Definition of the Prognostic Role of MGMT Promoter Methylation Value by Pyrosequencing in Newly Diagnosed IDH Wild‐Type Glioblastoma Patients Treated with Radiochemotherapy: A Large Multicenter Study

Background. O6‐methylguanine (O6‐MeG)‐DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild‐type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) ≤2, and radio‐chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time‐dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut‐off of 15% for MGMT methylation. The 2‐year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p <0.00001). However, we also found a non‐linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0–4%, 18.9 months for MGMT in 4–40%, and 29.9 months for MGMT in 40– 100%. Conclusions. Our findings suggested a non‐linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild‐type glioblastoma patients treated with chemoradiotherapy

Bimodal Approach for Noise Figures of Merit Evaluation in Quantum-Limited Josephson Traveling Wave Parametric Amplifiers

The advent of ultra-low noise microwave amplifiers revolutionized several research fields demanding quantum-limited technologies. Exploiting a theoretical bimodal description of a linear phase-preserving amplifier, in this contribution we analyze some of the intrinsic properties of a model architecture (i.e., an rf-SQUID based Josephson Traveling Wave Parametric Amplifier) in terms of amplification and noise generation for key case study input states (Fock and coherents). Furthermore, we present an analysis of the output signals generated by the parametric amplification mechanism when thermal noise fluctuations feed the device.Comment: 5 pages, 6 figure

Experimental Characterization of RF-SQUIDs Based Josephson Traveling Wave Parametric Amplifier Exploiting Resonant Phase Matching Scheme

This study presents recent advancements in Josephson Traveling Wave Parametric Amplifiers (JTWPAs) developed and tested at Istituto Nazionale di Ricerca Metrologica within the Detector Array Readout with Traveling Wave AmplifieRS project framework. Combining Josephson junctions with superconducting coplanar waveguides, JTWPAs offer advanced capabilities for quantum-limited broadband microwave amplification and the emission of non-classical microwave radiation. The work delves into the architecture, optimization, and experimental characterization of a JTWPA with a Resonant Phase-Matching mechanism, highlighting signal gains and idler conversion factors in relation to pump power and signal frequency

Real-Life Clinical Data of Cabozantinib for Unresectable Hepatocellular Carcinoma

Introduction: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4-14.8) and 5.1 (3.3-6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3-4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials

Detector Array Readout with Traveling Wave Amplifiers

Reducing noise to the quantum limit over a large bandwidth is a fundamental requirement for future applications operating at millikelvin temperatures, such as the neutrino mass measurement, the next-generation X-ray observatory, the CMB measurement, the dark matter and axion detection, and the rapid high-fidelity readout of superconducting qubits. The read out sensitivity of arrays of microcalorimeter detectors, resonant axion-detectors, and qubits, is currently limited by the noise temperature and bandwidth of the cryogenic amplifers. The Detector Array Readout with Traveling Wave Amplifers project has the goal of developing high-performing innovative traveling wave parametric amplifers with a high gain, a high saturation power, and a quantum-limited or nearly quantum-limited noise. The practical development follows two diferent promising approaches, one based on the Josephson junctions and the other one based on the kinetic inductance of a high-resistivity superconductor. In this contribution, we present the aims of the project, the adopted design solutions and preliminary results from simulations and measurements

Broadband Parametric Amplification in DARTWARS

Superconducting parametric amplifiers offer the capability to amplify feeble signals with extremely low levels of added noise, potentially reaching quantum-limited amplification. This characteristic makes them essential components in the realm of high-fidelity quantum computing and serves to propel advancements in the field of quantum sensing. In particular, Traveling-Wave Parametric Amplifiers (TWPAs) may be especially suitable for practical applications due to their multi-Gigahertz amplification bandwidth, a feature lacking in Josephson Parametric Amplifiers (JPAs), despite the latter being a more established technology. This paper presents recent developments of the DARTWARS (Detector Array Readout with Traveling Wave AmplifieRS) project, focusing on the latest prototypes of Kinetic Inductance TWPAs (KITWPAs). The project aims to develop a KITWPA capable of achieving 20 dB of amplification. To enhance the production yield, the first prototypes were fabricated with half the length and expected gain of the final device. In this paper, we present the results of the characterization of one of the half-length prototypes. The measurements revealed an average amplification of approximately 9 dB across a 2 GHz bandwidth for a KITWPA spanning 17 mm in length

Progress in the development of a KITWPA for the DARTWARS project

DARTWARS (Detector Array Readout with Traveling Wave AmplifieRS) is a three years project that aims to develop high-performing innovative Traveling Wave Parametric Amplifiers (TWPAs) for low temperature detectors and qubit readout (C-band). The practical development follows two different promising approaches, one based on the Josephson junctions (TWJPA) and the other one based on the kinetic inductance of a high-resistivity superconductor (KITWPA). This paper presents the advancements made by the DARTWARS collaboration to produce a first working prototype of a KITWPA.Comment: 3 pages, 4 figures. Proceeding of Pisa15th Meeting conferenc

Nonlinear Behavior of Josephson Traveling Wave Parametric Amplifiers

Recent advancements in quantum technologies and advanced detection experiments have underscored the pressing need for the detection of exceedingly weak signals within the microwave frequency spectrum. Addressing this challenge, the Josephson Traveling Wave Parametric Amplifier (JTWPA) has been proposed as a cryogenic front-end amplifier capable of approaching the quantum noise limit while providing a relevant bandwidth. This research is centered on a comprehensive numerical investigation of the JTWPA, without resorting to simplifications regarding the nonlinearity of the essential components. Specifically, this study focuses on a thorough examination of the system, characterized by coupled nonlinear differential equations representing all components of the device. Proper input and output signals at the device's boundaries are considered. The analysis of the output signals undergoing the parametric amplification process involves a detailed exploration of phase-space dynamics and Fourier spectral analysis of the output voltage. This study is conducted while considering the parameters ruling the response of the device under pump and signal excitations. In addition to the expected signal amplification, the findings reveal that the nonlinear nature of the system can give rise to unforeseen phenomena, depending on the system's operational conditions, which include: the generation of pump tone harmonics, modulation of the signal gain, and incommensurate frequency generation effects that are not easily accommodated by simplistic linearized approaches

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk