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Objectives: Lower bilobectomy (LBL) leaves a residual pleural space potentially associated with adverse postoperative outcomes. In selected patients, right sleeve lower lobectomy (RSLL) with anastomosis between the middle lobe bronchus and intermediate bronchus is feasible. The outcomes of RSLL and LBL have not been compared. The aim of this study was to compare post-operative and long-term outcomes of RSLL and LBL in patients with lung cancer., Methods: We retrospectively included patients managed by RSLL or LBL at our referral chest-surgery institution between 2001 and 2019. Post-operative complications and mortality were compared. Kaplan-Meier curves were plotted to compare overall and disease-free survival rates., Results: We identified 23 patients with RSLL and 96 with LBL. Postoperative mortality was 9 % after RSLL and 5 % after LBL (p = 0.41). Bronchial fistula developed in 3 (13 %) RSLL patients and 6 (6 %) LBL patients (p = 0.23). Pleural space complications were significantly less common after RSLL (4/23 [17 %] vs. 45/96 [47 %], p = 0.03). Long-term vital capacity was significantly higher in the RSLL group (91 % vs. 64 %, p < 0.01). Five-year survival did not differ significantly between groups (84 % vs. 72 %, p = 0.09)., Conclusions: RSLL was associated with similar postoperative mortality and long-term survival compared to LBL. However, pleural space complications were less common and lung function was better after RSLL than after LBL. When feasible, RSLL may deserve preference over LBL in patients with lung cancer managed at highly experienced centres., Competing Interests: Declaration of competing interest The other authors have no disclosure to declare for this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to propose a deep learning-based approach to detect pulmonary embolism and quantify its severity using the Qanadli score and the right-to-left ventricle diameter (RV/LV) ratio on three-dimensional (3D) computed tomography pulmonary angiography (CTPA) examinations with limited annotations., Materials and Methods: Using a database of 3D CTPA examinations of 1268 patients with image-level annotations, and two other public datasets of CTPA examinations from 91 (CAD-PE) and 35 (FUME-PE) patients with pixel-level annotations, a pipeline consisting of: (i), detecting blood clots; (ii), performing PE-positive versus negative classification; (iii), estimating the Qanadli score; and (iv), predicting RV/LV diameter ratio was followed. The method was evaluated on a test set including 378 patients. The performance of PE classification and severity quantification was quantitatively assessed using an area under the curve (AUC) analysis for PE classification and a coefficient of determination (R²) for the Qanadli score and the RV/LV diameter ratio., Results: Quantitative evaluation led to an overall AUC of 0.870 (95% confidence interval [CI]: 0.850-0.900) for PE classification task on the training set and an AUC of 0.852 (95% CI: 0.810-0.890) on the test set. Regression analysis yielded R² value of 0.717 (95% CI: 0.668-0.760) and of 0.723 (95% CI: 0.668-0.766) for the Qanadli score and the RV/LV diameter ratio estimation, respectively on the test set., Conclusion: This study shows the feasibility of utilizing AI-based assistance tools in detecting blood clots and estimating PE severity scores with 3D CTPA examinations. This is achieved by leveraging blood clots and cardiac segmentations. Further studies are needed to assess the effectiveness of these tools in clinical practice., Competing Interests: Disclosure of Interests The authors declare that they have no competing interest., (Copyright © 2023 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: The efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown., Methods: In this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR)., Results: 35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%-96%) among evaluable patients (n = 32), and 95% (95% CI 70-100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15-23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1-19). Treatment toxicity was manageable, without toxic death., Conclusion: HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DM: Consulting/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Bionest Partners, BMS, Incyte, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Simon-Kutcher & Partners, Servier, Taiho. Honoraria for lectures: Amgen, AstraZeneca, Bayer, BMS, Foundation Medicine, Incyte, Leo Pharma, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Servier, Veracyte, Viatris. Personal fees for a writing engagement: Medscape. Travel expenses for medical congresses: Amgen, Bayer, BMS, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Servier, Viatris. BV: none. MF: honoraria for lectures: Novartis. Travel expenses for medical congresses: Ipsen. RG: Consulting/advisory role: Pierre Fabre, BMS, Servier, MSD. Honoraria for lectures: MSD, Servier, Ipsen, BMS, Viatris. Travel expenses for medical congresses: MSD, Ipsen, Roche, Pierre Fabre, Advanced Accelerator Applications (AAA). CC: none. JE: Consulting/advisory role: MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, Servier, Beigene. Travel expenses for medical congresses: Amgen. Research funding (institutional): BMS, Beigene. MPG: honoraria: Servier, BMS. Travel expenses for medical congresses: AAA, Bayer, Servier, Amgen. LBG: honoraria: AstraZeneca, Servier, KSK, MSD, Bayer, Eisai. DS: travel expenses for medical congresses: Servier, Pierre Fabre. EDB: none. TDB: Consulting/advisory role: Terumo, Boston Scientific. Research funding (institutional): Quantum, Terumo. DG: honoraria for lectures: Merck Serono, Amgen, Sanofi, Servier. PD: Consulting/advisory role: MSD. Honoraria for lectures: AstraZeneca, MSD. Travel expenses for medical congresses: MSD. LL: none. VB: Consulting/advisory role: Merck Serono, Ipsen, Bayer, Eisai, BMS, Roche, AstraZeneca. Honoraria for lectures: Merck Serono, Novartis, Roche, Bayer, MSD, Amgen, Ipsen, AstraZeneca. Travel expenses for medical congresses: Amgen, Merck Serono, Sanofi Genzyme, Bayer, Roche, MSD, Ipsen, AstraZeneca. Research funding (institutional): Merck Serono. MG: none. JPP: none. MD: honoraria for advisory boards or as a presenter in symposium: Merck Serono, MSD, Amgen, Roche, Bayer, Ipsen, Pfizer, Servier, Pierre Fabre, Lilly, Sanofi, Servier, Daiichi Sankyo., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: In 2022, the French Society of Radiology together with the French Society of Thoracic Imaging and CentraleSupelec organized their 13th data challenge. The aim was to aid in the diagnosis of pulmonary embolism, by identifying the presence of pulmonary embolism and by estimating the ratio between right and left ventricular (RV/LV) diameters, and an arterial obstruction index (Qanadli's score) using artificial intelligence., Materials and Methods: The data challenge was composed of three tasks: the detection of pulmonary embolism, the RV/LV diameter ratio, and Qanadli's score. Sixteen centers all over France participated in the inclusion of the cases. A health data hosting certified web platform was established to facilitate the inclusion process of the anonymized CT examinations in compliance with general data protection regulation. CT pulmonary angiography images were collected. Each center provided the CT examinations with their annotations. A randomization process was established to pool the scans from different centers. Each team was required to have at least a radiologist, a data scientist, and an engineer. Data were provided in three batches to the teams, two for training and one for evaluation. The evaluation of the results was determined to rank the participants on the three tasks., Results: A total of 1268 CT examinations were collected from the 16 centers following the inclusion criteria. The dataset was split into three batches of 310, 580 and 378 C T examinations provided to the participants respectively on September 5, 2022, October 7, 2022 and October 9, 2022. Seventy percent of the data from each center were used for training, and 30% for the evaluation. Seven teams with a total of 48 participants including data scientists, researchers, radiologists and engineering students were registered for participation. The metrics chosen for evaluation included areas under receiver operating characteristic curves, specificity and sensitivity for the classification task, and the coefficient of determination r 2 for the regression tasks. The winning team achieved an overall score of 0.784., Conclusion: This multicenter study suggests that the use of artificial intelligence for the diagnosis of pulmonary embolism is possible on real data. Moreover, providing quantitative measures is mandatory for the interpretability of the results, and is of great aid to the radiologists especially in emergency settings., Competing Interests: Disclosure of Interests The authors declare that they have no known competing financial or personal relationships that could be viewed as influencing the work reported in this paper., (Copyright © 2023 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed., Competing Interests: Declaration of interests DEO-L reports honoraria from BMUC and unrestricted grants from Janssen for consensus nuclear medicine meetings in 2020 and 2022, outside the submitted work. LF reports grants from Bristol Myers Squibb and Banque Publique d’Investissement; honoraria for lectures from GE Healthcare, Fujifilm, and Median Technologies; support for attending meetings from Guerbet; participation on a safety monitoring board with Pandas Prodige; and research collaborations with Philips, Ariana Pharma, Evolucare, and Dassault Systems, outside the submitted work. EL reports royalties or licences from Springer, outside the submitted work. DK reports grants from Merck and honoraria from Merck Sharp & Dohme and Pfizer, outside the submitted work. SK reports an advisory role and study material from Novartis, Amgen, Somatex, Daiichi Sankyo, Gilead, AstraZeneca, Pfizer, Eli Lilly, MSD, and Roche for the submitted work; consulting fees from Eli Lilly and MSD; honoraria from AstraZeneca, Eli Lilly, and Pfizer; support for attending meetings from Roche, Daiichi Sankyo, and Eli Lilly; participation on boards with Novartis, Amgen, Somatex, pfm medical, MSD, Daiichi Sankyo, Seagen, Gilead Science, Agendia, Exact Science, Roche, Sonoscape, Eli Lilly, AstraZeneca, and Pfizer; and leadership in other boards with AGO, WSG, and ESMO, outside the submitted work. IM reports honoraria supported by Eli Lilly, Novartis, Pfizer, Seagen, Gilead, and Accuray, outside the submitted work. WMHO reports grants from Pfizer and AstraZeneca, travel grants from Daiitchi, and participation on an advisory board with GE, outside the submitted work. KH reports personal fees from Bayer, Sofie Biosciences, SIRTEX, Adacap, Curium, Endocyte, IPSEN, Siemens Healthineers, GE Healthcare, Amgen, Novartis, Y-mAbs, Aktis Oncology, Theragnostics, Pharma15, Debiopharm, AstraZeneca, and Janssen; non-financial support from ABX; and grants and personal fees from BTG, outside the submitted work. FC reports honoraria from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck Sharp, Meus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, priME Oncoloy, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, and Touchime, and support for attending meetings from Pfizer and Roche, outside the submitted work. BL reports participation on boards for AstraZeneca, Pfizer, Eli Lilly, Daiichi-Sankyo, Novartis, Pierre Fabre, Breast International Group Executive Committee, EORTC Breast Cancer Group, and Swedish Association of Breast Oncologists, outside the submitted work. WK reports consulting fees from Mint Medical and honoraria from Bristol Myers Squibb, outside the submitted work. CD reports consulting fees from Terumo, Sitex, and PSI CRO; honoraria from Ipsen; and a chairing role for EORTC Imaging Group, outside the submitted work. ES reports royalties from Springer; honoraria from Cancerodigest, Curio Science, Egis, Eli Lilly, Exact Sciences, Gilead, high5md, MSD, Novartis, and Pfizer; support for attending meetings from Egis, Gilead, Novartis, Pfizer, and Roche; participation on boards with AstraZeneca, Eli Lilly, Exact Sciences, Novartis, Oncompass Medicine, and Stowarzyszenie Rozowy Motyl; stock options from AstraZeneca, Eli Lilly, and Pfizer; receipt of equipment from AstraZeneca and Eli Lilly; and interests with Amgen, AstraZeneca, Eli Lilly, Novartis, OBI Pharma, Pfizer, Roche, and Samsung, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Despite the increasing importance of digital resources in modern life over the past decades, little is known about the impact of internet-based solutions on patient's health. We aimed to study the potential benefit of a digital platform helping patients to deal with abnormal chest CT scan revealing possible lung cancer., Methods: We set up a fast-track lung cancer diagnosis pathway through a secure online platform. Patient-generated information combined with online review of their imaging enables preplanning of further investigations ahead of clinical assessment. We compared outcomes of "self-referred" patients (patient group), who directly fill out the online questionnaire, to general practitioner-driven patients (GP group), who were referred by their GP., Results: From June 2021 to June 2022, we included 125 patients (61% males, median age 67 years, IQR 56.9-72.5): 41% in the patient group and 59% in the GP group. No difference was found between groups in terms of time from contact to first appointment (median 5 days in both groups, P = .6), percentage of pathways including prebooked tests (94% vs. 92%, P = .6), number of scheduled invasive procedures (median 1, IQR 1-2 vs. 2, IQR 1-2, P = .4) and in final cancer diagnosis (76% vs. 78%, P = .4)., Conclusion: A lung cancer diagnosis pathway directly accessible by patients through a secure online platform was feasible and as efficient as the usual general practitioner pathway. It demonstrated the benefit of leaning on new digital tools in order to answer to the new challenges of a patient-centered health care system., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clove oil (CO) is a powerful antioxidant essential oil (EO) with anti-inflammatory, anesthetic, and anti-infective properties. It can be therefore considered a good candidate for wound-healing applications, especially for chronic or diabetic wounds or burns, where the balance of reactive oxygen species (ROS) production and detoxification is altered. However, EOs require suitable formulations to be efficiently administered in moist wound environments. Chitosan hydrophobically modified by an ionic interaction with oleic acid (chitosan oleate, CSO) was used in the present work to stabilize CO nanoemulsions (NEs). The dimensions of the NE were maintained at around 300 nm as the volume distribution for up to six months, and the CO content did not decrease to under 80% over 4 months, confirming the good stabilizing properties of CSO. The antioxidant properties of the CO NE were evaluated in vitro by a 2,2-diphenil-2-picrylhydrazyl hydrate (DPPH) assay, and in fibroblast cell lines by electron paramagnetic resonance (EPR) using α -phenyl- N -tert-butyl nitrone (PBN) as a spin trap; a protective effect was obtained comparable to that obtained with α -tocopherol treatment. In a murine burn model, the ability of CO formulations to favor macroscopic wound closure was evidenced, and a histological analysis revealed a positive effect of the CO NE on the reparation of the lesion after 18 days. Samples of wounds at 7 days were subjected to a histological analysis and parallel dosage of lipid peroxidation by means of a thiobarbituric acid-reactive substances (TBARS) assay, confirming the antioxidant and anti-inflammatory activity of the CO NE.

Introduction: Eligibility criteria definition for a lung cancer screening (LCS) is an unmet need. We hypothesised that patients with a history of atheromatous cardiovascular disease (ACVD) associated with tobacco consumption are at risk of lung cancer (LC). The main objective is to assess LC prevalence among patients with ACVD and history of tobacco consumption by using low-dose chest CT scan. Secondary objectives include the evaluation LCS in this population and the constitution of a biological biobank to stratify risk of LC., Methods and Analysis: We are performing a monocentric 'single-centre' prospective study among patients followed up in adult cardiovascular programmes of vascular surgery, cardiology and cardiac surgery recruited from 18 November 2019 to 18 May 2021. The inclusion criteria are (1) age 45-75 years old, (2) history of ACVD and (3) history of daily tobacco consumption for 10 years prior to onset of ACVD. Exclusion criteria are symptoms of LC, existing follow-up for pulmonary nodule, fibrosis, pulmonary hypertension, resting dyspnoea and active pulmonary infectious disease. We targeted the inclusion of 500 patients. After inclusion (V0), patients are scheduled for a low-dose chest CT and blood and faeces harvesting within 7 months (V1). Each patient is scheduled for a follow-up by telephonic visits at month 3 (V2), month 6 (V3) and month 12 (V4) after V1. Each patient is followed up until 1 year after V1 (14 February 2023). We measure LC prevalence and quantify the National Lung Screening Trial and Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON) trial eligibility criteria, radiation, positive screening, false positivity, rate of localised LC diagnosis, quality of life with the Short Form 12 (SF-12) and anxiety with the Spielberger State-Trait Anxiety Inventory A and B (STAI-YA and STAI-YB, respectively), smoking cessation and onset of cardiovascular and oncological events within 1 year of follow-up. A case-control study nested in the cohort is performed to identify clinical or biological candidate biomarkers of LC., Ethics and Dissemination: The study was approved according the French Jardé law; the study is referenced at the French 'Agence Nationale de Sécurité du Médicament et des Produits de Santé' (reference ID RCB: 2019-A00262-55) and registered on clinicaltrial.gov. The results of the study will be presented after the closure of the follow-up scheduled on 14 February 2023 and disseminated through peer-reviewed journals and national and international conferences., Trial Registration Number: NCT03976804., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: In the Cancer Core Europe Consortium (CCE), standardized biomarkers are required for therapy monitoring oncologic multicenter clinical trials. Multiparametric functional MRI and particularly diffusion-weighted MRI offer evident advantages for noninvasive characterization of tumor viability compared to CT and RECIST. A quantification of the inter- and intraindividual variation occurring in this setting using different hardware is missing. In this study, the MRI protocol including DWI was standardized and the residual variability of measurement parameters quantified., Methods: Phantom and volunteer measurements (single-shot T2w and DW-EPI) were performed at the seven CCE sites using the MR hardware produced by three different vendors. Repeated measurements were performed at the sites and across the sites including a traveling volunteer, comparing qualitative and quantitative ROI-based results including an explorative radiomics analysis., Results: For DWI/ADC phantom measurements using a central post-processing algorithm, the maximum deviation could be decreased to 2%. However, there is no significant difference compared to a decentralized ADC value calculation at the respective MRI devices. In volunteers, the measurement variation in 2 repeated scans did not exceed 11% for ADC and is below 20% for single-shot T2w in systematic liver ROIs. The measurement variation between sites amounted to 20% for ADC and < 25% for single-shot T2w. Explorative radiomics classification experiments yield better results for ADC than for single-shot T2w., Conclusion: Harmonization of MR acquisition and post-processing parameters results in acceptable standard deviations for MR/DW imaging. MRI could be the tool in oncologic multicenter trials to overcome the limitations of RECIST-based response evaluation., Key Points: • Harmonizing acquisition parameters and post-processing homogenization, standardized protocols result in acceptable standard deviations for multicenter MR-DWI studies. • Total measurement variation does not to exceed 11% for ADC in repeated measurements in repeated MR acquisitions, and below 20% for an identical volunteer travelling between sites. • Radiomic classification experiments were able to identify stable features allowing for reliable discrimination of different physiological tissue samples, even when using heterogeneous imaging data., (© 2022. The Author(s).)

Background: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on reporting and interpretation of imaging findings yet offer no guidance on a standardised imaging protocol tailored to patients with mCRC. Imaging protocol heterogeneity remains a challenge for the reproducibility of conventional imaging end-points and is an obstacle for research on novel imaging end-points., Patients and Methods: Acknowledging the recently highlighted potential of radiomics and artificial intelligence tools as decision support for patient care in mCRC, a multidisciplinary, international and expert panel of imaging specialists was formed to find consensus on mCRC imaging protocols using the Delphi method., Results: Under the guidance of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging and Gastrointestinal Tract Cancer Groups, the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the EORTC-ESOI-ESGAR core imaging protocol was identified., Conclusion: This consensus protocol attempts to promote standardisation and to diminish variations in patient preparation, scan acquisition and scan reconstruction. We anticipate that this standardisation will increase reproducibility of radiomics and artificial intelligence studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these imaging standards across recruiting centres., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.H. reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from Y-mAbs, all outside the submitted work. L.B. is a cofounder of Collective Minds Radiology. R.C. reports travel support by Bracco Imaging. T.D. reports honorary fees and travel support by Siemens, Canon, Bayer, b.e. imaging and research grants by Siemens Healthineers, Bayer, Guerbet and b.e. imaging. E.L. reports receiving research grants from AIRC and from the Italian Ministry of Health, and faculty remuneration from ESMIT (European School of Multimodality Imaging and Therapy) and MI&T Congressi. D.E.O.-L. received expert remuneration from EAU for participating in PET PSMA Consensus Meeting in January 2022. The remaining authors declare that they have no conflict of interest related to this study. W.G.K. reports personal fees from Bristol-Myers Squibb., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Lesion/tissue segmentation on digital medical images enables biomarker extraction, image-guided therapy delivery, treatment response measurement, and training/validation for developing artificial intelligence algorithms and workflows. To ensure data reproducibility, criteria for standardised segmentation are critical but currently unavailable., Methods: A modified Delphi process initiated by the European Imaging Biomarker Alliance (EIBALL) of the European Society of Radiology (ESR) and the European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group was undertaken. Three multidisciplinary task forces addressed modality and image acquisition, segmentation methodology itself, and standards and logistics. Devised survey questions were fed via a facilitator to expert participants. The 58 respondents to Round 1 were invited to participate in Rounds 2-4. Subsequent rounds were informed by responses of previous rounds., Results/conclusions: Items with ≥ 75% consensus are considered a recommendation. These include system performance certification, thresholds for image signal-to-noise, contrast-to-noise and tumour-to-background ratios, spatial resolution, and artefact levels. Direct, iterative, and machine or deep learning reconstruction methods, use of a mixture of CE marked and verified research tools were agreed and use of specified reference standards and validation processes considered essential. Operator training and refreshment were considered mandatory for clinical trials and clinical research. Items with a 60-74% agreement require reporting (site-specific accreditation for clinical research, minimal pixel number within lesion segmented, use of post-reconstruction algorithms, operator training refreshment for clinical practice). Items with ≤ 60% agreement are outside current recommendations for segmentation (frequency of system performance tests, use of only CE-marked tools, board certification of operators, frequency of operator refresher training). Recommendations by anatomical area are also specified., (© 2022. The Author(s).)

Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this cascade can thus represent a new pharmacological option to prevent DR progression. To this aim, proper in vitro models are crucial for drug discovery, as they allow to better identify promising effective molecules. Considering that endothelial cells are key elements in DR and that hyperglycemia triggers the PKCβII/HuR/VEGF pathway, we set up two distinct in vitro models applying two different stimuli. Namely, human umbilical vein endothelial cells were exposed to phorbol 12-myristate 13-acetate, which mimics diacylglycerol whose synthesis is triggered by diabetic hyperglycemia, while human retinal endothelial cells were treated with high glucose for different times. After selecting the optimal experimental conditions able to determine an increased VEGF production, in search of molecules useful to prevent DR development, we investigated the capability of troxerutin, an antioxidant flavonoid, to counteract not only the rise of VEGF but also the activation of the PKCβII/HuR cascade in both in vitro models. The results show the capability of troxerutin to hinder the hyperglycemia-induced increase in VEGF in both models through PKCβII/HuR pathway modulation. Further, these data confirm the key engagement of this cascade as an early event triggered by hyperglycemia to promote VEGF expression. Finally, the present findings also suggest the potential use of troxerutin as a preventive treatment during the early phases of DR., Competing Interests: Author LL was employed by Bausch & Lomb—Iom S.p.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fahmideh, Marchesi, Campagnoli, Landini, Caramella, Barbieri, Govoni and Pascale.)

Introduction: Radiological response assessment to immune checkpoint inhibitor is challenging due to atypical pattern of response and commonly used RECIST 1.1 criteria do not take into account the kinetics of tumor behavior. Our study aimed at evaluating the tumor growth rate (TGR) in addition to RECIST 1.1 criteria to assess the benefit of immune checkpoint inhibitors (ICIs)., Methods: Tumor real volume was calculated with a dedicated computed tomography (CT) software that semi-automatically assess tumor volume. Target lesions were identified according to RECIST 1.1. For each patient, we had 3 measurement of tumor volume. CT-1 was performed 8-12 weeks before ICI start, the CT at baseline for ICI was CT0, while CT + 1 was the first assessment after ICI. We calculated the percentage increase in tumor volume before (TGR1) and after immunotherapy (TGR2). Finally, we compared TGR1 and TGR2. If no progressive disease (PD), the group was disease control (DC). If PD but TGR2 < TGR1, it was called LvPD and if TGR2 ⩾ TGR1, HvPD., Results: A total of 61 patients who received ICIs and 33 treated with chemotherapy (ChT) were included. In ICI group, 18 patients were HvPD, 22 LvPD, 21 DC. Median OS was 4.4 months (95% CI: 2.0-6.8, reference) for HvPD, 7.1 months (95% CI 5.4-8.8) for LvPD, p  = 0.018, and 20.9 months (95% CI: 12.5-29.3) for DC, p  < 0.001. In ChT group, 7 were categorized as HvPD, 17 as LvPD and 9 as DC. No difference in OS was observed in the ChT group (p = 0.786)., Conclusion: In the presence of PD, a decrease in TGR may result in a clinical benefit in patients treated with ICI but not with chemotherapy. Monitoring TGR changes after ICIs administration can help physician in deciding to treat beyond PD., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Caroline Caramella: has acted as a consultant of AstraZeneca, BMS, MSD, and Roche Benjamin Besse: has conducted research funded by Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda and Tiziana Pharm 4D Pharma, Abbvie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. Andrea Ardizzoni: Grants from BMS and Celgene; Personal Fees from BMS, MSD, Eli Lilly, Boehringer, Pfizer and Celgene. The other authors declare no potential conflicts of interest., (© The Author(s), 2022.)

Background: Programmed cell death protein-1 (PD-1) expression has been associated with activation and exhaustion of both the CD4 and CD8 populations in advanced non-small cell lung cancer (aNSCLC). Nevertheless, the impact of the balance between circulating CD8 + PD-1 + and CD4 + PD-1 + in patients treated with immune checkpoint blockers (ICB) is unknown., Methods: The CD8 + PD-1 + to CD4 + PD-1 + ratio (PD-1-Expressing Ratio on Lymphocytes in a Systemic blood sample, or 'PERLS') was determined by cytometry in fresh whole blood from patients with aNSCLC before treatment with single-agent ICB targeting PD-1 or programmed cell death-ligand 1 (PD-L1 (discovery cohort). A PERLS cut-off was identified by log-rank maximization. Patients treated with ICB (validation cohort) or polychemotherapy (control cohort) were classified as PERLS+/- (above/below cut-off). Circulating immune cell phenotype and function were correlated with PERLS. A composite score (good, intermediate and poor) was determined using the combination of PERLS and senescent immune phenotype as previously described in aNSCLC., Results: In the discovery cohort (N=75), the PERLS cut-off was 1.91, and 11% of patients were PERLS+. PERLS + correlated significantly with median progression-free survival (PFS) of 9.63 months (95% CI 7.82 to not reached (NR)) versus 2.69 months (95% CI 1.81 to 5.52; p=0.03). In an independent validation cohort (N=36), median PFS was NR (95% CI 7.9 to NR) versus 2.00 months (95% CI 1.3 to 4.5; p=0.04) for PERLS + and PERLS-, respectively; overall survival (OS) followed a similar but non-significant trend. In the pooled cohort (N=111), PERLS + correlated significantly with PFS and OS. PERLS did not correlate with outcome in the polychemotherapy cohort. PERLS did not correlate with clinical characteristics but was significantly associated with baseline circulating naïve CD4 + T cells and the increase of memory T cells post-ICB treatment. Accumulation of memory T cells during treatment was linked to CD4 + T cell polyfunctionality. The composite score was evaluated in the pooled cohort (N=68). The median OS for good, intermediate and poor composite scores was NR (95% CI NR to NR), 8.54 months (95% CI 4.96 to NR) and 2.42 months (95% CI 1.97 to 15.5; p=0.001), respectively. The median PFS was 12.60 months (95% CI 9.63 to NR), 2.58 months (95% CI 1.74 to 7.29) and 1.76 months (95% CI 1.31 to 4.57; p<0.0001), respectively., Conclusions: Elevated PERLS, determined from a blood sample before immunotherapy, was correlated with benefit from PD-(L)1 blockers in aNSCLC., Competing Interests: Competing interests: BD: speakers bureaus or educational events from Roche, Pfizer, AstraZeneca, Chiesi, Amgen, Lilly; support for attending meetings and/or travel from AZ, Pfizer, Oxyvie. MN: no competing interest to declare, EA: support for attending meetings and/or travel from: Mundipharma; lectures and educational activities: Sanofi Genzymes. RF: senior advisory board meetings for MSD. LC, J-MJ, LB, JG, AD, F-XD: no competing interest to declare. LM: sponsored research: Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Stilla, Inivata. Consulting, advisory role: Roche Diagnostics, Takeda, Roche. Lectures and educational activities: Bristol Myers Squibb, Tecnofarma, Roche, Takeda. Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche. Mentorship program with key opinion leaders: funded by AstraZeneca. CC: no competing interest to declare. AM: senior advisory board meetings for MSD, BMS, AstraZeneca/Medimmune, Sanofi, Pfizer, Roche/Genentech, Merck Serono. Consulting services to Sanofi, Roche/Genentech. Speakers bureau of MSD, BMS, AstraZeneca/Medimmune, Sanofi, Roche/Genentech, Merck Serono. BB: sponsored research at Gustave Roussy Cancer Center 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. NC: sponsored research at Gustave Roussy Cancer Center from AstraZeneca, GSK, Roche, Sanofi, Cytune Pharma, Gilead, Servier., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Accumulating evidence suggests that a high tumour burden has a negative effect on anticancer immunity. The concept of tumour burden, simply defined as the total amount of cancer in the body, in contrast to molecular tumour burden, is often poorly understood by the wider medical community; nonetheless, a possible role exists in defining the optimal treatment strategy for many patients. Historically, tumour burden has been assessed using imaging. In particular, CT scans have been used to evaluate both the number and size of metastases as well as the number of organs involved. These methods are now often complemented by metabolic tumour burden, measured using the more recently developed 2-deoxy-2-[ 18 F]-fluoro-D-glucose (FDG)-PET/CT. Serum-based biomarkers, such as lactate dehydrogenase, can also reflect tumour burden and are often also correlated with a poor response to immune-checkpoint inhibitors. Other circulating markers (such as circulating free tumour DNA and/or circulating tumour cells) are also attracting research interest as surrogate markers of tumour burden. In this Review, we summarize evidence supporting the utility of tumour burden as a biomarker to guide the use of immune-checkpoint inhibitors. We also describe data and provide perspective on the various tools used for tumour burden assessment, with a particular emphasis on future therapeutic strategies that might address the issue of inferior outcomes among patients with cancer with a high tumour burden., (© 2021. Springer Nature Limited.)

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., (© 2021. European Society of Radiology.)

Tissue repair and regeneration is an interdisciplinary field focusing on developing bioactive substitutes aimed at restoring pristine functions of damaged, diseased tissues. Biomaterials, intended as those materials compatible with living tissues after in vivo administration, play a pivotal role in this area and they have been successfully studied and developed for several years. Namely, the researches focus on improving bio-inert biomaterials that well integrate in living tissues with no or minimal tissue response, or bioactive materials that influence biological response, stimulating new tissue re-growth. This review aims to gather and introduce, in the context of Italian scientific community, cutting-edge advancements in biomaterial science applied to tissue repair and regeneration. After introducing tissue repair and regeneration, the review focuses on biodegradable and biocompatible biomaterials such as collagen, polysaccharides, silk proteins, polyesters and their derivatives, characterized by the most promising outputs in biomedical science. Attention is pointed out also to those biomaterials exerting peculiar activities, e.g., antibacterial. The regulatory frame applied to pre-clinical and early clinical studies is also outlined by distinguishing between Advanced Therapy Medicinal Products and Medical Devices.

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., (© 2021. The Author(s).)

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., Competing Interests: Conflicts of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura Mezquita reports receiving research sponsorship from Bristol-Myers Squibb and Boehringer Ingelheim; consulting and advisory roles in Roche Diagnostics and Takeda; lectures and educational activities in Bristol-Myers Squibb, Tecnofarma and Roche; receiving travel, accommodations and expenses from Roche; and participation in the mentorship program with key opinion leaders, funded by AstraZeneca. Edouard Auclin reports receiving travel expenses from Mundipharma and lectures and educational activities in Sanofi Genzymes. Lizza Hendriks reports no conflicts related to the current manuscript; however, outside of current manuscript LH reports receiving research funding from Roche, Boehringer Ingelheim and AstraZeneca (all institution); advisory board roles in Boehringer, BMS, Lilly, Roche, Pfizer, Takeda, MSD and Boehringer Ingelheim (all institution); and speaker roles in MSD; receiving travel/conference reimbursements from Roche and BMS (self); participation in the mentorship program with key opinion leaders, funded by AstraZeneca; receiving fees for educational webinars from Quadia (self); and participation in interview sessions funded by Roche (institution). Anas Gazzah reports receiving travel, accommodation and congress registration expenses from Boehringer Ingelheim, Novartis, Pfizer and Roche; consultant/expert roles in Novartis; roles principal/sub-investigator of clinical trials for Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Iris Servier, Janssen, Kura Oncology, Kyowa Kirin Pharm, Lilly, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Rigontec Gmbh, Roche, Sanofi-Aventis, Sierra Oncology, Taiho Pharma, Tesaro Inc., Tioma Therapeutics Inc. and Xencor; receiving research grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche and Sanofi; receiving on-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer and Roche. David Planchard reports consulting, advisory roles or lectures in AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; roles in clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure and Daiichi Sankyo; receiving travel and accommodation expenses from AstraZeneca, Roche, Novartis, prIME Oncology and Pfizer. Benjamin Besse reports Sponsored research sponsorship from Gustave Roussy Cancer Center Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda and Tiziana Pharma. Julien Adam reports advisory board roles in AstraZeneca and Bayer and honoraria from MSD and BMS. Remaining authors nothing to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.

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 T 2 ∗ . 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., (© 2020 International Society for Magnetic Resonance in Medicine.)

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 in vitro ., Results: In the ICI discovery cohort ( N = 37), SIP cut-off was 39.5%, 27% of patients were SIP + . In the ICI validation cohort ( N = 46), SIP + status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP + status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8 + T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population ( N = 83), SIP + status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort ( N = 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. See related commentary by Salas-Benito et al., p. 374 ., (©2020 American Association for Cancer Research.)

Purpose: The purpose of this study was to compare efficacy and tolerance between radiofrequency ablation (RFA) and surgery for the treatment of oligometastatic lung disease., Materials and Methods: This retrospective study reviewed patients treated in two institutions for up to 5 pulmonary metastases with a maximal diameter of 4cm and without associated pleural involvement or thoracic lymphadenopathy. Patient demographics, tumor characteristics, treatment outcome, and length of hospital stay were compared between the two groups. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and pulmonary or local tumor progression rates., Results: Among 204 patients identified, 78 patients (42 men, 36 women; mean age, 53.3±14.9 [SD]; age range: 15-81 years) were treated surgically, while 126 patients (59 men, 67 women; mean age, 62.2±10.8 [SD]; age range: 33-80 years) were treated by RFA. In the RFA cohort, patients were significantly older (P<0.0001), with more extra-thoracic localisation (P=0.015) and bilateral tumour burden (P=0.0014). In comparison between surgery and RFA cohorts, respectively, the 1- and 3-year OS were 94.8 and 67.2% vs. 94 and 72.1% (P=0.46), the 1- and 3-year PFS were 49.4% and 26.1% vs. 38.9% and 14.8% (P=0.12), the pulmonary progression rates were 39.1% and 56% vs. 41.2% and 65.3% (P>0.99), and the local tumour progression rates were 5.4% and 10.6% vs. 4.8% and 18.6% (P=0.07). Tumour size>2cm was associated with a significantly higher local tumor progression in the RFA group (P=0.010). Hospitalisation stay was significantly shorter in the RFA group (median of 3 days; IQR=2 days; range: 2-12 days) than in the surgery group (median of 9 days; IQR=2 days; range: 6-21 days) (P<0.01)., Conclusion: RFA should be considered a minimally-invasive alternative with similar OS and PFS to surgery in the treatment of solitary or multiple lung metastases measuring less than 4cm in diameter without associated pleural involvement or thoracic lymphadenopathy., (Copyright © 2020 Soci showét showé françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

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 T790M 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 EGFR , v-Raf murine sarcoma viral oncogene homolog B ( BRAF ), anaplastic lymphoma kinase ( ALK ) or ROS proto-oncogene 1 ( ROS1 ), and who had an available evaluation of chronic KI plasma exposure. Suboptimal plasma concentrations were observed in 51% (26/51) of cases. In EGFR -mutant cases failing first-generation KIs, EGFR 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.

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: BRAF V600E 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., (©2020 American Association for Cancer Research.)

Purpose: The second edition of the artificial intelligence (AI) data challenge was organized by the French Society of Radiology with the aim to: (i), work on relevant public health issues; (ii), build large, multicentre, high quality databases; and (iii), include three-dimensional (3D) information and prognostic questions., Materials and Methods: Relevant clinical questions were proposed by French subspecialty colleges of radiology. Their feasibility was assessed by experts in the field of AI. A dedicated platform was set up for inclusion centers to safely upload their anonymized examinations in compliance with general data protection regulation. The quality of the database was checked by experts weekly with annotations performed by radiologists. Multidisciplinary teams competed between September 11 th and October 13 th 2019., Results: Three questions were selected using different imaging and evaluation modalities, including: pulmonary nodule detection and classification from 3D computed tomography (CT), prediction of expanded disability status scale in multiple sclerosis using 3D magnetic resonance imaging (MRI) and segmentation of muscular surface for sarcopenia estimation from two-dimensional CT. A total of 4347 examinations were gathered of which only 6% were excluded. Three independent databases from 24 individual centers were created. A total of 143 participants were split into 20 multidisciplinary teams., Conclusion: Three data challenges with over 1200 general data protection regulation compliant CT or MRI examinations each were organized. Future challenges should be made with more complex situations combining histopathological or genetic information to resemble real life situations faced by radiologists in routine practice., (Copyright © 2020 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: The purpose of this study was to create an algorithm to detect and classify pulmonary nodules in two categories based on their volume greater than 100 mm 3 or not, using machine learning and deep learning techniques., Materials and Method: The dataset used to train the model was provided by the organization team of the SFR (French Radiological Society) Data Challenge 2019. An asynchronous and parallel 3-stages pipeline was developed to process all the data (a data "pre-processing" stage; a "nodule detection" stage; a "classifier" stage). Lung segmentation was achieved using 3D U-NET algorithm; nodule detection was done using 3D Retina-UNET and classifier stage with a support vector machine algorithm on selected features. Performances were assessed using area under receiver operating characteristics curve (AUROC)., Results: The pipeline showed good performance for pathological nodule detection and patient diagnosis. With the preparation dataset, an AUROC of 0.9058 (95% confidence interval [CI]: 0.8746-0.9362) was obtained, 87% yielding accuracy (95% CI: 84.83%-91.03%) for the "nodule detection" stage, corresponding to 86% specificity (95% CI: 82%-92%) and 89% sensitivity (95% CI: 84.83%-91.03%)., Conclusion: A fully functional pipeline using 3D U-NET, 3D Retina-UNET and classifier stage with a support vector machine algorithm was developed, resulting in high capabilities for pulmonary nodule classification., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

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.

Purpose: Hyperprogressive disease (HPD), fast progression (FP), and early death (ED) have been described in 13.8%, 4.7%, and 5.6% and in 5.1%, 2.8%, and 6.8%, respectively, of patients with non-small-cell lung cancer (NSCLC) treated with single-agent programmed cell death ligand 1 inhibitors (ICI) or chemotherapy, respectively. Whether FP/ED and HPD represent overlapping patterns is unknown., Patients and Methods: FP, ED, and HPD were retrospectively assessed in patients with NSCLC treated with single-agent ICI or chemotherapy. Eligibility required 2 computed tomography (CT) scans before and 1 CT scan during treatment. (1) HPD, (2) FP, (3) ED were defined as (1) RECIST version 1.1 progression at first CT scan and tumor growth rate variation per month > 50%, (2) ≥ 50% increase in the sum of the longest diameters of target lesions within 6 weeks from baseline, and (3) death as a result of radiologic progression within 12 weeks from baseline CT scan, respectively., Results: Of 406 ICI-treated NSCLC, 56 patients (13.8%), 9 patients (2.2%), and 36 patients (8.8%) were HPD, FP, and ED, respectively. Eight (14.2%) and 20 (35.7%) of 56 patients with HPD were also FP and ED. ED significantly correlated with baseline Eastern Cooperative Oncology Group performance status ≥ 2 compared with HPD (33% v 13%, P = .02). Overall survival was significantly longer for HPD (3.4 months [95% CI, 2.7 to 4.0 months]) compared with FP (0.7 months [95% CI, 0.6 to 0.8 months]); HR, 0.18 [95% CI, 0.08 to 0.42]; P < .0001) and ED (1.4 months [95% CI, 1.3 to 1.6 months]); HR, 0.19 [95% CI, 0.11 to 0.34]); P < .0001), whereas it did not differ between FP and ED (HR, 1.3 [95% CI, 0.56 to 3.0]; P = .55). Of 59 patients with NSCLC treated with single-agent chemotherapy, the HPD, FP, and ED rates were 5.1%, 1.7%, and 6.7%, respectively., Conclusion: FP, ED, and HPD represent distinct progression patterns with limited overlap and different survival outcomes.

Collagen, thanks to its biocompatibility, biodegradability and weak antigenicity, is widely used in dressings and scaffolds, also as electrospun fibers. Its mechanical stability can be improved by adding polycaprolactone (PCL), a synthetic and biodegradable aliphatic polyester. While previously collagen/PCL combinations were electrospun in solvents such as hexafluoroisopropanol (HFIP) or trifluoroethanol (TFE), more recently literature describes collagen/PCL nanofibers obtained in acidic aqueous solutions. A good morphology of the fibers represents in this case still a challenge, especially for high collagen/PCL ratios. In this work, thanks to preliminary rheological and physicochemical characterization of the solutions and to a Design of Experiments (DOE) approach on process parameters, regular and dimensionally uniform fibers were obtained with collagen/PCL ratios up to 1:2 and 1:1 w/w. Collagen ratio appeared relevant for mechanical strength of dry and hydrated fibers. WAXS and FTIR analysis showed that collagen denaturation is related both to the medium and to the electrospinning process. After one week in aqueous environment, collagen release was complete and a concentration dependent stimulatory effect on fibroblast growth was observed, suggesting the fiber suitability for wound healing. The positive effect of collagen on mechanical properties and on fibroblast biocompatibility was confirmed by a direct comparison of nanofiber performance after collagen substitution with gelatin.

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 p < 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; p < 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 p < 0.0001., Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.

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.

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.

Chronic wounds, such as pressure ulcers, diabetic ulcers, venous ulcers and arterial insufficiency ulcers, are lesions that fail to proceed through the normal healing process within a period of 12 weeks. The treatment of skin chronic wounds still represents a great challenge. Wound medical devices (MDs) range from conventional and advanced dressings, up to skin grafts, but none of these are generally recognized as a gold standard. Based on recent developments, this paper reviews nanotechnology-based medical devices intended as skin substitutes. In particular, nanofibrous scaffolds are promising platforms for wound healing, especially due to their similarity to the extracellular matrix (ECM) and their capability to promote cell adhesion and proliferation, and to restore skin integrity, when grafted into the wound site. Nanotechnology-based scaffolds are emphasized here. The discussion will be focused on the definition of critical quality attributes (chemical and physical characterization, stability, particle size, surface properties, release of nanoparticles from MDs, sterility and apyrogenicity), the preclinical evaluation (biocompatibility testing, alternative in vitro tests for irritation and sensitization, wound healing test and animal wound models), the clinical evaluation and the CE (European Conformity) marking of nanotechnology-based MDs.

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., Competing Interests: Competing interests: CB has acted as a board advisor for BMS, has been a speaker for Merck and has received travel fees from Amgen and Pfizer. NC-G has received research grants from Cytune Pharma, GSK and Sanofi. She has acted as a board advisor for AstraZeneca and has been a speaker for Sanofi and AstraZeneca. CM has acted as consultant of BMS and Merck. ER has acted as a consultant for BMS, Novartis and Roche, and has received travel fees from BMS and Novartis. RS has received travel fees from AstraZeneca. CM has acted as a consultant from Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi and Orion. He is the principal or subinvestigator of clinical trials for Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveopharmaceuticals, Bayer, Beigene, Blueprint, BMS, BoeringerIngelheim, Celgene, Chugai, Clovis, DaiichiSankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, InnatePharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, LytixBiopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, NektarTherapeutics, Novartis, Octimet, Oncoethix, OncopeptidesAB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro and Xencor. J-CS has received consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen and Takeda. He has been a full-time employee of MedImmune since September 2017. He is a shareholder of AstraZeneca and Gritstone. CR has acted as a consultant of Amgen, BMS, GSK, Merck, Novartis and Roche. ED has received research grants from Roche, Servier, AstraZeneca, Merck Serono, BMS, MSD, Amgen, Accuray and Boerhinger. He has received personal fees from Roche, AstraZeneca, Merck Serono, Amgen, Accuray and Boerhinger., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 1 -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 s ) 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 s values > 0.7), whereas the PET-DCE correlations were mainly low to moderate (absolute r s 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.

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.

Inhaled/oral insulin have been investigated as an alternative to injectable insulin, but are met with unsatisfactory outcomes. Transdermal administration bears several advantages unmet by inhalation/oral delivery, but macromolecular drugs permeation is poor. This study explored microwave to elicit transdermal insulin permeation, and compared against conventional permeation enhancers (fatty acids) in vitro/in vivo. The transdermal insulin permeation was promoted by microwave (2450 MHz/1 mW) > oleic acid (monounsaturated) ~ linoleic acid (double unsaturated bonds). The linolenic acid (triple unsaturated bonds) or combination of microwave/fatty acid reduced skin insulin permeation. Transdermal insulin permeation enhancement was attributed to epidermal lipid bilayer fluidization (CH) and corneocyte shrinkage due to keratin condensation (OH/NH, CO), which had aqueous pore enlarged to facilitate insulin transport. Its reduction by linolenic acid, a molecularly larger and rigid fatty acid with higher surface tension, was due to reduced fatty acid permeation into epidermis and minimal skin microstructural changes. The oleic acid, despite favoured skin microstructural changes, did not provide a remarkably high insulin permeation due to it embedded in skin as hydrophobic shield to insulin transport. Microwave penetrates skin volumetrically with no chemical residue retention. It alone promoted insulin absorption and sustained blood glucose level reduction in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 3 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.

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.

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., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Laura MezquitaConsulting or Advisory Role: Roche, Roche Diagnostics, Takeda Speakers’ Bureau: Roche, Bristol-Myers Squibb, Tecnofarma Travel, Accommodations, Expenses: Roche, Bristol-Myers SquibbAurélie SwalduzHonoraria: Roche, Bristol-Myers Squibb, Takeda, AZD Consulting or Advisory Role: Eli Lilly, Pfizer, Bristol-Myers Squibb Travel, Accommodations, Expenses: Takeda, Pfizer, Boehringer Ingelheim, RocheKaren HowarthEmployment: Inivata Stock and Other Ownership Interests: Inivata Research Funding: Inivata Patents, Royalties, Other Intellectual Property: Patent pendingDavid PlanchardHonoraria: Prime Oncology, Peer CME Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Roche, Pfizer, MSD Oncology, Celgene, MedImmune, BeiGene Research Funding: AstraZeneca/MedImmune (Inst),, Bristol-Myers Squibb (Inst),, Boehringer Ingelheim (Inst), Eli Lilly (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Sanofi/Aventis (Inst), Taiho Pharmaceutical (Inst), Daiichi Sankyo (Inst), AbbVie (Inst)Gonzalo RecondoConsulting or Advisory Role: Roche, Amgen, Pfizer Travel, Accommodations, Expenses: AstraZeneca, PfizerFrank De KievitEmployment: Inivata Travel, Accommodations, Expenses: InivataVincent PlagnolEmployment: Inivata, Genomics Stock and Other Ownership Interests: Inivata, Genomics Patents, Royalties, Other Intellectual Property: Inivata patentsEtienne RouleauHonoraria: AstraZeneca (Inst), Roche (Inst), Bristol-Myers Squibb (Inst), AstraZeneca Research Funding: AstraZeneca (Inst) Travel, Accommodations, Expenses: AstraZeneca, Bristol-Myers SquibbPierre FournelConsulting or Advisory Role: Bristol-Myers Squibb, Amgen, MSD Oncology, Eli Lilly, AstraZeneca, Pfizer, AbbVie, Takeda, Roche, AstraZeneca, Amgen, Eli Lilly, Pfizer, Bristol-Myers-Squibb, MSD Oncology Research Funding: Bristol-Myers Squibb (Inst), AstraZeneca (Inst), Amgen (Inst), Pfizer (Inst), Pfizer/EMD Serono (Inst), Ipsen (Inst) Travel, Accommodations, Expenses: Novartis, Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, AstraZeneca, Amgen, Bristol-Myers Squibb, MSD OncologyCaroline CaramellaHonoraria: Bristol-Myers Squibb Honoraria: MSD Oncology, PfizerClaire TissotConsulting or Advisory Role: Roche, Bristol-Myers Squibb, AstraZeneca, MSD OncologyJulien AdamConsulting or Advisory Role: Roche, Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme Research Funding: Pierre Fabre (Inst), Merck Sharp & Dohme (Inst)Samuel WoodhouseEmployment: Inivata Patents, Royalties, Other Intellectual Property: Patents related to fusion technology used by Inivata and in this articleEdouard AuclinHonoraria: Sanofi Genzyme, MundipharmaJordi RemonConsulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD Oncology, AstraZeneca, Roche, Inivata, OSE ImmunotherapeuticsClive MorrisEmployment: Inivata Leadership: Inivata Stock and Other Ownership Interests: InivataEmma GreenEmployment: Inivata Stock and Other Ownership Interests: InivataChristophe MassardConsulting or Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Debiopharm Group, Roche, Ipsen, Janssen, Eli Lilly, MSD Oncology, Novartis, Pfizer, Sanofi, Orion, Tahio, Blueprint Medicines, Innate Pharma, PharmaMarMaurice PérolConsulting or Advisory Role: Eli Lilly, Roche, Pfizer, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Amgen, Takeda, Chugai Pharma Research Funding: AstraZeneca (Inst), Roche (Inst), Takeda (Inst) Travel, Accommodations, Expenses: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, PfizerBenjamin BesseResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Eli Lilly (Inst), Onxeo (Inst), Bristol-Myers Squibb (Inst), Inivata (Inst), AbbVie (Inst), Amgen (Inst), Biogen (Inst), Blueprint Medicines (Inst), Celgene (Inst), GlaxoSmithKline (Inst), Ignyta (Inst), Ipsen (Inst), Merck (Inst), MSD Oncology (Inst), Nektar (Inst), PharmaMar (Inst), Sanofi (Inst), Spectrum Pharmaceuticals (Inst), Takeda (Inst), Tiziana Therapeutics (Inst)Pierre SaintignyHonoraria: HTG Molecular Diagnostics, Inivata, ArcherDx, Bristol-Myers Squibb, Roche Molecular Diagnostics, Roche, AstraZeneca, Novartis, Bristol-Myers Squibb Foundation, Illumina No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

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., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)