The impact of the length of proximal margin on the prognosis in adenocarcinoma of gastroesophageal junction: A real-world study and strategies.

BACKGROUND: The optimal proximal margin (PM) length for Siewert II/III adenocarcinoma of the esophagogastric junction (AEJ) remains unclear. This study aimed to determine the optimal PM length using an abdominal approach to guide surgical decision-making. METHODS: A prospective study analyzed 304 consecutive patients diagnosed with Siewert II/III AEJ between January 2019 and December 2021. Total gastrectomy was performed via the abdominal approach, and PM length was measured on fixed gross specimens. X-Tile software determined the optimal PM cut-point based on progression-free survival (PFS). Univariate analyses compared baseline characteristics across PM groups, while survival analyses utilized Kaplan-Meier estimation and Cox proportional hazards regression for assessing the impact of margin length on survival. Multivariable analyses were conducted to adjust for confounding variables. RESULTS: The study included 264 AEJ cases classified as Siewert II (71.97%) or III (28.03%). The median gross PM length was 1.0 cm (IQR: 0.5 cm-1.5 cm, range: 0 cm-6 cm). PM length ≥1.2 cm was associated with a lower risk of disease progression compared to PM length 0.4 cm on PFS (HR = 0.41, 95% CI 0.20-0.84, P = 0.015). Moreover, PM ≥ 1.2 cm improved prognosis in subgroups of T4 or N3, tumor size <4 cm, Siewert II, and Lauren classification. CONCLUSIONS: For Siewert type II/III AEJ, a proximal margin length ≥1.2 cm (1.65 cm in situ) is associated with improved outcomes. These findings offer valuable insights into the association between PM length and outcomes in Siewert II/III AEJ, providing guidance for surgical approaches and aiding clinical decision-making to enhance patient outcomes.

Analysis of risk factors and prevention strategies for functional delayed gastric emptying in 1243 patients with distal gastric cancer.

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.

[Value of Magnetic Resonance Imaging Findings in Differential Diagnosis between the Adult Reversible Splenial Lesion Syndrome and Ischemic Infarction of the Splenium of the Corpus Callosum].

Objective To evaluate the magnetic resonance imaging (MRI) findings in differential diagnosis between the adult reversible splenial lesion syndrome (RESLES) and ischemic infarction of the splenium of the corpus callosum (SCC). Methods The MRI findings and clinical data of 7 RESLES patients and 13 patients with ischemic infarction of SCC who were clinically diagnosed and treated in our center from May 2015 to June 2017 were analyzed retrospectively. The main MRI findings included location,morphology,signal intensity,maximum cross-sectional area,diffusion weighted imaging (DWI),and apparent diffusion coefficient (ADC) value. Results On the MRI findings of 7 RESLES patients (5 males and 2 females),the centers of all lesions of the SCC were located in the midline of SCC,the lesion shapes were round,ellipse,or spindle,and the distribution of the lesions was bilateral and symmetric as the center of the midline of SCC. The lesions were hyperintense on DWI,and the mean maximum cross-sectional area of lesions was (56.9±32.6) mm2 and the mean ADC value was (0.3963±0.0715) ×10-3 mm2/s. On the review MRI,all the lesions disappeared (mean interval:10 days). On the MRI findings of 13 patients with ischemic infarction of SCC (10 males and 3 females),the lesions were irregular or patchy in shape and were almost laterally and asymmetrically distributed. The lesions were hyperintense on DWI,and the mean maximum cross-sectional area was (55.1±43.9) mm2 and the mean ADC value was (0.4978±0.0123) ×10-3 mm2/s. The mean maximum cross-sectional area (t=0.096,P=0.925) and the ADC value (t=-1.988,P=0.062) were not significantly different between RESLES group and ischemic infarction of SCC group. Conclusions The location,morphology,and distribution of the SCC lesions and the co-existence of other lesions in the brain are helpful for the differential diagnosis between RESLES and ischemic infarction of SCC. However,the mean maximum cross-sectional area and the ADC value show no obvious difference between these two diseases.

Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma.

OBJECTIVE: To evaluate the effects of fiber-modified hexon-chimeric recombinant oncolytic adenovirus targeting cancer associated fibroblasts (CAFs) on the gastric CAFs and the transplantation tumor mice model of gastric carcinoma (GC). RESULTS: Compared with BJ cells and GPFs, the reproduction and infectivity of P9, P9-4C or GP adenoviruses were markedly higher in gastric CAFs. In addition, P9, P9-4C or GP had a significantly relatively more killing effect on gastric CAFs compared with GPFs, and have less oncolytic effect in BJ cells. Furthermore, in transplantation tumor mice model of GC we found significantly higher hexon protein expression in tumor tissues, more decreasing tumor growth and increasing inhibitory rates after treatment of P9, P9-4C or GP adenoviruses compared with Ad adenovirus. MATERIALS AND METHODS: Based on the construction of the recombinant oncolytic adenoviruses pRCAdHVR48-SDF1p-Ad/EGFP (Ad, as control) with the E1A gene transcription regulated by stromal-derived factor 1 (SDF1) promoter and the hexon replaced by hexon-chimeric (H5HVR48) gene, three fiber-modified hexon-chimeric oncolytic adenovirus through the modification fiber protein by insertion of different short peptides specifically binding to fibroblast activation protein (FAP), including pRCAdHVR48-SDF1p-FAP-P9/EGFP (P9), pRCAdHVR48-SDF1p-FAP-P9-4C/EGFP (P9-4C), pRCAdHVR48-SDF1p-FAP-GP/EGFP (GP), and their corresponding replication-defective adenovirus in parallel were reconstructed. Then the reproduction, infectivity and killing ability of the four above recombinant adenoviruses were evaluated in gastric CAFs compared with gastric para-mucosa fibroblasts (GPFs) and neonatal human foreskin fibroblasts (BJ). Furthermore, transplantation tumor mice model of GC was established, and then treated by the four above recombinant adenoviruses. Tumor size and tumor growth inhibitory rates were calculated, and histomorphology by HE staining and hexon expressions by immunohistochemistry were evaluated in tumor tissues. CONCLUSIONS: The fiber-modified hexon-chimeric recombinant oncolytic adenovirus targeting CAFs can relatively specifically kill gastric CAFs and inhibit GC cells growth in vivo.

Experimental study on sustained-release 5-Fluorouracil implantation in canine peritoneum and para-aortic abdominalis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Influence of ERCC1 and ERCC4 polymorphisms on response to prognosis in gastric cancer treated with FOLFOX-based chemotherapy.

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.

[Anti-tumor effect of gene-viral therapeutic system CNHK300-murine endostatin on nude mouse gastric cancer].

OBJECTIVE: To investigate the anti-tumor effect of a novel gene-viral therapeutic system CNHK300-murine endostatin (CNHK300-mE) on gastric cancer. METHODS: SGC-7901 gastric cancer cells (5 x 10(7) cells/mouse) were injected s.c. into the right flank of Balb/c nude mice, grown to 4-5 mm to demonstrate tumor take, and 10(9) pfu/100 microl CNHK300-mE virus was injected into tumors. Tumor sizes were measured with calipers every other day. Serum samples were obtained by retro-orbital puncture and level of endostatin expression in serum was quantitated by ELISA. Fifteen days after treatment, all mice were sacrificed and tumors were excised for immunohistochemical staining of PCNA, hexon and vWF. Tumor cell apoptosis was detected by TUNEL method. RESULTS: From the 7th day post-treatment, the bearing tumors of mice treated with CNHK300-mE were significantly smaller than those of control group treated with PBS. Seven days after treatment, expression of endostatin was (2115 +/- 770) ng/ml, significantly higher than that of control group. Immunohistochemical staining indicated that hexon was expressed in treated tumor cells, and PCNA LI (label index) [(55.0+/-1.4)% vs control (74.1 +/- 0.4)%, P<0.05], microvessel density (MVD) of CNHK300-mE treated tumors decreased significantly. Apoptosis obviously increased in tumor cells[(78.4 +/- 9.1)% vs control (15.2 +/- 0.5)%, P<0.01]. Apoptosis bodies and crystal grid were found in tumor cell nuclear by electron microscope. CONCLUSIONS: Gene-viral therapeutic system CNHK300-murine endostatin can replicate in gastric cancer cells. The mouse endostatin gene cloned into CNHK300-mE expressed in high level. CNHK300-mE may induce tumor cells apoptosis, reduce the expression of PCNA and efficiently suppress gastric cancer growth through inhibiting tumor angiogenesis.

[CNHK200-hA-a gene-viral therapeutic system and its antitumor effect on lung cancer].

OBJECTIVE: To develop a novel vector system, which combines the advantages of the gene therapy, antiangiogenic therapy and virus therapy, and to observe its effect on lung cancer. METHODS: Human angiostatin gene hA(k1-5) was inserted into the genome of the replicative virus specific for the tumor cells by virus recombination technology. The expression of hA(k1-5), its effect on tumor growth in vitro and in vivo were studied. RESULTS: A new kind of gene-viral vector system, designated as CNHK200-hA(k1-5), in which the E1b55 000 gene was deleted but the E1a gene of adenovirus preserved, was constructed. The novel vector system possessed the same property as the replicative virus ONYX-015, which replicates in p53- tumor cells but not in normal cells, thus specifically kills tumor cells. In vitro, CNHK200-hA and Ad-hA both could kill A549 tumor cells but the latter needed 100 times more MOI to achieve the same amplitude of cell killing. In vivo, the therapeutic effect of CNHK200-hA on human lung cancer A549 xenograft in nude mice was significantly better than that of Ad-hA and that of tumor-replicative virus ONYX-015. CONCLUSION: CNHK200-hA(k1-5), a novel vector is constructed in which the angiostatin gene is inserted into the genome of the replicative adenovirus cytotoxic to p53-negative tumor cells. It has the advantages of specific tumor targeting, high level gene expression in tumor cells, and potent tumoricidal activity.

[Efficacy of intraoperative hypotonic peritoneal chemo-hyperthermia combined with early postoperative intraperitoneal chemotherapy on gastric cancer].

BACKGROUND & OBJECTIVE: Abdominal recurrence from exfoliated cancer cells contributes a lot to treatment failure of advanced gastric cancer. Intraperitoneal chemotherapy, which has been proved effective in eliminating exfoliated cancer cells in abdominal cavity, is a hot topic on treatment of gastric cancer. This study was to explore application of combined therapy of intraoperative hypotonic peritoneal chemo-hyperthermia and early postoperative intraperitoneal chemotherapy to gastric cancer. METHODS: A total of 156 gastric cancer patients were randomized into 3 groups, and underwent the combined therapy (treatment group 1), intraoperative chemotherapy (treatment group 2), and peritoneal lavage with distilled water (control group), respectively. RESULTS: The 2-year survival rate of treatment group 1 was significantly higher than that of control group (88.4% vs. 65.2%, P < 0.05). The 3-year survival rate of treatment group 1 was significantly higher than those of treatment group 2, and control group (71.1% vs. 50.0%, and 45.6%, P < 0.05). Occurrence of liver metastasis was significantly lower in treatment groups 1 and 2 than in control group (7.7%, and 10.2% vs. 27.3%, P < 0.05). CONCLUSIONS: Combined therapy of intraoperative hypotonic chemo-hyperthermia and early postoperative intraperitoneal chemotherapy is effective for gastric cancer. Intraperitoneal chemotherapy can be used to prevent postoperative liver metastasis of gastric cancer.

Potent antitumoral effects of a novel gene-viral therapeutic system CNHK300-mEndostatin in hepatocellular carcinoma.

BACKGROUND: The expression of therapeutic gene and its anti-tumor effects will be augmented and a synergism of oncolytic virus with the therapeutic gene is speculated. This study was undertaken to assess the anti-tumor effects of a novel gene-viral therapeutic system CNHK300-mEndostatin (CNHK300-mE) in hepatocellular carcinoma (HCC). METHODS: A novel gene-viral therapeutic system named CNHK300-mE was constructed using the human telomerase reverse transcriptase (hTERT) promoter to drive the expression of the adenovirus E1A gene and cloning the therapeutic gene mouse endostatin into the adenovirus genome. By the tissue culture infectious dose 50 (TCID50) method and cytoviability assay, the replicative and cytolytic capabilities of CNHK300-mE in two HCC lines (HepGII and Hep3B) and one normal cell line (MRC-5) were analyzed, and the transgene expressions of mouse endostatin in vitro and in vivo were detected by Western blotting and ELISA assay. Tumor growth suppression and anti-angiogenesis effects in vivo were investigated using nude mice xenografts model derived from SMMC-7721 HCC cells. RESULTS: The 3296-fold replicating capacity of CNHK300-mE in HCC cell lines versus in the normal cell line at 96 hours post infection and the 25-fold effective dose for killing 50% cells (ED50) in the normal cell line versus HCC cell lines, which were both superior to ONYX-015, were observed. Tumor growth suppression of CNHK300-mE superior to either Ad-mE or ONYX-015 was demonstrated (P < 0.01) and the anti-angiogenic effects in vivo superior to Ad-mE were also observed with immunohistochemical staining of von Willebrand factor. In comparison with non-replicative adenovirus Ad-mE, the transgene expression of mE mediated by CNHK300-mE was significantly higher in vitro (P < 0.005) and in vivo (P < 0.05). CONCLUSION: Being capable of replicating in and lysing the telomerase-positive HCC cells and mediating effective expression of the therapeutic gene in vitro and in vivo, the novel gene-viral therapeutic system CNHK300-mE is potentially effective in the treatment of HCC.

[Treatment of hepatocellular carcinoma with a novel gene-viral therapeutic system CNHK300-murine endostatin].

OBJECTIVE: To investigate the anti-tumor effects of a novel gene-viral therapeutic system CNHK300-murine endostatin (CNHK300-mE) in hepatocellular carcinoma (HCC). METHODS: A novel gene-viral therapeutic system named CNHK300-mE was constructed by employing the human telomerase reverse transcriptase (hTERT) promoter to drive the expression of adenovirus E1A gene and cloning the therapeutic gene murine endostatin (mE) into the adenovirus genome. Hepatocellular cells of the HepGII and Hep3B lines and normal fibroblasts of the MRC-5 line were cultured and infected with the viruses CNHK300-mE, ONYX-015, replicative adenovirus without therapeutic gene, and Ad-mE, non-replicative adenovirus with the same therapeutic gene. Ninety-six hours after the infection, tissue culture infectious dose 50 method was used to detect the titer of virus in the supernatants. MTT method was used to examine the cytolytic capability. The expression of E1A and mE were examined by Western blotting. ELISA assay was used to detect the transgene expression of mouse endostatin. Healthy nude Balb/c mice were injected with hepatic cancer cells of the SMMC 7221 line. Forty mice with tumors 5 approximately 8 mm in diameter were randomly divided into 4 groups of 20 mice: CNHK300-mE group (CNHK300-mE was injected into the tumor once every other day for 5 times), Ad-mE group (Ad-mE was injected), ONYX-015group (ONYX-015 was injected), and control group (diluent of virus was injected). 3, 7, 14, 21, and 28 days after the initial injection the size of tumor was examined. 48 hours after the finish of the whole course of treatment, the mice were killed. ELISA was used to detect the expression of mE in blood. The growth of tumor was examined by HE staining, The angiogenesis in the tumor was observed by immunohistochemistry with von Willebrand factor and The proliferation of transplanted tumor was observed by immunohistochemistry with adenovirus envelop protein hexon. RESULTS: Ninety-six hours after the infection of the cells by CNHK300-mE virus was replicated by 6329 +/- 1830 and 25 136 +/- 6890 times in the HepGII and Hep3B cells respectively, 3296 and 12 824 times higher than in the MRC-5 cells respectively. The replication multiples of ONYX-015 virus in the HepGII and Hep3B cells were 2040 +/- 450 and 3980 +/- 740 times respectively, both significantly lower than those of CNHK300-mE virus (both P < 0.05). However, no remarkable replication of Ad-mE virus was seen in the Western blotting showed the expression of therapeutic gene mE in HepGII and Hep3B cells infected with CNHK300-mE on Ad-mE. Hep3B cells, the band of CNHK300-mE being thicker than that of Ad-mE and the band of Ad-mE being similar to that of CNHK300-mE in the MRC-5 cells. ELISA showed that the expression of mE protein in the HepGII cells infected by CNHK300-mE virus increased time-dependently during the period of 7 days after virus infection, significantly higher than the expression in the HepGII cells infected by Ad-mE virus (P < 0.05). The tumors of the CNHK300-mE virus-infected mice were significantly smaller than those of the Ad-mE and ONYX-015-infected mice (both P < 0.01). ELISA showed that the mE protein content in the blood of the CNHK300mE-infected mice was significantly higher than that of the Ad-mE group (P < 0.05). Hexon immunohistochemistry showed patchy and diffuse positive staining related to apoptosis and necrosis of tumor cells in the transplanted tumors of the CNHK300-mE virus-infected mice, however, only sporadic positive staining was seen in the Ad-mE virus-infected mice. CONCLUSION: Being capable of specifically replicating in the telomerase-positive HCC cells and mediating effective expression of therapeutic gene in vitro and in vivo, the novel gene-viral therapeutic system CNHK300-mE holds potential for treatment of HCC.