IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling.

BACKGROUND: Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood. METHODS: The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al . RESULTS: In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients. CONCLUSION: Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

Long-term nutritional status after total gastrectomy was comparable to proximal gastrectomy but with much less reflux esophagitis and anastomotic stenosis.

Aim: To compare the long-term nutritional status, reflux esophagitis and anastomotic stenosis, between total gastrectomy (TG) and proximal gastrectomy (PG). Methods: Patients who underwent PG or TG in this single institution between January 2014 and December 2016 were included in this study. The inclusion and exclusion criteria were defined. One-to-one propensity score matching (PSM) by the demographic and pathological characteristics was performed to compare the long-term outcomes between the two groups. The primary endpoint was long-term nutritional status, and the second endpoints were reflux esophagitis and anastomotic stenosis. Long-term nutritional status was valued by percentage of body mass index (%BMI), body weight, and blood test including total protein, prealbumin, hemoglobin and total leukocytes. Results: Totally 460 patients received PG or TG in our institution for the treatment between January 2014 and December 2016 and according to the inclusion and exclusion criteria 226 cases were included in this study finally. There was no significant difference as to nutritional status in the end of first 5 years after PG or TG. While reflux esophagitis and anastomotic stenosis were significantly higher in the PG group than in the TG group (54.4% versus 26.8%, p < 0.001; 14.9% versus 4.5%, p=0.015; respectively). Overall survival rates were similar between the two groups after PSM (5-year survival rates: 65.4% versus 61.5% in the PG and TG groups, respectively; p = 0.54). The rate of carcinoma of remnant stomach after PG was 3.5% in this group of patients. Conclusions: TG should be more aggressively recommended for the similar nutritional status, significantly lower reflux esophagitis and anastomotic stenosis, and free of carcinoma of remnant stomach compared with PG.

Peking prognostic score is a useful prognostic factor in patients with gastric cancer liver metastases receiving hepatectomy.

Background: The present work evaluated how Peking prognostic score (PPS), the new prognostic index determined according to sarcopenia and lymphocyte-to-C-reactive protein ratio (LCR), was a prognostic factor for patients with gastric cancer liver metastases (GCLM) who received hepatectomy. Methods: This work extracted information about patients with GCLM who underwent hepatectomy from June 2012 to May 2018. The PPS of the patients was calculated from sarcopenia status and LCR before surgery, and patients were then divided into three groups based on their PPS. This work also carried out univariate and multivariate analyses for identifying variables that were linked with overall survival (OS) together with recurrence-free survival (RFS) after hepatectomy among three groups according to PPS. Results: This work included 108 GCLM cases who received hepatectomy. All cases were classified into 3 groups, i.e., 26 (24.1%), 48 (44.4%), and 34 (31.5%) in groups 0-2, separately. PPS exhibited positive relation with age (p < 0.001), body mass index (BMI; p = 0.012), and liver metastasis number. The relapse rate after hepatectomy in patients with GCLM was 69.4%. Additionally, the remnant liver relapse rates of groups 0-2 were 80.0, 68.7, and 53.5%. Patients in group 0 had significantly increased remnant liver relapse rates when compared with those in groups 0 and 1. PPS was significantly related to relapse patterns (p = 0.003). Relative to group 0, those of the other 2 groups showed dismal OS [hazard ratio (HR) = 3.98, 7.49 for groups 1 and 2; p < 0.001] along with RFS (HR = 3.65, 5.33 for groups 1 and 2; p < 0.001). As revealed by multivariate analysis, PPS independently predicted OS (p < 0.001) together with RFS (p < 0.001). Conclusion: The PPS could be an easy nutrition-inflammation prognostic scoring system and an independent preoperative predictor of survival for GCLM cases after hepatectomy.

No long-term survival benefit with sustained-release 5-fluorouracil implants in patients with stages II and III gastric cancer.

BACKGROUND: The prognosis of gastric cancer in an advanced stage remains poor. The exact efficacy of the use of intraoperative sustained-release chemotherapy with 5-fluorouracil (5-FU) in advanced-stage gastric cancer is still unelucidated. AIM: To explore the long-term survival benefit of using sustained-release 5-FU implants in stage II and stage III gastric cancer patients. METHODS: Patients with gastric cancer in a locally advanced stage and who underwent an R0 radical resection between Jan 2014, to Dec 2016, in this single institution were included. Patients with pathological diagnoses other than adenocarcinoma were excluded. All included patients were grouped according to whether intraoperative sustained-release (SR) chemotherapy with 5-FU was used or not (NSR). The primary end-point was 5-year overall survival. Kaplan-Meier method with log-rank test was used to analyze the overall survival of patients and Cox analysis was used to analyze prognosis factors of these patients. RESULTS: In total, there were 563 patients with gastric cancer with locally advanced stage, who underwent an R0 radical resection. 309 patients were included in the final analysis. 219 (70.9%) were men, with an average age of 58.25 years. Furthermore, 56 (18.1%) received neoadjuvant chemotherapy, and 191 (61.8%) were in TNM stage III. In addition, 158 patients received intraoperative sustained-release chemotherapy with 5-FU and were included in the SR group, while the other 161 patients were included in the NSR group. The overall complication rate was 12.94% in the whole group and 10.81%, 16.46% in SR and NSR groups, respectively. There were no significant differences between the two groups in overall survival and complication rate (P > 0.05). The multivariate cox analysis indicated that only N Stage and neoadjuvant therapy were independent influencing factors of survival. CONCLUSION: Intraoperative sustained-release chemotherapy usage with 5-FU, did not improve the survival of patients who underwent an R0 radical resection in locally advanced stage of gastric cancer.

Hyperthermic intraperitoneal chemotherapy for patients with gastric cancer based on laboratory tests is safe: a single Chinese center analysis.

PURPOSE: About 15%-40% of gastric cancer patients have peritoneal metastasis, which leads to poor prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) is considered to be an effective treatment for these patients. This study evaluated the efficacy and safety of HIPEC in patients with gastric cancer diagnosed from laboratory tests. METHODS: The clinical and pathological data of 63 patients with gastric cancer who underwent HIPEC in 2017-2021 were prospectively recorded. Fifty-five patients underwent cytoreductive surgery + HIPEC, and eight patients received HIPEC alone. The factors associated with HIPEC safety and efficacy were analyzed. The primary endpoint was overall survival. RESULTS: The average patient age was 54.84 years and 68.3% of patients were male. Moreover, 79.4% of patients had a peritoneal carcinoma index (PCI) score of ≤ 7 and 61.9% had a completeness of cytoreduction score of 0. Because of peritoneal metastasis, 29 patients (46.03%) were classified as stage IV. Laboratory tests showed no differences in pre-HIPEC blood test results compared to post-HIPEC results after removing the effects of surgery. HIPEC treatment did not cause obvious liver or kidney damage. Serum calcium levels decreased significantly after HIPEC (P = 0.0018). The Karnofsky performance status (KPS) score correlated with the patient's physical function and improved after HIPEC (P = 0.0045). In coagulation tests, FDP (P < 0.0001) and D-dimer (P < 0.0001) levels increased significantly and CA242 (P = 0.0159), CA724 (P < 0.0001), and CEA (P < 0.0014) levels decreased significantly after HIPEC. Completeness of cytoreduction score was an independent prognostic factor. HIPEC did not show a survival benefit in patients with gastric cancer (P = 0.5505). CONCLUSION: HIPEC is a safe treatment for patients with gastric cancer with peritoneal metastasis based on the laboratory tests. However, the efficacy of this treatment on gastric-derived peritoneal metastases requires further confirmation.

Dynamic monitoring revealed a slightly prolonged waiting time for total gastrectomy during the COVID-19 pandemic without increasing the short-term complications.

We aimed to determine the pattern of delay and its effect on the short-term outcomes of total gastrectomy before and during the coronavirus disease 2019 (COVID-19) pandemic. Overlaid line graphs were used to visualize the dynamic changes in the severity of the pandemic, number of gastric cancer patients, and waiting time for a total gastrectomy. We observed a slightly longer waiting time during the pandemic (median: 28.00 days, interquartile range: 22.00-34.75) than before the pandemic (median: 25.00 days, interquartile range: 18.00-34.00; p = 0.0071). Moreover, we study the effect of delayed surgery (waiting time > 30 days) on short-term outcomes using postoperative complications, extreme value of laboratory results, and postoperative stay. In patients who had longer waiting times, we did not observe worse short-term complication rates (grade II-IV: 15% vs. 19%, p = 0.27; grade III-IV: 7.3% vs. 9.2%, p = 0.51, the short waiting group vs. the prolonged waiting group) or a higher risk of a longer POD (univariable: OR 1.09, 95% CI 0.80-1.49, p = 0.59; multivariable: OR 1.10, 95% CI 0.78-1.55, p = 0.59). Patients in the short waiting group, rather than in the delayed surgery group, had an increased risk of bleeding in analyses of laboratory results (plasma prothrombin activity, hemoglobin, and hematocrit). A slightly prolonged preoperative waiting time during COVID-19 pandemic might not influence the short-term outcomes of patients who underwent total gastrectomy.

Prognostic Significance of Preoperative Sarcopenia in Patients With Gastric Cancer Liver Metastases Receiving Hepatectomy.

Background: The present work focused on assessing the role of computed tomography (CT)-determined sarcopenia in the prognosis of patients with gastric cancer liver metastases (GCLM) receiving hepatectomy. Methods: We analyzed data collected from GCLM cases that underwent hepatectomy between March 2011 and July 2017. The third lumbar vertebra (L3) level skeletal muscle index (SMI) was analyzed by abdominal CT to determine the sarcopenia before surgery. The thresholds for CT-based sarcopenia of sex-specific L3 SMI were ≤ 34.9 cm2/m2 and ≤ 40.8 cm2/m2 for female and male, separately We determined overall survival (OS) and recurrence-free survival (RFS)by univariate and multivariate analyses. Results: The cohort enrolled altogether 114 patients with GCLM receiving hepatectomy (average age: 62.6 years, male: 79.8%), and 58 (50.8%) patients had sarcopenia. The mean SMI was 34.2 in patients with sarcopenia compared to 42.7 in patients without sarcopenia (p < 0.001). The 1-, 3-, and 5-year OS rates in patients with GCLM after hepatectomy were 78.1, 43.7, and 34.3%, respectively. The 1-, 3-, and 5-year RFS rates in patients were 49.8, 33.6, and 29.3%, respectively. Sarcopenia was related to an advanced age (≥65.0 years) (p = 0.009), reduced BMI (<18.5 kg/m2) (p < 0.001) and number of liver metastases (>1) (p = 0.025). Sarcopenia had a significant associated with the patterns of recurrence (p < 0.001). In addition, patients with sarcopenia had a significant difference in number of liver metastases in comparison with those without sarcopenia (p = 0.025). We discovered from multivariate analysis that sarcopenia independently predicted RFS [hazard ratio (HR) = 1.76; 95% confidence interval (CI)= 1.18-2.35, p = 0.007]. Nevertheless, sarcopenia was not the prognostic factors that independently predicted OS (HR = 1.62; 95% CI = 0.57-2.73; p = 0.330). Conclusions: In conclusion, we showed that CT-determined sarcopenia was the facile and effective prognostic factor for RFS inpatients with GCLM after hepatectomy. Patients with sarcopenia are associated with an increased tumor recurrence risk, and thereby customized treatment should be applied.

The Impact of Immune Microenvironment on the Prognosis of Pancreatic Ductal Adenocarcinoma Based on Multi-Omics Analysis.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor characterized by rapid progression, early metastasis, high recurrence, and limited responsiveness to conventional therapies. The 5-year survival rate of PDAC is extremely low (<8%), which lacks effective prognostic evaluation indicators. In this study, we used xCell to analyze infiltrating immune cells in a tumor and through the univariate and multivariate Cox analyses screened out two prognosis-related immune cells, CD4+TN and common lymphoid progenitor (CLP), which were used to construct a Cox model and figure out the risk-score. It was found that the constructed model could greatly improve the sensitivity of prognostic evaluation, that the higher the risk-score, the worse the prognosis. In addition, the risk-score could also identify molecular subtypes with poor prognosis and immunotherapy sensitivity. Through transcriptome and whole-exome sequencing analysis of PDAC dataset from The Cancer Genome Atlas (TCGA), it was found that copy number deletion and low expression of CCL19 might be crucial factors to affect the risk-score. Lastly, validation of the above findings was confirmed not only in Gene Expression Omnibus (GEO) datasets but also in our PDAC patient samples, Peking2020 cohort.

Investigation of the factors influencing surgical treatment of duodenal gastrointestinal stromal tumors.

BACKGROUND: Duodenal gastrointestinal stromal tumor (DGIST) is a rare tumor with a specific anatomic site and biological characteristics. As the incidence of lymph node metastasis is very low, the main treatment method is surgery. Two main surgical techniques (local resection and Whipple) are performed in patients with DGISTs. The critical question is which surgical technique to choose. AIM: To identify factors influencing the choice of surgery for DGISTs. METHODS: The clinicopathological data of patients with DGISTs who underwent surgery between January 1999 and January 2021 were analyzed. We used the Student's t-test or Mann-Whitney U-test and the χ 2 test or Fisher's exact test to determine the differences between the two groups of patients. Furthermore, we used logistic analysis to identify the relevant factors and independent factors related to the type of surgery. The Kaplan-Meier method was used to analyze the patient's survival information and Cox regression analysis was performed to determine prognostic risk factors. RESULTS: Overall, 86 patients were analyzed, including 43 men (50%) and 43 women (50%). We divided the patients into two groups based on surgical technique (local resection or Whipple surgery). There were no differences in the age, mitotic figures, and complications between the two groups; however, the tumor size, tumor location, risk grade, postoperative hospital stay, and abdominal drainage time were significantly different. Based on univariate logistic analysis, the Whipple procedure was chosen if the tumor size was ≥ 5.0 cm, the tumor was located in the descending part of the duodenum, or the risk grade was medium or high. In our research, the five-year overall survival rate of patients was more than 90%. We also describe two DGIST patients with liver metastases at first diagnosis and analyzed their management in order to provide advice on complicated cases. CONCLUSION: The Whipple procedure was performed if the primary tumor was in the descending part of the duodenum, tumor size was ≥ 5.0 cm, or the tumor risk grade was medium or high.

Disease-Specific Survival of AJCC 8th Stage II Gastric Cancer Patients After D2 Gastrectomy.

The association between the risk factors and long-term prognosis in patients with stage II gastric cancer after radical gastrectomy has been fully revealed. The purpose of this study was to investigate the independent risk factors for treatment failure in stage II gastric cancer. Demographic, clinical, and pathological information of 247 stage II gastric cancer patients who underwent radical D2 gastrectomy in our department between January 2011 and December 2014 were collected and retrospectively analyzed. The relationship between and long-term clinical outcomes of stage II gastric cancer was analyzed using t-tests, chi-square tests, receiver operating characteristic (ROC) analysis, time-dependent ROC analysis, K-M curves, and a Cox regression model. The median follow-up of 247 stage II gastric cancer patients was 5.49 years (range: 0.12-8.62 years). The Kaplan-Meier estimated 3-year and 5-year DSS rates of the study group were 92.7% (95% CI 89.4-95.9) and 88.7% (95% CI 84.7-92.7), respectively. Higher age (>70 vs. ≤70, log-rank p = 0.0406), nerve invasion (positive vs. negative, log-rank p = 0.0133), and non-distal gastrectomy (distal partial gastrectomy vs. other surgical methods, log-rank p = 0.00235) had worse prognoses compared to controls. Univariate and multivariate analyses of disease-specific survival showed that these three factors were independent prognostic factors for patients with stage II disease. The area under time-dependent ROC curve (AUC) is 0.748 of 5-year survival and c-index is 0.696 based on the three-marker model drawn for stage II patients. Subgroup analyses showed an interaction between tumor location and nerve invasion. The age, perineural invasion, and surgical approach are independent prognostic factors for disease-specific survival after radical gastrectomy. Tumor location may be an important confounding factor for outcomes by affecting surgical methods and the hazards of nerve invasion.

Recent progress in nanomaterials for nucleic acid delivery in cancer immunotherapy.

The combination of gene therapy and immunotherapy has the potential to systemically promote anti-tumor effects while reducing adverse reactions. Small interfering RNA (siRNA) has generated great interest in biology, engineering and medicine, especially for cancer treatment due to its ability to knock down genes of interest. Nanomaterials play significant roles in the design of delivery systems of siRNA, and nanomaterial-mediated siRNA delivery in cancer immunotherapy is one of the most important directions for future clinical cancer treatment. Here, we review the recent advances in nanomaterial mediated targeted delivery of siRNA to dendritic cells (DCs), tumor-associated macrophages (TAMs), immune checkpoint inhibitors, B lymphocytes, natural killer cells (NKs), and immunosuppressive cytokines. Fundamental challenges in nucleic acid delivery enabled by bio-barriers, its promising solution strategies and future directions are also reviewed.

Radiofrequency ablation vs hepatic resection for solitary colorectal liver metastasis: a meta-analysis.

AIM: To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection (HR) for solitary colorectal liver metastases (CLM). METHODS: A literature search was performed to identify comparative studies reporting outcomes for both RFA and HR for solitary CLM. Pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model. RESULTS: Seven nonrandomized controlled trials studies were included in this analysis. These studies included a total of 847 patients: 273 treated with RFA and 574 treated with HR. The 5 years overall survival rates in the HR group were significantly better than those in the RFA group (OR: 0.41, 95% CI: 0.22-0.90, P = 0.008). RFA had a higher rate of local intrahepatic recurrence compared to HR (OR: 4.89, 95% CI: 1.73-13.87, P = 0.003). No differences were found between the two groups with respect to postoperative morbidity and mortality. CONCLUSION: HR was superior to RFA in the treatment of patients with solitary CLM. However, the findings have to be carefully interpreted due to the lower level of evidence.