Interest for studying cosmic neutrinos using deep-sea detectors has increase after the discovery of a diffuse flux of cosmic neutrinos by the IceCube collaboration and the possibility of wider multi-messenger studies with the observations of gravitational waves. The ANTARES detector was the first neutrino telescope in seawater, operating successfully in the Mediterranean Sea for more than a decade and a half. All challenges related to the operation in the deep sea were accurately addressed by the collaboration. Deployment and connection operations became smoother over time; data taking and constant re-calibration of the detector due to the variable environmental conditions were fully automated. A wealth of results on the subject of astroparticle physics, particle physics and multi-messenger astronomy have been obtained, despite the relative modest size of the detector, paving the way to a new generation of larger undersea detectors. This review summarizes the efforts by the ANTARES collaboration that made the possibility to operate neutrino telescopes in seawater a reality and the results obtained in this endeavor.

On February 13th, 2023, the KM3NeT/ARCA telescope detected a neutrino candidate with an estimated energy in the hundreds of PeV. In this article, the observation of this ultrahigh-energy neutrino is discussed in light of null observations above tens of PeV from the IceCube and Pierre Auger observatories. Performing a joint fit of all experiments under the assumption of an isotropic E−2 flux, the best-fit single-flavor flux normalization is E2Φν+ν¯1f=7.5×10−10 GeV cm−2 s−1 sr−1 in the 90% energy range of the KM3NeT event. Furthermore, the ultrahigh-energy data are then fit together with the IceCube measurements at lower energies, either with a single power law or with a broken power law, allowing for the presence of a new component in the spectrum. A slight preference for a break in the PeV regime is found for one of the three investigated IceCube samples and no such preference for the other two. In all cases, the observed tension between KM3NeT and other datasets is mild to moderate (1.6σ–2.9σ), and increased statistics are required to resolve this apparent tension and better characterize the neutrino landscape at ultrahigh energies.

Oscillations of atmospheric muon and electron neutrinos produce tau neutrinos with energies in the GeV range, which can be observed by the ORCA detector of the KM3NeT neutrino telescope in the Mediterranean Sea. First measurements with ORCA6, an early subarray corresponding to about 5 S_τ=0.48_-0.33^+0.5 . This translates into a ντ charged-current cross section measurement of σ_τ^meas=(2.5_-1.8^+2.6)×10^-38 cm2 nucleon−1 at the median ντ energy of 20.3 GeV. The result is consistent with the measurements of other experiments. In addition, the current limit on the non-unitarity parameter affecting the τ-row of the neutrino mixing matrix was improved, with α33 > 0.95 at the 95

Background. Immune checkpoint inhibitors (ICIs) are effective treatments for patients with metastatic melanoma, including patients with brain metastasis (BM). However, half of patients with melanoma BM have intracranial progression within 6 months after the start of ICIs. We investigated whether size affects response to ICIs in patients with melanoma BM. Methods. In this single-center cohort study, patients with melanoma BM who were treated with ICIs between 2012 and 2021 were included. Clinical and radiologic features were collected at baseline. Longest axial diameter of all BMs was measured on baseline and follow-up MRI, and segmentation was performed for all BMs on baseline MRI. Lesion-level logistic regression analysis and patient-level survival analysis were performed for early BM progression (ie, within 6 months after start of ICIs) and intracranial progression-free survival (PFS), respectively. Results. A total of 82 patients were included with a total of 464 BMs. At baseline, 37.8% of patients had >= 4 BMs and 53.7% of patients had at least one BM with a diameter >= 10 mm. In multivariable analysis on the lesion level, baseline BM diameter was associated with early BM progression (odds ratio 1.10, 95%CI 1.05-1.15, P < .001). On the patient level, having at least one BM >= 10mm was associated with shorter intracranial PFS (hazard ratio 2.08, 95%CI 1.64-5.56, P < .001). Conclusions. Large BM diameter was associated with a higher risk of early progression after the start of ICIs. Therefore, local therapy should be considered for patients who are treated with ICIs and who have melanoma BMs >= 10 mm.

Lorentz invariance is a fundamental symmetry of spacetime and foundational to modern physics. One of its most important consequences is the constancy of the speed of light. This invariance, together with the geometry of spacetime, implies that no particle can move faster than the speed of light. In this article, we present the most stringent neutrino-based test of this prediction, using the highest-energy neutrino ever detected to date, KM3-230213A. If we assume an extragalactic source as the origin, the arrival of this event, with an energy of $$22{0}_{-110}^{+570} \; {\mbox{PeV}}$$ 22 0 − 110 + 570 PeV , sets a constraint on $$\delta \equiv {c}_{\nu }^{2}-1\, < \,4.{2}_{-3.7}^{+9.2}\times 1{0}^{-22}$$ δ ≡ c ν 2 − 1 < 4 . 2 − 3.7 + 9.2 × 1 0 − 22 .

Supplementary Table S1. Representativeness of study participants.

Excel spreadsheets of mass spectrometry analysis

Figure S4. Mutational landscape stratified by cohort.

Supplementary Table S2. Inclusion and exclusion criteria.

Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head-to-head comparison of several techniques to analyze circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in 20 patients with metastatic melanoma. In this study, we investigated whether diagnostic leukapheresis (DLA) combined with multimarker flow cytometry (FCM) increased the detection of CTCs in blood compared to the CellSearch platform. Additionally, we characterized cfDNA at the level of somatic mutations, extent of aneuploidy and genome-wide DNA methylation. Both CTCs and cfDNA measures were compared to tumor markers and extracranial tumor burden on radiological imaging. Compared to the CellSearch method applied on peripheral blood, DLA combined with FCM increased the proportion of patients with detectable CTCs from 35% to 70% (P = 0.06). However, the median percentage of cells that could be recovered by the DLA procedure was 29%. Alternatively, cfDNA mutation and methylation analysis detected tumor load in the majority of patients (90% and 93% of samples successfully analyzed, respectively). The aneuploidy score was positive in 35% of all patients. From all tumor measurements in blood, lactate dehydrogenase (LDH) levels were significantly correlated to variant allele frequency (P = 0.004). Furthermore, the presence of CTCs in DLA was associated with tumor burden (P < 0.001), whereas the presence of CTCs in peripheral blood was associated with number of lesions on radiological imaging (P < 0.001). In conclusion, DLA tended to increase the proportion of patients with detectable CTCs but was also associated with low recovery. Both cfDNA and CTCs were correlated with clinical parameters such as LDH levels and extracranial tumor burden.

Figure S3. Correlation between TML and TMB.

Supplementary Figure S1. Accrual flowchart including reasons for ineligibility.

Supplementary Table S6. Baseline characteristics of all included patients, regardless of evaluability according to protocol definition.

Table S3. Representativeness of study participants.

Excel spreadsheet of differentially expressed genes in CD14+ monocytes

Supplementary Figure S2. Genomic biomarkers of clinical benefit to ICB.

Supplementary Figure S3. Association between immune marker gene expression and clinical benefit to ICB.

AbstractPurpose: The treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid mismatch repair deficiency/microsatellite-instable (dMMR/MSI) tumors, and in-depth biomarker analyses were performed to inform precision immunotherapy approaches. Patients and Methods: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol, a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response or stable disease ≥16 weeks). Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies. Results: A total of 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% [95% confidence interval (CI), 53–70], with an objective response in 45% (95% CI, 36–54). After a median follow-up of 14.5 months (95% CI, 13–19), the median progression-free survival was 18 months (95% CI, 9–not reached), and the median overall survival was not reached. Whereas CB was not, or only weakly, associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, in which markers of adaptive immunity dominated the biomarker landscape. Conclusions: Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of a good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor type–specific biomarkers for guiding immunotherapy.

A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single-center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty-six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty-five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM-free survival since ECM diagnosis was significantly longer (p = .02) in previously treated patients (29.0 [IQR 12.6-57.0] months) compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM-free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC.

Figure S2. Best overall responses for all evaluable patients.