Publications by authors named "Caroline Caramella"

71 Publications

Can MRI differentiate surrounding vertebral invasion from reactive inflammatory changes in superior sulcus tumor?

Eur Radiol 2021 May 15. Epub 2021 May 15.

Department of Radiology, Gustave Roussy Cancer Campus, 114 Rue Edouard Vaillant, Villejuif, 94800, Paris, France.

Objectives: Vertebral invasion is a key prognostic factor and a critical aspect of surgical planning for superior sulcus tumors. This study aims to further evaluate MRI features of vertebral invasion in order to distinguish it from reactive inflammatory changes.

Methods: Between 2000 and 2016, a retrospective study was performed at a single institution. All patients with superior sulcus tumors undergoing surgery, including at least two partial vertebrectomies, were included. An expert radiologist evaluated qualitative and quantitative MRI signal intensity characteristics (contrast-to-noise ratio [CNR]) of suspected involved and non-involved vertebrae. A comparison of CNR of invaded and sane vertebrae was performed using non-parametric tests. Imaging data were correlated with pathological findings.

Results: A total of 92 surgical samples of vertebrectomy were analyzed. The most specific sequences for invasion were T1 and T2 weighted (92% and 97%, respectively). The most sensitive sequences were contrast enhanced T1 weighted fat suppressed and T2 weighted fat suppressed (100% and 80%). Loss of extrapleural paravertebral fat on the T1-weighted sequence was highly sensitive (100%) but not specific (63%). Using quantitative analysis, the optimum cut-off (p < 0.05) to distinguish invasion from reactive inflammatory changes was CNR > 11 for the T2-weighted fat-sat sequence (sensitivity 100%), CNR > 9 for contrast-enhanced T1-weighted fat-suppressed sequence (sensitivity 100%), and CNR < - 30 for the T1-weighted sequence (specificity 97%). Combining these criteria, 23 partial vertebrectomies could have been avoided in our cohort.

Conclusion: Qualitative and quantitative MRI analyses are useful to discriminate vertebral invasion from reactive inflammatory changes.

Key Points: • Abnormal signal intensity in a vertebral body adjacent to a superior sulcus tumor may be secondary to direct invasion or reactive inflammatory changes. • Accurate differentiation between invasion and reactive inflammatory changes significantly impacts surgical planning. T1w and T2w are the best sequences to differentiate malignant versus benign bone marrow changes. The use of quantitative analysis improves MRI specificity. • Using contrast media improves the sensitivity for the detection of tumor invasion.
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http://dx.doi.org/10.1007/s00330-021-08001-wDOI Listing
May 2021

Lung cancer screening: French radiologists should prepare for it.

Diagn Interv Imaging 2021 Apr 25;102(4):197-198. Epub 2021 Feb 25.

Department of Radiology, Hôpital Marie Lannelongue, Institut d'Oncologie Thoracique, Paris-Saclay University, 92350 Le Plessis-Robinson, France.

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http://dx.doi.org/10.1016/j.diii.2021.02.004DOI Listing
April 2021

Dual-energy CT angiography reveals high prevalence of perfusion defects unrelated to pulmonary embolism in COVID-19 lesions.

Insights Imaging 2021 Feb 17;12(1):24. Epub 2021 Feb 17.

Department of Radiology, Fondation Hôpital Saint Joseph, 185 rue Raymond Losserand, 75014, Paris, France.

Background: Lung perfusion defects (PDs) have been described in COVID-19 using dual-energy computed tomography pulmonary angiography (DE-CTPA). We assessed the prevalence and characteristics of PDs in COVID-19 patients with suspected pulmonary embolism (PE) and negative CTPA.

Methods: This retrospective study included COVID-19 and non-COVID-19 pneumonia groups of patients with DE-CTPA negative for PE. Two radiologists rated the presence of PD within the lung opacities and analyzed the type of lung opacities and PD pattern (i.e. homogeneous or heterogeneous). The clinical, biological, radiological characteristics including time from first symptoms and admission to DE-CTPA, oxygen requirements, CRP, D-dimer levels, duration of hospital admission and death were compared within the COVID-19 group between patients with (PD +) or without PD (PD-).

Results: 67 COVID-19 and 79 non-COVID-19 patients were included. PDs were more frequent in the COVID-19 than in the non-COVID-19 group (59.7% and 26.6% respectively, p < 0.001). Patterns of PDs were different, with COVID-19 patients exhibiting heterogenous PDs (38/40, 95%) whereas non-COVID-19 patients showed mostly homogeneous perfusion defects (7/21 heterogeneous PDs, 33%), p < 0.001. In COVID-19 patients, most consolidations (9/10, 90%) exhibited PDs while less than a third of consolidations (19/67, 28%) had PDs in non-COVID-19 patients. D-dimer, oxygen levels and outcome were similar between COVID-19 PD + and PD- patients; however, time between admission and DE-CTPA was longer in PD + patients (median [IQR], 1 [0-7] and 0 [0-2]; p = 0.045).

Conclusion: Unlike in bacterial pneumonia, heterogeneous PDs within lung opacities are a frequent feature of COVID-19 pneumonia in PE-suspected patients.
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http://dx.doi.org/10.1186/s13244-021-00972-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887542PMC
February 2021

Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy.

Eur J Cancer 2021 Mar 27;145:221-229. Epub 2021 Jan 27.

Pathology Department, Gustave Roussy, Villejuif, France. Electronic address:

Background: The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. We aimed to determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC.

Methods: This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as ≥10% density. The primary end-point was overall survival (OS).

Results: Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status ≤1 and 63% had adenocarcinoma histology. High-TIL was observed in 22% patients and associated with OS (hazard ratio [HR] 0.48; 95% confidence interval [95% CI]: 0.28-0.81) and progression-free survival [PFS] (HR = 0.40; 95% CI: 0.25-0.64). Median PFS was 13.0 months (95% CI: 5.0-not reached) with high-TIL versus 2.2 months (95% CI: 1.7-3.0) with the presence of a low TIL count (low-TIL). Median OS for high-TIL was not reached (95% CI: 12.2-not reached) versus 8.4 months (95% CI: 5.0-11.6) in the low-TIL group. High-TIL was associated with the overall response rate (ORR) and disease control rate (DCR) (both, P < .0001). Among the chemotherapy cohort, 69% were male, 89% were smokers, 86% had performance status ≤1 and 90% had adenocarcinoma histology. High-TIL was seen in 37%. Median PFS and OS were 5.7 months (95% CI: 4.9-6.7) and 11.7 months (95% CI: 9.3-13.0), respectively, with no association with TILs.

Conclusions: High-TIL was associated with favourable outcomes in a real-world immunotherapy cohort of patients with NSCLC, but not with chemotherapy, suggesting that TILs may be useful in selecting patients for immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2020.10.017DOI Listing
March 2021

Cannabis use and lung cancer: time to stop overlooking the problem?

Eur Respir J 2021 May 20;57(5). Epub 2021 May 20.

Thoracic Surgery and Pneumology Dept, Marie Lannelongue Hospital, Paris Saint Joseph Hospital and Paris Saclay University, Le Plessis-Robinson, France

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http://dx.doi.org/10.1183/13993003.04132-2020DOI Listing
May 2021

Incorporating radiomics into clinical trials: expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers.

Eur Radiol 2021 Jan 25. Epub 2021 Jan 25.

European Imaging Biomarkers Alliance (EIBALL), European Society of Radiology, Vienna, Austria.

Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. KEY POINTS: • Data-driven processes like radiomics risk false discoveries due to high-dimensionality of the dataset compared to sample size, making adequate diversity of the data, cross-validation and external validation essential to mitigate the risks of spurious associations and overfitting. • Use of radiomic signatures within clinical trials requires multistep standardisation of image acquisition, image analysis and data mining processes. • Biological correlation may be established after clinical validation but is not mandatory.
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http://dx.doi.org/10.1007/s00330-020-07598-8DOI Listing
January 2021

Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer.

Cancers (Basel) 2020 Dec 14;12(12). Epub 2020 Dec 14.

Cancer Medicine Department, Gustave Roussy, 94805 Villejuif, France.

Kinase inhibitors (KI) have dramatically improved the outcome of treatment in patients with non-small cell lung cancer (NSCLC), which harbors an oncogene addiction. This study assesses KI plasma levels and their clinical relevance in patients chronically exposed to KIs. Plasma samples were collected in NSCLC patients receiving erlotinib, gefitinib, osimertinib, crizotinib, or dabrafenib (with or without trametinib) for at least three months between November 2013 and February 2019 in a single institution. KI drug concentrations were measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry and compared to published data defining optimal plasma concentration. The main outcome was the rate of samples with suboptimal KI plasma concentrations. Secondary outcomes included its impact on mutation emergence in patients receiving a first-generation epidermal growth factor receptor (EGFR) KI. Fifty-one samples were available from 41 patients with advanced NSCLC harboring driver genetic alterations, including , v-Raf murine sarcoma viral oncogene homolog B (), anaplastic lymphoma kinase () or ROS proto-oncogene 1 (), and who had an available evaluation of chronic KI plasma exposure. Suboptimal plasma concentrations were observed in 51% (26/51) of cases. In -mutant cases failing first-generation KIs, exon 20 p.T790M mutation emergence was detected in 31% (4/13) of samples in optimal vs. none in suboptimal concentration (0/5). Suboptimal plasma concentrations of KIs are frequent in advanced NSCLC patients treated with a KI for at least three months and might contribute to treatment failure.
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http://dx.doi.org/10.3390/cancers12123758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764991PMC
December 2020

Clarification of Definitions of Hyperprogressive Disease During Immunotherapy-Reply.

JAMA Oncol 2021 Jan;7(1):137

Cancer Medicine Department, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

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http://dx.doi.org/10.1001/jamaoncol.2020.5591DOI Listing
January 2021

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI).

Cancers (Basel) 2020 Sep 30;12(10). Epub 2020 Sep 30.

Cancer Medicine Department, Gustave Roussy, 94805 Villejuif, France.

Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms.

Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications.

Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1-12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9-1.5] and mOS [1.9 mo.; 95%CI, 1.5-2.4; < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2-5.6] and OS [HR 4.53; 95% CI, 1.8-11.1], both < 0.0001.

Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.
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http://dx.doi.org/10.3390/cancers12102827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599488PMC
September 2020

AZTEK: Adaptive zero TE k-space trajectories.

Magn Reson Med 2021 02 16;85(2):926-935. Epub 2020 Sep 16.

Université Paris-Saclay, CEA, CNRS, Inserm, BioMaps, Orsay, France.

Purpose: Because of short signal lifetimes and respiratory motion, 3D lung MRI is still challenging today. Zero-TE (ZTE) pulse sequences offer promising solutions as they overcome the issue of short . Nevertheless, as they rely on continuous readout gradients, the trajectories they follow in k-space are not adapted to retrospective gating and inferred motion correction.

Theory And Methods: We propose AZTEK (adaptive ZTE k-space trajectories), a set of 3D radial trajectories featuring three tuning parameters, to adapt the acquisition to any moving organ while keeping seamless transitions between consecutive spokes. Standard ZTE and AZTEK trajectories were compared for static and moving phantom acquisitions as well as for human thoracic imaging performed on 3 volunteers (1 healthy and 2 patients with lung cancer).

Results: For the static phantom, we observe comparable image qualities with standard and AZTEK trajectories. For the moving phantom, spatially coherent undersampling artifacts observed on gated images with the standard trajectory are alleviated with AZTEK. The same improvement in image quality is obtained in human, so details are more delineated in the lung with the use of the adaptive trajectory.

Conclusion: The AZTEK technique opens the possibility for 3D dynamic ZTE lung imaging with retrospective gating. It enables us to uniformly sample the k-space for any arbitrary respiratory motion gate, while preserving static image quality, improving dynamic image quality and guaranteeing continuous readout gradient transitions between spokes, which makes it appropriate to ZTE.
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http://dx.doi.org/10.1002/mrm.28483DOI Listing
February 2021

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

JCO Precis Oncol 2020 2;4. Epub 2020 Apr 2.

Department of Medical Oncology, Centre Léon Bérard Lyon, France.

Purpose: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with -positive NSCLC and its impact on outcomes.

Patients And Methods: Patients with advanced -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 and 27 for 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 fusion detection. Higher detection was observed for fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). -resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total -resistance mutations identified occurred after next-generation TKI therapy. was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. 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 -resistance mutations correlated with poor overall survival (median, 26.9 months NR for single mutation; = .003) and progression-free survival to subsequent therapy (median 1.7 6.3 months; = .003).

Conclusion: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of 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.
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http://dx.doi.org/10.1200/PO.19.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448797PMC
April 2020

Successful Switch to Vemurafenib Plus Cobimetinib After Dabrafenib Plus Trametinib Toxicity in BRAF-Mutant Metastatic Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2021 Jan 5;22(1):e54-e56. Epub 2020 Aug 5.

Medical Oncology Department, Gustave Roussy, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2020.07.013DOI Listing
January 2021

Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy.

Clin Cancer Res 2021 Jan 4;27(2):492-503. Epub 2020 Sep 4.

Gustave Roussy Cancer Campus, Laboratory of Immunomonitoring in Oncology, CNRS-UMS 3655 and INSERM-US23, Villejuif, France.

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.

Experimental Design: The percentage of CD28, CD57, KLRG1 among CD8 T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP CD8 T cells were assessed .

Results: In the ICI discovery cohort ( = 37), SIP cut-off was 39.5%, 27% of patients were SIP. In the ICI validation cohort ( = 46), SIP status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, = 0.02]. SIP status was significantly associated with circulating specific immunephenotypes, lower CD8 T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population ( = 83), SIP status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort ( = 61), 11% of patients were SIP. SIP status did not correlate with outcomes upon PCT.

Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1420DOI Listing
January 2021

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

Clin Cancer Res 2020 12 28;26(23):6242-6253. Epub 2020 Aug 28.

Centre de Biochimie Structurale (CBS), INSERM, CNRS, Université de Montpellier, Montpellier, France.

Purpose: The limited knowledge on the molecular profile of patients with -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 mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with -mutant NSCLC.

Experimental Design: This was a prospective study of 78 patients with advanced -mutant NSCLC, enrolled in 27 centers across France. Blood samples ( = 208) were collected from BRAF-TT-naïve patients ( = 47), patients nonprogressive under treatment ( = 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. structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.

Results: 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 -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 , and .

Conclusions: ctDNA sequencing is clinically relevant for the detection of -activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in -mutant NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1037DOI Listing
December 2020

Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma.

J Immunother Cancer 2020 08;8(2)

Department of Radiation Oncology, Radiomics Team, Molecular Radiotherapy INSERM U1030, University Paris-Saclay, Faculty of Medicine, Gustave Roussy Cancer Campus, Villejuif, France

Background: A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma.

Patients And Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics.

Results: 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5-2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2-1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS.

Conclusion: When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation.

Trial Registration Number: NCT01557114.
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http://dx.doi.org/10.1136/jitc-2020-000627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443273PMC
August 2020

F-FDG PET and DCE kinetic modeling and their correlations in primary NSCLC: first voxel-wise correlative analysis of human simultaneous [18F]FDG PET-MRI data.

EJNMMI Res 2020 Jul 30;10(1):88. Epub 2020 Jul 30.

Université Paris-Saclay, CEA, CNRS, Inserm, BioMAPs, 91401, Orsay, France.

Objectives: To decipher the correlations between PET and DCE kinetic parameters in non-small-cell lung cancer (NSCLC), by using voxel-wise analysis of dynamic simultaneous [18F]FDG PET-MRI.

Material And Methods: Fourteen treatment-naïve patients with biopsy-proven NSCLC prospectively underwent a 1-h dynamic [18F]FDG thoracic PET-MRI scan including DCE. The PET and DCE data were normalized to their corresponding T-weighted MR morphological space, and tumors were masked semi-automatically. Voxel-wise parametric maps of PET and DCE kinetic parameters were computed by fitting the dynamic PET and DCE tumor data to the Sokoloff and Extended Tofts models respectively, by using in-house developed procedures. Curve-fitting errors were assessed by computing the relative root mean square error (rRMSE) of the estimated PET and DCE signals at the voxel level. For each tumor, Spearman correlation coefficients (r) between all the pairs of PET and DCE kinetic parameters were estimated on a voxel-wise basis, along with their respective bootstrapped 95% confidence intervals (n = 1000 iterations).

Results: Curve-fitting metrics provided fit errors under 20% for almost 90% of the PET voxels (median rRMSE = 10.3, interquartile ranges IQR = 8.1; 14.3), whereas 73.3% of the DCE voxels showed fit errors under 45% (median rRMSE = 31.8%, IQR = 22.4; 46.6). The PET-PET, DCE-DCE, and PET-DCE voxel-wise correlations varied according to individual tumor behaviors. Beyond this wide variability, the PET-PET and DCE-DCE correlations were mainly high (absolute r values > 0.7), whereas the PET-DCE correlations were mainly low to moderate (absolute r values < 0.7). Half the tumors showed a hypometabolism with low perfused/vascularized profile, a hallmark of hypoxia, and tumor aggressiveness.

Conclusion: A dynamic "one-stop shop" procedure applied to NSCLC is technically feasible in clinical practice. PET and DCE kinetic parameters assessed simultaneously are not highly correlated in NSCLC, and these correlations showed a wide variability among tumors and patients. These results tend to suggest that PET and DCE kinetic parameters might provide complementary information. In the future, this might make PET-MRI a unique tool to characterize the individual tumor biological behavior in NSCLC.
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http://dx.doi.org/10.1186/s13550-020-00671-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392998PMC
July 2020

Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives.

Br J Cancer 2020 09 27;123(6):885-897. Epub 2020 Jul 27.

Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany.

The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.
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http://dx.doi.org/10.1038/s41416-020-0994-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492252PMC
September 2020

Immunotherapy discontinuation - how, and when? Data from melanoma as a paradigm.

Nat Rev Clin Oncol 2020 11 7;17(11):707-715. Epub 2020 Jul 7.

Department of Medicine, Gustave Roussy, Villejuif, France.

The optimal duration of therapy in patients receiving immune-checkpoint inhibitors (ICIs) is a new but crucial question that has arisen owing to the observation of durable remissions in >85% of patients with metastatic melanoma who stop receiving an anti-PD-1 antibody after a complete response (CR). Long-term treatment-free remissions have also been seen, albeit much less frequently, in patients receiving ICIs for other forms of cancer who have a CR. Despite these promising observations, the optimal duration of treatment with ICIs remains unknown and requires further investigation in randomized controlled trials. In the absence of prospective data, some general criteria to guide the safe cessation of ICIs can be proposed, at least for patients with melanoma, in whom ICI cessation after a confirmed CR and at least 6 months of treatment is generally deemed safe. In this Perspective, we describe the available data on ICI interruption in patients with melanoma and in those with various other cancers. We also address the patient management implications of stopping ICI therapy.
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http://dx.doi.org/10.1038/s41571-020-0399-6DOI Listing
November 2020

Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non-Small Cell Lung Cancer.

JAMA Oncol 2020 07;6(7):1039-1046

UMR (Unité Mixte de Recherche) 1281, Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Commissariat à l'énergie Atomique et Aux Énergies Alternatives, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, Villejuif, France.

Importance: Hyperprogressive disease (HPD) is an aggressive pattern of progression reported for patients treated with programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) inhibitors as a single agent in several studies. However, the use of different definitions of HPD introduces the risk of describing different tumoral behaviors.

Objective: To assess the accuracy of each HPD definition to identify the frequency of HPD and the association with poorer outcomes of immune-checkpoint inhibitor (ICI) treatment in patients with advanced non-small cell lung cancer (NSCLC) and to provide an optimized and homogenized definition based on all previous criteria for identifying HPD.

Design, Setting, And Participants: This retrospective cohort study included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors from November 1, 2012, to April 5, 2017, in 8 French institutions. Measurable lesions were defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on at least 2 computed tomographic scans before the initiation of ICI therapy and 1 computed tomographic scan during treatment. Data were analyzed from November 1, 2012, to August 1, 2019.

Exposures: Advanced NSCLC and treatment with PD-1/PD-L1 inhibitors.

Main Outcomes And Measures: Association of the definition with the related incidence and the HPD subset constitution and the association between each HPD definition and overall survival. All dynamic indexes used in the previous proposed definitions, such as the tumor growth rate (TGR) or tumor growth kinetics (TGK), were calculated before and during treatment.

Results: Among the 406 patients with NSCLC included in the analysis (259 male [63.8%]; median age at start of ICI treatment, 64 [range, 30-91] years), the different definitions resulted in incidences of the HPD phenomenon varying from 5.4% (n = 22; definition based on a progression pace >2-fold and a time to treatment failure of <2 months) to 18.5% (n = 75; definition based on the TGR ratio). The concordance between these different definitions (using the Jaccard similarity index) varied from 33.3% to 69.3%. For every definition, HPD was associated with poorer survival (range of median overall survival, 3.4 [95% CI, 1.9-8.4] to 6.0 [95% CI, 3.7-9.4] months). The difference between TGR before and during therapy (ΔTGR) was the most correlated with poor overall survival with an initial plateau for a larger number of patients and a slower increase, and it had the highest ability to distinguish patients with HPD from those with progressive disease not classified as HPD. In addition, an optimal threshold of ΔTGR of greater than 100 was identified for this distinction.

Conclusions And Relevance: The findings of this retrospective cohort study of patients with NSCLC suggest that the previous 5 definitions of HPD were not associated with the same tumor behavior. A new definition, based on ΔTGR of greater than 100, appeared to be associated with the characteristics expected with HPD (increase of the tumor kinetics and poor survival). Additional studies on larger groups of patients are necessary to confirm the accuracy and validate this proposed definition.
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http://dx.doi.org/10.1001/jamaoncol.2020.1634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290708PMC
July 2020

CT Texture Analysis Challenges: Influence of Acquisition and Reconstruction Parameters: A Comprehensive Review.

Diagnostics (Basel) 2020 Apr 28;10(5). Epub 2020 Apr 28.

IR4M-UMR8081, CNRS, Univ Paris Sud, University Paris Saclay, Rue Ampère, 91405 Orsay CEDEX, France.

Texture analysis in medical imaging is a promising tool that is designed to improve the characterization of abnormal images from patients, to ultimately serve as a predictive or prognostic biomarker. However, the nature of image acquisition itself implies variability in each pixel/voxel value that could jeopardize the usefulness of texture analysis in the medical field. In this review, a search was performed to identify current published data for computed tomography (CT) texture reproducibility and variability. On the basis of this analysis, the critical steps were identified with a view of using texture analysis as a reliable tool in medical imaging. The need to specify the CT scanners used and the associated parameters in published studies is highlighted. Harmonizing acquisition parameters between studies is a crucial step for future texture analysis.
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http://dx.doi.org/10.3390/diagnostics10050258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277097PMC
April 2020

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

Eur Radiol 2020 Sep 23;30(9):5021-5028. Epub 2020 Apr 23.

Imaging Department, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.

Objectives: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients.

Methods: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed.

Results: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001.

Conclusion: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy.

Key Points: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.
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http://dx.doi.org/10.1007/s00330-020-06784-yDOI Listing
September 2020

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression.

J Thorac Oncol 2020 03 13;15(3):383-391. Epub 2019 Dec 13.

Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address:

Introduction: In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown.

Methods: Patients with advanced NSCLC with known baseline genomic alteration (GA) (EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, STK11, TP53) on tissue were divided into three groups on the basis of their disease progression pattern: iCNS, extra-CNS only (noCNS), or both (cCNS). All patients with available plasma ctDNA were included and were analyzed by next-generation sequencing InVisionFirst-Lung. ctDNA was considered positive if at least one GA was detected. Cell-free tumor DNA was analyzed in cerebrospinal fluid when available.

Results: Out of 517 patients screened, 247 were included: 54 had iCNS, 99 had noCNS, and 94 had cCNS progressive disease (64, 128, and 110 ctDNA samples, respectively). CtDNA was positive in 52% iCNS versus 84% in noCNS and 92% in cCNS (p < 0.00001), with lower detection of driver (37% versus 77% and 73%, respectively) and resistance alterations (6% versus 45% and 44%). Patients with iCNS and positive ctDNA were more at risk of extra-CNS progression (32% versus 7%, p = 0.026). In 12 patients with iCNS, ctDNA was positive in six (50%) plasma and in 10 (83%) paired cerebrospinal fluid (p = 0.193).

Conclusions: Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS.
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http://dx.doi.org/10.1016/j.jtho.2019.11.024DOI Listing
March 2020

Association of the prognostic model iSEND with PD-1/L1 monotherapy outcome in non-small-cell lung cancer.

Br J Cancer 2020 02 25;122(3):340-347. Epub 2019 Nov 25.

University of Miami, Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA.

Background: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR).

Methods: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events.

Results: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort.

Conclusion: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.
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http://dx.doi.org/10.1038/s41416-019-0643-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000664PMC
February 2020

Baseline metabolic tumor burden on FDG PET/CT scans predicts outcome in advanced NSCLC patients treated with immune checkpoint inhibitors.

Eur J Nucl Med Mol Imaging 2020 05 21;47(5):1147-1157. Epub 2019 Nov 21.

Gustave Roussy, Department of Medical Oncology, Thoracic Unit, Villejuif, France.

Purpose: We aimed to evaluate if imaging biomarkers on FDG PET are associated with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs).

Methods: In this retrospective monocentric study, we included 109 patients with advanced NSCLC who underwent baseline FDG PET/CT before ICI initiation between July 2013 and September 2018. Clinical, biological (including dNLR = neutrophils/[leukocytes minus neutrophils]), pathological and PET parameters (tumor SUVmax, total metabolic tumor volume [TMTV]) were evaluated. A multivariate prediction model was developed using Cox models for progression-free survival (PFS) and overall survival (OS). The association between biomarkers on FDG PET/CT and disease clinical benefit (DCB) was tested using logistic regression.

Results: Eighty patients were eligible. Median follow-up was 11.6 months (95%CI 7.7-15.5). Sixty-four and 52 patients experienced progression and death, respectively. DCB was 40%. In multivariate analyses, TMTV > 75 cm and dNLR > 3 were associated with shorter OS (HR 2.5, 95%CI 1.3-4.7 and HR 3.3, 95%CI 1.6-6.4) and absence of DCB (OR 0.3, 95%CI 0.1-0.9 and OR 0.4, 95%CI 0.2-0.9). Unlike TMTV, dNLR was a significant prognostic factor for PFS (HR 1.9, 95%CI 1.1-3.3) along with anemia (HR 1.9, 95%CI 1.2-3.8). No association was observed between tumor SUVmax and PFS or OS.

Conclusion: Baseline tumor burden (TMTV) on FDG PET/CT scans and inflammatory status (dNLR) were associated with poor OS and absence of DCB for ICI treatment in advanced NSCLC patients, unlike tumor SUVmax, and may be used together to improve the selection of appropriate candidates.
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http://dx.doi.org/10.1007/s00259-019-04615-xDOI Listing
May 2020

Correction to: Focus on Recommendations for the Management of Non-small Cell Lung Cancer.

Cardiovasc Intervent Radiol 2020 Jan;43(1):168

Interventional Radiology, Gustave Roussy, Villejuif, France.

The authors would like to apologize for the misspelling of one of the co-authors names.
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http://dx.doi.org/10.1007/s00270-019-02370-yDOI Listing
January 2020

F-18-Dopa Positron Emission Tomography/Computed Tomography Is More Sensitive Than Whole-Body Magnetic Resonance Imaging for the Localization of Persistent/Recurrent Disease of Medullary Thyroid Cancer Patients.

Thyroid 2019 10;29(10):1457-1464

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France.

Elevated postoperative serum calcitonin (Ctn) level indicates persistent/recurrent disease in patients with medullary thyroid carcinoma (MTC). Its location is a challenge. The aim of our study was to compare the disease detection rates of F-18-Dopa (fluoro dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT), whole-body (WB) magnetic resonance imaging (MRI), F-18-FDG (fluorodeoxyglucose) PET/CT, WB CT scanning, neck ultrasonography, and bone scintigraphy in MTC patients with increased Ctn levels and unknown localization of the source. We compared the independent reading of each imaging procedure with a reference assessment for structural disease defined by pathology or concordance between two imagings or with subsequent follow-up. The detection rate of each imaging modality was determined in per patient, per organ, and per lesion analysis. Thirty-six consecutive patients (21 females, mean age: 57 years, sporadic MTC in 26 cases, median serum Ctn level: 760 pg/mL; range: 21-10,121) were analyzed. The reference assessment localized disease in 24 (64%) patients with 74 lesions detected in the thyroid bed (8), in neck lymph nodes (15), mediastinal lymph nodes (6), lungs (1), liver (2), bones (3), and other site (1). At the patient level, the detection rates were 64% (CI 0.48-0.80) for F-18-Dopa PET/CT with early acquisitions, 40% (CI 0.24-0.56) for F-18-FDG PET/CT, 40% (CI 0.24-0.56) for WB MRI, and 48% (CI 0.31-0.66) for WB CT scan. In MTC patients with increased Ctn and no known distant metastases, F-18-Dopa PET/CT is more sensitive to detect structural disease than any other imaging modality, including WB MRI.
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http://dx.doi.org/10.1089/thy.2018.0351DOI Listing
October 2019

Hepatic Intra-Arterial Chemotherapy With Immunotherapy in NSCLC.

J Thorac Oncol 2019 10 11;14(10):e215-e216. Epub 2019 Jul 11.

Cancer Medicine Department, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.07.001DOI Listing
October 2019