Perioperative treatment and biomarker analysis of LP002, an anti-PD-L1 antibody, plus chemotherapy in resectable gastric and gastroesophageal junction cancer.

BACKGROUND: The addition of immune checkpoint inhibitors to perioperative chemotherapy in operable gastric or gastroesophageal junction (GEJ) cancer has become one of the research hotspots, while reliable biomarkers for efficacy are lacking. We conducted a phase 1 trial to assess the safety and efficacy of LP002, an anti-PD-L1 antibody, plus chemotherapy as perioperative treatment in patients with gastric or GEJ cancer. METHODS: We enrolled patients with resectable and PD-L1 positive gastric or GEJ cancers. Eligible patients received three preoperative and six postoperative cycles of intravenous LP002 with cisplatin and 5-fluorouracil, repeated every 2 weeks. The primary endpoint was safety. Secondary endpoints included rate of margin-free (R0) resection and pathological complete response (pCR). We also characterized changes in the tumor immune microenvironment using multiplex immunofluorescence (MIF) staining and next-generation sequencing (NGS) with pre- and post-treatment tumor samples. RESULTS: Thirty patients were enrolled, of whom 28 had GEJ cancer. With a median follow-up of 7.9 months, all patients completed preoperative treatment, and 27 patients underwent surgery. Twenty-four patients underwent R0 resection. Six patients (20.0%) had Mandard tumor regression grade (TRG) 1-3, including one achieving pCR. Twenty-seven patients had treatment-related adverse events (TRAEs), while grade 3-4 TRAEs were observed in 11 patients. No treatment-related deaths occurred. MIF staining revealed that TRG 1-3 group was associated with a higher density of PD-L1+/CD68+ cells in the pre-treatment tumor parenchyma than TRG 4-5 group (p = 0.048). NGS studies with paired pre- and post-treatment tumor samples revealed the disappearance of pre-existing mutations, the emergence of new mutations, and variations in the abundance of mutations after preoperative LP002 and chemotherapy. Meanwhile, tumor mutational burden decreased in patients with TRG 1-3 (p = 0.0313). CONCLUSIONS: LP002 plus cisplatin and 5-fluorouracil are safe in patients with gastric or GEJ cancer, and patient selection via appropriate biomarkers is needed in the future.

Azaphilone Alkaloids with Anti-inflammatory Activity from Fungus Penicillium sclerotiorum cib-411.

Nine new azaphilone alkaloids, penazaphilones A-I (1-9), were isolated from the solid fermented rice culture of Penicillium sclerotiorum cib-411. The structures of compounds 1-9 were elucidated based on HRESIMS, NMR, and CD spectroscopic data. The structures of 5 and 8 were confirmed by X-ray crystallographic analyses. Biological evaluation showed that compounds 1, 5, 6, and 8 inhibited the production of nitric oxide (NO) on RAW 264.7 cells stimulated by lipopolysaccharide with IC50 values of 15.29, 9.34, 9.50, and 7.05 µM, respectively. Meanwhile, they did not exhibit obvious cytotoxicity at a concentration of 50.0 µM.

Association between polymorphisms of TP53 and MDM2 and prostate cancer risk in southern Chinese.

Alterations in the TP53 and MDM2 genes appear to be important in the development of many human tumors, but evidence is conflicting on associations between polymorphisms in these genes and risk of prostate cancer (PCa). The influence of TP53 codon 72, MDM2 SNP309, and MDM2 C1797G polymorphisms in southern Chinese PCa patients was investigated. In the comparison of genotype distributions of TP53 codon 72 between cases and controls, the adjusted odds ratios for PCa associated with the Pro/Pro, Arg/Pro, and Arg/Arg genotypes were 1.00, 1.89 (95% CI = 1.20-2.97), and 2.01 (95% CI = 1.11-3.64), respectively; however, MDM2 SNP309 and C1797G did not show any significant difference between cases and controls. When TP53 and MDM2 polymorphisms were combined based on the numbers of variant risk alleles (i.e., G-allele of TP53 codon 72, G-allele of MDM2 SNP309, and G-allele of MDM2 C1797G), individuals with 3-5 variants had a 1.56-fold greater risk of PCa than those with 0-2 variants (95% CI = 1.07-2.26). Moreover, subjects with 0-2 variants had 33.3% positive p53 expression, whereas subjects with 3-5 variants had 23.3% p53 expression (P = 0.39). These findings suggest that TP53 and MDM2 polymorphisms play a role in PCa susceptibility in southern Chinese Han population.

p53 codon 72 increased biochemical recurrence risk after radical prostatectomy in a southern Chinese population.

INTRODUCTION: Alterations in P53 and murine double minute 2 (MDM2) genes appear to be important in the development of many human tumors. We investigated the potential prognostic roles of p53 codon 72 and MDM2 309 and 1797 polymorphisms in prostate cancer after radical prostatectomy. PATIENTS AND METHODS: Fifty southern Chinese with prostate cancer undergoing radical prostatectomy were included in this study. All polymorphisms were detected by PCR-RFLP. Their prognosis on biochemical recurrence was assessed using Kaplan-Meier analysis and Cox regression model. RESULTS: p53 codon 72 GG genotype was associated with increased biochemical recurrence compared with CG+CC genotypes and poorer PSA-free survival. It was also noted that GG genotype was an independent risk factor for biochemical recurrence after radical prostatectomy on multivariate analysis. No statistical difference was observed in MDM2 polymorphisms and prostate cancer prognosis. CONCLUSION: Our data revealed that p53 codon 72 GG genotype carriers more frequently show biochemical recurrence than CG+CC genotypes carriers.