Safety and efficacy of multi-target TKI combined with nivolumab in check-point inhibitor-refractory patients with advanced NSCLC: a prospective, single-arm, two-stage study.

BACKGROUND: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. METHODS: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. RESULTS: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. CONCLUSION: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. TRIAL REGISTRATION: NCT04507906 August 11, 2020.

Dual-Specificity Phosphatase 4 Promotes Malignant Features in Colorectal Cancer Through Cyclic-AMP Response Element Binding Protein/Protein Kinase CAMP-Activated Catalytic Subunit Beta Activation.

INTRODUCTION: Previous studies have demonstrated that Dual-specificity phosphatase 4 (DUSP4) plays an important role in the progression of different tumor types. However, the role and mechanism of DUSP4 in colorectal cancer (CRC) remain unclear. AIMS: We investigate the role and mechanisms of DUSP4 in CRC. METHODS: Immunohistochemistry was used to investigate DUSP4 expression in CRC tissues. Cell proliferation, apoptosis and migration assays were used to validate DUSP4 function in vitro and in vivo. RNA-sequence assay was used to identify the target genes of DUSP4. Human phosphokinase array and inhibitor assays were used to explore the downstream signaling of DUSP4. RESULTS: DUSP4 expression was upregulated in CRC tissues relative to normal colorectal tissues, and DUSP4 expression showed a significant positive correlation with CRC stage. Consistently, we found that DUSP4 was highly expressed in colorectal cancer cells compared to normal cells. DUSP4 knockdown inhibits CRC cell proliferation, migration and promotes apoptosis. Furthermore, the ectopic expression of DUSP4 enhanced CRC cell proliferation, migration and diminished apoptosis in vitro and in vivo. Human phosphokinase array data showed that ectopic expression of DUSP4 promotes CREB activation. RNA-sequencing data showed that PRKACB acts as a downstream target gene of DUSP4/CREB and enhances CREB activation through PKA/cAMP signaling. In addition, xenograft model results demonstrated that DUSP4 promotes colorectal tumor progression via PRKACB/CREB activation in vivo. CONCLUSION: These findings suggest that DUSP4 promotes CRC progression. Therefore, it may be a promising therapeutic target for CRC.

Rationale and design of a multicenter, randomized phase II trial of durvalumab with or without multitarget tyrosine kinase inhibitor as maintenance treatment in extensive-stage small-cell lung cancer patients (DURABLE study).

INTRODUCTION: Durvalumab is a check-point inhibitor against programmed death ligand-1 (PD-L1), and anlotinib is a new orally administered multitarget tyrosine kinase inhibitor (TKI). Both agents have been approved in China. Preclinical and clinical trials have suggested that antiangiogenic therapy has the potential to alleviate immunosuppression and showed synergetic effect when combined with ICIs. However, it is unclear that whether this combination is effective when initiated as maintenance treatment in ES-SCLC patients. METHODS: This is a multicenter, randomized, phase II study. A total of 64 eligible patients who do not experience disease progression after four cycles platinum-based chemotherapy combined with durvalumab will be randomized to durvalumab with anlotinib or durvalumab alone until disease progression, withdrawal of consent, or unacceptable toxicity. The primary endpoint is PFS (from randomization); secondary endpoint was OS and PFS (from diagnosis), objective response rate (ORR); disease control rate (DCR) and duration of response (DOR), safety and tolerability assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. DISCUSSION: We conduct a phase II study to investigate the safety and efficacy of durvalumab combined with anlotinib as maintenance treatment in ES-SCLC patients.

A randomized double-blind trial of TQB2450 with or without anlotinib in pretreated driver-negative non-small cell lung cancer.

OBJECTIVE: Immune monotherapy as second-line treatment confers only modest survival benefit on non-small cell lung cancer (NSCLC) patients with no mutated driver genes, necessitating combination treatment strategies. This phase Ib trial investigated the efficacy and safety of anti-PD-L1 antibody TQB2450 plus antiangiogenic drug anlotinib for NSCLC. MATERIALS AND METHODS: Pretreated stage IIIB or IV NSCLC patients with wild-type EGFR/ALK and minimally one measurable lesion were randomized 1:1:1 to receive TQB2450 1200 mg plus placebo, or TQB2450 1200 mg plus anlotinib 10 or 12 mg. The primary outcome was progression-free survival (PFS) and the secondary outcomes included objective response rate (ORR). RESULTS: Thirty-three patients received TQB2450 plus placebo and 34 patients each received TQB2450 plus anlotinib 10 mg and 12 mg. At the data cutoff, the median PFS was 8.7 months (95% CI 6.1-17.1) in the TQB2450 plus anlotinib group and 2.8 months (95% CI 1.4-4.7) in the TQB2450 only group. The ORR reached 30.9% (95% CI 20.2%-43.3%) in the TQB2450 plus anlotinib group and was 3.0% (95% CI 0.1%-15.8%) in the TQB2450 only group. In patients with PD-L1 ≥ 1%, the ORR was 50.0% (95% CI 33.4%-66.6%) for TQB2450 plus anlotinib and 5.3% (95% CI 0.1%-26.0%) for TQB2450 plus placebo. No new safety signals were observed. CONCLUSION: Anlotinib plus TQB2450 demonstrated promising antitumor activities in advanced NSCLC patients without EGFR and ALK alterations and the toxicities were overall manageable. The study findings support the continued development of TQB2450 plus anlotinib for advanced NSCLC patients without driver gene alterations.

Houttuynia cordata Thunb repairs steroid-induced avascular necrosis of the femoral head through regulating NF-κB signaling pathway.

To investigate the influences of Houttuynia cordata Thunb (HCT) in steroid-induced avascular necrosis of the femoral head (SANFH), we conducted a comprehensive study evaluating the effects of HCT on various aspects. Cell Counting Kit-8 assay was used to examine bone marrow stem cells (BMSCs) cell viability. Flow cytometry and lactate dehydrogenase detection assay were conducted to determine cell apoptosis. The levels of apoptosis-related proteins, osteogenic-related markers, inflammatory factors, and nuclear factor kappa B (NF-κB) pathway-associated proteins were determined via western blotting. Hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays were utilized to verify the effects of HCT in SANFH rats. Our findings revealed that HCT could enhanced cell viability and arrested cell apoptosis in dexamethasone (Dex)-treated BMSCs. Dex increased the levels of cleaved caspase-3, Bcl2-associated X, interleukin (IL)-1ß, IL-18, IL-6, p65, and inhibitor of NF-κB kinase ß (IKKß), while this promoting trend was weakened by HCT. Moreover, pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB signaling pathway) further increased the inhibitory role of apoptosis and the levels of IL-1ß, IL-18, and IL-6 and the promotional effect of the levels of RUNX2 and ALP in Dex-treated BMSCs. The in-vivo assays showed that HCT decreased the percentage of empty lacunae, apoptosis, and the levels of IL-1ß, IL-18, IL-6, p65, and IKKß in SANFH rats. In conclusion, our study demonstrated that HCT relieved SANFH, which might be possibly achieved by NF-κB pathway.

Exploring Possible Ways to Enhance the Potential and Use of Natural Products through Nanotechnology in the Battle against Biofilms of Foodborne Bacterial Pathogens.

Biofilms enable pathogenic bacteria to survive in unfavorable environments. As biofilm-forming pathogens can cause rapid food spoilage and recurrent infections in humans, especially their presence in the food industry is problematic. Using chemical disinfectants in the food industry to prevent biofilm formation raises serious health concerns. Further, the ability of biofilm-forming bacterial pathogens to tolerate disinfection procedures questions the traditional treatment methods. Thus, there is a dire need for alternative treatment options targeting bacterial pathogens, especially biofilms. As clean-label products without carcinogenic and hazardous potential, natural compounds with growth and biofilm-inhibiting and biofilm-eradicating potentials have gained popularity as natural preservatives in the food industry. However, the use of these natural preservatives in the food industry is restricted by their poor availability, stability during food processing and storage. Also there is a lack of standardization, and unattractive organoleptic qualities. Nanotechnology is one way to get around these limitations and as well as the use of underutilized bioactives. The use of nanotechnology has several advantages including traversing the biofilm matrix, targeted drug delivery, controlled release, and enhanced bioavailability, bioactivity, and stability. The nanoparticles used in fabricating or encapsulating natural products are considered as an appealing antibiofilm strategy since the nanoparticles enhance the activity of the natural products against biofilms of foodborne bacterial pathogens. Hence, this literature review is intended to provide a comprehensive analysis of the current methods in nanotechnology used for natural products delivery (biofabrication, encapsulation, and nanoemulsion) and also discuss the different promising strategies employed in the recent and past to enhance the inhibition and eradication of foodborne bacterial biofilms.

Efficacy and safety of first-line anlotinib-based combinations for advanced non-small cell lung cancer: a three-armed prospective study.

Background: The evidence of combined therapies of multi-target agents in first-line treatment of advanced non-small cell lung cancer (NSCLC) was limited. This study aimed to evaluate the safety and efficacy of anlotinib combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), chemotherapy, or immune checkpoint inhibitor (ICI) in advanced NSCLC. Methods: This open-label, three-arm, prospective study (NCT03628521) enrolled untreated locally advanced/metastatic NSCLC patients. Patients with EGFR mutation NSCLC received anlotinib and erlotinib (cohort A). Patients without EGFR/ALK/ROS1 mutation received anlotinib combined with carboplatin plus pemetrexed/gemcitabine (cohort B), or sintilimab (cohort C). The primary outcomes were safety and objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Treatments were performed for at least 2 cycles and efficacy was evaluated every 2 cycles using RECIST version 1.1. Safety was assessed throughout the study. Results: A total of 30, 30, and 22 patients were enrolled in cohorts A, B, and C, respectively. There were 3 patients did not complete the treatment in cohort A. In cohorts A and B, ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 77.3% and 60.0% of patients, respectively. The most common TRAEs were rash (10.0%) and decreased platelet count (30.0%) in cohorts A and B, respectively. The ORRs were 92.9% and 60.0% in cohorts A and B, respectively, and DCRs were 96.4% and 96.7%, respectively. The ORR and incidence of ≥ grade 3 TRAEs of cohort C were, which 72.7% and 54.5%, which had been published previously. Median PFSs [95% confidence interval (CI)] were 21.6 (15.6 to 24.9), 13.0 [10.5 to not estimated (NE)], and 15.6 (12.9 to NE) months in cohorts A, B, and C, respectively. Median OS was 28.1 (95% CI: 21.82 to NE) months in cohort B. The 24-month OS rates in cohorts A and C were 87.1% and 83.9%, respectively. Conclusions: Anlotinib-based combinations with EGFR-TKI, chemotherapy, and ICI are well-tolerated and encouraging as first-line therapies for advanced NSCLC, which could be verified in future studies. Anlotinib-based combination might provide multiple choices for first-line treatment in patients with advanced NSCLC.

Rationale and design of a phase II trial of dacomitinib in advanced non-small cell lung cancer patients with uncommon epidermal growth factor receptor mutations: a prospective and single arm study (DANCE study).

BACKGROUND: Dacomitinib is a second-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). ARCHER-1050 showed that this agent can improve progression-free survival and overall survival in advanced non-small cell lung cancer patients with sensitive EGFR mutation compared to gefitinib. However, it is unclear whether dacomitinib is effective in patients with sensitizing uncommon EGFR mutations in exon 18-21. The aim of this study is to investigate the safety and efficacy of dacomitinib in these patients. METHODS: This is a single arm, prospective, open label and phase II trial. Sample size will be calculated by a minimax two-stage design method based on the following parameters: α = 0.075, 1-ß = 0.9, P0 = 0.20, P1 = 0.45 and a dropout rate of 10%. A total of 30 eligible patients will be included. Patients will receive continuous oral therapy with dacomitinib (45 mg/day) until disease progression, withdrawal of consent, or unacceptable toxicity, whichever occurs first. The primary endpoint is objective response rate (ORR) per RECIST version 1.1, as assessed by investigators' review. The second endpoint is disease control rate (DCR), PFS, OS, and safety. DISCUSSION: We conduct a single arm, phase II study to investigate the safety and efficacy of dacomitinib in advanced NSCLC patients with sensitizing uncommon EGFR mutations. The results of the DANCE study will provide new data regarding efficacy and safety of these patients. TRIAL REGISTRATION: NCT04504071.

SPRY1 promotes cell proliferation and inhibits apoptosis by activating Hedgehog pathway in acute myeloid leukemia.

OBJECTIVE: The aim of this study was to determine the biological function of Sprouty 1 (SPRY1) on acute myeloid leukemia (AML), and to investigate the potential mechanism. METHODS: The expression of SPRY1 and the prognostic values of SPRY1 were assessed through the analysis of the Cancer Genome Atlas. Meanwhile, the expression of SPRY1 in AML cells was determined by qRT-PCR and western blot. Then, the biological function of SPRY1 on the proliferation, cell cycle and apoptosis in K-562 and HL-60 cells were tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony-formation assay, 5-ethynyl-20-deoxyuridine assay and flow cytometry. Additionally, the protein expressions were measured by western blot. RESULTS: We found that SPRY1 was markedly overexpressed in the cells of the patients with AML, and the patients with AML having a high SPRY1 expression has a bad prognosis. The proliferation and cell cycle progression in K-562 and HL-60 cells were notably promoted by SPRY1 overexpression, but inhibited by SPRY1 knockdown. Meanwhile, the apoptosis of K-562 and HL-60 cells was significantly repressed by SPRY1 overexpression and facilitated by SPRY1 knockdown. In addition, we found that SPRY1 overexpression significantly activated the Hedgehog pathway in AML cells. The function of SPRY1 on the proliferation, cell cycle and apoptosis was reversed by Gli1 in K-562 and HL-60 cells. DISCUSSION: Identifying new biomarkers and exploring the pathogenesis of AML is urgent to improve the disease surveillance for patients with AML. CONCLUSIONS: SPRY1 could facilitate cell proliferation and cell cycle progression, and suppress cell apoptosis via activating the Hedgehog pathway in AML.

Polyphenolic Antibacterials for Food Preservation: Review, Challenges, and Current Applications.

Natural alternatives replacing artificial additives have gained much attention in the consumer's view because of the growing search for clean label products that are devoid of carcinogenic and toxic effects. Plant polyphenols are considered as suitable alternative natural preservatives with antioxidant and antimicrobial properties. However, their uses in the food industry are undermined by a series of limitations such as low solubility and stability during food processing and storage, lack of standardization, and undesirable organoleptic properties. Different approaches in the use of polyphenols have been proposed in order to overcome the current hurdles related to food preservation. This review article specifically focuses on the antibacterial activity of plant-derived polyphenols as well as their applications as food preservatives, main challenges, and other trends in the food industry.

Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC.

INTRODUCTION: Although the interaction between tumor immune microenvironment and angiogenesis has been well established, evidence supporting the chemo-free combination of immune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors in treatment-naive patients with advanced NSCLC is insufficient. This report provides the efficacy and safety of sintilimab combined with anlotinib as first-line therapy for advanced NSCLC from a phase 1b trial (NCT03628521). METHODS: Eligible patients who were treatment-naive and had unresectable stage IIIB/C or IV NSCLC without EGFR/ALK/ROS1 mutations received sintilimab (200 mg, day 1) and anlotinib (12 mg, day 1-14) every 3 weeks till disease progression or unacceptable toxicity. Baseline programmed death-ligand 1 expression and tumor mutation burden status was assessed in all patients. The primary end points were objective response rate and safety. RESULTS: A total of 22 patients received sintilimab and anlotinib. Median follow-up was 15.8 months (range: 8.3-19.3). Sixteen patients achieved confirmed partial response with an objective response rate of 72.7% (95% confidence interval [CI]: 49.8%-89.3%) and disease control rate of 100% (95% CI: 84.6%-100%). Median progression-free survival was 15 months (95% CI: 8.3 m, not reached), and the 12-month progression-free survival rate was 71.4% (95% CI: 47.2%-86.0%). The incidence rate of grade 3 or higher treatment-related adverse events was 54.5%, and grade 3 hypertension was predominant (two of 22, 9.1%). No grade 4 treatment-related adverse events were observed, and one case of grade 5 immune-related pneumonitis occurred. CONCLUSIONS: To the best of our knowledge, this is the first study that assessed an anti-programmed cell death protein 1 antibody combined with a multitarget antiangiogenic tyrosine kinase inhibitor in the frontline setting for patients with NSCLC. In view of its encouraging efficacy, durability, and safety profile, sintilimab plus anlotinib represents a novel chemotherapy-free regimen in this patient population.

Identification of Ferroptosis-Related Genes Signature Predicting the Efficiency of Invasion and Metastasis Ability in Colon Adenocarcinoma.

Background: Colon adenocarcinoma (COAD) is one of the most prevalent cancers worldwide and has become a leading cause of cancer death. Although many potential biomarkers of COAD have been screened with the bioinformatics method, it is necessary to explore novel markers for the diagnosis and appropriate individual treatments for COAD patients due to the high heterogeneity of this disease. Epithelial-to-mesenchymal transition (EMT)-mediated tumor metastasis suggests poor prognosis of cancers. Ferroptosis is involved in tumor development. EMT signaling can increase the cellular sensitivity to ferroptosis in tumors. The aim of our study is finding novel prognostic biomarkers to determine COAD patients for predicting efficiency of metastasis status and targeting precise ferroptosis-related therapy. Methods: A novel gene signature related to metastasis and ferroptosis was identified combing with risk model and WGCNA analysis with R software. The biological functions and predictive ability of the signature in COAD were explored through bioinformatics analysis. Results: We established a four-gene prognostic signature (MMP7, YAP1, PCOLCE, and HOXC11) based on EMT and ferroptosis related genes and validated the reliability and effectiveness of this model in COAD. This four-gene prognostic signature was closely connected with metastasis and ferroptosis sensitivity of COAD. Moreover, WGCNA analysis further confirmed the correlation between PCOLCE, HOXC11, and liver and lymphatic invasion of COAD. Conclusion: The four genes may become potential prognostic biomarkers to identify COAD patients with metastasis. Moreover, this four-gene signature may be able to determine the COAD suitable with ferroptosis induction therapy. Finally, PCOLCE2 and HOXC11 were selected individually because of their novelties and precise prediction ability. Overall, this signature provided novel possibilities for better prognostic evaluation of COAD patients and may be of great guiding significance for individualized treatment and clinical decision.

Analysis of the clinical effect of osimertinib on 90 cases with advanced lung adenocarcinoma.

BACKGROUND: Primary or secondary drug resistance of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) is a new challenge in the treatment of advanced non-small cell lung cancer (NSCLC). Osimertinib is a third-generation EGFR-TKI, and its efficacy and safety in NSCLC patients with first-generation EGFR-TKI resistance, especially lung adenocarcinoma, are not yet clear. The purpose of this study was to observe the efficacy and adverse reactions of osimertinib in the treatment of patients with advanced lung adenocarcinoma. METHODS: From January 2017 to December 2018, 90 patients with advanced (stage IV) lung adenocarcinoma were diagnosed in Shanghai Chest Hospital. The disease of these patients (94.4%) progressed after first-line EGFR-TKI treatment, and 43.3% of patients received third-line or beyond third-line treatment. The efficacy and adverse reactions of osimertinib treatment were observed. RESULTS: Among 90 patients with advanced lung adenocarcinoma, 57 (63.3%) achieved partial response (PR), 27 (30.0%) had stable disease (SD), and 6 (6.7%) had progressive disease (PD). The objective response rate (ORR) was 63.3%, and the disease control rate (DCR) was 93.3%. The median progression-free time (mPFS) was 10.41 months (95% CI: 8.91-11.91 months), and the median overall survival (mOS) was 31.37 months (95% CI: 26.37-36.37 months). The incidence of adverse events of degree 3 and above was 7.78%. The main adverse events were diarrhea (28.9%) and rash (24.4%). After symptomatic treatment, the incidence of adverse events was significantly reduced. CONCLUSIONS: Osimertinib has a definite curative effect in the treatment of patients with advanced lung adenocarcinoma, and the incidence of adverse reactions is low.

High-level gain of mesenchymal-epithelial transition factor (MET) copy number using next-generation sequencing as a predictive biomarker for MET inhibitor efficacy.

BACKGROUND: In clinical oncology, targeted next-generation sequencing (NGS) has become an integral part of the routine molecular diagnostics repertoire. However, a consensus is yet to be agreed on the optimal mesenchymal-epithelial transition factor (MET) copy number (CN) cut-off value based on NGS data that could predict the MET-amplified non-small cell lung cancer (NSCLC) patients who could benefit from MET tyrosine kinase inhibitor (TKI) therapy. In this study, we aimed to identify the criteria to define MET amplification derived from NGS data. METHODS: Sequencing data from matched plasma and tissue samples from 40 MET-amplified NSCLC patients were used to derive a normalization method, referred to as adjusted copy number (adCN). Clinical outcomes from an additional 18 MET TKI-treated NSCLC patients with solely MET-amplified cancers were analyzed to validate the adCN cut-offs. RESULTS: AdCN, calculated as the absolute CN generated from NGS relative to the maximum mutant allele fraction (maxMAF) per sample, was demonstrated to have a high correlation with MET CN in tissue and plasma samples (R2=0.73). Using a cut-off value of 5.5 and 13, tertile stratification of adCN was able to distinguish patients with high-level MET amplification. The MET TKI-treated patients with adCN >13, categorized as high-level amplification, had significantly longer progression-free survival (PFS) than those with adCN <13 (P=0.009), suggesting that adCN positively correlated with the response to MET TKI. CONCLUSIONS: We derived a normalization method that could reflect the relative CN and distinguish MET-amplified NSCLC patients with high-level gene amplification who were sensitive to crizotinib, suggesting adCN could potentially serve as a predictive biomarker for MET TKI response.

Prognostic Value of Pre-Autologous Stem Cell Transplantation PET/CT in Diffuse Large B-Cell Lymphoma: The Deauville Score Is Prognostically Superior to ΔSUVmax.

OBJECTIVE: The predictive value of pre-autologous stem cell transplantation (pre-ASCT) positron emission tomography/computed tomography (PET/CT) scans according to different criteria remains elusive in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 46 DLBCL patients treated with pre-ASCT were enrolled in the present study, and two methods, Deauville score and maximal standardized uptake value reduction (ΔSUVmax), were used to evaluate the PET/CT scans before transplantation. RESULTS: In patients with Deauville 1-3 and ≥4, the 2-year progression-free survival (PFS) rates were 82.8 and 11.8% (p < 0.001), respectively, while the 2-year overall survival (OS) rates were 89.7 and 41.2%, respectively (p < 0.001). When using the ΔSUVmax cut-off of 66% criterion, in patients with a ΔSUVmax of >66 and ≤66%, the 2-year PFS rates were 78.1 and 7.1%, respectively (p < 0.001), while the 2-year OS rates were 87.5 and 35.7%, respectively (p < 0.001). In the univariate analysis, the ΔSUVmax, Deauville score, NCCN-IPI and serum lactate dehydrogenase levels were significantly correlated with the 2-year PFS/OS. Furthermore, the multivariate analysis revealed that the Deauville score was an independent prognostic factor for 2-year PFS. CONCLUSION: The present results indicate that PET/CT scans at pre-ASCT can predict the survival of DLBCL patients, and the Deauville score is better than ΔSUVmax in prognostic prediction.

Circulating DNA-Based Sequencing Guided Anlotinib Therapy in Non-Small Cell Lung Cancer.

Anlotinib is a multitargeted antiangiogenic drug, and its clinical predictor for responsive non-small cell lung cancer (NSCLC) patients is still elusive. Here, tumor-specific target capture is used to profile the circulating DNA of ALTER0303 (evaluating NSCLC clinical antitumor efficacy through anlotinib therapy) study participants. The results indicate that patients receiving no benefit can be mainly excluded via analysis of ARID1A and BRCA2 genetic profiling. For patients with no durable benefit and durable clinical benefit patients, three predictors: germline and somatic mutation burden (G+S MB), nonsynonymous and synonymous mutation burden (N+S MB), and unfavorable mutation score of circulating DNA profiling are identified. Through integrating the advantages and disadvantages of three independent predictors, the tumor mutation index (TMI) is established as a prediction model and the patients who are very likely to benefit more from anlotinib therapy are identified. Furthermore, the IDH1 exon 4 mutation is identified as an unfavorable factor for anlotinib therapy under TMI-based stratification, and the TMI plus IDH1 exon 4 mutation status potentially predicts response to anlotinib. Collectively, this study provides a circulating DNA sequencing-based stratification method for identifying anlotinib responders via a noninvasive approach, and thus potentially improves the clinical outcome of NSCLC patients receiving third-line therapy.

Discovery of Antibacterial Dietary Spices That Target Antibiotic-Resistant Bacteria.

Although spice extracts are well known to exhibit antibacterial properties, there is lack of a comprehensive evaluation of the antibacterial effect of spices against antibiotic-resistant bacteria. In the present study, ethanolic extracts from a total of 67 spices were comprehensively investigated for their in vitro antibacterial activities by agar well diffusion against two common food-borne bacteria, Staphylococcus aureus and Salmonella enteritidis, with multi-drug resistance. Results showed that S. aureus was generally more sensitive to spice extracts than S. enteritidis. Of the 67 spice extracts, 38 exhibited antibacterial activity against drug-resistant S. aureus, while only four samples were effective on drug-resistant S. enteritidis. In addition, 11 spice extracts with inhibition zones greater than 15 mm were further verified for their broad-spectrum antibacterial properties using another 10 drug-resistant S. aureus strains. It was found that five spice extracts, including galangal, fructus galangae, cinnamon, yellow mustard seed, and rosemary, exhibited the highest antibacterial capacity. Further cytotoxicity of these 11 spices was determined and LC50 values were found to be more than 100 µg/mL except for galangal, rosemary, and sage, whose LC50 values were 9.32 ± 0.83, 19.77 ± 2.17, and 50.54 ± 2.57, respectively. Moreover, the antioxidant activities (ferric-reducing antioxidant power (FRAP) and trolox equivalent antioxidant capacity (TEAC) values) and total phenolic content (TPC) of spice extracts were determined to establish possible correlations with the antibacterial activity. Although the antibacterial effect was positively correlated with the antioxidant activities and TPC, the correlation was weak (r < 0.5), indicating that the antibacterial activity could also be attributed to other components besides antioxidant polyphenols in the tested spice extracts. In conclusion, dietary spices are good natural sources of antibacterial agents to fight against antibiotic-resistant bacteria, with potential applications as natural food preservatives and natural alternatives to antibiotics in animal feeding.

Characterization of Antibiotic Resistance Genes, Plasmids, Biofilm Formation, and In Vitro Invasion Capacity of Salmonella Enteritidis Isolates from Children with Gastroenteritis.

Objectives: The primary aim of this study was to investigate the presence of antibiotic resistance genes (ARGs) and plasmid replicon types for 75 multidrug-resistant (MDR) Salmonella Enteritidis isolates from children with gastroenteritis. We also evaluated the association among biofilm formation, in vitro invasion capacity, and antibiotic resistance phenotypes. Materials and Methods: Twenty-two ARGs and 18 different plasmid incompatibility types were investigated using polymerase chain reaction (PCR) and DNA sequencing. In vitro invasion capacity of S. Enteritidis isolates possessing different antibiotic resistance patterns was assessed using the Caco2 human intestinal epithelial cell line and biofilm formation was performed in a 96-well polystyrene well format using crystal violet detection. Results: The presence of plasmid-mediated quinolone resistance genes and ß-lactamase genes was established using PCR amplification. All the tested S. Enteritidis isolates that were fluoroquinolone resistant possessed gyrA mutations and 50% also possessed mutations in parC. MDR S. Enteritidis isolates containing three (29/75) or four (21/75) plasmid replicon types were predominant and 71/75 carried both FIIs and FIC replicon-type plasmids. MDR isolates were strong or moderate biofilm producers and a significant positive association (p < 0.05) between antibiotic resistance and biomass of biofilms was observed in the strains assayed. A ceftiofur-resistant strain was significantly more invasive (p < 0.01) than the other isolates. Conclusions: We observed a high incidence of ARGs and diversity of plasmids in S. Enteritidis isolates from children. Biofilm formation and invasion capacity highlight a significant hazard to public health.

Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Prospective, Single-Arm, Phase II Study.

LESSONS LEARNED: The findings of this prospective, single-arm, phase II study showed that neoadjuvant erlotinib was well tolerated and might improve the radical resection rate in patients with stage IIIA-N2 epidermal growth factor receptor mutation-positive non-small cell lung cancer (NSCLC).Erlotinib shows promise as a neoadjuvant therapy option in this patient population.Next-generation sequencing may be useful for predicting outcomes with preoperative tyrosine kinase inhibitors (TKIs) in patients with NSCLC.Large-scale randomized controlled trials investigating the role of TKIs in perioperative therapy, combining neoadjuvant and adjuvant treatments to enhance personalized therapy for patients in this precision medicine era, are warranted. BACKGROUND: Information on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as neoadjuvant therapy in non-small cell lung cancer (NSCLC) is scarce. We evaluated whether neoadjuvant erlotinib improves operability and survival in patients with stage IIIA-N2 EGFR mutation-positive NSCLC. METHODS: We conducted a prospective, single-arm, phase II study. Patients received erlotinib 150 mg per day for 56 days in the neoadjuvant period. The primary endpoint was the radical resection rate. RESULTS: Nineteen patients were included in the final analysis. After erlotinib treatment, 14 patients underwent surgery. The radical resection rate was 68.4% (13/19) with a 21.1% (4/19) rate of pathological downstaging. The objective response rate was 42.1%; 89.5% (17/19) of patients achieved disease control, with a 10.3-month median disease-free survival among patients who underwent surgery. Among all 19 patients who received neoadjuvant therapy, median progression-free survival (PFS) and overall survival were 11.2 and 51.6 months, respectively. Adverse events (AEs) occurred in 36.8% (7/19) of patients, with the most common AE being rash (26.3%); 15.8% experienced grade 3/4 AEs. Quality of life (QoL) improvements were observed after treatment with erlotinib for almost all QoL assessments. Effects of TP53 mutation on prognosis were evaluated in eight patients with adequate tissue samples. Next-generation sequencing revealed that most patients had a TP53 gene mutation (7/8) in addition to an EGFR mutation. No TP53 mutation, or very low abundance, was associated with longer PFS (36 and 38 months, respectively), whereas high abundance was associated with short PFS (8 months). CONCLUSION: Neoadjuvant erlotinib was well tolerated and may improve the radical resection rate in this patient population. Next-generation sequencing may predict outcomes with preoperative TKIs.