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Colorectal cancer (CRC) is one of the most common malignancies. Although CRC treatment has been significantly improved, patient survival remains low because most patients already have advanced disease at diagnosis. Early screening and diagnosis of tumors is critical; however, the current tissue biopsy and radiological evaluation methods have very limited effectiveness. Therefore, establishing new convenient and non-invasive biomarkers is urgently needed for timely detection, therapeutic assessment, and prognostic prediction. At present, non-coding RNAs (ncRNAs) have attracted research attention owing to their potential oncological applications.The long ncRNA epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) is overexpressed in multiple malignancies including CRC. The present study examined the circulating EGFR-AS1 level in CRC, and the results showed that EGFR-AS1 could be considered an indicator of tumor burden.Elevated circulating EGFR-AS1 levels were detected in CRC cases (n=128) compared with control cases comprising endoscopy confirmed CRC-free individuals [n=64, median expression normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 1.578These results highlight the potential of EGFR-AS1 as a diagnostic biomarker in CRC.

The types of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients who could obtain significant clinical benefit from the dual inhibition of EGFR/vascular EGFR (VEGFR) pathways remain unclear. No consensus has been reached on the significance of smoking habits in clinical benefit obtained from EGFR-TKI plus anti-angiogenic agents.PubMed, EMBASE, and Cochrane databases for all phase II/III randomized clinical trials (RCTs) investigating the efficacy of EGFR-TKI combined with anti-angiogenic agents stratified by smoking habits (updated October 2021) were searched systematically. The primary outcomes were the pooled HRs for PFS/OS in smokers and non-smokers, and differences in efficacy of EGFR-TKI plus anti-angiogenic treatment between smokers and non-smokers, measured by difference in PFS and OS.Seven phase II/III RCTs involving 1452 patients were identified. The pooled analysis demonstrated that EGFR-TKI plus anti-angiogenic agent could decrease the risk of progression by 40% (HR, 0.60; 95%CI 0.48-0.75) in smokers when compared with EGFR-TKI alone, but not in non-smokers (HR, 0.92; 95%CI 0.68-1.25). The comparison analysis further demonstrated that EGFR-mutated NSCLC patients who smoked obtained greater progression-free survival (PFS) benefit from treatment with EGFR-TKI plus anti-angiogenic agents (HR, 0.68; 95%CI 0.51-0.91). Consistent with the results for PFS, smokers receiving EGFR-TKI plus anti-angiogenic agents appeared to exhibit better overall survival (OS) than non-smokers but not to a statistically significant degree (HR, 0.60; 95%CI 0.23-1.52). Meta-regression analysis revealed no significant effect of the line of treatment (P = 0.52), trial phase (P = 0.52), EGFR-TKI type (P = 0.13), or anti-angiogenic agent type (P = 0.50) on PFS effect sizes under multivariate models.Comprehensive analysis suggested that EGFR-TKI plus anti-angiogenic agents led to favorable PFS among smoking EGFR-mutant patients, comparable to nonsmokers, which might provide a useful guide for clinicians.

Current therapeutic regimens for patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated colorectal cancer show unsatisfactory efficacy. To improve outcomes in this area, we assessed the safety and efficacy of a new protocol using vemurafenib and cetuximab combined with FOLFIRI (5-fluorouracil/leucovorin/irinotecan) in patients with BRAF V600E-mutated colorectal cancer.This was an investigator-initiated, open-label, single-arm, phase II trial conducted in patients with BRAF V600E-mutated advanced colorectal cancer. Patients were eligible to receive FOLFIRI combined with vemurafenib and cetuximab. The primary end-point was the objective response rate, and the secondary end-points included disease control rate, progression-free survival, overall survival and safety. This trial is registered with ClinicalTrials.gov, NCT03727763.Between 12th January 2018, and 18th June 2021, we screened 27 patients, 21 of which were enrolled in this study. Efficacy analysis showed that objective response rates were 81.0% (17/21; 95% confidence interval [CI] 57.4-93.7) in the intention-to-treat population and 85.0% (17/20, 95%CI 61.0-96.0) in the per-protocol population; two patients achieved complete response, and 15 patients achieved a partial response. In the entire cohort, the median progression-free survival was 9.7 months (95%CI 6.3-10.9), and the median overall survival for all patients was 15.4 months (95%CI 8.5-15.4). The most common adverse events (grade 3 to 4) were neutropenia (8/21), anaemia (3/21) and skin rash (3/21).Vemurafenib and cetuximab can be safely combined with the FOLFIRI regimen, showing promising antitumour activity and tolerable toxicity in patients with BRAF V600E-mutated advanced colorectal cancer. This regimen warrants a further randomised study in phase III clinical trials.

Purpose:Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non–small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641).Patients and Methods:Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone.Results:Overall, 300 treatment-naïve patients with stage IIIB–IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24–0.88; P = 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04–0.50; P = 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs).Conclusions:Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.

Other driver mutations in 22 discordant cases.

Kaplan-Meier curves for progression-free survival (A) EGFR detected in ctDNA/tissue of the 112 patients for EGFR-TKI efficacy analysis. (B) EGFR dominance analysis according to ctDNA or tissue of patients in (A). (C) Discordance of EGFR dominance analyzed by ctDNA or tissue of the 73 patients with EGFR detected in both ctDNA and tissue (D) Progression-free survival according to mutation clusters in ctDNA (n=85). (E) Progression-free survival according to mutation clusters in tissue (n=100). ctDNA=circulating free tumor-derived DNA. HR=hazard ratio.

BACKGROUND: The concordance between mutations detected from plasma and tissue is critical for treatment choices of patients with advanced lung adenocarcinoma. METHODS: We prospectively analyzed the association of the serum tumor markers with the concordance between blood and tissue genomic profiles from 185 patients with advanced lung adenocarcinoma. The concordance was defined according to 3 criteria. Class 1 included all targetable driver mutations in 8 genes; class 2 included class 1 mutations plus mutations in KRAS, STK11, and TP53; class 3 included class 2 mutations plus tumor mutation burden (TMB) status. RESULTS: Collectively, 150 out of 185 patients had mutations in both tissue and plasma samples, while one patient was mutation-negative for both, resulting a concordance of 81.6%. The concordance rate for class 1 mutations was 80%, and 65% and 69% for class 2 and class 3, respectively. Carbohydrate antigen 19-9 (CA19-9) or cytokeratin 19 (CYFRA21-1) levels higher than the normal upper limit predicted the concordance of tissue and blood results in class 1 (P=0.005, P=0.011), class 2 (P=0.011, P0.99, P>0.99). When the sum score for 4 serum tumor markers was greater than 35, both class 1, class 2, and class 3 reached a predictive threshold of 90%. CONCLUSIONS: Serum tumor markers can be used as easy and practical clinical predictors of concordance in mutation profiles between blood and tissue samples from patients with advanced lung adenocarcinoma.

Background DICER is a key RNase III enzyme that cleaves processes miRNAs into their mature form. It is remarkably down-regulated in most epithelial ovarian cancer (EOC) and the down-regulation is associated with high grade malignancy as well as poor clinical outcomes. In this study, we aimed to discover a lncRNA interacting with DICER to participate in the process of microRNAs maturation and as a result promoting development of EOC. Methods We conducted a RIP-seq aimed at DICER and we obtained its chromosomal location by aligning the sequence in PubMed. And the lncRNA was named DATOC-1 (DICER Associated Transcript 1 in Ovarian Cancer). We tested relative expression of DATOC-1 in 53 EOC and 7 adjacent ovarian samples by qRT-PCR. Then the expression in EOC patients derived from The Cancer Genome Atlas (TCGA) were analysed to identify DATOC-1-based signatures for EOC prognosis with survival analysis. Lastly, shRNA Screening and lentiviral transduction was used to determine the function of DATOC-1 in vitro and in vivo. Results We identified the lncRNA RP5-1120P11.1 as DATOC-1, which highly expressed in EOC tissues than in adjacent. And Kaplan-Meier analysis indicated that the patients with EOC that expressed high levels of DATOC-1 had a worse prognosis and shorter disease OS compared with DATOC-1 low-expressed patients. In addition, DATOC-1 were further identified participating in EOC cell proliferation, cell cycle regulation and cell invasion. And knockdown of DATOC-1 inhibits tumor progression in vivo. Furthermore, knockdown of DATOC-1 increased the expression of miR7. The evidence showed that miR7 functioning as a tumor suppressor gene in EOC. Conclusions Our research shows that DATOC-1 can inhibit the development of EOC and is a promising therapeutic target.

Purpose: Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non–small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641). Patients and Methods: Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone. Results: Overall, 300 treatment-naïve patients with stage IIIB–IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24–0.88; P = 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04–0.50; P = 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). Conclusions: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.

Purpose Our study intended to explore how low-dose anti-angiogenic drugs affected anti-tumor immunity of tumor-infiltrating exhausted CD8+T cells and achieved better clinical response when combined with immunotherapy. We set out to find potential targets or predictive biomarker on CD8+T cells for immunotherapy. Methods We tested different doses of anti-VEGFR2 antibody combined with anti-PD1 antibody to treat LUAD in vivo and analyzed tumor-infiltrating CD8+T cells by flow cytometry. CD8+T cells overexpressing LAYN were co-cultured with LA795 cell lines to identify the function of LAYN in CD8+T cells. We also analyzed clinical samples from advanced LUAD patients treated with anti-angiogenesis therapy combined with immunotherapy. Results Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody treatment delayed tumor growth and prolonged the survival time of tumor-bearing mice. The number of tumor-infiltrating CD8+T cells was reduced and the expression of LAYN was down-regulated in tumor-infiltrating CD8+T cells in the low-dose anti-VEGFR2 combination group. It was found that LAYN inhibited the killing function of CD8+T cells. In patients with advanced LUAD who received anti-angiogenesis therapy combined with immunotherapy, the LAYN+CD8+T cell subpopulation in good responders was significantly higher than that in poor responders. Furthermore, we demonstrated the expression of LAYN was regulated by upstream transcription factor NR4A1. Conclusion Low-dose anti-VEGFR2 antibody combined with anti-PD1 antibody therapy promoted anti-tumor immunity and the downregulation of LAYN in tumor-infiltrating CD8+T cells played an important role in this process. These findings had implications for improving the efficacy of immune checkpoint blockade therapy and further optimized clinical treatment guidelines in advanced LUAD.

Background BRAF V600E mutation represents a group of colorectal carcinoma with poor prognosis. Although treatment strategies have been recommended after clinical investigations, the progression-free survival is short and unsatisfying. Case presentation Here, we present the case of a 28-year-old male diagnosed with ascending colon adenocarcinoma with multiple liver metastases. Treatment with FOLFIRI plus cetuximab and vemurafenib achieved partial response, following which the patient received conversion surgery with clear resection margin. After disease recurrence, he received combination treatment of nivolumab and regorafenib. Until August 2020, the patient achieved a partial response with more than 12 months progression-free survival. Circulating tumor DNA (ctDNA) was monitored during the patient's treatment. His ctDNA fractions exhibited significant elevation two months before disease progression. As a comparison, the tumor markers were not elevated until the patient was confirmed PD through CT imaging. Conclusion This case exemplifies how liquid biopsy and ctDNA sequencing can aid in real-time molecular characterization of tumors.

IL-10 is critical for Foxp3+ regulatory T cell (Tregs)–mediated immune suppression, but how to efficiently upregulate IL-10 production in Tregs remains unclear. In this article, we show that human IL-10+ FOXP3+–induced regulatory T cell (iTreg) generation can be dramatically promoted by inhibiting GSK3 activity. IL-10+ FOXP3+ iTregs induced by GSK3 inhibition exhibit classical features of immune-suppressive T cells. We further demonstrate that IL-10+ iTregs exhibit enhanced suppressive function in both IL-10–dependent and –independent manners. The enhanced suppressive function of IL-10+ Tregs is not due to a single factor such as IL-10, although IL-10 may mediate this enhanced suppressive function to some extent. Mechanistically, the increased transcriptional activity of IL-10 promoter and the enhanced expression of C-Maf and BLIMP1 coordinately facilitate IL-10 expression in human iTregs under GSK3 inhibition. Our study provides a new strategy to generate human immune-suppressive IL-10+ FOXP3+ Tregs for immunotherapies.

Background Previous studies have suggested the efficacy of HER2 antibody (trastuzumab) in scrotal Paget's disease with HER2 amplification or overexpression. However, no report about the effectiveness of HER2 inhibitor (pyrotinib) in those patients has been provided until now. Case presentation We present a case of a Chinese patient with bone-metastatic scrotal Paget's disease harboring triple uncommon HER2 mutations (R678Q/S310Y/S310F). Due to poor conditions (severe anemia, thrombocytopenia, ECOG PS3), this patient could not tolerate traditional chemotherapy and radiotherapy. Then, the patient participated in a registered clinical trial (NCT03239015) about basket trial for intractable cancer. The patient received pyrotinib (400 mg po qd) and achieved a partial response for 4.0 months. Conclusion This is the first report describing a patient with scrotal Paget's disease harboring triple uncommon HER2 mutation who responds well to pyrotinib. This case suggested that HER2 mutation is also a potential biomarker for treatment in extramammary Paget's disease and pyrotinib may be an ideal choice for these patients.

Background: Tumor mutation burden (TMB) is novel biomarker of promising predict value in prediction of immune checkpoint inhibitors (ICPis) in non-small cell lung cancer (NSCLC). However, the distribution of TMB in epidermal growth factor receptor ( EGFR )-mutant advanced lung adenocarcinoma (LUAD) patients and the impact on overall survival (OS) time are not well demonstrated. Methods: Information regarding gene mutations and patients’ survival time in advanced LUAD was downloaded from The Cancer Genome Atlas (TCGA) database. The diversity of TMB in different EGFR - mutant types was observed and the predicted value of TMB for OS as well as other co-mutations were analyzed. The diversity of TMB was also observed in another Chinese cohort of advanced LUAD patients. Results: The median TMB values of EGFR wild-type, other types of EGFR mutations, exon 19 deletions and L858R were 6.12, 5.66, 3.77 and 4.72, differences between wild-type and EGFR sensitive mutations (exon 19 deletion or L858R) were significant (P EGFR -mutant advanced LUAD patients. Distribution of TMB in another Chinese cohort had the same trend. Conclusions: In advanced LUAD patients, TMB was lower in patients with EGFR -mutant group than EGFR wild group. TMB was a negative prognostic biomarker of OS in EGFR -mutant LUAD patients, especially when TP53 was mutated together.

Background: Metastasis suppressor 1 (MTSS1), a potential metastasis suppressor gene associated with tumor progression, may play an important role in cancer development. Our previous study demonstrated that MTSS1 was downregulated significantly when gastric cancer (GC) progressed and metastasized, suggesting that MTSS1 may be involved in the physiopathologic mechanism of GC. Purpose: The objective of this study was to evaluate the effect of MTSS1 expression on the biological behavior of gastric cancer cell both in vitro and in vivo. Materials and methods: The gain-and-loss function of MTSS1 in GC cells were analyzed after transfection with pEGFP-N1-MTSS1 and ShRNA431. Proliferation and invasion abilities were measured by means of plate clone formation assay and transwell assay. To further explore the underlying mechanism of MTSS1-induced tumor restrain, cell cycle distribution was analyzed using flow cytometry. Results: The results revealed that overexpression of MTSS1 significantly reduced proliferation, migration and invasion of GC cells in vivo and in vitro, while downregulation of MTSS1 had the opposite biological manifestations. Moreover, overexpression of MTSS1 induced accumulation of GC cells in G2/M phase, increased phosphorylated Cdc2 expression and decreased Cdc25C and cyclinB1 levels, suggesting MTSS1 could cause G2/M cell cycle arrest. Conclusion: Our data provided insight into an important role for MTSS1 in suppressing tumor cell proliferation, invasion and migration, indicating that MTSS, as a functional tumor suppressor in GC, could be a potential therapeutic target to prevent GC metastasis.

Background The present study aimed to evaluate the effects of concomitant proton pump inhibitor (PPI) use on immune checkpoint inhibitor (ICI) efficacy among advanced cancer patients. Methods and Materials A systematic literature search of electronic database was performed to identify all potential reports. Then, meta-analyses were conducted to obtain pooled HRs with 95% CIs, which reveal the influence of PPI use on PFS and OS in patients receiving ICI treatment. Results A total of 7 studies with 3,647 advanced cancer patients fulfilled the inclusion criteria. The impact of PPI use was then evaluated on 3,340 patients for PFS and 3,647 patients for OS. Concomitant PPI use has a detrimental effect on the efficacy of ICIs that PPI use increased the risk of progression by 28% (HR = 1.28, 95% CI 1.17–1.40; I2 = 31.3%, Q test P = .21) when compared to those not receiving PPIs. Similarly, the meta-analysis showed that PPI use was also associated with shorter OS of advanced cancer patients receiving ICIs that PPI use increased risk of death by 39% (HR = 1.39, 95% CI 1.26–1.54; I2 = 36.5%, Q test P = .16). Sensitivity analysis showed that the pooled HRs were constant after excluding one study at a time, and no significant publication biases were detected. Conclusion The meta-analysis suggested that concomitant PPI use is significantly associated with low clinical benefit in ICI treatment, revealing a significantly reduced PFS and OS in advanced cancer patients receiving ICIs who are also exposed to PPI.

BACKGROUND: Primary squamous cell carcinoma of pancreas (SCCP) is an extremely rare pathological subtype of pancreatic cancer of ductal origin. Due to its rarity, most previous studies on SCCP focused on case reports or series and the clinio-pathological characteristics of SCCP patients remain unclear. METHODS: A retrospective analysis of SCCP patients registered in the Surveillance, Epidemiology and End Results (SEER) database from 1988 to 2016 were performed, and clinical characteristics and prognosis of these patients were also further determined. RESULTS: A total of 373 patients diagnosed with SCCP were identified. Most SCCP patients 154/243 (63.4%) SCCP patients had distant metastases. The prognosis of SCCP patients was poor with a median overall survival (mOS) of only 3.0 months (95% CI, 2.0–5.0). The 6-month, 1-year and 2-years survival rate were 25.6%, 13.2% and 5.7%, respectively. The prognosis of SCCP patients became much worse with the increasing age (P=0.01) and distant metastases (P

Recurrent inactivated mutations in central precocious puberty-associated gene MKRN3 lead to lung cancer proliferation and progression through PABPC1 ubiquitination–mediated global protein synthesis. MKRN3 is a bona fide tumor suppressor, and MKRN3-PABPC1 deregulation represents a key pathway in NSCLC oncogenesis., Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non–small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell–specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry–based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor., Graphical Abstract

Background: Functional heterogeneity among TP53 mutations necessitates a need to dissect the prognostic potential of TP53 mutations at different sites or against different molecular background. Methods: The information of TP53 mutations and overall survival time among 7572 patients with metastatic cancers in the MSK-IMPACT clinical sequencing cohort were collected. The effects of TP53 mutations on survival were conducted using the Kaplan-Meier approach, log-rank test and Cox regression model in pan-cancer, and in major subtypes of lung, breast, and colon cancers. Findings: Mutations in exons 4, 5, 6, 7, 8, and 10, p.R342*, p.Y220C, and p.G245S were identified as potential pan-cancer poor prognosticators (p < 0.05 for all). R213* was identified as a significant poor prognosticator only in metastatic lung adenocarcinoma (p = 0.01). The negative prognostic effect of mutated TP53 was statistically significant in lung adenocarcinoma patients harboring EGFR p.L858R (p = 0.002), but not in those with exon 19 deletion (p = 0.173). Compared with wild-type TP53, higher risk of death correlated with TP53 mutational status located in exon 4, 5, 6, 7, or 8 among patients with metastatic breast invasive ductal carcinoma. In addition, p.R282W substitution was significantly associated with poor prognosis in metastatic colon adenocarcinoma (mCOAD), while TP53 mutation was also significantly negative associated with poor survival in COAD patients carrying driving mutations (KRAS or RAS/RAF). Interpretation: The prognostic values of TP53 mutation depended on cancer type and concurrent genomic abnormality. Our results may facilitate prognosis, patient identification for further investigation, and development of TP53 -targeted anti-cancer therapy. Funding: This work was supported by the Logistics Support Department of PLA [grant number 19BJZ03, 2019], Military Medicine Fund of Changzheng Hospital [grant number 2019CZJS208-1, 2019], Science and Technology Commission of Shanghai Municipality [grant number17511103403, 2017], Medical Innovation Research Project of Shanghai Science and Technology Commission (grant number 20Y11914400, 2020), Chinese National Natural Science Funding [grant number 82002522, 2020]and State Key Program for Chronic non- communicable Disease Prevention and Control of the Ministry of Science and Technology, China (grant number 2017YFC1309202, 2017). Declaration of Interest: All authors declare no conflicts of interest.

The addition of trastuzumab to chemotherapy regimen is the standard of care for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer; however, most patients eventually acquire trastuzumab resistance. Although some resistance mechanisms to trastuzumab-based regimens have been proposed, further understanding is required for developing therapeutic strategies to overcome the resistance. In the present work, we attempted to determine the possible resistance mechanism to trastuzumab in a patient with HER2-positive stage IV gastric adenocarcinoma. In this study, we first report the nucleotide change c.1899-1G>A at the intron 15 acceptor splice site promoting exon 16 deletion of HER2 as the potential mechanism of trastuzumab resistance in HER2-positive gastric adenocarcinoma. Key Points The combination of trastuzumab with chemotherapy is considered to be the standard therapy for HER2-positive advanced gastric cancer (GC), but most of the patients eventually acquire trastuzumab resistance. The mechanisms of resistance to trastuzumab in GC are poorly characterized. To the best of the authors' knowledge, this study is the first to implicate HER2 c.1899-1G>A, which results in exon 16 skpping, as the acquired resistance mechanism to trastuzumab in HER2-positive gastric adenocarcinoma. This work provides insights into the potential molecular mechanism of trastuzumab resistance, which is crucial in developing effective therapeutic strategies for HER2-positive GC patients refractory to trastuzumab.

Background Subgroup analysis of clinical trials of PD-1/PD-L1 inhibitors have reported ethnic differences in outcomes. We systematically collected published data and performed a meta-analysis to compare therapeutic efficacy in Asian and non-Asian patients receiving PD-1/PD-L1 inhibitors. Methods Eligible studies included phase II and III prospective clinical trials with available subgroup data on Asian versus non-Asian populations. Overall survival (OS) and progression-free survival (PFS) were used to evaluate differences in outcome between Asian versus non-Asian cancer patients. Results A total of 11,020 cancer patients from 19 prospective randomized controlled clinical trials were included. The overall estimated HR for OS was 0.69 with 95% CI of 0.61–0.77 in Asian versus 0.82 with 95% CI of 0.77–0.88 in non-Asian patients. The estimated hazard ratio (HR) for PFS measured 0.54 (95% CI, 0.32–0.76) and 0.69 (95% CI, 0.54–0.85) in Asian and non-Asian patients, respectively. Pooled ratios of OS HRs and PFS HRs reported in Asian versus non-Asian cancer patients were 0.84 (95% CI, 0.75–0.94) and 0.78 (95% CI, 0.59–0.97), respectively. Conclusions This meta-analysis shows for the first time that Asian cancer patients have a significantly improved survival benefit than non-Asian patients receiving PD-1/PD-L1 inhibitor-based therapy.

To compare the efficacy and safety profile of S-1-based versus non-S-1-based chemotherapy as first-line treatment in mCRC. Relevant randomized controlled trials (RCTs) were obtained from PubMed, Embase, and Ovid databases and the Cochrane library from database set up in May 2018. The RCTs of S-1-based monotherapy or combination therapy as first-line treatment were selected. The impact of S-1-based chemotherapy on progression-free survival (PFS) and overall survival (OS) was assessed by pooling data via RevMan 5.3. Meta-analysis of 10 RCTs showed that S-1-based chemotherapy significantly improved PFS (HR 0.90, 95% CI 0.84–0.97, P = 0.006). In subgroup analysis, there was a statistically significant increase in PFS when S-1-based chemotherapy was compared with 5-FU-based (HR 0.92, 95% CI 0.84–1.00, P = 0.04) or capecitabine-based chemotherapy (HR 0.85, 95% CI 0.73–0.99, P = 0.04). The meta-analysis of OS (HR 0.95, 95% CI 0.86–1.05, P = 0.36), overall response rate (ORR) (HR 0.99, 95% CI 0.84–1.17, P = 0.90), and disease control rate (DCR) (HR 1.61, 95% CI 0.87–3.00, P = 0.13) showed no statistical significance between S-1-based and non-S-1-based chemotherapy. The statistically significant differences in the meta-analysis indicated less incidence of graded 3–4 leucopenia (OR = 0.30, 95% CI 0.13–0.71, P = 0.006) and hand–foot syndrome (HFS) (OR = 0.24, 95% CI 0.10–0.58, P = 0.001) in the S-1-based chemotherapy, and there was no statistically significant difference for other adverse events. S-1-based chemotherapy in mono or combined therapy was an attractive alternative to standard first-line regimen for patients of mCRC.

This article reports a case of advanced metastatic low-grade sarcoma. The patient was diagnosed with an inoperable large (14 × 12 cm) lesion on his neck in September 2015 and underwent two ineffective chemotherapies in the following 4 months. Interestingly, although several pathologists could not agree on the histopathological diagnosis, the precise molecular pathological diagnosis was obtained using next-generation sequencing (NGS) and finally brought excellent therapeutic effects. The patient was detected to have CARS-ALK fusion by NGS and then was successfully treated with crizotinib orally. He received surgical resection of primary and metastatic lesions after tumor shrinkage. The combined treatment brought a durable response for 40 months. Although the tumor recurred in July 2019, the patient has been responding well to the second-line ALK tyrosine kinase inhibitor alectinib to date. We performed whole genome sequencing on the patient's primary, metastatic, and recurrent tumors and did comprehensive genomic analysis. Furthermore, our analysis results revealed that a whole genome duplication event might have happened during tumorigenesis of this case. Key Points To our best knowledge, this is the first report of a very successful treatment with first- and second-line ALK tyrosine kinase inhibitors for CARS-ALK fusion–positive metastatic low-grade sarcoma. Molecular pathological result can guide precision treatment for sarcoma, even when the exact histopathology cannot be obtained. Multiple samples from this patient were analyzed using whole genome sequencing. Results provided detailed genomic characteristics and showed tumor evolution of this low-grade sarcoma case. A whole genome duplication event might have happened during tumorigenesis of this low-grade sarcoma case.

IL-10 is critical for Foxp3(+) regulatory T cell (Tregs)–mediated immune suppression, but how to efficiently upregulate IL-10 production in Tregs remains unclear. In this article, we show that human IL-10(+) FOXP3(+)–induced regulatory T cell (iTreg) generation can be dramatically promoted by inhibiting GSK3 activity. IL-10(+) FOXP3(+) iTregs induced by GSK3 inhibition exhibit classical features of immune-suppressive T cells. We further demonstrate that IL-10(+) iTregs exhibit enhanced suppressive function in both IL-10–dependent and –independent manners. The enhanced suppressive function of IL-10(+) Tregs is not due to a single factor such as IL-10, although IL-10 may mediate this enhanced suppressive function to some extent. Mechanistically, the increased transcriptional activity of IL-10 promoter and the enhanced expression of C-Maf and BLIMP1 coordinately facilitate IL-10 expression in human iTregs under GSK3 inhibition. Our study provides a new strategy to generate human immune-suppressive IL-10(+) FOXP3(+) Tregs for immunotherapies.

The prognostic value of TP53 in advanced non-small-cell lung cancer (NSCLC) is unclear. Whether different mutated exon has different prognostic value is unknown. We sought to reveal the prognostic value of TP53 in advanced NSCLC, as well as the correlation with EGFR mutation.Information regarding TP53 and EGFR alterations and patients' survival time in advanced NSCLC was downloaded from the Cancer Genome Atlas Database. We further subdivided TP53 and EGFR mutation into subgroups based on different mutation exon, and then evaluated the distribution of different mutation exon as well as the prognostic value.Overall, 1441 pieces of data from 1441 metastatic NSCLC patient were collected. Mutation rate of TP53 was 56.1% (809/1441). TP53 mutation was a negative prognostic factor for OS. The estimated survival time for wild type TP53 and mutated TP53 was 27.0 months (95% CI, not reached) and 19 months (95% CI, 16.62 to 21.38), respectively, (p 0.001). We divided TP53 mutations into 4 groups, OS in these 4 groups was 27 months (95% CI, not reached), not reached, 21 months (95% CI, 17.16 to 24.84) and 13 months (95% CI, 10.39 to 15.61). The difference was statistically significant (p 0.001). Patients with EGFR exon 19/21 or non-exon 19/21 mutation demonstrated a higher rate of mutated type TP53 than EGFR wild type patients. Survival curve in EGFR wild type patients indicated that TP53 wild type patients had the best prognosis. In patients with exon 19/21 mutated EGFR, the trend was the same (P 0.001).TP53 mutation is a negative prognostic factor in advanced NSCLC, different mutated exon has different prognostic value. When coupled with EGFR mutation, we can predict the prognosis of advanced NSCLC patients more accurately.

In patients without tissue availability at presentation, the analysis of cell-free DNA derived from liquid biopsy samples, in particular from plasma, represents an established alternative for providing epidermal growth factor receptor (EGFR) mutational testing for treatment decision-making. Compared with quantitative polymerase chain reaction and digital polymerase chain reaction-targeted methods, next-generation sequencing can provide more information about tumor molecular alterations, especially EGFR mutations. Here, we present a case of a patient with non-small cell lung cancer (NSCLC) harboring 3 uncommon mutations of EGFR-R670W in exon 17 and H833V, and H835L in exon 21, as shown by next-generation sequencing of plasma cell-free DNA. To the best of our knowledge, this is the first case report of a patient harboring the R670W mutation. The patient responded well to second-generation tyrosine kinase inhibitors (TKIs). T790M is an acquired resistant mutation in patients with R670W, H833V, and H835L. This is also the first case of a patient harboring the H833V/H835L/T790M triple mutation; the patient had a good response to the third-generation TKI osimertinib. In this work, we also performed a literature review on the clinical characteristics of NSCLC patients with the H833V/H835L double mutation, together with a descriptive analysis about their response to EGFR TKI monotherapy as a first-line treatment, according to data from previous case reports. The results showed that the cohort of NSCLC patients with H833V/H835L responded well to EGFR TKIs; thus, before treatment in clinical practice, screening for EGFR mutations should be conducted and EGFR TKIs should be preferred in NSCLC patients with H833V/H835L mutations.

Bao-Dong Qin,*Xiao-Dong Jiao,* Ling-Yan Yuan,Ke Liu,Yuan-Sheng Zang Department of Medical Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China *These authors contributed equally to this work Introduction: Adenosquamous carcinoma (ASC) of the bile duct is a rare diagnosis with poorly understood clinicopathological characteristics and disease progression, so identification of the features associated with ASC patient survival is warranted. Materials and methods: A population cohort study was performed using prospectively extracted data from the Surveillance, Epidemiology and End Results (SEER) database for patients with histological diagnoses of ASC of the bile duct from 1973 to 2013. Results: A total of 106 patients with ASC of the bile duct were included (mean age 68.1±13.5 years). Lesions from 58 patients were in the extrahepatic bile duct and 34 were located at the ampulla of Vater. Fifty-seven patients were categorized with a regional stage, 15 had localized disease, and 30 had distant disease. Most (60.4%) patients received cancer-directed surgery, and radiation was performed in 14.1% of cases. The 1-year, 2-year, and 5-year overall survival (OS) for patients with ASC of the bile duct was 30.1%, 11.3%, and 3.7%, respectively. Cancer-directed surgery offered 10 additional months of OS for patients with ASC of the bile duct and median OS was 14.0, 6.0, and 6.0 months for ampulla of Vater, extrahepatic bile duct, and intrahepatic bile duct cases, respectively. A multivariate Cox analysis showed that lesions in the ampulla of Vater (HR=0.51, 95% CI 0.26–0.99) and having surgery (HR=0.34, 95% CI 0.14–0.81) were independent protective prognostic factors for these patients. Conclusion: Cancer-directed surgery and a primary lesion site of the ampulla of Vater may suggest favorable prognosis for patients with ASC of the bile duct. Keywords: adenosquamous carcinoma, bile duct, prognosis, SEER database

// Miaomiao Wang 1 , Ying Liu 1 , Wenzheng Fang 1 , Ke Liu 1 , Xiaodong Jiao 1 , Zhan Wang 1 , Jiejun Wang 1 and Yuan-Sheng Zang 1 1 Department of Medical Oncology, Changzheng Hospital, Shanghai 200070, China Correspondence to: Jiejun Wang, email: jiejunw@csco.org.cn Yuan-Sheng Zang, email: doctorzangys@163.com Keywords: SNAT1, osteosarcoma, prognosis, metastasis, MMP9 Abbreviations: OS: Osteosarcoma Received: March 10, 2017 Accepted: May 22, 2017 Published: September 05, 2017 ABSTRACT Background: SLC38A1/SNAT1 has been found to play an essential role in human development, but its role in osteosarcoma (OS) has yet to be evaluated. The purpose of this study was to assess the expression of SLC38A1/SNAT1 in patients with OS, and further investigate the mechanisms by which it affects tumor growth and metastasis. Methods: Tissue microarray blocks and immunohistochemical studies were carried out to assess the expression of SNAT1 in 165 OS specimens. Its correlation with clinicopathological characteristics was then analyzed. The function of SNAT1 in OS cells was investigated by silencing SNAT1 using SNAT1-shRNA in vitro and in vivo . Results: SNAT1 was highly expressed in 85% OS and significantly closely associated with pulmonary metastasis. Patients with high SNAT1 expression survived for shorter periods than those with low SNAT1 expression. Suppression of endogenous SNAT1 led to inhibition of cell proliferation, cell colony formation, and cell migration in vitro , and retarded tumor growth in xenograft models. Silencing SNAT1 reduced expression of MMP9, vimentin, fibronectin, p-Akt, p-mTOR, and VEGF. Conclusions: Our results indicated that increased expression of SNAT1 is a common event in OS. SNAT1 played an essential role in the development and progression of osteosarcoma, which may serve as a prognostic and therapeutic marker of OS.