 0.17-0.81) were related to overall survival. The evaluation of architectural pattern in metastases in stage IV patients provides further information for physicians about patient prognosis. This information might be included in clinical trials in patients with stage IV lung adenocarcinoma.

TTF-1-positive Metastatic Endometrioid Carcinoma: A Case Report and Review of Literature of a Potential Diagnostic Pitfall.

A 75-year-old female patient, nonsmoker was addressed to our institution for a fracture of C5 vertebra with spinal cord compression by a tumor mass invading surrounding soft tissue. She had a previous history of breast ductal carcinoma and endometrioid carcinoma. Biopsy of the tumor mass showed a TTF-1-positive carcinoma. Molecular study showed a E545K mutation of PIK3CA. Lung imaging showed multiple nodules evocative of metastasis rather than a primitive tumor. Reviewing of slides of endometrioid carcinoma showed areas positive for TTF1, and the same E545K mutation was found in endometrial tumor. The final diagnosis was endometrioid metastatic carcinoma with aberrant TTF-1 expression. A subset of endometrial neoplasm expresses TTF-1, this situation might be confusing especially in case of metastatic disease.

Profiling of circulating tumor DNA in plasma of non-small cell lung cancer patients, monitoring of epidermal growth factor receptor p.T790M mutated allelic fraction using beads, emulsion, amplification, and magnetics companion assay and evaluation in future application in mimicking circulating tumor cells.

Cell-free plasma DNA (cfDNA) and mimicking circulating tumor cells (mCTCs) have demonstrated tremendous potential for molecular diagnosis of cancer and have been rapidly implemented in specific settings. However, widespread clinical adoption still faces some obstacles. The purpose was to compare the performance of a BEAMing (beads, emulsion, amplification, and magnetics) assay (OncoBEAM™-epidermal growth factor receptor [EGFR] [Sysmex Inostics]) and a next-generation sequencing assay (NGS; 56G Oncology panel kit, Swift Bioscience) to detect the p.T790M EGFR mutation in cfDNA of non-small cell lung cancer (NSCLC) patients. CfDNA samples (n = 183) were collected within our hospital from patients having a known EGFR sensitizing mutation, and presenting disease progression while under first-line therapy. EGFR mutations were detected using NGS in 42.1% of samples during progression in cfDNA. Testing using the OncoBEAM™-EGFR assay enabled detection of the p.T790M EGFR mutation in 40/183 NSCLC patients (21.8%) versus 20/183 (10.9%), using the NGS assay. Samples that were only positive with the OncoBEAM™-EGFR assay had lower mutant allelic fractions (Mean = 0.1304%; SD ± 0.1463%). In addition, we investigated the detection of p.T790M in mCTCs using H1975 cells. These cells spiked into whole blood were enriched using the ClearCellFX1 microfluidic device. Using the OncoBEAM™-EGFR assay, p.T790M was detected in as few as 1.33 tumoral cells/mL. Overall, these findings highlight the value of using the OncoBEAM™-EGFR to optimize detection of the p.T790M mutation, as well as the complementary clinical value that each of the mutation detection assay offers: NGS enabled the detection of mutations in other oncogenes that may be relevant to secondary resistance mechanisms, whereas the OncoBEAM™-EGFR assay achieved higher sensitivity for detection of clinically actionable mutations.

Novel insights into the systemic treatment of lung cancer malignant pleural effusion.

Lung cancer is the most common fatal malignancy worldwide. Approximately 75% of non-small-cell lung cancer (NSCLC) patients are diagnosed at an advanced or a metastatic stage. Since 2007, NSCLC patients with malignant pleural effusion (MPE) are staged as M1 disease. During the last decades, chemotherapeutic agents failed to offer a significant improvement of survival in patients with metastatic disease. The current review aims to summarize the actual situation of the recently developed therapies in patients with lung cancer and MPE.

Cross-platform comparison for the detection of RAS mutations in cfDNA (ddPCR Biorad detection assay, BEAMing assay, and NGS strategy).

CfDNA samples from colon (mCRC) and non-small cell lung cancers (NSCLC) (CIRCAN cohort) were compared using three platforms: droplet digital PCR (ddPCR, Biorad); BEAMing/OncoBEAM™-RAS-CRC (Sysmex Inostics); next-generation sequencing (NGS, Illumina), utilizing the 56G oncology panel (Swift Biosciences). Tissue biopsy and time matched cfDNA samples were collected at diagnosis in the mCRC cohort and during 1st progression in the NSCLC cohort. Excellent matches between cfDNA/FFPE mutation profiles were observed. Detection thresholds were between 0.5-1% for cfDNA samples examined using ddPCR and NGS, and 0.03% with BEAMing. This high level of sensitivity enabled the detection of KRAS mutations in 5/19 CRC patients with negative FFPE profiles. In the mCRC cohort, comparison of mutation results obtained by testing FFPE to those obtained by testing cfDNA by ddPCR resulted in 47% sensitivity, 77% specificity, 70% positive predictive value (PPV) and 55% negative predictive value (NPV). For BEAMing, we observed 93% sensitivity, 69% specificity, 78% PPV and 90% NPV. Finally, sensitivity of NGS was 73%, specificity was 77%, PPV 79% and NPV 71%. Our study highlights the complementarity of different diagnostic approaches and variability of results between OncoBEAM™-RAS-CRC and NGS assays. While the NGS assay provided a larger breadth of coverage of the major targetable alterations of 56 genes in one run, its performance for specific alterations was frequently confirmed by ddPCR results.

New Nitric Oxide Donor NCX 1443: Therapeutic Effects on Pulmonary Hypertension in the SAD Mouse Model of Sickle Cell Disease.

Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416 and was similarly reduced by daily NCX1443 gavage. Compared with WT mice, SAD mice exhibited higher levels of HO-1, endothelial NO synthase, and PDE5 but similar levels of lung cyclic guanosine monophosphate. Cultured pulmonary artery smooth muscle cells from SAD mice grew faster than those from WT mice and had higher PDE5 protein levels. Combining NCX1443 and a PDE5 inhibitor suppressed the growth rate difference between SAD and WT cells and induced a larger reduction in hypoxic PH severity in SAD than in WT mice. By amplifying endogenous protective mechanisms, NCX1443 in combination with PDE5 inhibition may prove useful for treating PH complicating SCD.

EBUS-TBNA Can Distinguish Sarcoid-Like Side Effect of Nivolumab Treatment from Tumor Progression in Non-Small Cell Lung Cancer.

With the expansion of immunotherapy in the treatment of lung cancer, clinicians have to face new clinical pictures and adapt their practice. We report the case of a 69-year-old man diagnosed with non-small cell lung cancer using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and treated with nivolumab as second-line therapy. After 8 injections of nivolumab, a new CT and PET scan revealed massive growth and increase in metabolism of hilar and mediastinal lymph nodes, whereas the size and metabolism of the left upper lobe lesion were reduced. A new EBUS-TBNA was thus performed and showed an epithelioid cell reaction compatible with sarcoidosis in the 3 punctured lymph nodes (stations 4R, 11L, 7). In the absence of cancer evolution, nivolumab was continued, and the CT after the twelfth injection showed stability.