Transcriptomic and metabolomic analyses reveal the importance of ethylene networks in mulberry fruit ripening.

Mulberry (Morus alba L.) is a climacteric and highly perishable fruit. Ethylene has been considered to be an important trigger of fruit ripening process. However, the role of ethylene in the mulberry fruit ripening process remains unclear. In this study, we performed a comprehensive analysis of metabolomic and transcriptomic data of mulberry fruit and the physiological changes accompanying the fruit ripening process. Our study revealed that changes in the accumulation of specific metabolites at different stages of fruit development and ripening were closely correlated to transcriptional changes as well as underlying physiological changes and the development of taste biomolecules. The ripening of mulberry fruits was highly associated with the production of endogenous ethylene, and further application of exogenous ethylene assisted the ripening process. Transcriptomic analysis revealed that differential expression of diverse ripening-related genes was involved in sugar metabolism, anthocyanin biosynthesis, and cell wall modification pathways. Network analysis of transcriptomics and metabolomics data revealed that many transcription factors and ripening-related genes were involved, among which ethylene-responsive transcription factor 3 (MaERF3) plays a crucial role in the ripening process. The role of MaERF3 in ripening was experimentally proven in a transient overexpression assay in apples. Our study indicates that ethylene plays a vital role in modulating mulberry fruit ripening. The results provide a basis for guiding the genetic manipulation of mulberry fruits towards sustainable agricultural practices and improve post-harvest management, potentially enhancing the quality and shelf life of mulberry fruits for sustainable agriculture and forestry.

Efficacy and safety of novel immune checkpoint inhibitor-based combinations versus chemotherapy as first-line treatment for patients with extensive-stage small cell lung cancer: A network meta-analysis.

BACKGROUND: Patients with extensive-stage small cell lung cancer (ES-SCLC) have an exceptionally poor prognosis and immune checkpoint inhibitors (ICIs) combined with etoposide-platinum is recommended as standard first-line therapy. However, which combination pattern is the best still remains unknown. This network meta-analysis was performed to compare the efficacy and safety of currently available patterns including an antiangiogenic agent containing regimen and probed into the most appropriate therapy for patients. METHODS: Hazard ratios (HRs) and odds ratios (ORs) were generated using R software. The outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (grade ≥ 3 adverse events [AEs]) were analyzed. RESULTS: A total of 10 randomized controlled trials (RCTs) involving 5544 patients were included for analysis. Drug combination patterns included adebrelimab, atezolizumab, durvalumab, durvalumab plus tremelimumab, ipilimumab, pembrolizumab, serplulimab, benmelstobart plus anlotinib, tislelizumab, tiragolumab plus atezolizumab and toripalimab in combination with chemotherapy. The novel antiangiogenic agent containing regimen benmelstobart + anlotinib + chemotherapy showed the highest possibility to present the best PFS and OS versus chemotherapy. Compared with ICI plus chemotherapy, it also achieved significantly better PFS and presented a tendency of OS benefit. As for safety and toxicity, patients treated with benmelstobart + anlotinib + chemotherapy and durvalumab + tremelimumab + chemotherapy suffered a higher likelihood of more grade ≥ 3 AEs without unexpected AEs. CONCLUSION: PD-1/PD-L1 inhibitors-based combinations are associated with significant improvement in both PFS and OS for treatment-naïve ES-SCLC patients. Benmelstobart plus anlotinib with chemotherapy (CT) yielded better survival benefit versus CT alone or other ICIs + CT with caution for more adverse effects along with the addition of an antiangiogenic agent.

Efficacy and Safety of Maintenance Therapy Using Cetuximab in Patients with Metastatic Colorectal Cancer: Retrospective Study.

Purpose: Cetuximab (CET) combined with chemotherapy significantly improved the survival in RAS and RAF wild-type metastatic colorectal cancer (mCRC) patients, while clinical evidence was lacking on the use of maintenance therapy (MT). The study aimed to explore the role of maintenance therapy following Cetuximab + chemotherapy and the optimal Cetuximab-based maintenance therapy regimen. Patients and Methods: We retrospectively reviewed data on the efficacy and safety of CET-based MT in patients with mCRC who achieved disease control after induction therapy. Results: Eighty-one patients with mCRC who achieved disease control after CET + chemotherapy induction were enrolled. Overall median progression-free survival (PFS) was 10.5 (95% CI = 8.8-12.2) months and median maintenance/observation PFS (mnPFS) was 6.0 (95% CI = 5.0-7.0) months. Among these 81 patients, 61 patients were prescribed MT (CET alone for 21 patients and CET + chemotherapy for 40 patients). Median PFS and mnPFS in the MT group were significantly longer than those for the non-MT group. Different MT regimens did not affect PFS and mnPFS significantly. Univariate and multivariate analysis demonstrated MT, complete response/partial response during induction therapy, and absence of peritoneal metastasis to be positively associated with longer PFS and mnPFS. Treatment-related adverse events (AEs) were tolerable during MT, and AE-related deaths were not observed. Conclusion: MT with CET or CET + chemotherapy was an appropriate option following initial induction chemotherapy for patients with RAS and RAF wild-type mCRC. This strategy endowed survival benefits and a tolerable safety profile.

A retrospective analysis of optimal timing of thoracic radiotherapy for driver gene-negative metastatic non-small cell lung cancer.

BACKGROUND: The optimal timing of thoracic radiotherapy (TRT) in driver-gene-negative metastatic non-small cell lung cancer (mNSCLC) patients was retrospectively investigated based on survival and safety profile. METHODS: The efficacy and safety data of driver-gene-negative mNSCLC patients treated with TRT during maintenance after first-line therapy was collected. Patients whose primary tumor and metastatic lesions remained no progression during maintenance and then received TRT were categorized as the NP (no progression) group, while patients who experienced slow progression during maintenance without reaching progressive disease and then received TRT were categorized as the SP (slow progression) group. The efficacy and adverse events of TRT were analyzed. RESULTS: In total, 149 driver-gene-negative mNSCLC patients treated with TRT during maintenance were enrolled into the study, with 119 in the NP group and 30 in the SP group. After a median follow-up of 30.83 (range: 26.62-35.04) months, the median progression-free survival (PFS) in the NP group was 11.13 versus 9.53 months in the SP group (HR 0.599, p = 0.017). The median overall survival (OS) in the NP group was 32.27 versus 25.57 months in the SP group (HR 0.637, p = 0.088). The median PFS after radiotherapy (rPFS) was 6.33 versus 3.90 months (HR 0.288, p < 0.001). The adverse events were tolerable and manageable in both groups without significant difference (p > 0.05). CONCLUSION: The addition of TRT during the pre-emptive no progression phase was associated with a significantly longer PFS than during the delayed slow progression phase and had an acceptable safety profile. Our results might support the earlier initiation of TRT after induction therapy for some patients with driver-gene-negative mNSCLC.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Morusinol Extracted from Morus alba Inhibits Cell Proliferation and Induces Autophagy via FOXO3a Nuclear Accumulation-Mediated Cholesterol Biosynthesis Obstruction in Colorectal Cancer.

The incidence rate of colorectal cancer (CRC) has been increasing significantly in recent years, and it is urgent to develop novel drugs that have more effects for its treatment. It has been reported that many molecules extracted from the root bark of Morus alba L. (also known as Cortex Mori) have antitumor activities. In our study, we identified morusinol as a promising anticancer agent by selecting from 30 molecules extracted from Morus alba L. We found that morusinol treatment suppressed cell proliferation and promoted apoptosis of CRC cells in vitro. Besides this, we observed that morusinol induced cytoprotective autophagy. The GO analysis of differentially expressed genes from RNA-seq data showed that morusinol affected cholesterol metabolism. Then we found that key enzyme genes in the cholesterol biosynthesis pathway as well as the sterol regulatory element binding transcription factor 2 (SREBF2) were significantly downregulated. Furthermore, additional cholesterol treatment reversed the anti-CRC effect of morusinol. Interestingly, we also found that morusinol treatment could promote forkhead box O3 (FOXO3a) nuclear accumulation, which subsequently suppressed SREBF2 transcription. Then SREBF2-controlled cholesterol biosynthesis was blocked, resulting in the suppression of cell proliferation, promotion of apoptosis, and production of autophagy. The experiments in animal models also showed that morusinol significantly impeded tumor growth in mice models. Our results suggested that morusinol may be used as a candidate anticancer drug for the treatment of CRC.

Persulfidation maintains cytosolic G6PDs activity through changing tetrameric structure and competing cysteine sulfur oxidation under salt stress in Arabidopsis and tomato.

Glucose-6-phosphate dehydrogenases (G6PDs) are essential regulators of cellular redox. Hydrogen sulfide (H2 S) is a small gasotransmitter that improves plant adaptation to stress; however, its role in regulating G6PD oligomerization to resist oxidative stress remains unknown in plants. Persulfidation of cytosolic G6PDs was analyzed by mass spectrometry (MS). The structural change model of AtG6PD6 homooligomer was built by chemical cross-linking coupled with mass spectrometry (CXMS). We isolated AtG6PD6C159A and SlG6PDCC155A transgenic lines to confirm the in vivo function of persulfidated sites with the g6pd5,6 background. Persulfidation occurs at Arabidopsis G6PD6 Cystine (Cys)159 and tomato G6PDC Cys155, leading to alterations of spatial distance between lysine (K)491-K475 from 42.0 Å to 10.3 Å within the G6PD tetramer. The structural alteration occurs in the structural NADP+ binding domain, which governs the stability of G6PD homooligomer. Persulfidation enhances G6PD oligomerization, thereby increasing substrate affinity. Under high salt stress, cytosolic G6PDs activity was inhibited due to oxidative modifications. Persulfidation protects these specific sites and prevents oxidative damage. In summary, H2 S-mediated persulfidation promotes cytosolic G6PD activity by altering homotetrameric structure. The cytosolic G6PD adaptive regulation with two kinds of protein modifications at the atomic and molecular levels is critical for the cellular stress response.

Real-World Efficacy and Safety of Thoracic Radiotherapy after First-Line Chemo-Immunotherapy in Extensive-Stage Small-Cell Lung Cancer.

(1) Background: At present, the efficacy and safety of thoracic radiotherapy (TRT) after chemo-immunotherapy (CT-IT) in patients with extensive-stage small-cell lung cancer (ES-SCLC) still remain unclear. The purpose of this study was to evaluate the role of TRT after CT-IT in patients with ES-SCLC. (2) Methods: From January 2020 to October 2021, patients with ES-SCLC treated with first-line anti-PD-L1 antibody plus platinum-etoposide chemotherapy were enrolled retrospectively. The survival data and adverse events data of patients treated with or without TRT after CT-IT were collected for analysis. (3) Results: A total of 118 patients with ES-SCLC treated with first-line CT-IT were retrospectively enrolled, with 45 patients with TRT and 73 patients without TRT after CT-IT. The median PFS and OS in the CT-IT + TRT group and CT-IT only group were 8.0 months versus 5.9 months (HR = 0.64, p = 0.025) and 22.7 months versus 14.7 months (HR = 0.52, p = 0.015), respectively. The median PFS and OS in all 118 patients treated with first-line CT-IT were 7.2 and 19.8 months with an ORR of 72.0%. In multivariate analyses, liver metastasis and response to CT-IT were shown to be independent prognostic factors of PFS (p < 0.05), while liver metastasis and bone metastasis were independent predictive factors of OS (p < 0.05). Although TRT was significantly associated with better PFS and OS in univariate analysis, the association of TRT and OS failed to reach statistical significance (HR = 0.564, p = 0.052) in multivariate analysis. There was no significant difference in adverse events (AEs) between two treatment groups (p = 0.58). (4) Conclusions: ES-SCLC patients treated with TRT after first-line CT-IT had prolonged PFS and OS with an acceptable safety profile. Further prospective randomized studies are necessary to explore the efficacy and safety of this treatment modality for ES-SCLC in future.

Hydrogen sulfide improves salt tolerance through persulfidation of PMA1 in Arabidopsis.

KEY MESSAGE: A new interaction was found between PMA1 and GRF4. H2S promotes the interaction through persulfidated Cys446 of PMA1. H2S activates PMA1 to maintain K+/Na+ homeostasis through persulfidation under salt stress. Plasma membrane H+-ATPase (PMA) is a transmembrane transporter responsible for pumping protons, and its contribution to salt resistance is indispensable in plants. Hydrogen sulfide (H2S), a small signaling gas molecule, plays the important roles in facilitating adaptation of plants to salt stress. However, how H2S regulates PMA activity remains largely unclear. Here, we show a possible original mechanism for H2S to regulate PMA activity. PMA1, a predominant member in the PMA family of Arabidopsis, has a non-conservative persulfidated cysteine (Cys) residue (Cys446), which is exposed on the surface of PMA1 and located in cation transporter/ATPase domain. A new interaction of PMA1 and GENERAL REGULATORY FACTOR 4 (GRF4, belongs to the 14-3-3 protein family) was found by chemical crosslinking coupled with mass spectrometry (CXMS) in vivo. H2S-mediated persulfidation promoted the binding of PMA1 to GRF4. Further studies showed that H2S enhanced instantaneous H+ efflux and maintained K+/Na+ homeostasis under salt stress. In light of these findings, we suggest that H2S promotes the binding of PMA1 to GRF4 through persulfidation, and then activating PMA, thus improving the salt tolerance of Arabidopsis.

Nitric oxide induces S-nitrosylation of CESA1 and CESA9 and increases cellulose content in Arabidopsis hypocotyls.

Nitric oxide (NO), a small signaling gas molecule, participates in several growth and developmental processes in plants. However, how NO regulates cell wall biosynthesis remains unclear. Here, we demonstrate a positive effect of NO on cellulose content that may be related to S-nitrosylation of cellulose synthase 1 (CESA1) and CESA9. Two S-nitrosylated cysteine (Cys) residues, Cys562 and Cys641, which are exposed on the surface of CESA1 and CESA9 and located in the cellulose synthase catalytic domain, were identified to be S-nitrosylated. Meanwhile, Cys641 was located on the binding surface of CESA1 and CESA9, and Cys562 was very close to the binding surface. Cellulose synthase complexes (CSCs) dynamics are closely associated with cellulose content. S-nitrosylation of CESA1 and CESA9 improved particles mobility and thus increased the accumulation of cellulose in Arabidopsis hypocotyl cells. An increase in hemicellulose content as well as an alteration in pectin content facilitated cell wall extension and contributed to cell growth, finally promoting elongation of Arabidopsis hypocotyls. Overall, our work provides a path to investigate the way NO affects the cellulose content of plants.

Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer.

Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.

Biomimetic Prussian blue nanozymes with enhanced bone marrow-targeting for treatment of radiation-induced hematopoietic injury.

There is an urgent medical need to develop effective therapies that can ameliorate damage to the radiation-exposed hematopoietic system. Nanozymes with robust antioxidant properties have a therapeutic potential for mitigating radiation-induced hematopoietic injury. However, enhancing nanozyme recruitment to injured tissues in vivo while maintaining their catalytic activity remains a great challenge. Herein, we present the design and preparation of a biomimetic nanoparticle, a mesenchymal stem cell membrane camouflaged Prussian blue nanozyme (PB@MSCM), which exhibits biocompatible surface properties and demonstrates enhanced injury site-targeting towards the irradiated murine bone marrow niche. Notably, the constructed PB@MSCM possessed redox enzyme-mimic catalytic activity and could scavenge overproduced reactive oxygen species in the irradiated bone marrow cells, both in vitro and ex vivo. More importantly, the administration of PB@MSCM significantly mitigated hematopoietic cell apoptosis and accelerated the regeneration of hematopoietic stem and progenitor cells. Our findings provide a new targeted strategy to improve nanozyme therapy in vivo and mitigate radiation-induced hematopoietic injury.

SMEK1 promotes lung adenocarcinoma proliferation and invasion by activating Wnt/ß-catenin signaling pathway.

PURPOSE: SMEK1, also known as PP4R3α, the regulatory subunit 3α of serine and threonine phosphatase PP4, participates in diversely critical biological processes such as the integration of centromere, deacetylation of histones, asymmetric divisions of neuroblast, and other crucial cellular activities. SMEK1 was formerly reported to play a part in carcinogenesis. This study aims to reveal the role of SMEK1 in lung adenocarcinoma and the underlying molecular mechanism. METHODS: Using immunohistochemical (IHC) staining, the protein level of SMEK1 in lung adenocarcinoma and adjacent non-tumor tissue was detected. The functional role of SMEK1 in cell proliferation and invasion was explored using cell counting kit-8 and Transwell assay, respectively. Xenograft tumor experiment was used to investigate the effect of SMEK1 on tumor growth in vivo. The alteration of Wnt/ß-catenin signaling pathway was detected by Western blotting, quantitative PCR, and dual-luciferase reporter assays. RESULTS: SMEK1 was highly expressed at the protein level in lung adenocarcinoma compared to the adjacent non-tumor tissue. In vitro, suppression of SMEK1 significantly decreased the proliferation, migration, and invasion of lung adenocarcinoma cell lines, while overexpression of SMEK1 enhanced above abilities. The xenograft model demonstrated that down-regulation of SMEK1 significantly inhibited tumor growth in vivo. In addition, we found that SMEK1 could positively regulate Wnt/ß-catenin signaling in lung adenocarcinoma cell lines. CONCLUSIONS: SMEK1 exerts a cancer-promoting effect in lung adenocarcinoma by activating Wnt/ß-catenin signaling.

Cardiac Substructures Dosimetric Predictors for Cardiac Toxicity After Definitive Radiotherapy in Esophageal Cancer.

PURPOSE: To investigate the predictive value of the cardiac substructures (CSs) dosimetric parameters for cardiac toxicity after definitive radiation therapy in locally advanced esophageal cancer. METHODS AND MATERIALS: Between August 2010 and January 2016, 716 patients with stage 2-3 esophageal cancer receiving definitive radiation therapy at 2 institutions were divided into training (n = 432) and external validation (n = 284) cohorts. Dose-volume histogram parameters for the whole heart (WH) and CSs were extracted. Competing risks and Cox regressions analyses were performed. The predictive performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC) and the Brier score. RESULTS: With a median follow-up of 93 months, 68 patients (15.7%) developed grade ≥3 cardiac events (G3+ CEs), with a median of 13.5 months to the first event. Multivariable analysis showed left ventricle, left anterior descending (LAD), and mean left circumflex (LCX) variables were significantly associated with G3+ CEs. The AUCs and Brier scores demonstrated favorable predictive accuracies of the models integrating these CS variables when predicting G3+ CEs in the training and validation cohorts. However, compared with the WH variables, the CS variables did not significantly improve the prediction of G3+ CEs. Nevertheless, when G3+ acute coronary syndrome and/or congestive heart failure (ACS/CHF) CE was the outcome of interest, models based on the LAD or LCX variables were superior to the WH variable models in training and validation cohorts. CONCLUSIONS: Models based on CS variables showed favorable predictive accuracy for G3+ CEs. The LAD and LCX variables significantly improved the prediction of G3+ ACS/CHF events compared with the WH variables. Radiation doses to CSs, such as LCX and LAD, should be monitored to help reduce the occurrence of significant CEs in patients with esophageal cancer undergoing definitive radiation therapy.

Afatinib treatment in a lung adenocarcinoma patient harboring a rare EGFR L747P mutation.

Classical activating alterations including exon 19 deletions and exon 21 L858R point mutations comprise the majority of epidermal growth factor receptor (EGFR) changes in non-small cell lung cancer. Patients with these exhibit excellent clinical responses to EGFR tyrosine kinase inhibitors (TKIs). However, rare alterations including point mutations, deletions, and insertions occur and are associated with poorer responses to EGFR TKIs. Herein, we report an unusual case of a patient with lung adenocarcinoma with an EGFR L747P mutation (c. 2239_2240TT>CC, p.L747P) that was initially misdiagnosed as EGFR exon 19 deletion by amplification refractory mutation system PCR, leading to gefitinib as first-line therapy. However, both the primary tumor, mediastinal lymph node, and brain metastasis progressed after 1 month. A re-examination of gene mutation status by next generation sequencing revealed an EGFR exon 19 L747P, and this case then responded to second-line chemotherapy and third-line afatinib.

Diagnostic Accuracy of the Apparent Diffusion Coefficient for Microvascular Invasion in Hepatocellular Carcinoma: A Meta-analysis.

Background and Aims: Microvascular invasion (MVI) is a major risk factor for the early recurrence of hepatocellular carcinoma (HCC) and it seriously worsens the prognosis. Accurate preoperative evaluation of the presence of MVI could greatly benefit the treatment management and prognosis prediction of HCC patients. The study aim was to evaluate the diagnostic performance of the apparent diffusion coefficient (ADC), a quantitative parameter for the preoperative diagnosis MVI in HCC patients. Methods: Original articles about diffusion-weighted imaging (DWI) and/or intravoxel incoherent motion (IVIM) conducted on a 3.0 or 1.5 Tesla magnetic resonance imaging (MRI) system indexed through January 17, 2021were collected from MEDLINE/PubMed, Web of Science, EMBASE, and the Cochrane Library. Methodological quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). The pooled sensitivity, specificity, and summary area under the receiver operating characteristic curve (AUROC) were calculated, and meta-regression analysis was performed using a bivariate random effects model through a meta-analysis. Results: Nine original articles with a total of 988 HCCs were included. Most studies had low bias risk and minimal applicability concerns. The pooled sensitivity, specificity and AUROC of the ADC value were 73%, 70%, and 0.78, respectively. The time interval between the index test and the reference standard was identified as a possible source of heterogeneity by subgroup meta-regression analysis. Conclusions: Meta-analysis showed that the ADC value had moderate accuracy for predicting MVI in HCC. The time interval accounted for the heterogeneity.

Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: A multicenter pooled analysis.

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

A Lung Cancer Patient Harboring a Rare Oncogenic EGFR Exon 20 V786M Mutation Responded to a Third-Generation Tyrosine Kinase Inhibitor: Case Report and Review of the Literature.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. There are many uncommon and rare mutations in the EGFR gene. The efficacy of the EGFR-TKIs is largely unknown for cancers harboring uncommon or rare EGFR mutations. Case Presentation: A 69-year-old woman was diagnosed with adenocarcinoma cT4N2M1c, stage IVB. Next-generation sequencing (NGS) confirmed a rare EGFR V786M mutation. During chemotherapy, immune checkpoint inhibitor (ICI), and anti-angiogenic treatment, no radiological response was observed. Subsequent third-generation EGFR TKI showed a remarkable therapeutic effect. Structural prediction revealed that the V786M mutation induces conformational change at the dimer interface, without altering the ATP binding to the EGFR tyrosine kinase domain (TKD). Consistently, docking simulations indicated that the affinity of ATP to the V786M mutant was not disturbed, which explained the TKI sensitivity. Conclusions: Our data confirmed the activating role on EGFR V786M mutation. Together with structural predictions and clinical evidence for activity of TKIs against EGFR V786M mutations, these findings warrant further investigation.

Association of microRNA polymorphisms with gastric cancer risk in the North Chinese Han population.

Background and Aims: MicroRNA (miRNA) was found as a class of endogenous, important regulators of gene expression and involved in the regulation of many biological processes such as cell proliferation, apoptosis, and differentiation. Increasing studies have suggested that miR-146a, miR-196a2, and miR-499 play important roles in the development processes of gastric cancer (GC). The aim of our study is to investigate whether three common miRNA polymorphisms are associated with the susceptibility of GC. Materials and Methods: MiR-146a rs2910164 (G > C), miR-196a2 rs11614913 (C > T), and miR-499 rs3746444 (A > G) were genotyped by Taq-man assays in the present case-control study (386 patients, 341 controls). The associations between the selected miRNA single-nucleotide polymorphisms (SNPs) and the risk of GC were estimated by odds ratio (OR) with 95% confidence interval using logistic regression analysis. Results: Our results showed that none of the three SNPs was associated with the risk of GC in allelic frequencies and multiple genetic models. Further stratified analysis with regard to clinical-pathological parameters of GC patients indicated that miR-146a rs2910164 SNP was strongly associated with age (OR = 0.53, P = 0.001) and gender (OR = 0.61, P = 0.006). Conclusions: The present study showed no association of the investigated miRNA SNPs with the risk of GC in the north Chinese population.