French early nationwide idecabtagene vicleucel chimeric antigen receptor T-cell therapy experience in patients with relapsed/refractory multiple myeloma (FENIX): A real-world IFM study from the DESCAR-T registry.

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.

Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

Inequality factors in access to early-phase clinical trials in oncology in France: results of the EGALICAN-2 study.

BACKGROUND: Investigation of the disparities in the access to experimental treatment in early-phase clinical trials is lacking. The objective of the EGALICAN-2 study was to identify the factors underpinning such inequalities. METHODS: A national prospective survey was conducted in 11 early-phase clinical trial centers (CLIP2) certified by the French National Cancer Institute. Sociodemographic, socioeconomic and medical data were collected. Univariate logistic regression models were carried out to estimate odds ratios and 90% confidence intervals associated with the effect of each study variable. A multivariate logistic regression model was built to explore the independent factors associated with the administration of the experimental treatment (C1D1). A post hoc analysis was carried out excluding female cancer patients. RESULTS: Between 2015 and 2016, 1355 patients referred from 11 CLIP2 centers in France were included in the study. Eight hundred and forty-eight patients received C1D1 (73%) and 320 patients (27%) were screening failure. Median age was 58 years (range 17-97 years) and 667 patients (54%) were female. Most patients had a metastatic disease (n = 751, 87%). In the multivariate logistic regression analysis, the significant independent factors associated with C1D1 were male sex, initial care received in a hospital with an early-phase unit and living in wealthy metropolitan areas (P values <0.05). In the post hoc analysis, the sex factor was no longer significant [odds ratio = 1.21 (95% confidence interval 0.86-1.70), P value = 0.271]. CONCLUSIONS: This study investigated the factors producing social inequalities in the context of early-phase clinical trials in oncology. Our research highlights factors of sex, care pathway and geographic location. Gynecological cancer was found to impact C1D1 significantly, unlike breast cancer. The results of this study should contribute to improve patient access to early-phase clinical trials.

Near single-photon imaging in the shortwave infrared using homodyne detection.

Low-light imaging is challenging in regimes where low-noise detectors are not yet available. One such regime is the shortwave infrared where even the best multipixel detector arrays typically have a noise floor in excess of 100 photons per pixel per frame. We present a homodyne imaging system capable of recovering both intensity and phase images of an object from a single frame despite an illumination intensity of ≈​1 photon per pixel. We interfere this weak signal which is below the noise floor of the detector with a reference beam that is ∼​300, 000 times brighter, record the resulting interference pattern in the spatial domain on a detector array, and use Fourier techniques to extract the intensity and phase images. We believe our approach could vastly extend the range of applications for low-light imaging by accessing domains where low-noise cameras are not currently available and for which low-intensity illumination is required.

Cell size and actin architecture determine force generation in optogenetically activated cells.

Adherent cells use actomyosin contractility to generate mechanical force and to sense the physical properties of their environment, with dramatic consequences for migration, division, differentiation, and fate. However, the organization of the actomyosin system within cells is highly variable, with its assembly and function being controlled by small GTPases from the Rho family. To understand better how activation of these regulators translates into cell-scale force generation in the context of different physical environments, here we combine recent advances in non-neuronal optogenetics with micropatterning and traction force microscopy on soft elastic substrates. We find that, after whole-cell RhoA activation by the CRY2/CIBN optogenetic system with a short pulse of 100 ms, single cells contract on a minute timescale in proportion to their original traction force, before returning to their original tension setpoint with near perfect precision, on a longer timescale of several minutes. To decouple the biochemical and mechanical elements of this response, we introduce a mathematical model that is parametrized by fits to the dynamics of the substrate deformation energy. We find that the RhoA response builds up quickly on a timescale of 20 s, but decays slowly on a timescale of 50 s. The larger the cells and the more polarized their actin cytoskeleton, the more substrate deformation energy is generated. RhoA activation starts to saturate if optogenetic pulse length exceeds 50 ms, revealing the intrinsic limits of biochemical activation. Together our results suggest that adherent cells establish tensional homeostasis by the RhoA system, but that the setpoint and the dynamics around it are strongly determined by cell size and the architecture of the actin cytoskeleton, which both are controlled by the extracellular environment.

Contributions to the revision of the genus Entoloma (Basidiomycota, Agaricales) in Europe: six new species from subgenus Cyanula and typification of E. incarnatofuscescens.

In anticipation of a phylogenetically revised monograph of Entoloma in Europe, six new species of subgenus Cyanula are described here. Entoloma cistocruentatum is associated with Cistus in Spain, E. dislocatum occurs in montane regions in Catalonia (Spain) and Tuscany (Italy), E. indikon is known from Denmark and three species are mainly distributed in the Nordic countries in Europe: E. calceus, E. perchalybeum and E. praecipuum. Entoloma incarnatofuscescens, from the /Rusticoides clade is neotypified. A fully amended description is given based on molecular evidence, which includes the recently described E. violaceoparkensis and E. klofacianum which became later synonyms. Citation: Noordeloos ME, Vila J, Jordal JB, Kehlet T, Brandrud TE, Bendiksen E, Moreau P-A, Dondl M, Lorås J, Larsson E, Dima B (2022). Contributions to the revision of the genus Entoloma (Basidiomycota, Agaricales) in Europe: six new species from subgenus Cyanula and typification of E. incarnatofuscescens. Fungal Systematics and Evolution 9: 87-97. doi: 10.3114/fuse.2022.09.06.

Access to early-phase clinical trials in older patients with cancer in France: the EGALICAN-2 study.

BACKGROUND: Access to clinical trials and especially early-phase trials (ECT) is an important issue in geriatric oncology. As cancer can be considered an age-related disease because the incidence of most cancers increases with age, new drugs should also be evaluated in older patients to assess their safety and efficacy. The EGALICAN-2 study was primarily designed to identify social and/or regional inequalities regarding access to ECT. We focused on the factors of inequalities in access to ECT in older patients. PATIENTS AND METHODS: During a 1-year period (2015-2016), a survey was conducted in 11 early-phase units certified by the French National Cancer Institute. RESULTS: A total of 1319 patients were included in the analyses: 1086 patients (82.3%) were <70 years and 233 patients (17.7%) were >70 years. The most common tumor types at referral in older patients were gastrointestinal (19.3%), hematological (19.3%), and thoracic tumors (18.0%). Most patients referred to the phase I unit had signed informed consent and the rate was similar across age (92.7% in younger patients versus 90.6% in older patients; P = 0.266). The rate of screening failure was also similar across age (28.5% in younger patients versus 24.3% in older patients; P = 0.219). Finally, in older patients, univariate analyses showed that initial care received in the hospital having a phase I unit was statistically associated with first study drug administration (odds ratio 0.49, 90% confidence interval 0.27-0.88; P = 0.045). CONCLUSIONS: Older patients are underrepresented in early clinical trials with 17.7% of patients aged ≥70 years compared with the number of new cases of cancer in France (50%). However, when invited to participate, older patients were prone to sign informed consent.

Managing hematological cancer patients during the COVID-19 pandemic: an ESMO-EHA Interdisciplinary Expert Consensus.

BACKGROUND: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. METHODS: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. RESULTS AND CONCLUSION: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.

Noise rejection through an improved quantum illumination protocol.

Quantum illumination protocols can be implemented to improve imaging performance in the low photon flux regime even in the presence of both background light and sensor noise. However, the extent to which this noise can be rejected is limited by the rate of accidental correlations resulting from the detection of photon or noise events that are not quantum-correlated. Here we present an improved protocol that rejects up to [Formula: see text] of background light and sensor noise in the low photon flux regime, improving upon our previous results by an order of magnitude. This improvement, which requires no information regarding the scene or noise statistics, will enable extremely low light quantum imaging techniques to be applied in environments previously thought difficult and be an important addition to the development of covert imaging, quantum microscopes, and quantum LIDAR.

Hygrophorus sect. Olivaceoumbrini: new boundaries, extended biogeography and unexpected diversity unravelled by transatlantic studies.

As currently delineated, Hygrophorus sect. Olivaceoumbrini is a polyphyletic assembly within subg. Colorati, encompassing glutinous and pigmented taxa. According to available literature, between a dozen and twenty species may belong in the section, mostly represented in continental and boreal forests of Europe and North America. However, the limited phylogenetic and biogeographic coverage of the genus does not presently allow for a reliable assessment of its taxonomic boundaries, nor does it provide a complete picture of species diversity within sect. Olivaceoumbrini. In an ongoing effort to confer an evolutionary backbone to Hygrophorus systematics, we assembled and analysed a dataset comprising 268 intercontinental sequences, including holotypes of 7 taxa previously not positioned phylogenetically, and enriched with collections from largely unexplored Mediterranean and Anatolian ecosystems. Overall, 30 clades are identified within 5 distinct lineages, including 11 species putatively new to science. Seven of these are formally described here as H. agathosmoides, H. albofloccosus, H. canadensis, H. limosus, H. marcocontui, H. pinophilus and H. pustulatoides spp. nov. This enriched coverage of section Olivaceoumbrini s.lat. calls for a re-evaluation of its natural boundaries into a core monophyletic clade, including H. olivaceoalbus and five closely related lookalikes, as well as the assignment of the section rank to the four remaining lineages: sect. Fuscocinerei sect. nov., sect. Limacini sect. nov., sect. Nudolidi sect. nov. and sect. Tephroleuci, respectively. We also stabilize the usage of six historical names, H. glutinifer, H. hyacinthinus, H. mesotephrus, H. olivaceoalbus, H. pustulatus and H. tephroleucus, through designation of two neotypes, three lectotypes and four epitypes. Citation: Bellanger J-M, Lebeuf R, Sesli E, et al. 2021. Hygrophorus sect. Olivaceoumbrini: new boundaries, extended biogeography and unexpected diversity unravelled by transatlantic studies. Persoonia 46: 272-312. https://doi.org/10.3767/persoonia.2021.46.10.

Complex roles of Rabs and SNAREs in the secretory pathway and plant development: a never-ending story.

Membrane trafficking is critical for cell compartmentation which allows the maintenance of specialised environments required for specific cellular activities. To achieve this goal, cells need to tightly regulate vesicle transport between donor and acceptor compartments. Several different protein families are involved: among them the SNAREs (65 genes) and the small GTPases Rabs (57 genes) show the highest number of isoforms and will be in the spotlight. We will focus on the roles of these proteins in the ER-Golgi-plasma membrane pathway to illustrate how Rabs and SNAREs are involved to achieve specific set of functions. LAY DESCRIPTION: Protein and lipid transport between the different compartments inside cells are critical for many physiological functions of organisms. To achieve this goal, cells have developed several vesicular transport systems between these compartments. Numerous different protein families are involved in these processes among which two protein families are the focus of the review in plant cells: the SNAREs and the small GTPases Rabs. These proteins are essentially controlling the different steps of the transport processes to warrant that proteins and lipids will reach the right compartments. The SNAREs are encoded by 65 genes meaning that plant cells synthesise 65 different SNARE proteins, and the small GTPases Rabs are encoded by 57 genes meaning that plant cells synthesise 57 different GTPases Rabs proteins. This high number of proteins illustrates the complexity of the vesicular transport systems existing between plant cell compartments. The review discusses the different roles of these proteins in these processes and particularly in the functioning of the secretory pathway which contributes to transport proteins and lipids to the cell surface. The review describes how the Rabs and SNAREs proteins are involved to achieve their respective set of functions in the different transport pathways of plant cells, and illustrates the tremendous complexity of these mechanisms.

Imaging through noise with quantum illumination.

The contrast of an image can be degraded by the presence of background light and sensor noise. To overcome this degradation, quantum illumination protocols have been theorized that exploit the spatial correlations between photon pairs. Here, we demonstrate the first full-field imaging system using quantum illumination by an enhanced detection protocol. With our current technology, we achieve a rejection of background and stray light of up to 5.8 and also report an image contrast improvement up to a factor of 11, which is resilient to both environmental noise and transmission losses. The quantum illumination protocol differs from usual quantum schemes in that the advantage is maintained even in the presence of noise and loss. Our approach may enable laboratory-based quantum imaging to be applied to real-world applications where the suppression of background light and noise is important, such as imaging under low photon flux and quantum LIDAR.

Stick-slip dynamics of cell adhesion triggers spontaneous symmetry breaking and directional migration of mesenchymal cells on one-dimensional lines.

Directional cell motility relies on the ability of single cells to establish a front-rear polarity and can occur in the absence of external cues. The initiation of migration has often been attributed to the spontaneous polarization of cytoskeleton components, while the spatiotemporal evolution of cell-substrate interaction forces has yet to be resolved. Here, we establish a one-dimensional microfabricated migration assay that mimics the complex in vivo fibrillar environment while being compatible with high-resolution force measurements, quantitative microscopy, and optogenetics. Quantification of morphometric and mechanical parameters of NIH-3T3 fibroblasts and RPE1 epithelial cells reveals a generic stick-slip behavior initiated by contractility-dependent stochastic detachment of adhesive contacts at one side of the cell, which is sufficient to trigger cell motility in 1D in the absence of pre-established polarity. A theoretical model validates the crucial role of adhesion dynamics, proposing that front-rear polarity can emerge independently of a complex self-polarizing system.

Twin-beam sub-shot-noise raster-scanning microscope.

By exploiting the quantised nature of light, we demonstrate a sub-shot-noise scanning optical transmittance microscope. Our microscope demonstrates, with micron scale resolution, a factor of improvement in precision of 1.76(9) in transmittance estimation gained per probe photon relative to the theoretical model, a shot-noise-limited source of light, in an equivalent single-pass classical version of the same experiment using the same number of photons detected with a 90% efficient detector. This would allow us to observe photosensitive samples with nearly twice the precision, without sacrificing image resolution or increasing optical power to improve signal-to-noise ratio. Our setup uses correlated twin-beams produced by parametric down-conversion, and a hybrid detection scheme comprising photon-counting-based feed-forward and a highly efficient CCD camera.

[Alcohol consumption and head and neck cancer]. / Consommation d'alcool et cancers ORL.

Alcohol is often considered as a simple co-factor, potentiating the carcinogenic effect of tobacco, in head and neck cancer. However, its own effect is less clear. It has been recognized by the International Agency for Research on Cancer (IARC) as a risk factor for head and neck cancer for many years. It seems that the risk is a function of the importance of consumption, with certain genetic predispositions. This risk can also decrease if consumption stops, with a prolonged interruption. In addition, alcohol consumption may have a negative influence on the prognosis of patients with this type of cancer. A preventive action is therefore essential, among other things via information to the patient provided by health providers.

En cancérologie ORL, l'alcool est souvent considéré comme un simple co-facteur, potentialisant l'effet carcinogène du tabac. Son effet propre est moins clair. Il est pourtant reconnu par le Centre International de Recherche sur le Cancer (CIRC) comme un facteur de risque de cancer ORL depuis de nombreuses années. Il semble que le risque soit fonction de l'importance de la consommation, avec la contribution de certaines prédispositions génétiques. Ce risque peut également diminuer en cas d'arrêt de la consommation, moyennant un arrêt prolongé. Par ailleurs, la consommation d'alcool pourrait avoir une influence néfaste sur le pronostic des patients atteints de ces cancers. Une action préventive est donc primordiale, entre autres interventions, via l'information du patient par le corps médical.

Early warning sensors for monitoring mercury in water.

Poly-4-vinylpyridine grafted poly(vinylidene difluoride) (P4VP-g-PVDF) nanoporous polymer electrodes were found to be sensitive for Hg(II) analysis. The fabrication and characterization of functionalized nanoporous membrane-electrodes by FESEM and FTIR are presented. Functionalized nanopore charge state versus a large range of pH (1-10) was investigated by registering the streaming potential. This isoelectric point is achieved at the pKa of P4VP (pH = 5). Mercury adsorption at solid-liquid interface obeys a Langmuir law. A protocol for accurate Hg(II) analysis at ppb level was established. Calibration curves were performed and different real water samples (mineral water, ground water, surface water) were spiked and analyzed. The resulting sensor is intended to be integrated into existing systems or used standalone as portable devices. A first generation prototype exhibiting its own integrated potentiostat, its software and set of membrane-electrode pads is presented.