OncoThAI

•With a ≥3-year follow-up in CheckMate 743, nivolumab + ipilimumab continued to provide long-term OS benefit in first-line MPM.•Clinical benefits remained consistent across patient subgroups, including epithelioid versus non-epithelioid histology.•Discontinuing nivolumab + ipilimumab due to TRAEs did not negatively impact long-term benefit.•Nivolumab + ipilimumab continues to be an efficacious first-line treatment option for patients with unresectable MPM. BackgroundIn the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up.Patients and methodsAdults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs).ResultsWith a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61–0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation.ConclusionsWith 3 years’ minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology. In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61–0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. With 3 years’ minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Previous studies reported a 2- to 17-fold higher risk of aortic complications (dilation or dissection) in patients with giant-cell arteritis (GCA). We aimed to determine whether or not GCA patients with large-vessel involvement demonstrated by positron emission tomography with F-fluorodeoxyglucose combined with computed tomography (FDG-PET/CT) have a higher risk of aortic complications. We conducted a retrospective multicenter study between 1995 and 2014. Patients were included if they fulfilled at least 3 American College of Rheumatology criteria for GCA, or 2 criteria associated with extratemporal biopsy-proven giant-cell vasculitis; they underwent at least 1 FDG-PET/CT scan at diagnosis or during follow-up; and the morphology of the aorta was assessed by medical imaging at diagnosis. Patients with an aortic complication at the time of diagnosis were excluded. Of the 130 patients included [85 women (65%), median age 70 (50-86)], GCA was biopsy proven in 77 (59%). FDG-PET/CT was performed at diagnosis in 63 (48%) patients and during the follow-up period in the 67 (52%) remaining patients. FDG-PET/CT was positive in 38/63 (60%) patients at diagnosis and in 31/67 (46%) patients when performed during follow-up (P = NS). One hundred four patients (80%) underwent at least 1 morphological assessment of the aorta during follow-up. Nine (9%) patients developed aortic complications (dilation in all and dissection in 1) at a median time of 33 (6-129) months after diagnosis. All of them displayed large-vessel inflammation on previous FDG-PET/CT. A positive FDG-PET/CT was significantly associated with a higher risk of aortic complications (P = 0.004).In our study, a positive FDG-PET/CT was associated with an increased risk of aortic complications at 5 years.

Background: Actinic keratosis (AK) is a common early in situ skin carcinoma caused by long-term sun exposure and usually develops on sun-exposed skin areas. Left untreated, AK may progress to squamous cell carcinoma. To prevent such risk, most clinicians routinely treat AK. Therapy options for AK include cryotherapy, topical treatments, curettage, excision surgery, and photodynamic therapy (PDT). Objective: The aim of this study is to assess the noninferiority, in terms of efficacy at 3 months, of a PDT protocol involving a new light-emitting device (PDT using the Phosistos protocol [P-PDT]) compared with the conventional protocol (PDT using the conventional protocol [C-PDT]) in the treatment of AK. Methods: In this randomized, controlled, multicenter, intra-individual, phase II noninferiority clinical study, subjects with AK of the forehead and scalp are treated with P-PDT on one area and with C-PDT on the contralateral area. In both areas, lesions are prepared and methyl aminolevulinate (MAL) is applied. Thirty minutes after MAL application, the P-PDT area is exposed to red light at low irradiance (1.3 mW/cm2) for 2.5 hours so that a light dose of 12 J/cm2 is achieved. In the control area (C-PDT area), a 37 J/cm2 red light irradiation is performed 3 hours after MAL application. Recurrent AK at 3 months is retreated. The primary end point is the lesion complete response rate at 3 months. Secondary end points include pain scores at 1 day, local tolerance at 7 days, lesion complete response rate at 6 months, cosmetic outcome at 3 and 6 months, and patient-reported quality of life and satisfaction throughout the study. A total of 45 patients needs to be recruited. Results: Clinical investigations are complete: 46 patients were treated with P-PDT on one area (n=285 AK) and with C-PDT on the contralateral area (n=285 AK). Data analysis is ongoing, and statistical results will be available in the first half of 2019. Conclusions: In case of noninferiority in efficacy and superiority in tolerability of P-PDT compared with C-PDT, P-PDT could become the treatment of choice for AK. Trial Registration: ClinicalTrials.gov NCT03076892; https://clinicaltrials.gov/ct2/show/NCT03076892 (Archived by WebCite at http://www.webcitation.org/779qqVKek) International Registered Report Identifier (IRRID): DERR1-10.2196/12990

BACKGROUND: Recent COVID crisis has demonstrated that modern society urgently needs an accessible protection against mass infections, especially viruses, as the new strains are appearing at an ever-increasing pace and cause severe harm to the population and the world economy. METHODS: We have developed an efficient phthalocyanine photosensitizer LASU, that is suitable for dyeing textiles and allows to prepare reusable self-disinfecting fabrics with strong antiviral properties. The safety profile of LASU was evaluated in accredited laboratories by several in vitro assays according to the OECD-guidelines. RESULTS: The textiles impregnated with LASU phthalocyanine showed a significant antiviral photodynamic effect even under moderate indoor and outdoor light. The dye did not show any genotoxic potential in human lymphocyte micronucleus assay. It showed a possible indication for eye irritation in human EpiOcular™ model and was phototoxic when tested in mouse BALB/c 3T3 cell test in the presence and absence of UVA-irradiation. CONCLUSION: Novel phthalocyanine-dyed textiles are suitable for general use as self-disinfecting antiviral barriers and materials in hospitals, households, and public places. The safety profile of LASU is the phototoxic effect which is related to LASU´s mode of action.

BACKGROUND: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment. METHODS: PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence.

OBJECTIVES: In patients with mesial temporal lobe epilepsy (mTLE) and normal MRI, anterior temporal lobectomy sparing the hippocampus might be considered because of the risk of post-operative memory deficit. However, it is unclear whether some patients with normal MRI and non-invasive EEG and semiological pattern highly suggestive of mesial temporal seizures demonstrate a seizure onset network sparing the hippocampus, potentially warranting surgery. METHODS: A retrospective study of 17 patients with mTLE epilepsy and normal MRI who underwent SEEG. Only patients whose non-invasive presurgical data suggested an unilateral mesial temporal epileptogenic zone (EZ), as defined by combination of ictal semiology and ictal EEG during scalp video-EEG, were included. SEEG data were analyzed using both visual and quantitative approaches. Two EZ organization were defined: (i) EZ involved the hippocampus at the onset of the ictal discharge (HIP group): (ii) patients in whom a delay>1sec was observed between the seizure onset and the involvement of the hippocampus (nHIP group). Non-invasive clinical and functional imaging data, as well as post-operative outcomes, were compared across groups. RESULTS: Eleven patients were included in HIP group and 6 in the nHIP group. In the nHIP group, the maximal epileptogenicity was in the amygdala in five patients and in the entorhinal cortex in one. The hippocampus normalized interictal spiking activity was not different between groups. None of the patients characteristics collected during the non-invasive presurgical workup was associated with the SEEG-based organization of the EZ. Twelve patients underwent a surgical resection, including temporal cortectomy sparing hippocampus in six. Seizure and neuropsychological post-operative outcomes were similar. CONCLUSION: In patients with MRI-normal mTLE, SEEG should be included in the surgical decision-making process because seizure organization cannot be predicted from non-invasive investigations. When hippocampus is not included in the EZ, temporal resection sparing the hippocampus can be considered.

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INTRODUCTION: The combined use of intraoperative MRI and awake surgery is a tailored microsurgical resection to respect functional neural networks (mainly the language and motor ones). Intraoperative MRI has been classically considered to increase the extent of resection for gliomas, thereby reducing neurological deficits. Herein, we evaluated the combined technique of awake microsurgical resection and intraoperative MRI for primary brain tumours (gliomas, metastasis) and epilepsy (cortical dysplasia, non-lesional, cavernomas). PATIENTS AND METHODS: Eighteen patients were treated with the commonly used "asleep awake asleep" (AAA) approach at Lille University Hospital, France, from November 2016 until May 2020. The exact anatomical location was insular with various extensions, frontal, temporal or fronto-temporal in 8 (44.4%), parietal in 3 (16.7%), fronto-opercular in 4 (22.2%), Rolandic in two (11.1%), and the supplementary motor area (SMA) in one (5.6%). RESULTS: The patients had a mean age of 38.4 years (median 37.1, range 20.8-66.9). The mean surgical duration was 4.1 hours (median 4.2, range 2.6-6.4) with a mean duration of intraoperative MRI of 28.8 minutes (median 25, range 13-55). Overall, 61% (11/18) of patients underwent further resection, while 39% had no additional resection after intraoperative MRI. The mean preoperative and postoperative tumour volumes of the primary brain tumours were 34.7 cc (median 10.7, range 0.534-130.25) and 3.5 cc (median 0.5, range 0-17.4), respectively. Moreover, the proportion of the initially resected tumour volume at the time of intraoperative MRI (expressed as 100% from preoperative volume) and the final resected tumour volume were statistically significant (p= 0.01, Mann-Whitney test). The tumour remnants were commonly found posterior (5/9) or anterior (2/9) insular and in proximity with the motor strip (1/9) or language areas (e.g. Broca, 1/9). Further resection was not required in seven patients because there were no remnants (3/7), cortical stimulation approaching eloquent areas (3/7) and non-lesional epilepsy (1/7). The mean overall follow-up period was 15.8 months (median 12, range 3-36). CONCLUSION: The intraoperative MRI and awake microsurgical resection approach is feasible with extensive planning and multidisciplinary collaboration, as these methods are complementary and synergic rather than competitive to improve patient oncological outcomes and quality of life.

OBJECTIVE: Photodynamic therapy (PDT) has become a well-established modality for the treatment of many cancers. Photodynamic eradication of tumor cells depends on the presence of a photosensitizer, oxygen and light. However, oxygen depletion during PDT is a well known problem. Modulation of light delivery could address this issue by counteracting tumor hypoxia, thereby improving tumor cell killing. This preclinical study was designed to validate an animal model incorporating 5-aminolaevulinic acid (5-ALA)-PDT using U87 glioblastoma cells. We aimed to evaluate the effects of light modulation for inducing specific tumoral lesions in this model (i.e., necrosis or apoptosis).MATERIALS AND METHODS: U87 glioblastoma cells were stereotactically engrafted into the brains of male fox1 rnu/rnu rats. Light delivery was studied after 5-ALA injection (100mg/kg i.p.). 26J of 635nm light was interstitially delivered to U87 tumor-bearing rats at a radiant power of either 30 mW (high fluence rate) or 4.8 mW (low fluence rate). In each group, half of the population received illumination in 2 fractions with a refractory interval of 120seconds, whereas the other half received continuous illumination.RESULTS: Twenty-two animals received 5-ALA-PDT, and the level of necrosis was scored. In the high-fluence-rate group, we observed a greater degree of tumor necrosis in rats receiving fractionated delivery than in rats receiving continuous illumination. Similar differences were not observed in the low-fluence-rate group, which exhibited only sparse necrosis. Higher morbidity and mortality rates were observed in the high-fluence-rate group.CONCLUSION: We have developed a reproducible and reliable rodent model for interstitial 5-ALA PDT. We found that the effects of 5-ALA-PDT are dependent on light delivery conditions. Although the low-fluence-rate treatment was better tolerated, 5-ALA-PDT induced more necrosis using fractionated delivery at a high fluence rate. These results require confirmation with further studies involving larger populations and additional fractionation schemes.

Six ans après le physicien Serge Haroche, un autre Français, qui détient aussi la nationalité américaine, reçoit le prix Nobel de physique. Gérard Mourou, né en 1944 à Albertville (France), est professeur émérite à l’École polytechnique (Palaiseau, France) et ancien professeur à l’université du Michigan (Ann Arbor, États-Unis). Il partage la moitié du prix Nobel avec Donna Strickland, de l’université de Waterloo (Ontario, Canada). Née en 1959 à Guelph, au Canada, elle était alors étudiante à l’époque de ces travaux portant sur les lasers. Elle est la troisième femme seulement à être récompensée en physique, après Marie Curie en 1903 et Maria Goeppert-Mayer en 1963. L’autre moitié de cette récompense prestigieuse revient à l’Américain Arthur Ashkin, 96 ans, de l’université Cornell (Ithaca, État de New York, États-Unis). Arthur Ashkin est désormais la personne la plus âgée à voir été lauréat d’un prix Nobel, toutes catégories confondues. Ces trois chercheurs ont un point commun : ils manipulent la lumière et leurs recherches ont abouti à de nouvelles utilisations des lasers en médecine.

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Background: While remnant liver function (RLF) gain after portal vein embolization (PVE) was reportedly higher than volume gain, some patients apparently fit for surgery develop post-hepatectomy liver failure (PHLF). This prospective study analyses the hepatic regeneration rates in terms of volume and function following a major hepatectomy (MH) preceded or not by PVE. Methods: Between 2012 and 2018, all non-cirrhotic candidates for MH had a volumetric-computed tomography evaluation and functional-single photon emission computed tomography (SPECT)-scintigraphy of RL preoperatively and postoperatively at day 7 (POD7) and 1 month (1M). RLF was calculated as intrinsic function (i.e., normalized to volume; %/min), and function/volume changes as relative ones (%). We investigated the impact of PVE on post-hepatectomy regeneration rates and related to 3-month outcome (I) in overall population (II) after excluding more risky patients (biliary drainage, severe complications) and (III) in PVE/no-PVE patients matched on remnant liver volume (RLV)/RLF (as the liver regeneration rate is proportional to the extent of resection). Results: overcompensation in no-PVE patients (1.27%/min; range, 1-1.5%/min; P=0.001). This was associated with significantly increased PHLF and morbi-mortality rates. Findings were similar after excluding patients with biliary drainage or severe complications or after matching patients on RLV or RLF. Conclusions: The current findings showed that some patients apparently fit for surgery after PVE are going to hepatic resection with some degree of disadvantage, displaying lower hepatic reserve and delayed functional recovery than no-PVE patients.

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Dans le cadre d’un projet de recherche destiné à améliorer les techniques d’analyse d’imagerie médicale, notamment employées pour repérer ou suivre certains cancers, nous avons mené une étude de recherche création. Celle-ci s’est focalisée sur la création d'un jeu de société sérieux visant à aborder de manière ludique les bénéfices et les limites de différentes techniques. Dans cette optique, nous avons exploré diverses solutions ludo-sérieuses vers lesquelles nous diriger, ce qui nous a mené à une analyse des processus pouvant être mobilisés. Nous présentons ici une revue de la littérature scientifique à ce sujet et clarifions les différentes formes d'applications pratiques qui émanent plus ou moins du concept de jeu, en les catégorisant. Par la suite, nous examinons les processus considérés pour élaborer un jeu de plateau à but utilitaire et plus particulièrement à but de partage de points de vue. Nous détaillons ainsi les étapes de conception que nous avons suivies, en mettant en évidence les diverses démarches employées et le résultat accompli.

Synopsis Many studies are devoted to functionalized metallic nanoparticles, for many applications: in Physics, due to their localized surface plasmon resonances; in Chemistry, due to their specific catalytic properties that depend on their surface nature; in Biology, due to their optical or magnetic properties coupled to their potential for targeting and vectorization of bioactive molecules within living cells. In this last domain, gold and silver nanoparticles are especially of interest and, for the control of their biological effects, it is very important to have a fine knowledge of the structural properties and the chemical stabilities of their functional ligands.