Machine learning algorithms to predict colistin-induced nephrotoxicity from electronic health records in patients with multidrug-resistant Gram-negative infection.

OBJECTIVES: Colistin-induced nephrotoxicity prolongs hospitalisation and increases mortality. The study aimed to construct machine learning models to predict colistin-induced nephrotoxicity in patients with multidrug-resistant Gram-negative infection. METHODS: Patients receiving colistin from three hospitals in the Clinical Research Database were included. Data were divided into a derivation cohort (2011-2017) and a temporal validation cohort (2018-2020). Fifteen machine learning models were established by categorical boosting, light gradient boosting machine and random forest. Classifier performances were compared by the sensitivity, F1 score, Matthews correlation coefficient (MCC), area under the receiver operating characteristic (AUROC) curve, and area under the precision-recall curve (AUPRC). SHapley Additive exPlanations plots were drawn to understand feature importance and interactions. RESULTS: The study included 1392 patients, with 360 (36.4%) and 165 (40.9%) experiencing nephrotoxicity in the derivation and temporal validation cohorts, respectively. The categorical boosting with oversampling achieved the highest performance with a sensitivity of 0.860, an F1 score of 0.740, an MCC of 0.533, an AUROC curve of 0.823, and an AUPRC of 0.737. The feature importance demonstrated that the days of colistin use, cumulative dose, daily dose, latest C-reactive protein, and baseline haemoglobin were the most important risk factors, especially for vulnerable patients. A cutoff colistin dose of 4.0 mg/kg body weight/d was identified for patients at higher risk of nephrotoxicity. CONCLUSIONS: Machine learning techniques can be an early identification tool to predict colistin-induced nephrotoxicity. The observed interactions suggest a modification in dose adjustment guidelines. Future geographic and prospective validation studies are warranted to strengthen the real-world applicability.

Heart Rate Estimation from Facial Image Sequences of a Dual-Modality RGB-NIR Camera.

This paper presents an RGB-NIR (Near Infrared) dual-modality technique to analyze the remote photoplethysmogram (rPPG) signal and hence estimate the heart rate (in beats per minute), from a facial image sequence. Our main innovative contribution is the introduction of several denoising techniques such as Modified Amplitude Selective Filtering (MASF), Wavelet Decomposition (WD), and Robust Principal Component Analysis (RPCA), which take advantage of RGB and NIR band characteristics to uncover the rPPG signals effectively through this Independent Component Analysis (ICA)-based algorithm. Two datasets, of which one is the public PURE dataset and the other is the CCUHR dataset built with a popular Intel RealSense D435 RGB-D camera, are adopted in our experiments. Facial video sequences in the two datasets are diverse in nature with normal brightness, under-illumination (i.e., dark), and facial motion. Experimental results show that the proposed method has reached competitive accuracies among the state-of-the-art methods even at a shorter video length. For example, our method achieves MAE = 4.45 bpm (beats per minute) and RMSE = 6.18 bpm for RGB-NIR videos of 10 and 20 s in the CCUHR dataset and MAE = 3.24 bpm and RMSE = 4.1 bpm for RGB videos of 60-s in the PURE dataset. Our system has the advantages of accessible and affordable hardware, simple and fast computations, and wide realistic applications.

Urine Galectin-3 binding protein reflects nephritis activity in systemic lupus erythematosus.

BACKGROUND: Lupus nephritis (LN) is a major and severe organ involvement in systemic lupus erythematosus (SLE), whose diagnosis and treatment necessitate to perform kidney biopsy, which is an invasive procedure. Non-invasive urine biomarkers are an active area of investigation to support LN diagnosis and management. OBJECTIVE: To investigate the role of urinary galectin-3 binding protein (u-Gal-3BP) as a candidate biomarker of renal disease in biopsy proven LN. PATIENTS AND METHODS: Levels of u-Gal-3BP were investigated in a cross-sectional fashion by ELISA in 270 subjects: 86 LN patients, 63 active SLE patients with no kidney involvement, 73 SLE patients with inactive disease and 48 age and sex-matched population-based controls (PBC). Moreover, urine samples were analysed separately by ELISA for additional markers of kidney pathology: neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule-1 (KIM-1) and galectin-3 (Gal-3). The concentrations of all studied molecules were normalized to urine creatinine levels. In 10 patients, post-treatment levels of the biomarkers were measured. RESULTS: Normalized u-Gal-3BP levels were higher in LN patients compared to the other groups (p < .0001). Comparing different LN classes, u-Gal-3BP levels were higher among patients with proliferative (class III/IV) and membranous (class V) as compared to mesangial (class II) forms (p = .04). In proliferative forms, u-Gal-3BP levels correlated with the activity index in renal biopsies (r = 0.42, p = .004). Moreover, in a subset of 10 patients with repeated kidney biopsy and urine sampling before and after induction treatment, a significant decrease of u-Gal-3BP was observed (p = .03). Among the other markers, KIM-1 was also able to discriminate LN from the other groups, while NGAL, OPN and Gal-3 could not in this cohort. CONCLUSION: Given its ability to discriminate LN patients from active non-renal and inactive SLE patients, the observed correlation with the activity index in renal biopsies, and its levels declining following treatment, u-Gal-3BP shows promise as a non-invasive urinary biomarker to help detecting and to monitor renal involvement in SLE patients and should be validated in larger cohorts.

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia.

Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.

Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant.

Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have an extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLIs) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), -15, and -18 to generate memory-like (ML) NK cells with enhanced antileukemia responses. We treated 9 pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells in a phase 1 trial. Patients received fludarabine, cytarabine, and filgrastim followed 2 weeks later by infusion of donor lymphocytes and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical and matched-related and -unrelated donors. After infusion, donor-derived ML NK cells expanded and maintained an ML multidimensional mass cytometry phenotype for >3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered interferon-γ production. After DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for >3 months, with 1 patient in remission for >2 years. No significant toxicity was experienced. This study demonstrates that, in a compatible post-HCT immune environment, donor ML NK cells robustly expand and persist with potent antileukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://clinicaltrials.gov as #NCT03068819.

Non-KREEP origin for Chang'e-5 basalts in the Procellarum KREEP Terrane.

Mare volcanics on the Moon are the key record of thermo-chemical evolution throughout most of lunar history1-3. Young mare basalts-mainly distributed in a region rich in potassium, rare-earth elements and phosphorus (KREEP) in Oceanus Procellarum, called the Procellarum KREEP Terrane (PKT)4-were thought to be formed from KREEP-rich sources at depth5-7. However, this hypothesis has not been tested with young basalts from the PKT. Here we present a petrological and geochemical study of the basalt clasts from the PKT returned by the Chang'e-5 mission8. These two-billion-year-old basalts are the youngest lunar samples reported so far9. Bulk rock compositions have moderate titanium and high iron contents  with KREEP-like rare-earth-element and high thorium concentrations. However, strontium-neodymium isotopes indicate that these basalts were derived from a non-KREEP mantle source. To produce the high abundances of rare-earth elements and thorium, low-degree partial melting and extensive fractional crystallization are required. Our results indicate that the KREEP association may not be a prerequisite for young mare volcanism. Absolving the need to invoke heat-producing elements in their source implies a more sustained cooling history of the lunar interior to generate the Moon's youngest melts.

Sub-basin scale inhomogeneity of mantle in the South China Sea revealed by magnesium isotopes.

The South China Sea (SCS) is the largest extensional basin in the western Pacific and was formed after rifting of the Euro-Asian continental margin. The nature of its underlying mantle remains enigmatic due to the lack of sampling of the seafloor's igneous crust. The International Ocean Discovery Program Expedition 349 cored seafloor basalts of the southwestern (Site U1433) and eastern (Site U1431) SCS sub-basins. The recovered basalt samples exhibit different source lithologies and geochemistries. The Mg isotopic compositions of seafloor basalts from these sites were investigated to elucidate the origin of this large-scale mantle inhomogeneity. Results indicate that the Site U1431 basalts have a mantle-like average δ26Mg value of -0.27‰ ± 0.06‰ (2SD; n = 10). Together with inhomogeneous Sr-Nd-Pb-Hf isotopic compositions, the Site U1433 basalts have an average δ26Mg value (-0.20‰ ± 0.06‰; 2SD; n = 8) higher than those of the Site U1431 basalts and normal mantle. Their heavier Mg isotopic compositions and low 206Pb/204Pb ratios (~17.7) indicate that the Site U1433 basalts were affected by the re-melting of detached continental-arc lithosphere in the sub-ridge mantle. The coupling of Mg and Sr-Nd isotopes provides robust evidence that the mantle-like δ26Mg values of the Site U1431 basalts resulted from mixing between detached continental arc lithosphere and the nearby Hainan plume, with respective supra- and sub-normal δ26Mg values. From the perspective of Mg isotope, the mantles of the southwestern and eastern sub-basins are compositionally inhomogeneous, with their mantle evolutionary histories being distinct.

Diagnosing intake and rationalizing toxicities associated with 5F-MDMB-PINACA and 4F-MDMB-BINACA abuse.

5F-MDMB-PINACA and 4F-MDMB-BINACA are synthetic cannabinoids (SCs) that elicit cannabinoid psychoactive effects. Defining pharmacokinetic-pharmacodynamic (PK-PD) relationships governing SCs and their metabolites are paramount to investigating their in vivo toxicological outcomes. However, the disposition kinetics and cannabinoid receptor (CB) activities of the primary metabolites of SCs are largely unknown. Additionally, reasons underlying the selection of ester hydrolysis metabolites (EHMs) as urinary biomarkers are often unclear. Here, metabolic reaction phenotyping was performed to identify key metabolizing enzymes of the parent SCs. Hepatic clearances of parent SCs and their EHMs were estimated from microsomal metabolic stability studies. Renal clearances were simulated using a mechanistic kidney model incorporating in vitro permeability and organic anionic transporter 3 (OAT3)-mediated uptake data. Overall clearances were considered in tandem with estimated volumes of distribution for in vivo biological half-lives (t1/2) predictions. Interactions of the compounds with CB1 and CB2 were investigated using a G-protein coupled receptor activation assay. We demonstrated that similar enzymatic isoforms were implicated in the metabolism of 5F-MDMB-PINACA and 4F-MDMB-BINACA. Our in vivo t1/2 determinations verified the rapid elimination of parent SCs and suggest prolonged circulation of their EHMs. The pronounced attenuation of the potencies and efficacies of the metabolites against CB1 and CB2 further suggests how toxic manifestations of SC abuse are likely precipitated by augmented exposure to parent SCs. Notably, basolateral OAT3-mediated uptake of the EHMs substantiates their higher urinary abundance. These novel insights underscore the importance of mechanistic, quantitative and systematic characterization of PK-PD relationships in rationalizing the toxicities of SCs.

Probing the Neutron Skin with Ultrarelativistic Isobaric Collisions.

Particle production in ultrarelativistic heavy ion collisions depends on the details of the nucleon density distributions in the colliding nuclei. We demonstrate that the charged hadron multiplicity distributions in isobaric collisions at ultrarelativistic energies provide a novel approach to determine the poorly known neutron density distributions and thus the neutron skin thickness in finite nuclei, which can in turn put stringent constraints on the nuclear symmetry energy.

Natural Clinopyroxene Reference Materials for in situ Sr Isotopic Analysis via LA-MC-ICP-MS.

Clinopyroxene is a major host mineral for lithophile elements in the mantle lithosphere, and therefore, its origin is vital for constraints on mantle evolution and melt generation. In situ Sr isotopic measurement of clinopyroxene has been available since the recent development of laser ablation multicollector inductively coupled plasma mass spectrometry (LA-MC-ICP-MS) in the 2000s. Therefore, there is an increasing demand for natural clinopyroxene reference materials for Sr isotope microanalysis. In this contribution, we present six natural clinopyroxene reference materials from South Africa (JJG1424) and China (YY09-47, YY09-04, YY09-24, YY12-01, and YY12-02) for Sr isotope microanalysis. The Sr content of these clinopyroxenes ranges from 50 to 340 µg g-1, which covers most natural clinopyroxene compositions. Homogeneity of these potential reference materials were investigated and evaluated in detail over a 2-year period using 193-nm nanosecond and 257-nm femtosecond laser systems coupled to either a Neptune or Neptune Plus MC-ICP-MS. Additionally, the major and trace element of these clinopyroxenes were examined by electron probe microanalyzer (EPMA) as well as solution and laser ICP-MS. The in situ 87Sr/86Sr values obtained for the six natural clinopyroxene reference materials agree well with data obtained using the thermal ionization mass spectrometer (TIMS) method. The Sr isotopic stability and homogeneity of these clinopyroxenes make them potential reference materials for in situ Sr microanalysis to correct instrumental fractionation or as quality control materials for analytical sessions. The new Sr isotope data provided here might be beneficial for microbeam analysis in the geochemical community.

Targeting the KDM4B-AR-c-Myc axis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer.

The histone demethylase KDM4B functions as a key co-activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti-androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next-generation anti-androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide-resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c-Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA, which regulates the sensitivity to next-generation AR-targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c-Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti-androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR-dependent c-Myc expression and overcome resistance to AR-targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The ubiquitinase ZFP91 promotes tumor cell survival and confers chemoresistance through FOXA1 destabilization.

The forkhead box A1 (FOXA1), one of the forkhead class of DNA-binding proteins, functions as a transcription factor and plays a vital role in cellular control of embryonic development and cancer progression. Downregulation of FOXA1 has reported in several types of cancer, which contributes to cancer cell survival and chemoresistance. However, the mechanism for FOXA1 downregulation in cancer remains unclear. Here, we report that the ubiquitination enzyme zinc finger protein 91 (ZFP91) ubiquitinates and destabilizes FOXA1, which promotes cancer cell growth. High level of ZFP91 expression correlates with low level of FOXA1 protein in human gastric cancer (GC) cell lines and patient samples. Furthermore, ZFP91 knockdown reduces FOXA1 polyubiquitination, which decreases FOXA1 turnover and enhances cellular sensitivity to chemotherapy. Taken together, our findings reveal ZFP91-FOXA1 axis plays an important role in promoting GC progression and provides us a potential therapeutic intervention in the treatment of GC.

STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling.

Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48-linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.

Multi-Focus Image Fusion and Depth Map Estimation Based on Iterative Region Splitting Techniques.

In this paper, a multi-focus image stack captured by varying positions of the imaging plane is processed to synthesize an all-in-focus (AIF) image and estimate its corresponding depth map. Compared with traditional methods (e.g., pixel- and block-based techniques), our focus-based measures are calculated based on irregularly shaped regions that have been refined or split in an iterative manner, to adapt to different image contents. An initial all-focus image is first computed, which is then segmented to get a region map. Spatial-focal property for each region is then analyzed to determine whether a region should be iteratively split into sub-regions. After iterative splitting, the final region map is used to perform regionally best focusing, based on the Winner-take-all (WTA) strategy, i.e., choosing the best focused pixels from image stack. The depth image can be easily converted from the resulting label image, where the label for each pixel represents the image index from which the pixel with the best focus is chosen. Regions whose focus profiles are not confident in getting a winner of the best focus will resort to spatial propagation from neighboring confident regions. Our experiments show that the adaptive region-splitting algorithm outperforms other state-of-the-art methods or commercial software in synthesis quality (in terms of a well-known Q metric), depth maps (in terms of subjective quality), and processing speed (with a gain of 17.81~40.43%).

Quantitative Multiplex Immunoassay for Profiling Bone Turnover Biomarkers in Human Bone Tissue Culture Supernatants.

Bone is a metabolically dynamic tissue that is continuously built up and broken down through anabolic and catabolic processes regulated by a variety of systemic and local signaling molecules. Here, we describe quantitative multiplex immunoassay analysis of supernatants collected from cultured human bone tissue fragments to profile local factors associated with the bone turnover process.

Recycled ancient ghost carbonate in the Pitcairn mantle plume.

The extreme Sr, Nd, Hf, and Pb isotopic compositions found in Pitcairn Island basalts have been labeled enriched mantle 1 (EM1), characterizing them as one of the isotopic mantle end members. The EM1 origin has been vigorously debated for over 25 years, with interpretations ranging from delaminated subcontinental lithosphere, to recycled lower continental crust, to recycled oceanic crust carrying ancient pelagic sediments, all of which may potentially generate the requisite radiogenic isotopic composition. Here we find that δ26Mg ratios in Pitcairn EM1 basalts are significantly lower than in normal mantle and are the lowest values so far recorded in oceanic basalts. A global survey of Mg isotopic compositions of potentially recycled components shows that marine carbonates constitute the most common and typical reservoir invariably characterized by extremely low δ26Mg values. We therefore infer that the subnormal δ26Mg of the Pitcairn EM1 component originates from subducted marine carbonates. This, combined with previously published evidence showing exceptionally unradiogenic Pb as well as sulfur isotopes affected by mass-independent fractionation, suggests that the Pitcairn EM1 component is most likely derived from late Archean subducted carbonate-bearing sediments. However, the low Ca/Al ratios of Pitcairn lavas are inconsistent with experimental evidence showing high Ca/Al ratios in melts derived from carbonate-bearing mantle sources. We suggest that carbonate-silicate reactions in the late Archean subducted sediments exhausted the carbonates, but the isotopically light magnesium of the carbonate was incorporated in the silicates, which then entered the lower mantle and ultimately became the Pitcairn plume source.

The composition and variation of the BCR CDR3s in gastric cancer.

Gastric cancer (GC) is the fourth most common type of cancer and the second most common cause of cancer-associated mortality worldwide. B cell-associated autoantibodies against tumor-associated antigens are attractive biomarkers for the development of noninvasive serological tests for the early detection of cancer. This is due to their specificity and stability in the sera. In the present study multiplex polymerase chain reaction and Illumina high-throughput sequencing (HTS) was used to study the composition and variation of the B cell receptor (BCR) complimentary-determining region 3 (CDR3) in GC. The peripheral blood, cancer tissues and peri-cancer tissues were included from 7 patients with GC. On average there was a total of 403,959 CDR3 sequences, with 72,367 unique CDR3 nt sequences and 61,709 unique CDR3 aa sequences per sample identified, which are critical for further understanding the BCR repertoire in GC. The details of GC CDR3s may accelerate the screening process for possible new autoantigens and may provide additional information necessary for generating effective B cell targeted diagnosis and therapeutic strategies.

BAG2 Overexpression Correlates with Growth and Poor Prognosis of Esophageal Squamous Cell Carcinoma.

Previous studies have suggested that Bcl2-associated athanogene 2 (BAG2) serves as a crucial regulator for tumorigenesis in multiple tumors. However, little is known about the effect of BAG2 on esophageal squamous cell carcinoma (ESCC). This study focused on investigating whether BAG2 functions as a cancer-promoting gene in ESCC. In this work, gene expression data and clinical information from the NCBI Gene Expression Omnibus (GEO), Oncomine and The Cancer Genome Atlas (TCGA) were collected and analyzed. Expression of BAG2 in ESCC was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). BAG2 was knocked down using small interference RNA (si-RNA) approach. Cell proliferation, migration and invasion were assessed by Cell Counting Kit-8 (CCK-8) and transwell assays. Molecular mechanism was detected by western blotting assay. The expression of BAG2 both in ESCC tissues and cells was upregulated and overexpression was associated with worsened prognosis. BAG2 silencing inhibited ESCC cell proliferation, migration and invasion, which was regulated by the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway. These results reveal contributions of BAG2 as a predictor and potential therapeutic target in ESCC.

Differential expression of circulating biomarkers of tumor phenotype and outcomes in previously treated non-small cell lung cancer patients receiving erlotinib vs. cytotoxic chemotherapy.

BACKGROUND: The objective of this study was to identify serum biomarkers capable of predicting clinical outcomes in previously-treated NSCLC patients with wild-type for EGFR activating mutations or insufficient tissue for mutation status determination. METHODS: Sixty-six Luminex immunoassays representative of biological themes that emerged from a re-analysis of transcriptome data from the Cancer Genome Atlas (TCGA) were evaluate against pretreatment serum specimens from previously-treated advanced NSCLC patients received either cytotoxic chemotherapy (n=32) or erlotinib (n=79). Known EGFR mutation positive cases were excluded from analysis. Associations of biomarkers with outcome parameters and their differential interaction with treatment for survival outcomes were assessed using multivariate Cox PH analyses. RESULTS: Our EMT-based transcriptomic analysis revealed a range of biological processes associated with angiogenesis, apoptosis, cachexia, inflammation, and metabolism emerging as those most highly associated with patient outcome. These processes were evaluated via surrogate serum biomarkers. A treatment-biomarker interaction analysis revealed that higher pretreatment levels of c-Met signaling biomarkers (i.e. HGF levels), pro-inflammatory/ pro-cachexia (e.g. IL-8, sIL-2Rα, FGF-2) processes and a pro-angiogenic (e.g. TGF-α, IL-8, VEGF) milieu were associated with inferior survival (HR=0.35, 0.29, 0.58, 0.50, 0.61, 0.45, respectively; all p<0.05) for patients receiving chemotherapy, relative to erlotinib. In contrast, high levels of decoy receptor for IL-1, sIL-1RII, and a high tissue vimentin/E-cadherin ratio were associated with a poor OS (HR=3.78; p=0.00055) in the erlotinib cohort. CONCLUSIONS: Contemporary precision medicine initiatives that pair patient tumor characteristics with the optimal therapy type may maximize the use of agents targeting EGFR in the treatment of NSCLC.

Long-Term Survival After Surgical Treatment of Thymic Carcinoma: A Retrospective Analysis from the Chinese Alliance for Research of Thymoma Database.

BACKGROUND: Thymic carcinoma is a type of rare and highly malignant tumor that originates from the thymic epithelium. Treatment and prognosis of thymic carcinoma remain controversial. We retrospectively analyzed survival data from a large-sample multicenter database in China. METHODS: The Chinese Alliance for Research of Thymoma constructed a retrospective database of patients with thymic epithelial tumors, which enrolled 1930 patients from January 1996 to August 2013, including 329 with thymic carcinomas. In this study, we analyzed clinical, pathologic, and treatment information, measured long-term survival rates, and identified relevant prognostic factors. RESULTS: Of 329 patients, R0 resection was performed in 211 (57.7 %), R1 in 34 (9.2 %), and R2 in 84 (22.5 %).The 3-, 5-, and 10-year survival rates were 78.3, 67.1, and 47.9 %, respectively. In univariate analysis, early Masaoka-Koga stage, R0 resection, and postoperative radiotherapy were associated with better overall survival.Early Masaoka-Koga stage and postoperative radiotherapy were also associated with disease-free survival. In multivariate analyses, R0 resection, Masaoka-Koga stage, and postoperative radiotherapy were significant prognostic factors of survival. CONCLUSIONS: Complete resection is the preferred primary treatment for thymic carcinoma. R0 resection, early Masaoka-Koga stage, and postoperative radiotherapy are significant predictors of improved survival.