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The ramp-up is a critical phase in the operations of a Tokamak, during which engineering and physics aspects must be taken into account to ensure stability, minimize flux consumption and avoid disruptions. Predicting ramp-up phases faces challenges such as nonlinearity, uncertainty on boundary and initial conditions and changes in the magnetic equilibrium. Our work uses the High-Fidelity Pulse Simulator (HFPS), a Python workflow based on JINTRAC. The input and output are in machine and code generic IMAS data format. The HFPS predicts the evolution of the current, temperature, main ion density and impurity density up to the separatrix. The self-consistent prediction of the density during the ramp-up represents the main element of novelty in this work. To this end, a closed feedback loop is set to match experimental line averaged density. QuaLiKiz (Citrin et al 2017 Plasma Phys. Control. Fusion 59 124005), TGLF (Staebler et al 2016 Phys. Plasmas 23 062518) and FRANTIC (Tamor 1981 J. Comput. Phys. 40 104119) are used to calculate turbulent fluxes and the source of neutrals respectively. QuaLiKiz and TGLF predict a transition from Trapped Electron Mode early in the discharge to Ion Temperature Gradient dominated turbulence. The results are compared to higher fidelity simulations with GKW, which show qualitative agreement. Good general agreement is reached between integrated modelling and experimental data, quantified by proposed measures of agreement. A large set of sensitivities to modelling choices and initial and boundary conditions is performed on four different discharges, to assess the robustness of the approach. more...

The development of a correlation-assisted direct time-of-flight (CA-dToF) pixel provides a novel solution for time-of-flight applications that combines low power consumption, robust ambient shot noise suppression, and a compact design. However, the pixel’s implementation introduces systematic errors, affecting its performance. We investigate the pixel’s robustness against various noise sources, including timing jitter, kTC noise, switching noise, and photon shot noise. Additionally, we address limitations such as the SPAD deadtime, and source follower gain mismatch and offset, identifying their impact on performance. The paper also proposes solutions to enhance the pixel’s overall reliability and to improve the pixel’s implementation. more...

Background Pulmonary rehabilitation (PR) is a well-established intervention for patients with COPD, but access, uptake and completion are low. This retrospective propensity-matched study aimed to analyse equivalence from a hybrid PR modality against conventional PR. Methods Between 2013 and 2019, 214 patients with COPD with valid baseline physical activity assessments enrolled in conventional PR for three times per week for 3 months. In 2021–2022, 44 patients with COPD enrolled in 3 months of hybrid PR, introducing two providers: once per week in the outpatient centre and two times per week in a primary care setting near the patient's home. All sessions were supervised. Propensity score matching (1:1) was performed. Equivalence between both programmes was analysed for exercise capacity with the equivalence margins of ±30 m on the 6-min walk distance (6MWD). Clinical outcomes, accessibility and adherence were compared using t-tests. Results 44 patients (mean±sd age 67±8 years; forced expiratory volume in 1 s (FEV1) 47±15% predicted; 6MWD 355±122 m) in the hybrid PR group were matched to 44 patients (mean±sd age 66±8 years; FEV1 46±17% predicted; 6MWD 354±103 m) in the conventional PR group. Equivalence on the increase in 6MWD could not be confirmed; nevertheless, both groups improved their 6MWD clinically significantly (hybrid PR change 63 m (90% CI 43–83 m); conventional PR change 39 m (90% CI 26–52 m)). Changes in quality of life and symptoms were similar. Dropout in hybrid PR (23%) was comparable to conventional PR (27%) (p=0.24). Adherence in both groups was high and accessibility was better for patients following hybrid PR. Conclusion Hybrid PR can be offered as an effective alternative to conventional PR, if patients are willing to take up the offer. more...

BackgroundOvarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models.MethodsA2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed.ResultsThe nature of TTFields-drug interaction was dependent on the drug’s underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control.ConclusionBy inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment. more...

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC. more...

Epithelial ovarian carcinoma (EOC) is a relatively rare malignancy but is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. At odds with other neoplasms, EOC is virtually insensitive to immune checkpoint inhibitors, correlating with a tumor microenvironment that exhibits poor infiltration by immune cells and active immunosuppression. Here, we comparatively summarize the humoral and cellular features of primary and metastatic EOC, comparatively analyze their impact on disease outcome, and propose measures to alter them in support of treatment sensitivity and superior patient survival. more...

Background. Lung transplantations are highly complex procedures, often conducted in frail patients. Through the addition of immunosuppressants, healing can be compromised, primarily leading to the development of bronchopleural fistulas. Although esophageal fistulas (EFs) after lung transplantation remain rare, they are associated with significant morbidity. We aimed to investigate the clinical presentation, diagnostic approaches, and treatment strategies of EF after lung transplantation. Methods. All patients who developed EF after lung transplantation at the University Hospitals Leuven between January 2019 and March 2022 were retrospectively reviewed and the clinical presentations, diagnostic approaches, and treatment strategies were summarized. Results. Among 212 lung transplantation patients, 5 patients (2.4%) developed EF. Three patients were male and median age was 39 y (range, 34–63). Intraoperative circulatory support was required in 3 patients, with 2 needing continued support postoperatively. Bipolar energy devices were consistently used for mediastinal hemostasis. All EFs were right-sided. Median time to diagnosis was 28 d (range, 12–48) and 80% of EFs presented as recurrent respiratory infections or empyema. Diagnosis was made through computed tomography (n = 3) or esophagogastroscopy (n = 2). Surgical repair with muscle flap covering achieved an 80% success rate. All patients achieved complete resolution, with only 1 patient experiencing a fatal outcome during a complicated EF-related recovery. Conclusion. Although EF after lung transplantation remains rare, vigilance is crucial, particularly in cases of right-sided intrathoracic infection. Moreover, caution must be exercised when applying thermal energy in the mediastinal area to prevent EF development and mitigate the risk of major morbidity. Timely diagnosis and surgical intervention can yield favorable outcomes. more...

Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host’s immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms. more...

Immune checkpoint inhibitors (ICI) have been revolutionary in the field of cancer therapy. However, their success is limited to specific indications and cancer types. Recently, the combination treatment of ICI and chemotherapy has gained more attention to overcome this limitation. Unfortunately, many clinical trials testing these combinations have provided limited success. This can partly be attributed to an inadequate choice of preclinical models and the lack of scientific rationale to select the most effective immune-oncological combination. In this review, we have analyzed the existing preclinical evidence on this topic, which is only limitedly available. Furthermore, this preclinical data indicates that besides the selection of a specific drug and dose, also the sequence or order of the combination treatment influences the study outcome. Therefore, we conclude that the success of clinical combination trials could be enhanced by improving the preclinical set up, in order to identify the optimal treatment combination and schedule to enhance the anti-tumor immunity. more...

The development of a correlation-assisted direct time-of-flight (CA-dToF) pixel provides a novel solution for time-of-flight applications that combines low power consumption, robust ambient shot noise suppression, and a compact design. However, the pixel's implementation introduces systematic errors, affecting its performance. We investigate the pixel's robustness against various noise sources, including timing jitter, kTC noise, switching noise, and photon shot noise. Additionally, we address limitations such as the SPAD deadtime, and source follower gain mismatch and offset, identifying their impact on performance. The paper also proposes solutions to enhance the pixel's overall reliability and to improve the pixel's implementation. [ABSTRACT FROM AUTHOR] more...

Tokamak à configuration variable (TCV), recently celebrating 30 years of near-continual operation, continues in its missions to advance outstanding key physics and operational scenario issues for ITER and the design of future power plants such as DEMO. The main machine heating systems and operational changes are first described. Then follow five sections: plasma scenarios. ITER Base-Line (IBL) discharges, triangularity studies together with X3 heating and N2 seeding. Edge localised mode suppression, with a high radiation region near the X-point is reported with N _2 injection with and without divertor baffles in a snowflake configuration. Negative triangularity (NT) discharges attained record, albeit transient, β _N ∼ 3 with lower turbulence, higher low-Z impurity transport, vertical stability and density limits and core transport better than the IBL. Positive triangularity L-Mode linear and saturated ohmic confinement confinement saturation, often-correlated with intrinsic toroidal rotation reversals, was probed for D, H and He working gases. H-mode confinement and pedestal studies were extended to low collisionality with electron cyclotron heating obtaining steady state electron iternal transport barrier with neutral beam heating (NBH), and NBH driven H-mode configurations with off-axis co-electron cyclotron current drive. Fast particle physics. The physics of disruptions, runaway electrons and fast ions (FIs) was developed using near-full current conversion at disruption with recombination thresholds characterised for impurity species (Ne, Ar, Kr). Different flushing gases (D2, H2) and pathways to trigger a benign disruption were explored. The 55 kV NBH II generated a rich Alfvénic spectrum modulating the FI fas ion loss detector signal. NT configurations showed less toroidal Alfvén excitation activity preferentially affecting higher FI pitch angles. Scrape-off layer and edge physics. gas puff imaging systems characterised turbulent plasma ejection for several advanced divertor configurations, including NT. Combined diagnostic array divertor state analysis in detachment conditions was compared to modelling revealing an importance for molecular processes. Divertor physics. Internal gas baffles diversified to include shorter/longer structures on the high and/or low field side to probe compressive efficiency. Divertor studies concentrated upon mitigating target power, facilitating detachment and increasing the radiated power fraction employing alternative divertor geometries, optimised X-point radiator regimes and long-legged configurations. Smaller-than-expected improvements with total flux expansion were better modelled when including parallel flows. Peak outer target heat flux reduction was achieved (>50%) for high flux-expansion geometries, maintaining core performance ( H _98 > 1). A reduction in target heat loads and facilitated detachment access at lower core densities is reported. Real-time control. TCV’s real-time control upgrades employed MIMO gas injector control of stable, robust, partial detachment and plasma β feedback control avoiding neoclassical tearing modes with plasma confinement changes. Machine-learning enhancements include trajectory tracking disruption proximity and avoidance as well as a first-of-its-kind reinforcement learning-based controller for the plasma equilibrium trained entirely on a free-boundary simulator. Finally, a short description of TCV’s immediate future plans will be given. more...