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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

As an important CXC chemokine, CXCL8 plays pleiotropic roles in immunological response. In teleost, CXCL8 is involved in cell migration and bacterial invasion. However, the immune antibacterial function of CXCL8 in Japanese flounder (Paralichthys olivaceus) (PoCXCL8) is largely scarce. In this research, we investigated the antibacterial property and leukocyte activation of PoCXCL8. PoCXCL8 consists of 100 amino acid residues, with a conserved chemokine CXC domain. PoCXCL8 was expressed in various tissues, with the highest level in liver and the lowest level in muscle, and sharply induced by V. harveyi or E. tarda in liver, spleen, and head kidney. In vitro, the recombinant PoCXCL8 (rPoCXCL8) could bind to Bacillus subtilis, Edwardsiella tarda, Escherichia coli, Pseudomonas fluorescens, Vibrio anguillarum, Vibrio harveyi, Staphylococcus aureus, and Micrococcus luteus, affect the growth of E. coli, E. tarda, M. luteus, and P. fluorescens, and have a direct bactericidal effect on E. coli and E. tarda. Moreover, rPoCXCL8 was able to bind the outer membranal protein rPilA of E. tarda. In addition, rPoCXCL8 could bind to PBLs, activating the PBLs activity including chemotaxis, proliferation, phagocytosis, reactive oxygen species, acid phosphatase activity. At same time, rPoCXCL8 could induce neutrophil to generate neutrophil extracellular traps (NETs) and promote the expression of inflammatory genes including IL-1β, IL6, MMP13, TNF-α, and NF-κB. In flounder, the presence of rPoCXCL8 could enhance the in vivo resistance to E. tarda in liver, spleen, and head kidney. Moreover, the PoCXCL8-deficient could attenuate the fish defense against E. tarda infection in in spleen and head kidney. In conclusion, these results provided new insights into the antibacterial properties of CXCL8 in P. olivaceus., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis., (© 2024. The Author(s).)

Competing Interests: Competing interests: No, there are no competing interests.

In this study, we reported a Gram-stain-negative, ovoid to rod-shaped, atrichous, and facultative anaerobe bacteria strain named YMD61 T , which was isolated from the intertidal sediment of Yangma island, China. Growth of strain YMD61 T occurred at 10.0-45.0 °C (optimum, 30.0 °C), pH 7.0-10.0 (optimum, 8.0) and with 0-3.0% (w/v) NaCl (optimum, 2.0%). Phylogenetic tree analysis based on 16 S rRNA gene or genomic sequence indicated that strain YMD61 T belonged to the genus Fuscovulum and was closely related to Fuscovulum blasticum ATCC 33,485 T (96.6% sequence similarity). Genomic analysis indicated that strain YMD61 T contains a circular chromosome of 3,895,730 bp with DNA G + C content of 63.3%. The genomic functional analysis indicated that strain YMD61 T is a novel sulfur-metabolizing bacteria, which is capable of fixing carbon through an autotrophic pathway by integrating the processes of photosynthesis and sulfur oxidation. The predominant respiratory quinone of YMD61 T was ubiquinone-10 (Q-10). The polar lipids of YMD61 T contained phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, five unidentified lipids, unidentified aminolipid and unidentified aminophospholipid. The major fatty acids of strain YMD61 T contained C 18:1 ω7c 11-methyl and summed feature 8 (C 18:1 ω 7c or/and C 18:1 ω 6c). Phylogenetic, physiological, biochemical and morphological analyses suggested that strain YMD61 T represents a novel species of the genus Fuscovulum, and the name Fuscovulum ytuae sp. nov. is proposed. The type strain is YMD61 T (= MCCC 1K08483 T  = KCTC 43,537 T )., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine., (© 2024. The Author(s).)

Interleukin-20 (IL-20), as an essential member of IL-10 family, plays vital roles in mammalian immunological response such as antimicrobial, inflammation, hematopoiesis, and immune diseases. In teleost, the study about immune antimicrobial function of IL-20 is largely scarce. In this article, we revealed the expression profiles and the immunological functions of the IL-20 (CsIL-20) in tongue sole Cynoglossus semilaevis. CsIL-20 is composed of 183 amino acid residues, with seven cysteine residues and a typical IL-10 domain which comprises six α-helices and two β-sheets, and shares 34.4-71.2 % identities with other teleost IL-20. CsIL-20 was constitutively expressed in a variety of tissues and regulated by bacterial invasion, and the recombinant CsIL-20 (rCsIL-20) could bind to different bacteria. In vitro rCsIL-20 could interact with the membrane of peripheral blood leukocytes (PBLs), leading to the attenuation of reactive oxygen species (ROS) production and acid phosphatase activity in PBLs. In line with In vitro results, In vivo rCsIL-20 could obviously suppressed the host immune against bacterial infection. Furthermore, knockdown of CsIL-20 in vivo could markedly enhance the host antibacterial immunity. Collectively, these observations offer new insights into the negative effect of CsIL-20 on antibacterial immunity., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically improve the clinical outcomes of non-small cell lung cancer (NSCLC) patients harboring EGFR -sensitive mutations. Despite the remarkable efficacy of first-and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is a primary contributor to the acquired resistance to first- and second-generation EGFR TKIs. Osimertinib, which is an irreversible third-generation EGFR TKI, was designed for EGFR -activating mutations as well as the EGFR T790M mutation in patients with advanced NSCLC and has demonstrated a convincing efficacy. However, acquired resistance to osimertinib after treatment inevitably occurs. The acquired resistance mechanisms to osimertinib are highly complicated and not fully understood, encompassing EGFR -dependent as well as EGFR -independent mechanisms. Treatment approaches for patients progressing from osimertinib have not been established. We present a case of a stage IV lung adenocarcinoma patient harboring EGFR L858R, acquired T790M after treatment with first-line gefitinib. She then acquired a new EML4-ALK gene fusion after treatment with osimertinib. A combination targeted therapy of osimertinib plus alectinib was initiated, with a progression-free survival of 5 months without any serious adverse reaction. After disease progression, EGFR C797S in cis was detected with a loss of the EML4-ALK fusion by targeted next-generation sequencing. Then therapy was changed to pemetrexed combined with bevacizumab plus camrelizumab, but no obvious effect was observed. The patient had achieved an overall survival of 31 months. As far as we know, this was the first reported case that an EGFR -mutant NSCLC patient-acquired ALK fusion mediating resistance to osimertinib, and sequential EGFR C797S mutation mediating resistance to combined targeted therapy with osimertinib and alectinib. Our case shows that EML4-ALK fusion is a rare but critical resistance mechanism to osimertinib, and C797S mutation in cis may be an underlying mechanism of acquired resistance mutation in double TKIs therapy. Furthermore, molecular detection and rebiopsy play important roles in the selection of therapeutic strategies when the disease progresses., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor., (© 2023 UICC.)

Objective: To explore the effects of hyperandrogenism (HA) on pregnancy outcomes in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Methods: A retrospective study was conducted on infertile women with PCOS undergoing IVF/ICSI-ET from January 2017 to June 2021 in our center. Patients were divided into HA group and NON-HA group according to the levels of testosterone. Propensity score matching (PSM) was used to balance the influence of female age and IVF/ICSI-ET for patients with gonadotropin-releasing hormone (GnRH)antagonist protocol and GnRH agonist protocol, separately. After the PSM procedure, 191 cases in HA group and 382 cases in NON-HA group, were included. Hormone levels and pregnancy outcomes were compared in the two groups. Results: The female age was comparable in two groups [HA: (29.6±3.7) vs NON-HA: (29.5±3.6), P =0.665]. The basal luteinizing hormone [(10.82±6.73) vs (7.76±5.30) IU/L], testosterone [(3.27±0.97) vs (1.60±0.59) nmol/L], free androgen index (7.13 vs 2.77), anti-mullerian hormone [(11.37±5.74) vs (9.67±4.67) ng/ml], fasting glucose [(5.18±0.49) vs (5.06±0.42) mmol/L], 1h glucose [(9.34±2.42) vs (7.99±2.21) nmol/L], 2 h glucose [(7.66±2.17) vs (6.64±1.84) nmol/L], 2 h insulin [(129.81±145.49) vs (97.51±86.92) mU/L], total cholesterol [(5.35±0.89) vs (4.92±0.92) mmol/L], triglycerides [(1.55±1.28) vs (1.33±0.77) mmol/L], and low density lipoprotein cholesterol levels [(3.38±0.66) vs (3.14±0.71) mmol/L] were significantly higher in HA group, compared with NON-HA group ( P <0.05). The initiated gonadotropin dose was higher in HA group than that in NON-HA group [(126.96±33.65) vs (137.60±38.12) U, P =0.001], but moderate-severe ovarian hyperstimulation syndrome (OHSS) rate was similar in two groups ( P >0.05). The rates of implantation, clinical pregnancy, miscarriage, and live birth were comparable between the two groups ( P >0.05). Also, in the subgroups, the rates of implantation, clinical pregnancy, live birth, and miscarriage were similar in HA group and NON-HA group. Conclusions: The risks of hormonal abnormality and glucose-lipid metabolic disorder were higher in PCOS women with HA, whereas satisfactory pregnancy outcomes could be achieved under proper ovarian stimulation undergoing IVF/ICSI-ET.

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated., Materials and Methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients., Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%)., Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jiao, Qin, Wang, Liu, Wu, Ling, Qin, Wang, Yuan, Barreto, Kim, Mak, Li, Xu, Qiu, Wu, Jin, Xu, Zhong, Yang, Chen, Zeng, Shi, Zhu, Ding, Jia, Liu, Zhou, Shen, Yao, Guo, Li, Zhou, Dong, Lu, Coleman, Akce, Akladios, Puccetti and Zang.)

Background: Tumor mutation burden (TMB) is a promising biomarker positively associated with the benefit of immunotherapy and that might predict the outcome of chemotherapy. We described the prognostic value of TMB in advanced gastric cancer and explored the underlying mechanism., Methods: We enrolled 155 TMB-evaluated advanced gastric cancer patients and analyzed the relationship between clinicopathological characteristics and both overall survival (OS) and progression-free survival (PFS) among 40 patients treated with first-line chemotherapy. We further verified the distribution of TMB and analyzed the potential mechanism underlying the prognosis based on The Cancer Genome Atlas (TCGA) database., Results: Among the 155 patients, 29 (18.7%) were TMB-high (TMB ≥ 10), roughly the same as the proportion in the TCGA data. Of the 40 patients receiving first-line chemotherapy, the median OS (7.9 vs . 12.1 months; HR 3.18; p = 0.0056) and PFS (4.4 vs . 6.2 months; HR 2.94; p = 0.0099) of the tissue-tested TMB (tTMB)-high patients were inferior to those of the tTMB-low patients. Similarly, unfavorable median OS (9.9 vs . 12.1 months; HR 2.11; p = 0.028) and PFS (5.3 vs . 6.5 months; HR 2.49; p = 0.0054) were shown in the blood-tested TMB (bTMB)-high than in the bTMB-low patients. The Cox analysis demonstrated that both tTMB-high and bTMB-high were significant independent predictors of dreadful OS and PFS. The differentially expressed genes (DEGs) according to TMB status were most significantly enriched in the downregulated metabolic pathway among the TMB-high patients., Conclusions: TMB-high advanced gastric cancer patients accounted for around one-sixth and had a poorer prognosis than TMB-low patients when treated with first-line chemotherapy. The potential mechanism might be the downregulated metabolic activity in TMB-high patients., Competing Interests: Author Bing Li was employed by the company Burning Rock Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Duan, Liu, Jiao, Qin, Li, He, Ling, Wu, Chen and Zang.)

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., (© 2022. The Author(s).)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: 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., Methods and Materials: 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., Results: 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)., Conclusion: 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., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (© 2021 AlphaMed Press.)

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., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

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, P<0.001), and class 3 (P=0.001, P=0.014). In class 1, the cutoff values of CA19-9 were 30, 36, and 284 U/mL to reach the concordance thresholds of 90%, 95%, and 100%, respectively (P=0.032, P=0.003, P=0.043). For CYFRA21-1, the cutoff values were 6, 18, and 52 µg/L (P=0.005, P=0.051, P=0.354). In class 2, the cutoff values for CYFRA21-1 were 18, 22, and 52 µg/L (P=0.001, P=0.001, P=0.052). In class 3, the cutoff values for CA19-9 were 36, 39, and 85 U/mL (P=0.003, P=0.001, P=0.008). For CYFRA21-1, the cutoff values were 22, 52, and 52 µg/L (P=0.900, P>0.99, 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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-543). Dr. XDJ reported funding support from the Logistics Support Department of PLA (19BJZ03) and Changzheng Hospital (2019CZJS208-1). Dr. YSZ reported funding support from the Project of Ministry of Science and Technology of China (2017YFC1309202), the Shanghai Distinguished Young Medical Talents Training Program (QNYXRC01) and the Medical Innovation Research Project of Shanghai Science and Technology Commission (20Y11914400). Dr. NI reported that he had got grants from Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim, TAIHO Pharmaceutical Co., Ltd.; and received fee from Eli Lilly Japan K.K, MSD K.K. Dr. BDQ reported funding support from Chinese National Natural Science Funding (grant number 81702249, 2017). The funder has no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. LS, HZW, YC, and JJZ reported that they are employees of Burning Rock Biotech. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). No potential conflicts of interest were reported.

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., (© AlphaMed Press 2020.)

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<0.01). Cancer-directed surgery, chemotherapy and radiotherapy could significantly prolong the survival time for SCCP patients (P<0.01 for all). Multivariate Cox analysis showed that only distant metastases were independent prognostic factors of worse survival in SCCP patients (HR =1.58, 95% CI, 1.18-2.12). Conversely, both cancer-directed surgery and chemotherapy were an independent protective factor that decreased the risk of death by 66% (HR =0.18, 95% CI, 0.11-0.29) and 46% (HR =0.54, 95% CI, 0.43-0.68) for SCCP patients., Conclusions: SCCP is a rare type of pancreatic malignancies with poor prognosis. The present study could provide some useful information for future management and prospective studies for SCCP patients., Competing Interests: Conflicts of Interest: All authors declare that there is no conflict of interest (available at http://dx.doi.org/10.21037/gs-20-317). The authors have no conflicts of interest to declare., (2021 Gland Surgery. All rights reserved.)

Background: Tumor mutation burden (TMB) has an important association with immunotherapy responses. TMB in the Chinese population has not been well established. Finding differences between the Chinese and Caucasian populations and elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction., Methods: Chinese cancer patients fresh tissue (n=2,177), formalin-fixed, paraffin-embed (FFPE) specimens (n=3,294), and pleural fluid (n=189) were profiled using a 295- or 520-gene next-generation sequencing (NGS) panel. The association of the TMB status with a series of molecular features and biological pathways was determined using bootstrapping., Results: TMB, measured by 295- or 520-cancer-related gene panels, was correlated with whole-exome sequencing (WES) TMB based on the in silico simulation in The Cancer Genome Atlas cohort. The median TMB of our data was slightly higher than that from the Foundation Medicine Inc. (FMI) dataset. TMB was also slightly different within the same cancer type between the Chinese and Caucasian population. We discovered that the underlying pathways of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 23-gene and a 16-gene signature to predict TMB prediction for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively, indicating a histology-specific mechanism for driving high-TMB in lung cancer., Conclusions: TMB varies among different ethnic populations. Our findings extend the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3807). Dr. SC, Dr. YSZ, Dr. HHZ, Dr. JY and Dr. TH report that they are employees of Burning Rock Biotech. The other authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

The present study aimed to evaluate the effect of liver metastases on the efficacy from the combination of PD-1/PD-L1 inhibitor with chemotherapy as first-line treatment in lung cancer using the meta-analysis. A total of 8 randomized controlled trials (RCTs) were included. In patients without liver metastases, PD-1/PD-L1 inhibitor plus chemotherapy could decrease the risk of progression by 40% and risk of death by 29% (HR = 0.60; 95%CI,0.55- 0.65 and HR = 0.71;95%CI,0.58-0.90 respectively). In patients with liver metastases, PD-1/PD-L1 inhibitor plus chemotherapy could decrease the risk of progression by 31% and risk of death by 21% (HR = 0.69;95%CI,0.58-0.81; and HR = 0.79; 95%CI,0.62-0.80, respectively). The pooled ratios of PFS-HRs and OS- HRs reported in lung cancer patients with liver metastases versus those without liver metastases were 1.11 (95%CI, 0.92-1.34) and 1.03 (95%CI, 0.80-1.35), respectively, suggesting that lung cancer patients with and without liver metastases could obtain comparable efficacy., Competing Interests: Declaration of Competing Interest All authors have declared no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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<0.001 and P<0.01). OS time of high TMB group was inferior to that of the low TMB group (24.03 months vs . not reached, P=0.0020). TMB and TP53 together will make more accurate prediction of OS in 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., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Journal of Thoracic Disease. All rights reserved.)

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., Competing Interests: The authors report no conflicts of interest in this work.

Currently, genomic characterization has become standard of care for tumor types such as non-small cell lung cancer, breast cancer, melanoma, and colorectal cancer. A deep understanding of genomic alterations in different tumor types would help identify potentially actionable genomic changes which occur across a wide variety of tumor types. A basket trial is a new type of clinical trial for which eligibility is based on the presence of a specific genomic alteration, irrespective of histology. Basket trials are phase II screening trials for the off-label use of a targeted drug in patients with the same genomic alterations for which it was approved. Intractable cancer refers to a type or condition of cancer which is unresponsive or resistant to treatment; intractable cancers may be classified into five subtypes as follows: hard-to-treat condition of common advanced cancer after multiple-line therapy, rare cancer in which no standard of care has been recommended, advanced cancer in which standard of care does not work well, cancer accompanied with organ dysfunction, and cancers in older or younger cancer patients. Previous studies have demonstrated that in basket trials, genomic-guided therapy yields clinical benefits in intractable cancer, thereby providing novel insights into the optimal clinical management of such cancers. In this review, we describe a novel way to classify intractable cancer, and summarize the current knowledge on such cancers. We additionally provide information on the role of basket trials in intractable cancer.

Introduction: Primary pulmonary salivary gland-type tumors (p-SGTs) are rare, with poorly understood clinicopathological characteristics and survival. There are only few case reports or small case series, and factors associated with survival need to be identified., Methods: A population cohort study was conducted using data from patients with histologically diagnosed primary p-SGTs in the Surveillance, Epidemiology and End Results (SEER) database between 1988 and 2013. Propensity-matching (PSM) analysis was performed to determine overall survival (OS) among patients with different pathological type. A prognostic nomogram was established, and its predictive accuracy and discriminative ability were determined by the concordance index (C-index)., Results: In total, 462 patients with p-SGT were identified including 315 patients with mucoepidermoid carcinoma (MEC), 139 patients with adenoid cystic carcinoma (ACC) and 8 patients with epithelial-myoepithelial carcinoma (EMC). The 1-, 5-, 10-, and 20-year OS rates of p-SGT patients were 79.6%, 68.5%, 62.7%, and 56.3%, respectively. Log-rank analysis in the matched cohort showed a significantly better prognosis for patients with p-SGT than those with non-SGT lung adenocarcinoma (P < 0.001). Cancer-directed surgery significantly improved median OS (P < 0.01). Radiotherapy did not prolong OS (P = 0.28, P = 0.70). Multivariate Cox analysis showed that older age (>58 years), larger lesions, metastases and poor differentiation were independent prognostic factors for worse survival, while cancer-directed surgery was an independent protective factor (HR = 0.18, 95% CI 0.11-0.29). Patients with MEC were younger with smaller tumors, lower ratio of lymph node or distant metastases as well as earlier stage than those with ACC, and there was no significant difference in survival between MEC and ACC patients. Six independent prognostic factors were identified and incorporated into the nomogram (C-index for survival = 0.88; 95% CI 0.84-0.92)., Conclusion: Pulmonary SGTs are uncommon, and older age, larger lesions, metastases, poor differentiation and cancer-directed surgery are independently associated with prognosis. Early detection and diagnosis increase OS for these patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: 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., Materials and Methods: 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., Results and Conclusion: 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors have profoundly altered the therapeutic landscape of several malignancies. The establishment of predictive biomarkers for checkpoint blockades is of the considerable importance in the identification of populations likely to experience a good response to immunotherapy and to maximize the therapeutic benefits. Several trials showed that the tumor mutation burden (TMB) could predict the response to immunotherapy, but some lower clinical benefit was also seen in cancer with high TMB. The imbalance between the strength of immune response and pretreatment tumor burden (TB) could also cause immunotherapy to fail in cancer patients. For this reason, we hypothesized that the TMB-TB ratio could predict the clinical benefit of checkpoint inhibitor immunotherapy and that PFS or ORRs should be used more often in patients with high TMB-TB ratio than in individuals with low TMB-TB ratios., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Gastric cancer patients with widespread metastasis, especially meningeal metastases, have an extremely prognosis and limited therapeutic choices., Case Presentation: We reported the case of a 39-year-old male patient with HER2-positive gastric cancer with bone and meningeal metastases. He presented with multiple bone metastases and received 3 cycles of docetaxel plus S1. However, he complained with headache and imaging examinations revealed leptomeningeal carcinomatosis. FISH revealed that tumor cells in the cerebrospinal fluid were HER-positive. Herceptin was added to the regimen, but the symptoms were not relieved, the patient suffered from dizziness and nausea. The chemotherapy regimen was switched d to lapatinib (orally at 1250 mg/day, every day), capecitabine (orally at 1000 mg/m2, bid for 2 weeks, followed by a 1-week rest interval, as 1 cycle) and Herceptin (390 mg/3 weeks). After 3 weeks of the new treatment, all the symptoms relieved. The clinical complete response was maintained for 3 months., Conclusions: Lapatinib/Capecitabine combination therapy is an alternative treatment strategy for leptomeningeal carcinomatosis of HER2-positive gastric cancer in which trastuzumab and/or chemotherapy essentially has no effect.

Objectives: Primary pulmonary leiomyosarcoma (PPL) is a rare diagnosis with poorly understood clinicopathological characteristics and disease progression. What we know is derived from limited case reports, so identification of features associated with patient survival is warranted., Materials and Methods: A population cohort study was conducted using prospectively extracted data from the Surveillance, Epidemiology and End Results (SEER) database for patients with histological diagnoses of PPL from 1973 to 2013 including demographic, treatment and outcome data., Results: A total of 231 patients with PPL were included (mean 65.8 ± 14.9 years-of-age). 43 were categorized with a regional stage, and 60 had localized stage, whereas 70 had distant stage. Most (60.4%) patients received cancer-directed surgery, and radiotherapy was performed for 14.1% of patients. Median overall survival (OS) was 14.0 months, and 1-, 3- and 5-year OS for PPL patients was 52.7%, 29.0% and 22.2%, respectively. Cancer-directed surgery significantly improved median OS for patients with PPL by almost 29.0 months (33.0 vs 4.0 months; p < .01). Multivariate Cox analysis showed that distant stage was independent prognostic factors for PPL (HR = 2.22, 95% CI 1.30-3.79). Conversely, cancer-directed surgery was an independent protective factor and this decreased risk of death by 57% (HR = 0.43, 95% CI 0.27-0.67) for patients with PPL., Conclusion: PPL is a rare pathological lung cancer, surgical resection and distant stage were associated with prognosis. In order to understand PPL more thoroughly, more cases with adequate information are required., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Nab-paclitaxel is a recently emerged chemotherapy drug, which is widely used for the treatment of multiple types of cancer. The prospects of this novel drug are very bright as a result of its higher efficacy and lower toxicity compared with paclitaxel. Hence, the side effect, even if rare, require attention in clinical practice. The present study described an unusual case of nab-paclitaxel-associated paralytic ileus. To the best of our knowledge, this is the first report to demonstrate that nab-paclitaxel may lead to acute intestinal obstruction. Since nab-paclitaxel will be used more frequently, this unusual side effect might be encountered by a clinical oncologist and must be treated correctly. This is the first reported case, to the best of our knowledge, of paralytic ileus caused by nab-paclitaxel, which will be widely used as a novel anticancer drug.

Objective: To evaluate the effects of different doses of lactulose on preventing oral morphine-induced constipation., Methods: From January 2011 to May 2012, a total of 112 patients received oral lactulose solution to prevent morphine-induced constipation at our hospital and their clinical data were retrospectively analyzed. The doses of morphine were adjusted according to the pain scores and lactulose was taken simultaneously. There were 52 males and 60 females. They were randomized into Group 30 ml/d (n = 40), Group 60 ml/d (n = 43) and Group 90 ml/d (n = 29). The incidences of constipation and adverse reactions were obtained at 1 week after the start of medicine. The measurement data were analyzed with analysis of variance. And the enumeration data were analyzed with χ(2), Kruskal-Wallis and Mann-Whitney U tests., Results: The incidence of constipation was 67.5% (27/40) in Group 30 ml/d, 46.5% (20/43) in Group 60 ml/d, and 37.9% (11/29) in Group 90 ml/d. And there were statistical differences (P = 0.036). The incidence of constipation in Group 30 ml was significantly higher than Group 90 ml/d (P = 0.015). No statistical difference existed in the incidence of constipation between Groups 30 ml/d and 60 ml/d (P = 0.054) or Groups 60 ml/d and 90 ml/d (P = 0.471). The incidence of vomiting was 34.5% (10/29) in Group 90 ml/d and it was significantly higher than 10.0% (4/40) in Group 30 ml/d (P = 0.013) and 9.3% (4/43) in Group 60 ml/d (P = 0.009). No statistical difference existed in the incidence of vomiting between Groups 30 ml/d and 60 ml/d (P = 0.915). The incidence of diarrhea was 17.2% (5/29) in Group 90 ml/d and it was significantly higher than 0 (0/40) in Group 30 ml/d (P = 0.007). No statistical difference existed in the incidence of diarrhea between Groups 30 ml/d and 60 ml/d (4.7% (2/43), P = 0.170) or Groups 60 ml/d and 90 ml/d (P = 0.072)., Conclusion: The correct dosage of lactulose for the prevention of oral morphine-induced constipation is 60 ml/d.

The aims of present study were to evaluate the efficacy of combining sunitinib with ionizing radiation (IR) on endothelial cells in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) were exposed to IR with or without sunitinib pretreatment. Apoptosis assay and cell cycle distribution were analyzed by flow cytometry. Clonogenic survival assay at 3 Gy dose with or without sunitinib was performed. The activity of phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway was detected by Western immunoblot. Lewis lung carcinoma mouse model was built to examine the effect of combination therapy on endothelial cells in vivo. Microvasculature changes were detected by immunohistochemistry using anti-CD31 antibody. Our results showed combination therapy of sunitinib and IR significantly increased apoptosis of endothelial cells and inhibited colony formation compared to sunitinib or radiotherapy alone. It also resulted in cell cycle redistribution (decreasing cells in S phase and increasing cells in G2/M phase). The activity of PI3K/Akt signal pathway was inhibited, which could be the potential mechanisms that account for the enhanced radiation response induced by sunitinib. In vivo analysis showed that combination therapy significantly decreased microvasculature formation. The results demonstrated that combination therapy of sunitinib and IR has the potential to increase the cytotoxic effects on endothelial cells.

Bacterial flagellin is known to induce potent immune response in vertebrate systems via the toll-like receptor (TLR) 5. As a result, flagellin has been studied extensively as a vaccine adjuvant. In a previous study, we examined the vaccine and adjuvant potentials of the flagellin (FliC) of the fish pathogen Edwardsiella tarda. We found that E. tarda FliC induced low protective immunity by itself but could function as a molecular adjuvant and potentiate the specific immune response induced by the E. tarda antigen Eta6. Since FliC is a large protein and organized into distinct structural domains, we wondered whether the immunostimulating effect observed with the full-length protein could be localized to a certain region. To investigate this question, we in the present study dissected the FliC protein into several segments according to its structural features: (i) N163, which consists of the conserved N-terminal 163 residues of FliC; (ii) M160, which consists of the variable middle 160 residues; (iii) C94, which consists of the conserved C-terminal 94 residues; (iv) NC257, which is an artificial fusion of N163 and C94. To examine the adjuvanticity of the FliC fragments, DNA vaccine plasmids expressing FliC fragments in fusion with Eta6 were constructed and used to immunize Japanese flounder. The results showed that N163 produced the best adjuvant effect, which, in respect to improvement in the relative percent survival of the vaccinated fish, was comparable to that of the full-length FliC. None of the other FliC fragments exhibited apparent immunopotentiating effect. Further analysis showed that N163 enhanced the production of serum specific antibodies and, like full-length FliC, significantly upregulated the expression of the genes that are possibly involved in innate and adaptive immunity. These results indicate that N163 is the immunodominant region of FliC and suggest that E. tarda FliC may induce immune responses in Japanese flounder via mechanisms alternative to that involving TLR5., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Edwardsiella tarda is a severe aquaculture pathogen with a broad host range that includes humans, animal, and fish. A gene (degP(Et)) encoding a DegP homologue was cloned from TX01, a pathogenic E. tarda strain isolated from diseased fish. DegP(Et) shares high sequence identities with the DegP proteins of several bacterial species. Functional analyses showed that degP(Et) could complement the temperature-sensitive phenotype of an Escherichia coli degP null mutant. Expression of degP(Et) in TX01 was modulated by growth phase and temperature, the latter possibly through the action of the sigma(E)-like factor. Overexpression of degP(Et) (i) enhanced the ability of TX01 to disseminate in fish blood at the advanced stage of infection, (ii) heightened the activity of type 2 autoinducer, and (iii) increased the expression of luxS and the genes encoding components of the virulence-associated type III secretion system. Recombinant DegP(Et) purified from E. coli was a serine protease that exhibited maximum activity at 40 degrees C and pH8.0. The proteolytic activity of recombinant DegP(Et) depended on the catalytic triad and the PDZ domains. Immunoprotective analyses showed that purified recombinant DegP(Et) was a protective immunogen that could induce the production of specific serum antibodies and elicit strong protective immunity in fish vaccinated with DegP(Et)., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Streptococcus iniae is a Gram-positive bacterium and a severe aquaculture pathogen that can infect a wide range of farmed fish species. In the summer of 2006, an epidemic broke out in a fish farm in north China, and examination of moribund fish (Japanese flounder) identified the possible etiological agent of the outbreak as a strain named SF1, which exhibited apparent virulence in a Japanese flounder infection model and conforms to the description of S. iniae by 16S rRNA sequence analysis and API 20 Strep test. Biochemical and random amplified polymorphic DNA analyses indicated that SF1 is of the serotype I. A putative iron-binding protein, Sip11, was identified from SF1 using a previously established molecular trap that selects exported proteins. Recombinant Sip11 was purified from Escherichia coli and found to be protective against SF1 infection when used as an injection vaccine administered intraperitoneally into Japanese flounder. To improve the vaccine potential of Sip11, an E. coli strain was constructed, which expresses and secrets recombinant Sip11 covalently linked to a carrier protein in the form of a chimera. Vaccination of Japanese flounder with live Sip11-secreting E. coli afforded complete protection upon the fish following lethal SF1 challenge. These results indicate that Sip11, especially when delivered by a live bacterial carrier, is an effective vaccine candidate against SF1 infection., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Edwardsiella tarda is a serious aquaculture pathogen that can infect many cultured fish species. The aim of this study was to investigate the potential importance of DNA adenine methylase (Dam) in E. tarda pathogenesis. The E. tarda dam gene (dam(Et)) was cloned from a pathogenic strain, TXD1, isolated from diseased fish. Dam(Et) shares high (70.2%) sequence identity with the Dam proteins of Yersinia enterocolitica and several other bacterial species. Recombinant Dam(Et) is able to complement a dam-deficient Escherichia coli strain and methylate the genomic DNA. Attenuation of dam(Et) expression by antisense RNA interference had no apparent effect on the growth of TXD1, but caused significant attenuation of overall bacterial virulence and altered several stress responses including spontaneous mutation, recovering from UV radiation and H(2)O(2) exposure, binding to host mucus, and dissemination in host blood and liver. In addition, attenuation of dam(Et) expression increased luxS expression and AI-2 activities in E. tarda. These results indicate that Dam(Et) is a virulence determinant and plays a role in the pathogenesis of TXD1, and that temporal expression of dam(Et) is essential for optimal bacterial infection., (Copyright 2009 Elsevier B.V. All rights reserved.)

Edwardsiella tarda is a severe aquaculture pathogen that can infect many different fish species cultured worldwide. Et49 is a major E. tarda antigen with weak immunoprotective potential. In this study, using Et49 as an example vaccine, the adjuvanticity of Freund's incomplete adjuvant (FIA), aluminum hydroxide, and aluminum phosphate adjuvant were evaluated in a Japanese flounder model. The results showed that the presence of FIA, aluminum hydroxide, and aluminum phosphate adjuvant increased the relative percent of survival of Et49-vaccinated fish by 47%, 19%, and 35%, respectively. Fish vaccinated with FIA-adjuvanted Et49 exhibited longer persistence of vaccine at the injection site and more severe intra-abdominal lesions than fish vaccinated with aluminum-adjuvanted Et49. Both aluminum adjuvants and, to a lesser degree, FIA augmented the production of specific serum antibodies, which reached the highest levels at 6 and 7 weeks post-vaccination. Passive immunization of Japanese flounder with sera from fish vaccinated with aluminum- and FIA-adjuvanted Et49 induced no protection against lethal E. tarda challenge. Examination of the transcription profile of immune-related genes showed that vaccination with aluminum-adjuvanted Et49 significantly enhanced the expression of the genes that are associated mainly with humoral immunity, whereas vaccination with FIA-adjuvanted Et49 induced the expression of a much broader spectrum of genes that are likely to be involved in humoral and innate cellular immunity. These results provide new insights to the action mechanisms of FIA and aluminum adjuvants in Japanese flounder and may be useful for the selection of adjuvant for vaccine formulations intended for Japanese flounder., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Escherichia coli DH5alpha is a genetically tailored laboratory strain that is commonly used for general cloning. In this study, the vaccine potential of DH5alpha was investigated. It was found that when used as a live vaccine, DH5alpha could afford effective protection upon Japanese flounder against Aeromonas hydrophila infection. Vaccination with purified outer membrane proteins and lipopolysaccharides of DH5alpha failed to induce protective immunity against A. hydrophila. Specific antibody production was observed in fish immunized with DH5alpha, which lasted at least 8 weeks and was enhanced by a booster injection during the vaccination process. Analysis of the transcription profiles of immune-related genes showed that vaccination with DH5alpha heightened the expression of the genes encoding factors that are likely involved in both specific and nonspecific immunities. Furthermore, compared to the control fish, fish vaccinated with DH5alpha/pAQ1, which is DH5alpha harboring the plasmid pAQ1 that expresses the coding element of a Vibrio harveyi antigen, exhibited significantly improved survival rates following V. harveyi and A. hydrophila challenges. These results demonstrate that DH5alpha possesses intrinsic immunoprotective potential against A. hydrophila. This property, together with the feature of cloning friendliness, should render DH5alpha useful in the construction of cross-protective vaccines., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Edwardsiella tarda is a severe aquaculture pathogen that can infect many important fish species cultured worldwide. The aim of this study was to evaluate the vaccine potential of an E. tarda antigen, Eta21, which was identified from a pathogenic E. tarda strain via the method of in vivo-induced antigen technology (IVIAT). Eta21 is 510-amino acid in length and shares approximately 58% sequence identity with a putative peptidase of several bacterial species. eta21 was subcloned into Escherichia coli, and recombinant Eta21 was purified as a histidine-tagged protein. When used as a subunit vaccine, purified recombinant Eta21 was effective against lethal E. tarda challenge in a Japanese flounder model. In order to improve the immunoprotective efficacy of Eta21, the chimera AgaV-Eta21 was constructed, which consists of Eta21 fused in-frame to the secretion domain of AgaV, an extracellular beta-agarase. E. coli DH5alpha harboring plasmid pTAET21, which constitutively expresses agaV-eta21, was able to produce and secret AgaV-Eta21 into the extracellular milieu. Vaccination of Japanese flounder with live DH5alpha/pTAET21 elicited immunoprotection that is significantly higher in level than that induced by vaccination with purified recombinant Eta21. Vaccination with DH5alpha/pTAET21 and recombinant Eta21 both induced the production of specific serum antibodies at four to eight weeks post-vaccination. Taken together, these results demonstrate that Eta21, especially that delivered by DH5alpha/pTAET21, is an effective vaccine candidate against E. tarda infection.

Edwardsiella tarda is an opportunistic pathogen that can infect humans, animal, and fish. Two E. tarda antigens, Eta6 and FliC, which are homologues to an ecotin precursor and the FliC flagellin, respectively, were identified by in vivo-induced antigen technology from a pathogenic E. tarda strain isolated from diseased fish. When used as a subunit vaccine, purified recombinant Eta6 was moderately protective against lethal challenge of E. tarda in a Japanese flounder model, whereas purified recombinant FliC showed no apparent immunoprotectivity. Similarly, DNA vaccines based on eta6 and fliC in the form of plasmids pEta6 and pFliC induced, respectively, moderate and marginal protection against E. tarda infection. To improve the vaccine efficacy of eta6, a chimeric DNA vaccine, pCE6, was constructed, which encodes Eta6 fused in-frame to FliC. pCE6 was found to induce significantly higher level of protection than pEta6. Likewise, another chimeric DNA vaccine, pCE18, which expresses FliC fused to a previously identified E. tarda antigen Et18, elicited significantly stronger protective immunity than the DNA vaccine based on et18 alone. Fish immunized with pEta6 and pCE6 produced specific serum antibodies and exhibited significantly enhanced expression of the genes encoding elements that are involved in both innate and adaptive immune responses. Furthermore, the induction magnitudes of most of these genes were significantly higher in pCE6-vaccinated fish than in pEta6-vaccinated fish.

Edwardsiella tarda is a gram-negative pathogen with a broad host range that includes humans, animals, and fish. Recent studies have shown that the LuxS/autoinducer type 2 (AI-2) quorum sensing system is involved in the virulence of E. tarda. In the present study, it was found that the E. tarda LuxS mutants bearing deletions of the catalytic site (C site) and the tyrosine kinase phosphorylation site, respectively, are functionally inactive and that these dysfunctional mutants can interfere with the activity of the wild-type LuxS. Two small peptides, 5411 and 5906, which share sequence identities with the C site of LuxS, were identified. 5411 and 5906 proved to be inhibitors of AI-2 activity and could vitiate the infectivity of the pathogenic E. tarda strain TX1. The inhibitory effect of 5411 and 5906 on AI-2 activity is exerted on LuxS, with which these peptides specifically interact. The expression of 5411 and 5906 in TX1 has multiple effects (altering biofilm production and the expression of certain virulence-associated genes), which are similar to those caused by interruption of luxS expression. Further study found that it is very likely that 5411 and 5906 can be released from the strains expressing them and, should TX1 be in the vicinity, captured by TX1. Based on this observation, a constitutive 5411 producer (Pseudomonas sp. strain FP3/pT5411) was constructed in the form of a fish commensal isolate that expresses 5411 from a plasmid source. The presence of FP3/pT5411 in fish attenuates the virulence of TX1. Finally, it was demonstrated that fish expressing 5411 directly from tissues exhibit enhanced resistance against TX1 infection.

Purpose: To investigate possible associations between sequence changes in the galactokinase gene (GALK1) and age-related cataract in a European population., Methods: Persons without lens opacities and persons with clinically significant age-related cataract were selected from those participating in the Collaborative Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract or from those attending the Section of Ophthalmology of the University of Parma for cataract surgery. Type and severity of the opacities were assessed by slit-lamp and retro-illumination lens photographs. Mutations in GALK1 were identified by PCR amplification of individual exons and flanking sequences and sequencing using fluorescent terminator technology in an ABI 377 Prism or 3100 automated DNA sequencer., Results: DNA samples were obtained from 115 individuals with clear lenses and from 185 individuals with cataract (106 with any nuclear, 88 with any cortical, and 25 with any posterior sub capsular cataract). 157 of the 185 patients with cataract (85%) were age-matched with a control within an age range of plus or minus 1 year. SNPs causing amino acid changes in the galactokinase protein were identified in exon 4; I184M, 1/115 control versus 0/185 cataractous individuals, p=0.38, exon 6; G274D, 0/115 control versus 1/185 cataractous individuals, p>0.99, and exon 7; V338A, 0/115 control versus 1/185 cataractous individuals, p>0.99. Thus, there were no significant differences in the distribution of sequence alterations resulting in amino acid changes between control and cataractous individuals. Eighty samples showed a C to T transition 43 bases into intron 7 (46 cataracts and 34 controls). Testing the distribution of the intron 7 findings showed Hardy-Weinberg equilibrium for both cases (p=0.73) and controls (p=0.51). There was no difference in C/T distribution between cases and controls (p=0.27)., Conclusions: In this northern Italian population age-related cataract does not appear to be associated with GALK1 alleles. Since this is due to a lack of sequence changes in both affected and control individuals, this study cannot rule out the possibility of an association in other populations.