Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: a 10-year real-world retrospective cohort study

AbstractsBackground and Aims: Checkpoint inhibitors (CPI) are accounting for increasing number of drug-induced liver injury (DILI) cases. We aimed to determine the incidence rate and risk factors associated with checkpoint inhibitor-induced liver injury (ChILI).Method: Prescription event monitoring was performed on all melanoma and renal cancer patients who received CPI at a tertiary centre between 2011 and 2021. ChILI cases were identified using the definitions, grading and causality assessment methods validated for DILI. We assessed risk factors associated with ChILI in CPInaïve patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterization and outcomes of ChILI.Results: Out of 432 patients received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 patient-months (95% CI 8.2-15.8). Probability of ChILI was highest in combination therapy (32%) with no new events occurred beyond 135 days of treatment. Risk factor analysis showed that combination therapy, female sex, higher baseline alanine transferase level and lower baseline alkaline phosphatase level were independently associated with higher risk of ChILI. In total, 99 patients were adjudicated to have ChILI from three centres.Although Common Terminology Criteria for Adverse Events (CTCAE) classified 20 patients (20.2%) to have ‘life-threatening’ grade 4 hepatitis, ChILI severity was graded as mild in 45 (45.5%) and moderate in the remaining 54 (54.5%) cases.Conclusion: The risk of ChILI in real-world is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after four and half 7 months. As CTCAE overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care

Atmospheric conditions and composition that influence PM2.5 oxidative potential in Beijing, China

Epidemiological studies have consistently linked exposure to PM2.5 with adverse health effects. The oxidative potential (OP) of aerosol particles has been widely suggested as a measure of their potential toxicity. Several acellular chemical assays are now readily employed to measure OP; however, uncertainty remains regarding the atmospheric conditions and specific chemical components of PM2.5 that drive OP. A limited number of studies have simultaneously utilised multiple OP assays with a wide range of concurrent measurements and investigated the seasonality of PM2.5 OP. In this work, filter samples were collected in winter 2016 and summer 2017 during the atmospheric pollution and human health in a Chinese megacity campaign (APHH-Beijing), and PM2.5 OP was analysed using four acellular methods: ascorbic acid (AA), dithiothreitol (DTT), 2,7-dichlorofluorescin/hydrogen peroxidase (DCFH) and electron paramagnetic resonance spectroscopy (EPR). Each assay reflects different oxidising properties of PM2.5, including particle-bound reactive oxygen species (DCFH), superoxide radical production (EPR) and catalytic redox chemistry (DTT/AA), and a combination of these four assays provided a detailed overall picture of the oxidising properties of PM2.5 at a central site in Beijing. Positive correlations of OP (normalised per volume of air) of all four assays with overall PM2.5 mass were observed, with stronger correlations in winter compared to summer. In contrast, when OP assay values were normalised for particle mass, days with higher PM2.5 mass concentrations (µgm−3) were found to have lower mass-normalised OP values as measured by AA and DTT. This finding supports that total PM2.5 mass concentrations alone may not always be the best indicator for particle toxicity. Univariate analysis of OP values and an extensive range of additional measurements, 107 in total, including PM2.5 composition, gas-phase composition and meteorological data, provided detailed insight into the chemical components and atmospheric processes that determine PM2.5 OP variability. Multivariate statistical analyses highlighted associations of OP assay responses with varying chemical components in PM2.5 for both mass- and volume-normalised data. AA and DTT assays were well predicted by a small set of measurements in multiple linear regression (MLR) models and indicated fossil fuel combustion, vehicle emissions and biogenic secondary organic aerosol (SOA) as influential particle sources in the assay response. Mass MLR models of OP associated with compositional source profiles predicted OP almost as well as volume MLR models, illustrating the influence of mass composition on both particle-level OP and total volume OP. Univariate and multivariate analysis showed that different assays cover different chemical spaces, and through comparison of mass- and volume-normalised data we demonstrate that mass-normalised OP provides a more nuanced picture of compositional drivers and sources of OP compared to volume-normalised analysis. This study constitutes one of the most extensive and comprehensive composition datasets currently available and provides a unique opportunity to explore chemical variations in PM2.5 and how they affect both PM2.5 OP and the concentrations of particle-bound reactive oxygen species

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Analysis of a prospective cohort of 470 Head and Neck Adenoid Cystic Carcinoma : prognosis analysis and therapeutic strategies evaluation

Introduction : Le carcinome adénoïde kystique (CAK) est un cancer rare survenant à tout âge avec une prédominance féminine. Aucun facteur de risque n'est connu. Bien que de croissance lente, il se caractérise par des récidives multiples et tardives. La chirurgie suivie de radiothérapie (RT) est le gold standard, mais la nécessité d'un curage cervical prophylactique (CC) ou d'une RT adjuvante chez les petits stades restent débattus. Les traitements des stades inopérables ou métastatiques restent du domaine de la recherche clinique. Le Réseau d'Expertise Français des Cancers Orl Rares (REFCOR) gère une base de données à partir de laquelle a été constituée la cohorte de CAK étudiée. Après une revue systématique sur les traitements aux stades récidivants ou métastatiques, les objectifs de cette thèse ont été d'étudier :Axe 1 : Les caractéristiques épidémiologiques de la population et les facteurs pronostiques.Axe 2 : L'influence du CC sur la Survie sans évènement (SSE) chez les patients cN0.Axe 3 : L'influence sur la SSE d'une radiothérapie post - opératoire (RT) chez les patients T1-T2 N0.Matériel et méthodes : Une cohorte prospective multicentrique a été constituée de 2009 à 2018. Les analyses ont été menées sur logiciel R après un contrôle qualité des données.Axe 1 : Le critère de jugement principal était la SSE.Axe 2 : Parmi les patients cN0 M0 opérés, une comparaison de la SSE entre les groupes ayant reçu ou non un CC (CC+/CC-) a été réalisée par score de propension.Axe 3 : Parmi les patients T1-T2 N0 M0, opérés, une comparaison de la SSE entre les groupes ayant bénéficié ou non d'une RT a été réalisée par score de propension.Résultats : Axe 1 : Sur 470 patients : âge moyen = 55 ans ; 59,4 % de femmes ; 60 % des tumeurs localisées aux glandes salivaires accessoires ; 58 % de stades T3 T4 ; 89 % cN0 ; 21 % grade III histologique. Les taux de survie globale, sans récidive, sans métastase et SSE à 5 ans étaient respectivement 85 %, 64 %, 62 % et 50 %. Après ajustement, l'âge ≥ à 65 ans, l'IMC < 16,5 et l'envahissement ganglionnaire cN+ sont les facteurs de mauvais pronostic identifiés.Axe 2 : Sur 322 patients cN0, 46 % ont eu un CC. Parmi eux, 7 présentaient un envahissement ganglionnaire histologique. Après score de propension, la durée médiane de SSE des patients CC+ était de 72 mois (intervalle de confiance (IC à 95 % [48-81]), contre 73 mois (IC 95 % [52-85]) pour les patients CC- (HR = 1,33 ; IC 95 % [0,82-2,16] ; p = 0,2).Axe 3 : Sur 115 patients T1-T2, 64 % ont eu une RT. Après score de propension, le taux de SSE à 4 ans du groupe RT était de 72 % [0,58 - 1] versus 50 % [0,30 - 0,84] pour le groupe sans RT (HR = 1,67 ; IC 95 % [0,24 - 1,5] ; p = 0,3). Conclusion :L'âge, l'IMC et le stade N sont les principaux facteurs de mauvais pronostic sur la SSE. La réalisation d'un CC chez les patients cN0 n'apporte pas de bénéfice en SSE ce qui suggère d'y surseoir. La RT post-opératoire à modulation d'intensité est le traitement de référence. A propos de son indication dans les petits stades, il existe une tendance à une meilleure SSE chez les patients T1T2N0 ayant bénéficié d'une RT post-opératoire. Il n'y a actuellement aucun consensus sur un schéma de chimiothérapie ou de thérapies ciblées dans le CAK. Les mutations MYB-NFIB, Notch 1 offrent des opportunités thérapeutiques. L'ouverture d'un espace Jupyter dédié au sein de l'entrepôt de données de santé APHP grâce à des fonds européens obtenus via le réseau EURACAN nous donne une belle perspective pour la recherche sur les cancers rares et en particulier le CAK.Introduction: Adenoid cystic carcinoma (ACC) is a rare cancer occurring at any age with a female predominance. No risk factors are known. Although slow growing, it is characterized by multiple and late recurrences. Surgery followed by radiotherapy (RT) is the gold standard, but the need for prophylactic neck dissection (ND) or adjuvant RT in small stages remains debated. Treatments for inoperable or metastatic stages remain in the field of clinical research. From a database managed by The French Network of Expertise for Rare head and neck Cancers (REFCOR), a CAK cohort studied was constituted. After a systematic review on treatments at recurrent or metastatic stages, the objectives of this thesis were to study:Axis 1: Epidemiological characteristics of the population and prognostic factorsAxis 2: The influence of CC on Event-Free Survival (EFS) in cN0 patients.Axis 3: The influence on EFS of postoperative radiotherapy (RT) in patients T1-T2 N0.Material and methods: A multicenter prospective cohort was formed from 2009 to 2018. Analyses were conducted on R software after data quality control.Axis 1: The primary outcome was EFS.Axis 2: Among the operated cN0 M0 patients, a comparison of the EFS between the groups who received or did not receive a NC (ND+/ND-) was carried out by propensity score.Axis 3: Among the patients T1-T2 N0 M0, operated, a comparison of the EFS between the groups who benefited or not from a RT was carried out by propensity score.Results: Axis 1: Out of 470 patients: average age = 55 years; 59.4% women; 60% of tumors localized to the accessory salivary glands; 58% of T3 T4; 89% cN0; 21% of grade III histological. The overall survival rates, without recurrence, without metastasis and EFS at 5 years were 85%, 64%, 62% and 50%, respectively. After adjustment, age ≥ 65, BMI < 16. 5 and cN+ lymph node invasion are the factors of poor prognosis identified.Axis 2: Out of 322 cN0 patients, 46% had ND. Of these, 7 had histological lymph node invasion. After propensity score, the median duration of EFS for ND+ patients was 72 months (95% confidence interval (CI) [48-81]), compared with 73 months (95% CI [52-85]) for ND- patients (HR = 1.33; 95% CI [0.82-2.16]; p = 0.2).Axis 3: Out of 115 T1-T2 patients, 64% had RT. After propensity score, the 4-year EFS rate of the RT group was 72% [0.58 - 1] versus 50% [0.30 - 0.84] for the group without RT (HR = 1.67; 95% CI [0.24 - 1.5]; p = 0.3).Conclusion: Age, BMI and stage N are the main unfavorable prognostic factors on EFS. The realization of a ND in cN0 patients does not seem to provide any benefit in terms of EFS, which would suggest that it should be postponed. Intensity-modulated postoperative RT is the reference treatment. Regarding its indication in the early stages, there is a trend for better EFS in T1T2N0 patients who have undergone postoperative RT. There is currently no consensus on a chemotherapy regimen or targeted therapies in ACC. MYB-NFIB, Notch 1 mutations offer therapeutic opportunities. The opening of a dedicated Jupyter space within the APHP health data warehouse thanks to European funds obtained through the EURACAN network gives us a great prospect for research on rare cancers and in particular ACC

Beyond Surgical Treatment in Adenoid Cystic Carcinoma of the Head and Neck : A Literature Review

Introduction: Adenoid cystic carcinoma (AdCC) is a rare tumour as it accounts for about 10% of all salivary gland neoplasms. It occurs in all age groups with a predominance of women, but no risk factors have been identified to date. Although AdCC behaves as a slow-growing tumour, it is characterized by multiple and late recurrences. Therefore, we aim to update the knowledge of the treatment options in advanced and recurrent cases. Materials and Methods: We performed a systematic literature review to provide a synthesis of the practical knowledge required for AdCC non-surgical management. Altogether, 99 out of the 1208 available publications were selected for analysis. Results: AdCC is described as a basaloid tumour consisting of epithelial and myoepithelial cells. Immunohistochemistry is useful for diagnosis (PS100, Vimentin, CD117, CKit, muscle actin, p63) and for prognosis (Ki67). Identified mutations could lead to therapeutic opportunities (MYB-NFIB, Notch 1). The work-up is mainly based on neck and chest CT scan and MRI, and PET-CT with 18-FDG or PSMA can be considered. Surgical treatment remains the gold standard in resectable cases. Post-operative intensity modulated radiotherapy is the standard of care, but hadron therapy may be used in specific situations. Based on the available literature, no standard chemotherapy regimen can be recommended. Conclusion: There is currently no consensus on the use of chemotherapy in AdCC, either concomitantly to RT in a postoperative setting or at a metastatic stage. Further, the available targeted therapies do not yet provide significant tumour response.Peer reviewe

Association of Mycoplasma Hominis and head and neck cancer with unknown primary

International audienceIntroduction: Beside HPV infection, there is currently no evidence of association between head and neck squamous cell carcinomas and microbial infections. We report the case of a cervical squamous cell carcinoma by Mycoplasma hominis.Case summary: A 20-year-old woman, consulted for a swelling on the left cervical side. Clinical examination found a large fixed mass. Biological tests found no evidence of infection. Biopsies of the cervical lesion diagnosed an HPV negative squamous cell carcinoma. Microbiological tests of 16sRNA identification showed the presence of Mycoplasma hominis in the 3 specimens. The patient was treated by induction chemotherapy associated to antibiotherapy, followed by chemo-radiotherapy.Discussion: The present case suggests that oropharyngeal infection by Mycoplasma hominis might be more frequent than expected, that 16sRNA is an efficient technique to isolate this pathogen and finally that further studies are required to document its potential oncogenic role in head and neck squamous cell carcinomas

Localized Talaromyces marneffei infection presenting as a tonsillar mass mimicking malignancy

Talaromyces marneffei is an opportunistic fungal infection seen in immunocompromised patients including those with HIV/AIDS. It is usually seen in patients who live in or are from tropical Asia. In HIV patients, oropharyngeal and laryngeal lesions are usually part of disseminated infection. We describe a case of 63-year-old Vietnamese male with history of HIV/AIDS who presented with localized T. marneffei tonsillar infection without disseminated disease. Imaging studies showed a right tonsillar mass with right cervical lymphadenopathy which was initially thought to be malignancy. The patient underwent biopsy of the mass and histology showed noncaseating granulomas on hematoxylin and eosin stain as well as yeast on Grocott methenamine silver stain. Fungal culture of the biopsy specimen grew suede-like grayish-white colonies with diffuse underlying deep red color pigment which was identified as Talaromyces marneffei. The patient was treated with intravenous liposomal amphotericin B and achieved resolution of symptoms and tonsillar mass. In HIV/AIDS patients who are either from endemic regions or with history of travel to endemic areas particularly Southeast Asia and China, T. marneffei infection should be considered in differential diagnoses of a tonsillar mass

Diagnosis with confidence: deep learning for reliable classification of laryngeal dysplasia

International audienceBackground Diagnosis of head and neck (HN) squamous dysplasias and carcinomas is critical for patient care, cure, and follow‐up. It can be challenging, especially for grading intraepithelial lesions. Despite recent simplification in the last WHO grading system, the inter‐ and intraobserver variability remains substantial, particularly for nonspecialized pathologists, exhibiting the need for new tools to support pathologists. Methods In this study we investigated the potential of deep learning to assist the pathologist with automatic and reliable classification of HN lesions following the 2022 WHO classification system. We created, for the first time, a large‐scale database of histological samples (>2000 slides) intended for developing an automatic diagnostic tool. We developed and trained a weakly supervised model performing classification from whole‐slide images (WSI). We evaluated our model on both internal and external test sets and we defined and validated a new confidence score to assess the predictions that can be used to identify difficult cases. Results Our model demonstrated high classification accuracy across all lesion types on both internal and external test sets (respectively average area under the curve [AUC]: 0.878 (95% confidence interval [CI]: [0.834–0.918]) and 0.886 (95% CI: [0.813–0.947])) and the confidence score allowed for accurate differentiation between reliable and uncertain predictions. Conclusion Our results demonstrate that the model, associated with confidence measurements, can help in the difficult task of classifying HN squamous lesions by limiting variability and detecting ambiguous cases, taking us one step closer to a wider adoption of AI‐based assistive tools