The adaptive Levin method

The Levin method is a classical technique for evaluating oscillatory integrals that operates by solving a certain ordinary differential equation in order to construct an antiderivative of the integrand. It was long believed that the method suffers from ``low-frequency breakdown,'' meaning that the accuracy of the computed integral deteriorates when the integrand is only slowly oscillating. Recently presented experimental evidence suggests that, when a Chebyshev spectral method is used to discretize the differential equation and the resulting linear system is solved via a truncated singular value decomposition, no such phenomenon is observed. Here, we provide a proof that this is, in fact, the case, and, remarkably, our proof applies even in the presence of saddle points. We also observe that the absence of low-frequency breakdown makes the Levin method suitable for use as the basis of an adaptive integration method. We describe extensive numerical experiments demonstrating that the resulting adaptive Levin method can efficiently and accurately evaluate a large class of oscillatory integrals, including many with saddle points

The Impact of Precipitation Regimes on Forest Fires in Yunnan Province, Southwest China

The amount, frequency, and duration of precipitation have important impact on the occurrence and severity of forest fires. To fully understand the effects of precipitation regimes on forest fires, a drought index was developed with number of consecutive dry days (daily precipitation less than 2 mm) and total precipitation, and the relationships of drought and precipitation with fire activities were investigated over two periods (i.e., 1982–1988 and 1989–2008) in five ecoregions of Yunnan Province. The results showed that precipitation regime had a significant relationship with fire activities during the two periods. However, the influence of the drought on fire activities varied by ecoregions, with more impacts in drier ecoregions IV-V and less impacts in the more humid ecoregions I–III. The drought was more closely related to fire activities than precipitation during the two study periods, especially in the drier ecoregions, indicating that the frequency and the duration of precipitation had significant influences on forest fires in the drier areas. Drought appears to offer a better explanation than total precipitation on temporal changes in fire regimes across the five ecoregions in Yunnan. Our findings have significant implications for forecasting the local fire dangers under the future climate change

Prognostic value of neutrophil-to-lymphocyte ratio in breast cancer

AbstractInflammation is an essential component of pathogenesis and progression of cancer. A high neutrophil-to-lymphocyte ratio (NLR) is considered as a prognostic indicator for breast cancer. This meta-analysis was conducted to establish the overall accuracy of the NLR test in the diagnosis of breast cancer. A comprehensive search of the literature was conducted by using PubMed, Web of Science and China National Knowledge Infrastructure (CNKI). Published studies dating up to July 2014 and 4,293 patients were enrolled in the present study. In order to evaluate the association between NLR and overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) or cancer specific survival (CSS), the hazard ratios (HRs) and their 95% confidence intervals (CIs) were extracted. OS was the primary outcome. The results suggested that increased NLR was a strong predictor for OS with HR of 2.28 (95% CI=1.08–4.80, Pheterogeneity<0.001). Stratified analyses indicated that a high NLR appeared to be a negative prognostic marker in Caucasian populations (HR=4.53, 95% CI=3.11–6.60, Pheterogeneity=0.096), multivariate analysis method (HR=2.10, 95% CI=1.52–2.89, Pheterogeneity=0.591), and mixed metastasis (HR=4.53, 95% CI=3.11–6.60, Pheterogeneity=0.096). Elevated NLR was associated with a high risk for DFS (HR=1.38, 95% CI=1.09–1.74, Pheterogeneity=0.050) and in subgroups of multivariate analysis (HR=1.64, 95% CI=1.25–2.14, Pheterogeneity=0.545) and mixed metastasis (HR=1.99, 95% CI=1.28–3.09, Pheterogeneity=0.992). In summary, NLR could be considered as a predictive factor for patients with breast cancer

Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial

Importance: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. // Objective: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. // Design, Setting, and Participants: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy–naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. // Intervention: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. // Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. // Results: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. // Conclusions and Relevance: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. // Trial Registration: ClinicalTrials.gov Identifier: NCT0341277

An Improved Detection of Circulating Tumor DNA in Extracellular Vesicles-Depleted Plasma

Circulating tumor DNA (ctDNA) in plasma has been used as a biomarker for cancer detection and outcome prediction. In this study, we collected the five precipitates (fractions 1–5) and leftover supernatant plasma component (fraction 6) by a sequential centrifugation in plasma samples from nine small cell lung cancer (SCLC) patients. The fractions 3, 5 and 6 were large vesicles, exosomes and extracellular vesicles (EVs)-depleted plasma, respectively. Fragment size analysis using DNAs from these fractions showed dramatical differences from a peak of 7–10 kb in fraction 1 to 140–160 bp in fraction 6. To determine ctDNA content, we performed whole genome sequencing and applied copy number-based algorithm to calculate ctDNA percentage. This analysis showed the highest ctDNA content in EV-depleted plasma (average = 27.22%), followed by exosomes (average = 22.09%) and large vesicles (average = 19.70%). Comparatively, whole plasma, which has been used in most ctDNA studies, showed an average of 23.84% ctDNA content in the same group of patients. To further demonstrate higher ctDNA content in fraction 6, we performed mutational analysis in the plasma samples from 22 non-small cell lung cancer (NSCLC) patients with known EGFR mutations. This analysis confirmed higher mutation detection rates in fraction 6 (14/22) than whole plasma (10/22). This study provides a new insight into potential application of using fractionated plasma for an improved ctDNA detection

Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: Results of a randomized phase III trial

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Eastern asian expert panel opinion: designing clinical trials of molecular targeted therapy for hepatocellular carcinoma

The largest burden of hepatocellular carcinoma (HCC) lies in Asia, secondary to hepatitis B virus (HBV) infection. Improved survival with sorafenib has fostered new research but many challenges remain in designing clinical trials. The disease, its management, and populations affected by it are heterogeneous worldwide and within Asia. An expert conference of Eastern Asian oncologists and hepatologists was convened to foster consensus in clinical trial design. The panel identified key areas that need to be addressed to facilitate clinical trials in Asia. Stratification by viral etiology is desirable within Asia and by region in global trials. Antiviral therapy should also be considered as a stratification factor and incorporated into HCC management in trials. The panel agreed that histological diagnosis is not required for trial entry and that Barcelona-Clinic Liver Cancer (BCLC) staging is acceptable for trials as long as portal hypertension can be better defined with standardized methodology. Consensus in treatment must be sought to allow multi-national trials and it must be recognized that first-line sorafenib is not largely feasible in Asia. Finally, Asian nations must be urged to participate in clinical trials, many of which are ongoing, to advance new treatment options in this challenging disease