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Systemic immunotherapies such as immune checkpoint blockade targeted at PD(L)1 and CTLA4 have demonstrated their ability to provide durable tumor responses and long-term overall survival benefits for some patients in several solid tumor types. However, a majority of patients remain resistant to these treatments and a significant proportion of them develop severe autoimmune and inflammatory adverse events. Preclinical studies have demonstrated that intratumoral injections of immunostimulatory products (oncolytics, pattern recognition receptor agonists,…) that are able to trigger type I IFN release and enhance tumor antigen presentation on immune cells could generate a strong antitumor immunity and overcome the resistance to systemic immune checkpoint blockade therapies. The intratumoral immunotherapy strategies that are currently in clinical development offer a unique therapeutic and exploratory setting to better understand the immune contexture across tumor lesions of patients with metastatic cancer. Also these local therapeutic products could turn cold tumors into hot and improve the response rates to cancer immunotherapies while diminishing their systemic exposure and toxicities. Intratumoral immunotherapies could prime or boost the immunity against tumors and therefore radically change the combinatorial therapeutic strategies currently pursued for metastatic and local cancers to improve their long-term survival. We aimed to review and discuss the scientific rationale for intratumoral immunotherapy, the challenges raised by this strategy in terms of drug development within clinical trials and the current state-of-the-art regarding the clinical practice of this innovative approach.

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

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.

Over the past two decades, targeted therapies have become cornerstone treatments for numerous cancers with oncogene addiction. Unfortunately, their effectiveness reduces over time and most patients who receive targeted therapies relapse within 12 months. The emergence of drug-resistance mechanisms in tumours paved the way for next-generation inhibitors. However, insufficient concentration of targeted therapy is a frequent but poorly explored mechanism of treatment failure. Additionally, the maximum tolerated dose (MTD) is not always reached in phase studies, and the recommended phase 2 dose is mostly based on benefit-risk ratio and pharmacokinetic considerations, which could result in a suboptimal dose. This scenario has led us to propose a new concept in clinical drug development: the late phase 1 study. The primary goal of this type of trial is to define an alternative MTD of a drug in patients who are chronically exposed and had an initial benefit from targeted therapy but subsequently progressed without an identified resistance alteration. Intrapatient dose escalation might increase drug concentration and restore drug activity or efficacy.

Advanced non-small cell lung cancer (NSCLC) remains a high unmet medical need. The first line standard-of-care therapy comprises concurrent chemotherapy-immunotherapy with pembrolizumab. Concurrent irradiation with pembrolizumab has been shown to significantly improve survival benefit compared with immunotherapy alone in a pooled analysis of 2 randomized phase 2 trials. We present the rationale and study design of the "PD-1 iNhibitor and chemotherapy with concurrent IRradiation at VAried tumor sites in advanced Non-small cell lung cAncer" (NIRVANA-Lung) trial (ClinicalTrials.gov identifier, NCT03774732). This study is a national multicenter 1:1 randomized phase III trial testing in 460 patients, the addition of multisite radiotherapy in advanced NSCLC treated with standard immune checkpoint inhibitors (pembrolizumab)-chemotherapy in first line. The primary objective of the trial is to compare the overall survival between the 2 arms at year 1 of the study. The secondary objective is to compare the progression-free survival and cancer-specific survival at year 1 and 2, as well as to determine quality of life, local and distant control in irradiated and nonirradiated sites at 6 months and year 1.

Background: Negative positron emission tomography/computed tomography (FDG-PET/CT) predicts the absence of viable seminoma cells in residual disease after chemotherapy in men with metastatic seminoma. In this study, we assessed whether men with good-prognosis metastatic seminoma could be treated with 2 cycles of etoposide-cisplatin (EP) followed by only one cycle of carboplatin (CARBO) based on a negative interim FDG-PET/CT, thereby limiting the burden of treatment and toxicity. Methods: In this non-randomised, multicentre, phase 2 trial (NCT01887340), we enrolled patients with good-prognosis metastatic seminoma (stage IIB, IIC and III with a good prognosis according to the Medical Research Council classification). All patients with baseline-positive FDG-PET/CT received EP for two cycles. After completing the first two cycles, the patients underwent a second FDG-PET/CT scan to assess the response between days 17 and 20. Patients with persistent positive FDG-PET/CT (based on local review) proceeded directly to two additional EP cycles (for a total of 4 cycles); those who achieved FDG-PET/CT negativity received only one cycle of CARBO AUC=7. The primary outcome was the proportion of patients with a negative FDG-PET/CT on interim assessment who received de-escalating chemotherapy. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Findings: Between June 2013 and July 2017, 102 patients were enrolled in the study. Three patients were deemed ineligible or not evaluable; thus, 99 patients received treatment. After the first 2 EP cycles, FDG-PET/CT was available in 98 pts. Overall, 67 patients (68.4%; 95% CI: 58.2-77.4) had a negative FDG-PET/CT and proceeded to a single CARBO cycle. Twenty-seven patients (27.6%; 95% CI: 19.0-37.5) still had a positive FDG-PET/CT after 2 EP cycles; overall, 31 patients received two additional cycles of EP. After a median follow-up of 39.4 months, only 9 patients relapsed (3/31 in the EP group and 6/67 in the CARBO group). The 3-year PFS rate was 90.0% (95% CI: 74.4-96.5) in the EP group and 90.2% (95% CI: 80.2-95.5) in the CARBO group. One patient died from sepsis during the first two cycles. Interpretation: De-escalating treatment based on a negative FDG-PET/CT after 2 cycles of chemotherapy appears to be safe and feasible in most men with good-prognosis metastatic seminoma. Trial Registration: The trial was registered at ClinicalTrials.gov (NCT01887340). Funding Statement: Programme Hospitalier de Recherche Clinique (PHRC) from the Institut National du Cancer (INCA), France. Declaration of Interests: Yohann Loriot: Dr Loriot reports grants from CELSIUS, grants from SANOFI, grants and personal fees from JANSSEN, personal fees from ASTELLAS, grants and personal fees from MSD, personal fees from ASTRA ZENECA, personal fees from BMS, personal fees from SEATTLE GENETICS, personal fees from PFIZER, personal fees from ROCHE, personal fees from IMMUNOMEDICS outside the submitted work; Matthieu Texier: Dr Texier has nothing to disclose; Stephane Culine: Dr Culine has nothing to disclose; Aude Flechon: Dr Flechon has nothing to disclose; Antoine Thierry-Vuillemin: Dr Thierry-Vuillemin reports personal fees from Pfizer, Astra Zeneca, Sanofi, Janssen, Novartis, Ipsen, Roche, Bristol-Myers Squibb, MSD, Astellas; Gwenaelle Gravis: Dr Gravis has nothing to disclose; Lionel Geoffrois: Dr Geoffrois reports personal fees from BMS, personal fees from NOVARTIS, personal fees and other from IPSEN, personal fees from PFIZER, personal fees from A-Z, personal fees from MSD, outside the submitted work; Christine Chevreau: Dr Chevreau has nothing to disclose; Marine Gross-Goupil: Dr Gross-Goupil has nothing to disclose; Philippe Barthelemy: Dr Barthelemy reports advisory board and travels from BMS, advisory board from MSD, advisory board and travels from IPSEN, advisory board from EUSAPHARMA, advisory board from NOVARTIS, advisory board and travels from ROCHE, advisory board and travels from PFIZER, advisory board and travels from JANSSEN, advisory board from ASTELLAS, outside the submitted work; Emmanuelle Bompas: Dr Bompas has nothing to disclose; Hakim Mahammedi : Dr Mahammedi reports personal fees from Bayer, personal fees from BMS , personal fees from Roche , personal fees from MSD , personal fees from Astra Zeneca , personal fees from Sanofi , personal fees and other from Janssen , personal fees and other from Astellas , outside the submitted work; Brigitte Laguerre: Dr Laguerre has nothing to disclose; Sophie Abadie Lacourtoisie : Dr Abadie Lacourtoisie has nothing to disclose; Carole Helissey: Dr Helissey reports personal fees from Sanofi, Janssen, Astellas and Roche; Sylvain Ladoire : Dr Ladoire reports grants from Pfizer, grants from Astellas, grants from Roche , grants from Novartis , grants from BMS, grants from Ipsen, grants from Janssen, grants from Sanofi, outside the submitted work; Christine Abraham: Dr Abraham has nothing to disclose; Christophe Massard: Dr Massard reports Consultant/Advisory fees from Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion; Serena Grimaldi: Dr Grimaldi has nothing to disclose; Karim Fizazi: Dr Fizazi reports Consultant/Advisory fees from Amgen, Astellas, Bayer, Jansen, Takeda, Sanofi, Orion, Essa, Genentech, Astra Zeneca, Clovis. Ethics Approval Statement: Written informed consent was obtained from all the patients. The study was approved by the ethics committee of Ile de France II (N°2013-02-12 MS1) and the French Healthcare Agency (N°130253B-12).

International audience; Background Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases. Methods We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18-70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m(2), or oxaliplatin 300 mg/m(2) plus irinotecan 200 mg/m(2), plus intravenous fluorouracil 400 mg/m(2)), or mitomycin-HIPEC (mitomycin 35 mg/m(2)) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394. Findings Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50.8 months (IQR 47.0-54.8), 3-year disease-free survival was 53% (95% CI 41-64) in the surveillance group versus 44% (33-56) in the second-look surgery group (hazard ratio 0.97, 95% CI 0.61-1.56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3-4 complications. The most common grade 3-4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients. Interpretation Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes. Copryright (C) 2020 Elsevier Ltd. All rights reserved.

BackgroundWe report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB Phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic tyrosine kinase inhibitor (nintedanib) with an anti-PD1 immunotherapy (pembrolizumab).MethodsPatients with aMM relapsing after at least one line of platinum doublet chemotherapy and not previously pre-exposed to IO were treated with a combination of oral nintedanib (150mg BID) & IV pembrolizumab (200mg Q3W) with a 7 days nintedanib lead-in preceding pembrolizumab initiation. Baseline and on-treatment (cycle D2, day 1 [C2D1]) fresh tumor & blood samples were prospectively phenotyped by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated on tumor secretome and plasma.Results30 aMM patients were treated and 29 evaluable for response. Median age was 68 years old (38–85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1–3) related to the combination were liver enzymes increase, fatigue, nausea, and diarrhea. 4 (13.3%) patients developed grade 3–5 immune- related AE. Patients died of cancer progression (n=14, 46.7%), myocarditis with thrombo-embolic event (n=1, 3.3%) and COVID-19 (n=1, 3.3%). Median follow-up was 14.8 months (95%CI [9.70–18.2]). Best Overall Response Rates (BORR) per RECISTv1.1 were Partial Response (PR, n=7/29; 24.1%), Stable Disease (SD, n=17/29; 58.6%) and Progressive Disease (n=5/29; 17.2%). Disease Control Rate (DCR) (defined as PR + SD) was 46.6% at 6 months. Patients with DCR at 6 months had significantly higher percentage of PDL1 expression on tumor cells (by Immuno-Histo-Chemistry, antibody clone SP263) and higher CD8+ T cells infiltrate in tumor biopsies (by FC) at screening. Upon treatment, soluble plasma rate of CXCL9 and CXCL13 increased in all patients, as well as tumor immune infiltrates estimated by deconvolution of tumor biopsies RNA-seq. But deconvoluted estimates of NK cells, T cells and myeloid dendritic cells infiltrates on baseline tumors and C2D1 biopsies were higher in patients with DCR at 6 months. Pre & on-treatment IL6 and IL8 rates in tumor secretome & plasma were higher in patients without DCR. Gene Set Enrichment Analyses on RNA-seq from screening biopsies highlighted an enrichment in E2F, MYC and KRAS gene pathways and lower expression of type 1 interferon signature in patients without DCR than those with DCR at 6 months.ConclusionsWith a BORR of 24% and a DCR of 47% at 6 months, pembrolizumab and nintedanib combination provided valuable therapeutic benefits for patients with aMM.Trial RegistrationClinicalTrialsgov, NCT02856425. Registered August 4, 2016 — Prospectively registered,https://clinicaltrials.gov/ct2/show/NCT02856425?term=PEMBIB&draw=2&rank=1.Ethics ApprovalThe protocol was first approved by the Agence Nationale de Sécurité du Médicament (ANSM) on June 24th 2016 (Ref #160371A-12). The protocol was also approved by the Ethical Committee (Comité de Protection des Personnes Ile de France 1) on Jul 12th 2016 (Ref #2016-mai-14236ND).

Background: We report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic TKI (nintedanib = [N]) with an anti-PD1 immunotherapy (pembrolizumab = [P]). Methods: Patients (Pts) with aMM that relapsed after at least one line of platinum-based combination were treated with a combination of oral [N] (150mg BID) & IV [P] (200mg Q3W) with 7 days [N] lead-in preceded [P] initiation. Baseline and on-treatment fresh tumor & blood samples were prospectively phenotyped immune cells by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated by multiplex ELISA on tumor secretome and plasma. Results: 30 aMM Pts were treated and 29 evaluable for response. Median age was 68 years old (38-85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1-3) related to the combination were liver enzymes increase, fatigue, nausea and diarrhea. 4 (13.3%) Pts developed grade 3-5 immune- related AE. Patients died of cancer progression (n=14), myocarditis with thrombo-embolic event (n=1) and COVID-19 (n=1). Median follow-up was 14.8 months (95%CI [9.70-18.2]). Best Overall Response Rates (BORR) were Partial Response (PR;n=7), Stable Disease (SD;n=17) and Progressive Disease (PD;n=5). Disease Control Rate (DCR) (defined as PR + SD) was 68.4% and 46.6% at 3 and 6 months, respectively. Analyses on fresh tumor biopsies showed that all patients increased their CD3+ T-cells and circulating levels of soluble PD1 and CXCL9 under treatment. Pts developing PR had significantly higher CD45+ and CD3+ tumor infiltrative cells at baseline compared to Pts with SD & PD as BORR. Pts with DCR at 6 months had significantly higher expression of integrins on circulating effector memory CD4+ & CD8+ T cells by FC, and higher NK, T, and myeloid dendritic cells infiltrates on baseline tumor RNAseq. Pre & on-treatment IL6 and IL8 levels in tumor secretome & plasma were higher among Pts with PD. Conclusions: With a BORR of 23% and a DCR of 47% at 6 months, [P]+[N] combination provided valuable therapeutic benefits for Pts with aMM. Flow cytometry and secretome on fresh baseline tumor biopsies are simple techniques which could be used to predict treatment efficacy in aMM Pts. Clinical trial identification: NCT02856425. Legal entity responsible for the study: Gustave Roussy. Funding: Funding: Boehringer Ingelheim;Drug supply: Boehringer Ingelheim & MSD;Sponsor: Gustave Roussy. Disclosure: C. Baldini: Financial Interests, Personal, Invited Speaker: Sanofi;Financial Interests, Personal, Invited Speaker: BMS;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Institutional, Research Grant: Seattle Genetics;Financial Interests, Institutional, Research Grant: Iteos;Financial Interests, Institutional, Invited Speaker: Tahio;Financial Interests, Institutional, Research Grant: BMS. N. Chaput: Financial Interests, Institutional, Research Grant: AstraZeneca;Financial Interests, Institutional, Research Grant: BMS;Financial Interests, Institutional, Research Grant: GSK;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Institutional, Research Grant: Sanofi;Financial Interests, Institutional, Research Grant: Cytune Pharma. G. Zalcman: Financial Interests, Personal, Invited Speaker, outside the submitted work: BMS;Financial Interests, Personal, Invited Speaker, outside the submitted work: MSD;Financial Interests, Personal, Invited Speaker, outside the submitted work: AstraZeneca;Financial Interests, Personal, Invited Speaker, outside the submitted work: Boehringer Ingelheim;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: Roche;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: Takeda;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: AstraZeneca;Non-Financial Interests, Personal, Advisory Board, outside the submitted work: AbbVie. C. Massard: Non-Financial Interests, Personal, Advisory Role: Amgen;Non-Financial Interests, Personal, Advisory Role: Astellas Pharma;Non-Financial Interests, Personal, Advisory Role: AstraZeneca;Non-Financial Interests, Personal, Advisory Role: Bayer;Non-Financial Interests, Personal, Advisory Role: BeiGene;Non-Financial Interests, Personal, Advisory Role: BMS;Non-Financial Interests, Personal, Advisory Role: Celgene;Non-Financial Interests, Personal, Advisory Role: Debiopharm Group;Non-Financial Interests, Personal, Advisory Role: Genentech/Roche;Non-Financial Interests, Personal, Advisory Role: Ipsen;Non-Financial Interests, Personal, Advisory Role: Janssen;Non-Financial Interests, Personal, Advisory Role: Lilly;Non-Financial Interests, Personal, Advisory Role: MSD;Non-Financial Interests, Personal, Advisory Role: Novartis;Non-Financial Interests, Personal, Advisory Role: Pfizer;Non-Financial Interests, Personal, Advisory Role: Sanofi;Non-Financial Interests, Personal, Advisory Role: Orion;Non-Financial Interests, Personal, Advisory Role: Taiho Pharmaceuticals;Non-Financial Interests, Personal, Advisory Role: Blueprint Medicinces;Non-Financial Interests, Personal, Advisory Role: Innate Pharma;Non-Financial Interests, Personal, Advisory Role: PharmaMar;Non-Financial Interests, Personal, Advisory Role: Faron Pharmaceuticals. J-C. Soria: Financial Interests, Personal, Stocks/Shares: AstraZeneca;Financial Interests, Personal, Stocks/Shares: Gritstone Oncology;Financial Interests, Personal, Stocks/Shares: Relay Therapeutics;Financial Interests, Personal, Member of the Board of Directors: Hookipa Pharmaceuticals;Financial Interests, Personal, Full or part-time Employment, sept 2017 to dec 2019: AstraZeneca. A. Marabelle: Financial Interests, Personal, Invited Speaker: Roche/Genentech;Financial Interests, Personal, Invited Speaker: BMS;Financial Interests, Personal, Invited Speaker: Merck Serono;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Personal, Invited Speaker: Amgen;Financial Interests, Personal, Invited Speaker: Sanofi;Financial Interests, Personal, Invited Speaker: Servier;Non-Financial Interests, Personal, Principal Investigator: Roche/Genentech;Non-Financial Interests, Personal, Principal Investigator: BMS;Non-Financial Interests, Personal, Principal Investigator: MSD;Non-Financial Interests, Personal, Principal Investigator: Pfizer;Non-Financial Interests, Personal, Principal Investigator: Lytix Pharma;Non-Financial Interests, Personal, Principal Investigator: Eisai;Non-Financial Interests, Personal, Principal Investigator: AstraZeneca;Non-Financial Interests, Personal, Principal Investigator: Tesaro;Non-Financial Interests, Personal, Principal Investigator: Chugai;Non-Financial Interests, Personal, Principal Investigator: Ose Immunotherapeutics;Non-Financial Interests, Personal, Principal Investigator: Sotio;Non-Financial Interests, Personal, Principal Investigator: Molecular Partners;Non-Financial Interests, Personal, Principal Investigator: IMCheck;Non-Financial Interests, Personal, Principal Investigator: Pierre Fabre;Non-Financial Interests, Personal, Principal Investigator: Adlai Nortye;Financial Interests, Personal, Stocks/Shares: Pegascy SAS;Financial Interests, Personal, Stocks/Shares: Centessa Pharmaceuticals;Financial Interests, Personal, Stocks/Shares: HiFiBio;Financial Interests, Personal, Stocks/Shares: Shattuck Labs;Financial Interests, Institutional, Research Grant: Merus;Financial Interests, Institutional, Research Grant: BMS;Financial Interests, Institutional, Research Grant: Boehringer Ingelheim;Financial Interests, Institutional, Research Grant: Transgene;Financial Interests, Institutional, Research Grant: Fondation MSD Avenir;Financial Interests, Institutional, Research Grant: Sanofi. All other authors have declared no conflicts of interest.

Career situation of first and presenting author Student for a master or a PhD. Introduction Immune checkpoint inhibitors anti PD-1 are monoclonal antibodies used in cancers.1 PD-1 ligand/PD-1 pathway antagonism between cancer cells and antitumoral cytotoxic CD8 T cells increase antitumoral immunity but is involved in autoimmune diseases (AID). Objectives Evaluate tolerance and efficacy of anti PD-1 in AID patients. Methods Patients had been included in REISAMIC registry (Registry of Severe Adverse Events of Immunomodulating Monoclonal Antibodies in Oncology) between June 1st, 2014, and December 31st, 2017. Patients were treated with anti-PD-1. Exclusion criteria were malignant hematologic disease, second advanced cancer or chronic viral infection. AID subtypes were defined for sensitivity analyses: diseases of clinical interest (DCI), prognostic interest (DPI) and vitiligo. One patient with pre-existing AID were matched on age, sex and cancer type with 3 patients without preexisting AID (controls). Analyses were adjusted for OMS status, corticosteroid, cerebral metastasis, LDH, albuminemia and neutrophil/lymphocyte ratio >3. Endpoints were grade ≥2 irAE free survival and overall survival (OS). Objective response rates (ORR) were described. Results 641 patients were included in REISAMIC. Among them, 69 patients were excluded. 572 patients had been included: 63 with AID and 509 controls. Among AID patients, we observed 38% DCI, 38% DPI and 24% vitiligo. DCI were Sjogren syndrome (n=4), rheumatoid arthritis (n=4), polymyalgia rheumatica/giant cell arteritis (n=2) and others. DPI were psoriasis (n=11), thyroiditis (n=8) and others. We matched 55 AID patients with 165 controls. Cancer type, TNM or AJCC grade, age and sex were similar between AID patients and controls. Overall survival (HR 0,67, IC95% [0,42–1,08], p=0,098) and irAE free survival (HR 1,27, IC95% [0,84–1,90], p=0,25) were not different between AID patients and controls. After vitiligo exclusion in sensitivity analyses, irAE free survival was shorter for AID patients than controls (HR 1,69, IC05% [1- 2,87], p=0,05) and more for DCI patients only (HR 2,66, IC95% [1,01–7], p=0,049). ORR were 35,5% and 28,5% for AID patients and controls respectively. Conclusions Preexisting AID should not be a contraindication for anti PD-1. We suspect that mechanisms involved in AID are important in irAE mechanism and antitumoral response. CD4 T cells and Th17 cells should be study in these situations. Reference Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018 Mar 23;359(6382):1350–5. Disclosure of Interest None declared.

387 Background: A negative FDG-positron emission tomography/computerized tomography (PET) predicts the absence of viable seminoma cells after chemotherapy in men with metastatic seminoma. In this study, we assessed whether patients (pts) with low-volume metastatic seminoma can be treated with 2 cycles of etoposide-cisplatin (EP) followed by only one cycle of carboplatin (CARBO) on the basis of a negative interim PET, thereby limiting the burden of toxicity. Methods: In this non-randomised, multiple-center, phase 2 trial (NCT01887340), we enrolled pts with low-volume metastatic seminoma (with good prognosis according to IGCCCG and the Medical Research Council classifications). All pts with baseline PET-positive received EP for two cycles. After completion of first two cycles, pts underwent a second PET to assess response. Patients with a persistent positive PET (based on local review) proceeded directly to two additional EP cycles (for a total of 4); those who achieved a PET-negative received only one cycle of CARBO (AUC=7). The primary outcome was the proportion of pts who were PET-negative on interim PET and received de-escalating chemotherapy. Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Results: Between June 2013 and July 2017, 102 pts were enrolled in the study. Three pts were deemed ineligible or not evaluable and thus 99 patients received treatment. After 2 first EP cycles, PET was available in 94 pts. Interim PET was negative in 68 pts (72%) and positive in 26 pts (28%). Overall, 63 pts (67.0%; 95% CI 57.5-76.5) were PET-negative and proceeded to one single cycle of CARBO. Overall, 24 (25.5%, 95% CI 17.1-34.9) patients had a PET positive after 2 EP and received 2 additional cycles of EP. After a median follow-up of 34.4 months, only 8 patients relapsed (2 in EP group and 6 in CARBO group). 2-year PFS rates were respectively 93.7% (95% CI 84.9-97.5) in the CARBO group and 92.9% (95% CI 77.4-98.0) in the EP group. Only one patient died during the 2 first cycles. Conclusions: De-escalating treatment based on a negative PET after 2 cycles of chemotherapy appears to be safe and feasible in the majority of patients with low-volume metastatic seminoma. Clinical trial information: NCT01887340.

Anti-PD1 antibodies are currently the first-line treatment for patients with metastatic BRAF wild- type melanoma, alone or combined with the anti-CTLA4 mAb, ipilimumab. To date, data on safety and the outcomes of patients treated with the anti-PD1 mAbs, pembrolizumab (PB) or nivolumab, combined with stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) are lacking. Patients with MBM treated with PB combined with SRS between 2012 and 2015 were retrospectively reviewed. The primary endpoint was neurotoxicity. The secondary endpoints were local control, distant intracranial control and overall survival (OS). Among 74 patients with MBM treated with SRS, 25 patients with a total of 58 MBM treated with PB combined with SRS within 6 months were included. Radionecrosis, occurring within a median time of 6.5 months, was observed in four metastases (6.8%) in four different patients. No significant other SRS-related adverse event had been reported. After a median follow-up of 8.4 months, local control had been achieved in 46 metastases (80%). The median time to local progression was 2 months. Perilesional oedema and intratumour haemorrhage appearing or increasing after SRS were mostly associated with local progression (P

9107 Background: HPD was described in 13.8% of NSCLC pts upon single-agent IO and correlated with high metastatic burden and poor prognosis. Other progression (PD) patterns as FP and ED within 12 weeks have been reported respectively in 4.7% and 5.6% of atezolizumab treated NSCLC pts. Whether FP/ED and HPD are different or overlapping patterns is currently unknown. Methods: We analyzed FP, ED and HPD in a multicentric (8 centers) retrospective cohort of IO treated NSCLC pts (11/2012-04/2017). Eligibility criteria required 2 CT scans before and one after IO start. HPD was defined as RECIST v 1.1 PD at first CT scan and a variation per month of tumor growth rate (TGR upon IO – TGR before IO) > 50%. ED was defined as deaths due to disease PD within 12 wks of IO start. FP was defined as ≥ 50% increase in the sum of long diameters within 6 weeks (wks) from baseline. The associations between PD patterns and pts’ characteristics were performed using Fisher or t-student tests. Median overall survival (mOS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: Out of 406 NSCLC pts, 46% were ≥65 years, 72% had non-squamous NSCLC, > 90% received single agent IO in ≥2 line. 56 (13.8%) were HPD by TGR analysis. Among 72 pts (18%) who performed a CT scan within 6 wks after IO start, 6 (8.3%) were FP. These 6 FP pts were also classified as HPD by TGR analysis, while the other 50 (89%) of 56 HPD pts were not FP. The rate of PD in ≥ 3 sites (54% vs 0%, p = 0.002), the rate of liver PD (62% vs 5%, p = 0.002), the baseline tumor burden (BTB) (mean 176± 26 mm vs 55 ± 6 mm, p < 0.0001) and the TGR upon IO (mean 439± 119% vs 216 ± 41%, p = 0.03) were significantly higher in FP pts compared to HPD pts who were not FP. At 4.4 months of median follow-up, FP pts had significantly worse mOS compared to HPD pts not FP [0.7 months (95% CI 0.6,0.8) vs 1.6 months (95% CI 1.1, 2.1); p = 0.02]. Of 406 IO treated pts, 46 (11%) were ED within 12 wks, and 21 (46%) of ED pts had also HPD by TGR analysis. Conclusions: FP and ED are not a surrogate of HPD. FP occurs in a small subgroup (11%) of HPD and correlates with more aggressive features (PD in ≥3 sites, liver-PD, high BTB, high TGR upon IO) and worse OS. ED within 12 wks overlapped with HPD for only 46% of pts.

6032 Background: In the randomized phase III Study CA209141, Nivolumab (N) demonstrated significant overall survival (OS) benefit with favorable safety profile for platinum refractory R/M SCCHN and is now approved for these patients (pts). The objectives of the study are to provide additional insight into the frequency of high-grade AEs related to N and the efficacy of N in real life. Methods: Between August and December 2017, 203 pts were included in the multicenter, non-controlled phase II TOPNIVO. The main inclusion criteria were patients with platinum refractory R/M SCCHN with progressive disease, ECOG 0-2. Pts received N 3mg/kg every 2 weeks intravenously over 30 minutes. Four pts did not receive N. We report here the safety during the first 6 months (mo) after inclusion and OS results on the first 199 treated pts. Results: Median age was 62 yr, 83% were male, 84% were ECOG 0-1, 16% 2. The primary site of cancer was oral cavity 26%, oropharynx 38%, larynx 16%, hypopharynx 21%. 33% had loco regional relapse, 32% metastatic disease and 35% both. 49% had received one prior line of chemotherapy and 30% two prior lines. 157 (79%) pts ended their treatment within the first six mo: 5 for AE related to N (pneumonitis 3 pts, hepatitis 1 pt, diarrhea 1 pt), 107 for progression, 33 for death (24 related to progression, 9 to intercurrent disease), 12 other. 132 pts (66%) experienced at least 1 AE grade ≥3. On the 226 AEs grade 3-4, 21 (mainly pneumopathy, lipase increase and asthenia) were related to N and occurred in 18 pts. On the 51 AEs grade 5, 3 were considered related to N (2 pneumonitis, 1 cardiac arrest). The median OS was 7.7 mo (CI 95% [6.0; 9.5]) in the whole population; 9.2 mo [6.8; 12.1] in the 167 pts with ECOG 0-1, 3.0 mo [1.1; 6.0] in the 32 pts with ECOG 2; 12.1 mo [7.6; NR] in the 64 pts with metastatic disease, 7.7 mo [5.0; 9.6] in the 66 pts with locoregional disease and 4.6 mo [3.1; 7.9] in the 69 pts with both. OS was similar in pts older or younger 70 yr. Conclusions: The interim analysis of the TOPNIVO study shows no additional toxicities of N compared to what has been described previously, confirms the previous results of OS and provides new survival data in subgroups of pts. Clinical trial information: NCT03226756.

Importance Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non–small cell lung cancer (NSCLC) are unknown. Objectives To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. Design, Setting, and Participants In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. Interventions The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. Main Outcomes and Measures The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Results Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350];P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69];P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Conclusions and Relevance Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

3531Background: Complete cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) allow to prolong survival in patients with colorectal peritoneal metastases (CRPM)...

Introduction Les anti-PD1 sont actuellement au premier plan dans l’arsenal therapeutique du melanome metastatique. Au cours de leur developpement, ils n’ont pas ete associes a la radiotherapie cerebrale (RC) mais dans la pratique courante, la RC doit etre discutee avant ou pendant le traitement par immunotherapie pour certains de nos patients. Nous avons etudie la tolerance et le devenir des patients traites par RC en mode stereotaxique (RCS) et pembrolizumab (PB) pour des metastases cerebrales de melanome (MCM). Materiel et methodes Tous les patients atteints de melanome metastatique adresses pour RCS entre septembre 2012 et novembre 2015 etaient selectionnes. Un examen clinique et une imagerie cerebrale (IRM) etaient realises avant la RCS et tous les 2 mois afin de colliger les effets secondaires, evaluer le controle cerebral local et a distance des lesions irradiees et la survie des patients. Observations Vingt-cinq patients traites par PB et RCS dans les 6 mois etaient inclus. Parmi ces 25 patients, 23 avaient deja recu divers traitements systemiques et/ou locaux des MCM (5 RCS, 3 RC de l’encephale in toto et 4 chirurgies). Le suivi median etait de 9 mois apres RCS (2–29 mois) et de 13 mois apres diagnostic de MCM (3–49 mois). Au total, 60 MCM ont ete traitees par CRS en 67 seances avec un nombre median de 2 lesions par patient. On rapportait 4 cas de radionecrose (6,7 %) dont une lesion de 20 mm traitee par 3 seances de 11 Grays (Gy). Onze lesions ont presente un saignement intratumoral apres RCS. Neuf d’entre elles etaient associees a une progression cerebrale generalisee ; une autre lesion correspondait a une radionecrose et la derniere a une pseudo progression. Le controle local des lesions traitees etait obtenu dans 80 % des cas. La progression locale survenait dans un delai median de 2 mois et a ete responsable du deces d’un seul patient. Seize patients presentaient une progression cerebrale a distance des zones traitees par RCS avec un taux de 48 % a 6 mois, 64 % a 1 an et un delai median de 3 mois (1–11 mois). Dix d’entre eux decedaient de l’evolution cerebrale de leur melanome. L’estimation de la survie globale etait de 15 mois apres diagnostic de MCM (IC95 % : 6,1–23,9), 14,5 mois apres RCS (IC95 % : 4,1–17,2) et 14 mois apres PB (IC95 % : 6,1–21,9). Discussion Le traitement combine par RCS et PB dans le traitement des MCM etait bien tolere. L’adjonction de l’immunotherapie a la RCS ne semble pas en augmenter les risques notamment de radionecrose et semblerait ameliorer le controle local. L’adjonction de la RCS au PB aurait pu faire esperer un effet abascopal et une amelioration de la survie sans progression et survie globale mais notre echantillon est trop petit pour etablir cette conclusion. Ces resultats sont en accord avec les donnees recentes rapportees lors de l’association de la RCS au nivolumab et necessitent d’etre confirmes par des etudes prospectives.

Structural analysis of nanocrystalline Silicon layers deposited on oxidized and non-oxidized silicon substrates and on glass substrates by low-energy plasma-enhanced chemical vapour deposition technique was fulfilled by means of transmission electron microscopy. Low magnification and high resolution observations of specimens performed in plan-view and cross section are described and discussed. These results are compared to those obtained by atomic force microscopy study. Growth modes and relevant structural changes are tentatively correlated to elaboration parameters.

Importance Vitiligo is an autoimmune skin disorder that reacts against melanocytes. The association of vitiligo with tumor response in patients with melanoma who undergo immunotherapy has been reported but is still controversial. Objective To prospectively evaluate the appearance of vitiligo in patients receiving pembrolizumab, a monoclonal antibody directed against the programmed death cell receptor. Design, Setting, and Participants This prospective observational study was conducted from January 1, 2012, through September 24, 2013, in a single tertiary care hospital with a unit dedicated to patients with melanoma. Sixty-seven patients with metastatic melanoma who received pembrolizumab treatment in the context of a phase 1 study were included and screened for the emergence of vitiligo. Data were collected from January 1, 2012, to February 28, 2014, and analyzed from February through December 2014. Main Outcomes and Measures Objective tumor response with regard to the occurrence of vitiligo in patients receiving pembrolizumab therapy. Correlation between vitiligo occurrence and overall survival was also estimated using the Kaplan-Meier product-limit method and compared with a log-rank test. To prevent guarantee- or lead-time bias, a landmark analysis approach after 12, 16, and 20 weeks of treatment was retained. Results Of the 67 patients included in the study, 17 (25%) developed vitiligo during pembrolizumab treatment and 50 (75%) did not. An objective (complete or partial) response to treatment was associated with a higher occurrence of vitiligo (12 of 17 [71%] vs 14 of 50 [28%]; P = .002). The time to onset of vitiligo ranged from 52 to 453 (median, 126) days from the start of treatment. Of the 17 patients with vitiligo, 3 (18%) had a complete response, 9 (53%) had a partial response, 3 (18%) had stable disease, and 2 (12%) had progressive disease at the final follow-up. All the patients treated with pembrolizumab who developed vitiligo were alive at the time of analysis, with a median follow-up of 441 days. Conclusions and Relevance Vitiligo, a clinically visible immune-related adverse event could be associated with clinical benefit in the context of pembrolizumab treatment.

Introduction L’anticorps monoclonal humanise anti-PD-1 MK-3475 a demontre des reponses durables chez les patients (pts) atteints de melanome avance. Nous avons evalue dans cette etude la tolerance et le profil des effets indesirables de MK-3475 chez les pts atteints de melanome avance traites dans notre institution. Patients et methodes Les pts ont ete inclus dans un essai de phase I evaluant MK-3475 aux doses suivantes : 10 mg/kg toutes les 2 semaines, 10 mg/kg toutes les 3 semaines, ou 2 mg/kg toutes les 3 semaines. La severite des effets indesirables a ete classee selon les criteres de terminologie standard pour les effets indesirables CTCAE, version 4.0. La duree moyenne du traitement et son intervalle de confiance ont ete estimes selon la methode de Kaplan-Meier. Observations Soixante-dix-huit pts ont ete traites dans cet essai entre decembre 2011 et aout 2013. L’âge median des pts etait de 55 ans (extremes 43–54). L’incidence de la mutation BRAF V600E etait de 33 % (26 pts). Un traitement prealable par ipilimumab ou inhibiteurs de BRAF a ete administre chez 23 (29 %) et 22 (28 %) pts, respectivement. Vingt (26 %) pts ont recu MK-3475 a 2 mg/kg toutes les 3 semaines, 23 (29 %) a 10 mg/kg toutes les 2 semaines, et 35 (45 %) a 10 mg/kg toutes les 2 semaines. La duree mediane de traitement par MK-3475 etait de 6,2 mois (IC 95 % 3,7–11,2). Resultats Les effets indesirables le plus frequemment rapportes etaient : asthenie, arthralgies, myalgies, prurit, eruptions cutanees, diarrhees et nausees. Des reactions liees a la perfusion ont ete observees chez 9 (12 %) pts. Tous ces effets indesirables etaient de grade 1 ou 2. Des effets indesirables potentiellement immuno-medies ont ete observes, comprenant des pneumopathies, dysthyroidies, diabete, colites et vitiligo. Une pneumopathie de grade 2 liee au traitement est survenue chez 2 pts (3 %) et a ete reversible a l’arret du traitement ou a l’instauration d’une corticotherapie. Des dysthyroidies (thyroidites et hypothyroidies) sont survenus chez 13 (17 %) pts. Une hypothyroidie de grade 2 liee au traitement a ete observee chez 8 (10 %) pts, necessitant un traitement substitutif. Des effets indesirables de grade 3 lies au traitement ont ete rapportes chez 8 (10 %) pts, a type d’epanchement pleural, diabete, hyperthyroidie, asthenie, thrombose arterielle etendue, nephrite interstitielle, colite, et anemie hemolytique. Cinq pts (6 %) sur 78 sont sortis de l’essai en raison d’effets indesirables grade 3. Cependant, aucun deces lie au traitement n’a ete rapporte. Discussion Des effets indesirables de grade 3 sont survenus chez 10 % des pts traites par l’anti-PD-1 MK-3475 et ont conduit a la sortie de l’essai chez 6 % des pts. Ces effets indesirables sont controlables en arretant le traitement et en instaurant un traitement adapte. Conclusion Nos donnees montrent que l’anti-PD-1 MK-3475 est bien tolere. La molecule peut etre administree avec des soins de support minimes.

Studies are conducted at the LCPC for investigating the role of infrastructures in road safety. In this context, tire/pavement contact characterization is a key point for both vehicle and road surface optimization. For this purpose, car industry usually instruments dedicated cars with wheel dynamometers but this procedure doesn’t offer the possibility to observe a large set of vehicles in practice. Regarding road management, it has been chosen to use the infrastructure itself as an instrument for acquiring the complete 6-components stress tensor. In this paper, a new test apparatus allowing this is shown, using a mechanically isolated part of the pavement. Validations are presented on a variety of situations such as emergency braking and constant speed driving. Correlations with inboard vehicle sensors measurements and numerical models have been worked out.Copyright © 2005 by ASME

Aim: ERMETIC is a French (IFCT) prospective study of EGFR and KRAS mutation evaluation by sequencing in patients with advanced NSCLC treated by E. The aim of the ERMETIC-2 project was to determine the prognostic impact of using alternative molecular techniques in the available tumor samples of the ERMETIC cohort. Methods: 239 patients (pts) with tumors were available for re-analyze by previously described alternative techniques (J Mol Diag 2014). Multivariate Cox model with performance status, histology, smoking status and initial number of metastatic sites was used for prognostic analysis. Results: Population included 59% of adenocarcinoma, 37% of women and 19% of non-smokers. Overall mutation rate is 46%: 31 EGFR mutations (13%) and 78 KRAS mutations (33%); 40 new mutations compared to previous study were found: 9 EGFR and 31 KRAS. In the ERMETIC 2 cohort, OS and PFS remained significantly (global test p Conclusions: 1. KRAS but not EGFR mutations were detected in higher proportion by alternative molecular techniques compared to sequencing. 2. KRAS mutations identified by more sensitive technique did not identified a group of patients with a different prognostic. Disclosure: All authors have declared no conflicts of interest.

The authors use a transposition island skin flap from the nasal dorsum for repair of the ala nasi. It is a modification of the stalk-flap advocated by Edgerton in 1967 to augment the columella. The flap is vascularized by branches of the anterior ethmoidal artery. The main modifications are;-the size of the flap which is 50 mm long and 15 mm wide;-the vascular pedicle is not dissected; this makes the flap very reliable;-the outstanding vascularization of this flap is corroborated by the fact that, in the same stage, it may be lined with a partially composite chondrocutaneous graft. The composite graft is taken from the concha and repaired with the Masson procedure. This flap is a very easy procedure for alar cutaneous repair for partial alar reconstruction, it is possible to fold the flap onto itself after resecting a 2 mm transverse skin strip, making the distal extremity a secondary skin island flap which ensures the lining of the proximal part. For total alar reconstruction and hemi-rhinoplasty; the flap is lined with a composite graft, which allows a one-stage thin reconstruction. The flap was used in 9 patients. In one case, there was a total skin necrosis, while half of the fasciomuscle layer survived.

Polymorphonuclear leukocyte (PMN) elastase is able to degrade the extra-cellular matrix components of cartilage. However, in vitro several proteinases can degrade elastin. The purpose of this study was to evaluate the role of the serine proteinases and metalloproteinases in the elastase activity measured in cartilage extracts from patients with osteoarthritis (OA), as well as in synovial fluid (SF) from patients with rheumatoid arthritis (RA) and OA.Elastase activity was determined using synthetic low molecular weight substrates and radiolabelled insoluble elastin. Aminophenyl mercuric acetate was used to activate the prometalloproteinases.Elastase activity, measured using synthetic substrates, was higher in BA SF (0.76 + 0.03 microU/ml, n = 12) than in OA SF (0.14 + 0.04 microU/ml, n = 12) (p0.001). This activity was inhibited by metal chelating agents: 86% inhibition in OA and 75% inhibition in RA. However, in RA SF the inhibitor of serine proteinase (PMSF) also induced a 40% inhibition. Elastase activity, measured using radiolabelled elastin, in OA SF and RA SF samples and in OA cartilage extract was very low, but increased following activation by mercurial agents. Again this activity was inhibited by metal chelating agents.Taken together these results indicate that elastase activity (measured by standard methods) in OA and RA SF is mainly due to metalloenzymes.

The effects of grass maturity on the mean retention time of liquid and particles, digestibility and duodenal nutrient flows were measured by feeding second cuts of perennial ryegrass to 3 fistulated lactating dairy cows over 2 successive periods (late June and mid-July, 28 and 49 d regrowth, respectively). Fresh forage was given ad libitum with 12% (dry matter (DM) basis) concentrate. The increase in maturity lowered grass nitrogen content, organic matter (OM) digestibility and non-ammoniacal nitrogen flow into the duodenum, but did not affect OM intake (13.2 kg/d). Neither the fractional outflow rate of liquid in the rumen (FOR; 17.3%/h) nor the concentrate total mean retention time (TMRT; 32.9 h) were affected. With maturity forage TMRT tended to increase (43.0-48.8 h), certainly because of the longer comminution time of coarse particles. These results were compared with data obtained 2 months earlier with the same cows fed on a maize silage diet (25% DM basis of the same concentrate) ad libitum (17.4 kg OM/d). Despite a lower total OM intake, FOR was much higher with the grass than with the maize silage diet (12.1%/h) and this may explain the lower retention time in the rumen of the small particles when grass diets were given (19.0 vs 24.3 h for maize silage diet).

The surgical treatment of basal cell epithelioma proceeds in two stages: excision which must result in eradication and therefore complete cure of the lesion, and repair which, on the face, must not only cover the loss of substance but also take into account cosmetic considerations. Repair may consist of: simple suture after adjustment of the surrounding skin provided it has enough laxity; skin graft preferably using whole-thickness skin taken in the pre- or retro-auricular or supraclavicular regions; regional autoplasty with sometimes a skin island flap, and finally distant flap or free cutaneous or musculocutaneous transplant.

The accuracy of Doppler examination was evaluated for the diagnosis of catheter-related venous thrombosis in 40 postoperative patients. Deep vein thrombosis was detected by venography in 15 patients and confirmed by the Doppler technique in a double blind study. Only one false-positive and one false-negative result were obtained with the Doppler technique. This technique appears to be valuable for the early diagnosis of catheter-related vein thrombosis, even in asymptomatic patients.

Basal-cell epitheliomas of the scalp are frequently observed on pre-existing chronic lesions: radiodermatitis or Jadassohn's sebaceous naevus. In cases where no irradiation has been given, basal-cell epitheliomas of the scalp should be treated by simple surgical excision. When irradiation has been applied, deep invasion must be recognized as an insufficient excision can often be fatal.