To observe local and systemic toxicity after sustained-release 5-fluorouracil (5-Fu) implantation in canine peritoneum and para-aortic abdominalis and the changes of drug concentration in the local implanted tissue with time.300 mg sustained-release 5-Fu was implanted into canine peritoneum and para-aorta abdominalis. Samples were taken 3, 5, 7 and 10 days after implantation for assessment of changes and systemic reactions. High performance liquid chromatography was applied to detect the drug concentrations of peritoneal tissue at different distances from the implanted site, lymphatic tissue of para-aortic abdominalis, peripheral blood and portal venous blood.10 days after implantation, the drug concentrations in the peritoneum, lymphatic tissue and portal vein remained relatively high within 5 cm of the implanted site. There appeared inflammatory reaction in the local implanted tissue, but no visible pathological changes such as cell degeneration and necrosis, and systemic reaction like anorexia, nausea, vomiting and fever.Sustained-release 5-Fu implantation in canine peritoneum and para-aortic abdominalis can maintain a relatively high tumour- inhibiting concentration for a longer time in the local implanted area and portal vein, and has mild local and systemic reactions. Besides, it is safe and effective to prevent or treat recurrence of gastrointestinal tumours and liver metastasis.
Abstract Gene-viral therapy, which uses replication-selective transgene-expressing viruses to manage tumors, can exploit the virtues of gene therapy and virotherapy and overcome the limitations of conventional gene therapy. Using a human telomerase reverse transcriptase-targeted replicative adenovirus as an antiangiogenic gene transfer vector to target new angiogenesis and making use of its unrestrained proliferation are completely new concepts in tumor management. CNHK300-mE is a selective replication transgene-expressing adenovirus constructed to carry mouse endostatin gene therapeutically. Infection with CNHK300-mE was associated with selective replication of the adenovirus and production of mouse endostatin in telomerase-positive cancer cells. Endostatin secreted from a human gastric cell line, SGC-7901, infected with CNHK300-mE was significantly higher than that infected with nonreplicative adenovirus Ad-mE in vitro (800 ± 94.7 ng/ml versus 132.9 ± 9.9 ng/ml) and in vivo (610 ± 42 ng/ml versus 126 ± 13 ng/ml). Embryonic chorioallantoic membrane assay showed that the mouse endostatin secreted by CNHK300-mE inhibited angiogenesis efficiently and also induced distortion of pre-existing vasculature. CNHK300-mE exhibited a superior suppression of xenografts in nude mice compared with CNHK300 and Ad-mE. In summary, we provided a more efficient gene-viral therapy strategy by combining oncolysis with antiangiogenesis.
Polymorphisms in the excision repair cross-complimentary group 1 (ERCC1)–excision repair cross-complimentary group 4 (ERCC4) genes have been implicated in the prognosis of various cancers. We conducted a cohort study to investigate the role of ERCC1–ERCC4 gene polymorphisms on the response to chemotherapy and the role of these two gene polymorphisms on the clinical outcomes of gastric cancer. Four hundred forty-seven patients with newly diagnosed and histopathologically confirmed primary gastric cancer were collected in our study and were followed up until March 2012. ERCC1 (rs11615, rs3212986C>A, and rs2298881) and ERCC4 (rs226466C>G, rs2276465, and rs6498486) were selected and genotyped. The overall chemotherapy response rate for treatment was 68 %. Carriers of the rs11615 TT and T allele and ERCC1 rs2298881 CC and C allele had a marginally significantly higher response rate to the chemotherapy. In the Cox proportional hazard model, the hazard ratios (HRs) for overall survival (OS) in patients carrying ERCC1 rs11615 TT genotype and T allele were 0.53 (0.29–0.95) and 0.63 (0.42–0.94), respectively. Similarly, we found a significant decreased risk of death from gastric cancer among patients carrying ERCC1 rs2298881 CC genotype and C allele when compared with CC genotype, and HRs (95 % confidence interval (CI)) of OS were 0.50 (0.24–0.98) and 0.62 (0.40–0.96), respectively. Moreover, individuals carrying ERCC1 rs11615 T allele and rs2298881 C allele could decrease a 0.62-fold risk of death from gastric cancer. This study reported a carriage of ERCC1 rs11615, and rs2298881 polymorphism can be used as a predictor of response to folinic acid/5-fluorouracil (5-FU)/oxaliplatin (FOLFOX)-based chemotherapy in gastric cancer patients.
Abstract Background Conventional single-energy CT can only provide a raw estimation of electron density (ED) for dose calculation by developing a calibration curve that simply maps the HU values to ED values through their correlations. Spectral CT, also known as dual-energy CT (DECT) or multi-energy CT, can generate a series of quantitative maps, such as ED maps. Using spectral CT for radiotherapy simulations can directly acquire ED information without developing specific calibration curves. The purpose of this study is to assess the feasibility of utilizing electron density (ED) maps generated by a novel dual-layer detector spectral CT simulator for dose calculation in radiotherapy treatment plans. Methods 30 patients from head&neck, chest, and pelvic treatment sites were selected retrospectively, and all of them underwent spectral CT simulation. Treatment plans based on conventional CT images were transplanted to ED maps with the same structure set, including planning target volume (PTV) and organs at risk (OARs), and the dose distributions were then recalculated. The differences in dose and volume histogram (DVH) parameters of the PTV and OARs between the two types of plans were analyzed and compared. Besides, gamma analysis between these plans was performed by using MEPHYSTO Navigator software. Results In terms of PTV, the homogeneity index (HI), gradient index (GI), D 2% , D 98% , and D mean showed no significant difference between conventional plans and ED plans. For OARs, statistically significant differences were observed in parotids D 50% , brainstem in head&neck plans, spinal cord in chest plans and rectum D 50% in pelvic plans, whereas the variance remained minor. For the rest, the DVH parameters exhibited no significant difference between conventional plans and ED plans. All of the mean gamma passing rates (GPRs) of gamma analysis were higher than 90%. Conclusion Compared to conventional treatment plans relying on CT images, plans utilizing ED maps demonstrated similar dosimetric quality. However, the latter approach enables direct utilization in dose calculation without the requirements of establishing and selecting a specific Hounsfield unit (HU) to ED calibration curve, providing an advantage in clinical applications.
327 Background: The optimal chemotherapeutic regimen for gastric cancer with peritoneal metastasis remains undefined. We evaluated the efficacy and safety of intraperitoneal and intravenous paclitaxel plus S-1 (NIPS Group) versus paclitaxel plus S-1 (PS Group) in gastric cancer patients with peritoneal metastasis. Methods: In this multicenter, randomized, controlled, phase 3 trial, patients were recruited from 9 cancer centers in China. Eligible patients were aged 18~75 years with an Eastern Cooperative Oncology Group performance status of 0~1, histologically confirmed gastric adenocarcinoma, peritoneal metastases from gastric cancer requiring definitive diagnosis by laparoscopy, without gastric outflow tract obstruction and intestinal obstruction, no prior treatment with chemotherapy, radiation therapy, targeted therapy or immunotherapy. Eligible patients were randomly assigned (2:1) to receive either intravenous paclitaxel at 50 mg/m² and intraperitoneal paclitaxel at 20 mg/m² on days 1 and 8, along with oral S-1 at a dose of 80 mg/m² on days 1~14, or intravenous paclitaxel at 70 mg/m² on days 1 and 8, along with oral S-1 at 80 mg/m² on days 1~14. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all participants. A sample size of 238 patients was calculated to provide 80% power with a one-sided alpha of 0.1, accounting for a 10% dropout rate. Survival was analyzed using Kaplan-Meier curves and compared with the log-rank test. Cox regression was used for multivariate analysis. A P -value < 0.05 was considered statistically significant. Results: From May 10, 2017, to March 9, 2022, 246 patients were screened and 222 were included in the modified intention-to-treat population, of whom 148 patients were assigned to the NIPS Group and 74 to the PS group. As of data cutoff (March 9, 2024), the median survival time was 19.4 months (95% CI, 17.1~22.9), in the NIPS group and 13.9 months (95% CI, 10.3~16.1) in the PS group (HR = 0.66; 95% CI 0.49 - 0.88; P = 0.005). The 1-year and 2-year overall survival rates were 69.6% and 37.2% in the NIPS group, compared to 54.1% and 20.3% in the PS group. The most common grade 3~4 adverse events were leukopenia (21.7% in the NIPS group, and 24.7% in the PS group) and neutropenia (19.9% in the NIPS group, and 23.4% in the PS group). No treatment-related deaths were reported. Conclusions: Intraperitoneal and intravenous paclitaxel plus S-1 significantly improved the overall survival compared to intravenous paclitaxel plus S-1 in gastric cancer patients with peritoneal metastasis, with manageable toxicity. Clinical trial information: ChiCTR-IIR-16009802.
Peritoneal dialysis (PD) is a safe and home-based treatment for end-stage renal disease (ESRD) patients. The direct thermal damage of abdominal organs is very rare.We report a peritoneal dialysis patient presented abdominal pain and feculent effluent 3 weeks after he instilled hot dialysis solution. In spite of emergency exploratory laparotomy and active treatment, the patient died of septic shock. Biopsy revealed necrosis and perforation of the intestines.Delayed bowel perforation by hot fluid is very rare. Standardized performance is of the first importance for peritoneal dialysis patients.
Intestinal ischemia-reperfusion (I/R) injury can occur in clinical settings such as organ transplantation, cardiopulmonary bypass and trauma. The noble gas helium attenuates I/R injury in a number of animal organs and thus may offer a strategy for reducing I/R-induced intestinal injury in clinical settings. In the present study, we used four different helium preconditioning (HPC) profiles to investigate the potential beneficial effect of HPC on I/R-induced intestinal injury. Male Sprague-Dawley rats were pretreated with three cycles of air breathing for 5 min combined with three cycles of breathing a 70% helium:30% oxygen mixture for either 2, 5, 10, or 15 min, after which they were subjected to 60-min intestinal ischemia and 60-min reperfusion. Sixty minutes after reperfusion, the intestinal tissues of the variously treated rats were analyzed using histology, immunohistochemistry, terminal dUTP nick-end labeling staining, myeloperoxidase activity assay, Western blotting, and enzyme-linked immunosorbent assay for tumor necrosis factor α and macrophage inflammatory protein 1α. Intestinal permeability was assayed by measuring fluorescein isothiocyanate–dextran release in blood samples. The results showed that the HPC profile consisting of three cycles of 10 or 15 min of helium breathing and three cycles of 5 min of air breathing reduced I/R-induced intestinal injury, cell apoptosis, and the inflammatory response. However, the 2- or 5-min helium breathing did not confer any protective effects. It seems that longer helium episodes should be used in HPC profiles designed to attenuate intestinal I/R injury.
Gastric cancer (GC) is a leading cause of cancer deaths, and an increased number of GC patients adopt to next-generation sequencing (NGS) to identify tumor genomic alterations for precision medicine.In this study, we established a hybridization capture-based NGS panel including 612 cancer-associated genes, and collected sequencing data of tumors and matched bloods from 153 gastric cancer patients. We performed comprehensive analysis of these sequencing and clinical data.35 significantly mutated genes were identified such as TP53, AKAP9, DRD2, PTEN, CDH1, LRP2 et al. Among them, 29 genes were novel significantly mutated genes compared with TCGA study. TP53 is the top frequently mutated gene, and tends to mutate in male (p = 0.025) patients and patients whose tumor located in cardia (p = 0.011). High tumor mutation burden (TMB) gathered in TP53 wild-type tumors (p = 0.045). TMB was also significantly associated with DNA damage repair (DDR) genes genotype (p = 0.047), Lauren classification (p = 1.5e-5), differentiation (1.9e-7), and HER2 status (p = 0.023). 38.31% of gastric cancer patients harbored at least one actionable alteration according to OncoKB database.We drew a comprehensive mutational landscape of 153 gastric tumors and demonstrated utility of target next-generation sequencing to guide clinical management.
Abstract Background Analysis of the risk factors associated with functional delayed gastric emptying after distal gastric cancer surgery to provide a basis for further reduction of the incidence of this complication. Methods Total of 1382 patients with distal gastric cancer from January 2016 to October 2018 were enrolled. Correlation analysis was performed in 53 patients with FDGE by logistic regression. Subgroup risk analysis was performed in 114 patients with preoperative pyloric obstruction. A Pearson Chi-square analysis was used to compare categorical variables between normal distribution groups. Meanwhile, a t test was used to compare continuous variables between groups. Odds ratio (OR) was used for comparison of the two groups, and it was summarized with its 95% confidence interval (CI) and p value using logistic regression. Result In multivariable analysis, age (OR 1.081, 95% CI, 1.047–1.117), BMI (OR 1.233, 95% CI, 1.116–1.363), preoperative pyloric obstruction (OR 3.831, 95% CI, 1.829–8.023), smaller volume of residual stomach (OR 1.838, 95% CI, 1.325–6.080), and anastomosis in greater curvature perpendicular (OR 3.385, 95% CI, 1.632–7.019) and in greater curvature parallel (OR 2.375, 95% CI, 0.963–5.861) were independent risk factors of FDGE. In the preoperative pyloric obstruction group, higher BMI (OR 1.309, 95% CI, 1.086–1.579) and preoperative obstruction time (OR 1.054, 95% CI, 1.003–1.108) were independent risk factors of FDGE and preoperative gastrointestinal decompression (OR 0.231, 95% CI, 0.068–0.785) was independent protective factor of FDGE. Conclusion Adequate gastrointestinal decompression should be performed before the operation to reduce the incidence of postoperative gastroparesis in patients with preoperative pyloric obstruction. We also could improve the surgical methods to reduce the occurrence of FDGE, such as controlling the size of the residual stomach, ensuring blood supply. Especially selecting an appropriate stapler and anastomosis during the anastomosis process, the occurrence of FDGE can be reduced.
Abstract Background CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. Methods The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. Results In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. Conclusions Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.
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