STEEL: Singularity-aware Reinforcement Learning

Batch reinforcement learning (RL) aims at leveraging pre-collected data to find an optimal policy that maximizes the expected total rewards in a dynamic environment. Nearly all existing algorithms rely on the absolutely continuous assumption on the distribution induced by target policies with respect to the data distribution, so that the batch data can be used to calibrate target policies via the change of measure. However, the absolute continuity assumption could be violated in practice (e.g., no-overlap support), especially when the state-action space is large or continuous. In this paper, we propose a new batch RL algorithm without requiring absolute continuity in the setting of an infinite-horizon Markov decision process with continuous states and actions. We call our algorithm STEEL: SingulariTy-awarE rEinforcement Learning. Our algorithm is motivated by a new error analysis on off-policy evaluation, where we use maximum mean discrepancy, together with distributionally robust optimization, to characterize the error of off-policy evaluation caused by the possible singularity and to enable model extrapolation. By leveraging the idea of pessimism and under some mild conditions, we derive a finite-sample regret guarantee for our proposed algorithm without imposing absolute continuity. Compared with existing algorithms, by requiring only minimal data-coverage assumption, STEEL significantly improves the applicability and robustness of batch RL. Extensive simulation studies and one real experiment on personalized pricing demonstrate the superior performance of our method in dealing with possible singularity in batch RL

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas

Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC

Extracorporeal Photopheresis for Steroid-refractory Chronic Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Aim: Recently, extracorporeal photopheresis (ECP) has become a promising therapeutic approach for steroid-refractory chronic graft-versus-host disease (cGVHD) because of its advantage over other therapies. The mechanism of action in ECP still remains to be elucidated. To investigate the evidence for clinical efficacy of ECP in the treatment of steroid-refractory cGVHD, we conducted a systematic search and meta-analysis comprising several databases and abstracts presented at recent annual meetings in the field. Methods: A systematic review of publications indexed in the PubMed, Embase, the Cochrane-controlled trials registry, the Cochrane Library, and ISI Web of knowledge were performed on January 10, 2015. Eight studies including 176 patients were identified. Meta-analyses were carried out to calculate the overall response rate (ORR) and complete response rate (CRR) of cGVHD and the organ-specific responses. Results: In patients with cGVHD, pooled ORR and CRR were 0.66 and 0.46, respectively, with organ-specific responses of 0.80 for skin, 0.79 for gut, 0.57 for oral mucosa, 0.57 for liver, 0.50 for eye, and 0.46 for joint involvement. Conclusion: The present analysis revealed a promising clinical benefit of ECP for patients with steroid-refractory cGVHD. Further prospective trials with larger cohorts are mandatory

Effect of Sodium Pyrophosphate on the Reverse Flotation of Dolomite from Apatite

In this study, the effect of sodium pyrophosphate (NaPP) on the separation of apatite from dolomite by flotation was systematically investigated. Flotation results revealed that NaPP could selectively depress the flotation of apatite, thus realizing the separation of apatite from dolomite. Further, the selective depression mechanism of NaPP was studied through zeta potential measurements, contact angle measurements, and X-ray photoelectron spectroscopy (XPS) analysis. The results demonstrated that the adsorption of sodium oleate (NaOL) onto apatite surface was depressed by the preferential interaction of NaPP with active Ca sites. For dolomite, while the presence of NaPP hindered the interaction of NaOL with active Ca sites, it appeared to enhance the reactivity with active Mg sites. Thus, the adsorption of NaOL onto dolomite surface was hardly influenced. In this way, the separation of apatite from dolomite was achieved

Effect of iodine value of sodium fatty acids on flotation of collophanite

The sodium fatty acids were firstly prepared by fatty acids with different iodine values which were from surfactant extraction using soybean oil fatty acid as raw material in this study. Effects of iodine value of sodium fatty acids on the flotation of collophanite were then investigated by flotation tests, contact angle measurements, adsorption tests, Krafft point measurements, foaming ability tests, and the resistance to the hard water measurements. Results show that the final flotation recovery was directly proportional to the iodine value of sodium fatty acid. Sodium fatty acid with higher iodine value has higher solubility and dispersity in the solutions, and stronger foaming ability and resistance to hard water. After interacting with collophanite, sodium fatty acid with higher iodine value made the mineral more hydrophobic, thus contributing to better flotation performances

Derived Neutrophil-Lymphocyte Ratio and C-Reactive Protein as Prognostic Factors for Early-Stage Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiation Therapy

Objectives: To explore the relationship between peripheral blood inflammation parameters and overall survival (OS) and progression-free survival (PFS) of early-stage non-small cell lung cancer patients who underwent stereotactic body radiotherapy (SBRT). Patients and methods: In this study, eligible patients treated with SBRT from 2013 to 2018, and both serum complete blood count and blood biochemical results were available prior to (within 60 days) radiotherapy were included. Results: A review of hospital registries identified 148 patients, and the 5-year OS and PFS of the entire cohort were 69.8% and 65.6%, respectively, with the median follow-up time was 52.8 months. Multivariable analysis showed that derived neutrophil-lymphocyte ratio (dNLR) ≥1.4 and C-reactive protein (CRP) ≥2.9 were statistically and independently associated with worse OS (HR = 4.62, 95% CI 1.89–11.27, p = 0.001; HR = 2.92, 95% CI 1.49–5.70, p = 0.002, respectively). The 5-year OS for patients with dNLR below and equal to or above the 1.4 were 85.3% and 62.9% (p = 0.002), respectively, and 76.7% for the low CRP group versus 58.5% for the high CRP group (p = 0.030). Higher serum level of post-treatment CRP also independent parameters for inferior PFS (HR = 4.83, 95% CI 1.28–18.25, p = 0.020). Conclusions: Our results demonstrate that dNLR and CRP are associated with the outcomes of early-stage NSCLC patients treated with SBRT, which may assist in selecting optimal nursing care and therapeutic scheme for every individual

Comparison of stereotactic body radiation therapy versus surgery for multiple primary lung cancers after prior radical resection: A multicenter retrospective study

Background: Patients who previously underwent surgical resection of initial primary lung cancer are at a high risk of developing multiple primary lung cancers (MPLCs). The purpose of this study was to compare the efficacy and safety between stereotactic body radiation therapy (SBRT) and surgery for MPLCs patients after prior radical resection for the first lung cancers. Methods: In this multicenter retrospective study, eligible MPLC patients with tumor diameter of 5.0 cm or less at N0M0 who underwent SBRT or reoperation between January 2013 and August 2020 were enrolled. The primary endpoint was the 3-year locoregional recurrence and treatment-related toxicity. Kaplan-Meier method was used to calculate survival rates. The χ2 test was adapted to assess the difference of categorical variables between the two subgroup patients. Results: A total of 203 (73 in the SBRT group and 130 in the surgery group) patients from three academic cancer centers were evaluated with a median follow-up of 38.3 months. The cumulative 1-, 2-, and 3-year incidences of locoregional recurrence were 5.6 %, 7.0 % and 13.1 % in the SBRT group versus 3.2 %, 4.8 % and 7.4 % in the surgery group, respectively [hazard ratio (HR), 1.97; 95 % confidence interval (CI), 0.74–5.24; P = 0.14]. The cancer-specific survival rates were 95.9 %, 94.5 % and 88.1 % versus 96.9 %, 94.6 % and 93.8 % in the SBRT and surgery groups respectively (HR, 1.72; 95 % CI, 0.67–4.44; P = 0.23). In the SBRT group, two patients (2.7 %) suffered from grade 3 radiation pneumonitis, while in the surgery group, grade 3 complications occurred in four (3.1 %) patients, and four cases were expired due to pneumonia or pulmonary heart disease within 90 days after surgery. Conclusions: SBRT is an effective therapeutic option with limited toxicity compared to surgery for patients with MPLCs after prior radical surgical resection, and it could be considered as an alternative treatment for those patients

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T‐cell receptor sequencing

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole‐exome sequencing (WES) and T‐cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non‐silent mutations from multi‐samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi‐cancers. IHC using antibodies against CD4, CD8, and PD‐L1 demonstrated scant T‐cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T‐cell clones shared across tumor regions in any of the patients, while over 94% of T‐cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi‐regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T‐cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma