Phase-diagram investigation of frustrated 1D and 2D Ising models in OEO-based Ising machine.

Ising machines have emerged as promising solvers for combinatorial optimization problems in recent years. In practice, these problems are often mapped into a frustrated Ising model due to randomness or competing interactions, which reduces the success ratio for finding the optimal solution. In this study, we simulate one-dimensional and two-dimensional frustrated Ising models in an Ising machine based on the optoelectronic oscillator. Our experiment aims to show the relationship between the Fourier mode of the coupling matrix and the spin distribution under frustration. The results prove the validity of the theoretical predictions and provide insights into the behavior of Ising machines in the presence of frustration. We believe it would help to develop a better strategy to improve the performance of Ising machines.

Low spurious optoelectronic oscillator achieved by frequency conversion filtering without deteriorating phase noise.

In order to obtain microwave signals with low spurs and low phase noise, we studied the residual phase noise of the frequency-conversion filtering oscillator and methods to improve its phase noise performance. We first analyze the influence of the dispersion of the intermediate frequency (IF) filter on the residual phase noise in the frequency conversion filtering process. Then, we use an electro-optic modulator to achieve up-conversion in the frequency conversion filtering and extend the intra-cavity delay with an optical fiber after the modulator. This allows the optoelectronic oscillator (OEO) to improve the phase noise performance while having a good suppression of spurs. The spurs suppression ratio of the proposed OEO is 80 dB with a fiber of about 1.6 km in the cavity. The phase noise of the proposed OEO is -130 dBc/Hz at 10 kHz offset from 10 GHz, which is 10 dB lower than our previous work.

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma.

This phase 1b/2, multicenter, open-label study evaluated ibrutinib plus durvalumab in relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). Patients were treated with once-daily ibrutinib 560 mg plus durvalumab 10 mg/kg every 2 weeks in 28-day cycles in phase 1b without dose-limiting toxicities, confirming the phase 2 dosing. Sixty-one patients with FL (n = 27), germinal center B-cell (GCB) DLBCL (n = 16), non-GCB DLBCL (n = 16), and unspecified DLBCL (n = 2) were treated. Overall response rate (ORR) was 25% in all patients, 26% in patients with FL, 13% in patients with GCB DLBCL, and 38% in patients with non-GCB DLBCL. Overall, median progression-free survival was 4.6 months and median overall survival was 18.1 months; both were longer in patients with FL than in patients with DLBCL. The most frequent treatment-emergent adverse events (AEs) in patients with FL and DLBCL, respectively, were diarrhea (16 [59%]; 16 [47%]), fatigue (12 [44%]; 16 [47%]), nausea (9 [33%]; 12 [35%]), peripheral edema (7 [26%]; 13 [38%]), decreased appetite (8 [30%]; 11 [32%]), neutropenia (6 [22%]; 11 [32%]), and vomiting (5 [19%]; 12 [35%]). Investigator-defined immune-related AEs were reported in 12/61 (20%) patients. Correlative analyses were conducted but did not identify any conclusive biomarkers of response. In FL, GCB DLBCL, and non-GCB DLBCL, ibrutinib plus durvalumab demonstrated similar activity to single-agent ibrutinib with the added toxicity of the PD-L1 blockade; the combination resulted in a safety profile generally consistent with those known for each individual agent.

A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors.

BACKGROUND: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. METHODS: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. RESULTS: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). CONCLUSIONS: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.

Statistical designs for early phases of cancer clinical trials.

The main purpose of a Phase I trial of a new antitumor agent is to determine the appropriate dosing regimen and characterize the safety profile of a new molecular or monoclonal antibody. Phase II cancer clinical trials are conducted to assess the efficacy of a new anticancer therapy and to determine whether it has sufficient activity against a specific type of tumor to warrant further development. In this paper, commonly used statistical designs, based on either frequentist approaches or Bayesian methods, for Phase I and Phase II cancer clinical trials are reviewed and discussed. Future directions of designing more efficient trial are explored.

Large-scale coherent Ising machine based on optoelectronic parametric oscillator.

Ising machines based on analog systems have the potential to accelerate the solution of ubiquitous combinatorial optimization problems. Although some artificial spins to support large-scale Ising machines have been reported, e.g., superconducting qubits in quantum annealers and short optical pulses in coherent Ising machines, the spin stability is fragile due to the ultra-low equivalent temperature or optical phase sensitivity. In this paper, we propose to use short microwave pulses generated from an optoelectronic parametric oscillator as the spins to implement a large-scale Ising machine with high stability. The proposed machine supports 25,600 spins and can operate continuously and stably for hours. Moreover, the proposed Ising machine is highly compatible with high-speed electronic devices for programmability, paving a low-cost, accurate, and easy-to-implement way toward solving real-world optimization problems.

Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma.

PURPOSE: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. METHODS: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers. RESULTS: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response. CONCLUSION: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.

Optoelectronic parametric oscillator.

Oscillators are one of the key elements in various applications as a signal source to generate periodic oscillations. Among them, an optical parametric oscillator (OPO) is a driven harmonic oscillator based on parametric frequency conversion in an optical cavity, which has been widely investigated as a coherent light source with an extremely wide wavelength tuning range. However, steady oscillation in an OPO is confined by the cavity delay, which leads to difficulty in frequency tuning, and the frequency tuning is discrete with the minimum tuning step determined by the cavity delay. Here, we propose and demonstrate a counterpart of an OPO in the optoelectronic domain, i.e., an optoelectronic parametric oscillator (OEPO) based on parametric frequency conversion in an optoelectronic cavity to generate microwave signals. Owing to the unique energy-transition process in the optoelectronic cavity, the phase evolution in the OEPO is not linear, leading to steady single-mode oscillation or multimode oscillation that is not bounded by the cavity delay. Furthermore, the multimode oscillation in the OEPO is stable and easy to realize owing to the phase control of the parametric frequency-conversion process in the optoelectronic cavity, while stable multimode oscillation is difficult to achieve in conventional oscillators such as an optoelectronic oscillator (OEO) or an OPO due to the mode-hopping and mode-competition effect. The proposed OEPO has great potential in applications such as microwave signal generation, oscillator-based computation, and radio-frequency phase-stable transfer.