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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. [ABSTRACT FROM AUTHOR]

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. This work attempted to determine the possible resistance mechanism to trastuzumab in a patient with HER2‐positive stage IV gastric adenocarcinoma. [ABSTRACT FROM AUTHOR]

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. This article reports the case of a patient with advanced low‐grade sarcoma with uncertain histopathological diagnosis. Next‐generation sequencing detected CARS‐ALK fusion, which allowed for successful treatment using ALK inhibitors. [ABSTRACT FROM AUTHOR]

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.