Objective:To investigate the therapeutic effects of the copper chelator ammonium tetrathiomolybdate (TTM) on rheumatoid arthritis (RA) in a mouse model.Methods:Twenty-four male dilution brown non-Agoutia/1 mice were randomly divided into 4 groups: a blank control group (Ctrl group, n=6), a collagen-induced arthritis (CIA) + phosphate buffer saline (PBS) treatment group (PBS group, n=6), a CIA+TTM treatment group (TTM group, n=6), and a CIA+Elesclomol treatment group (Eles group, n=6). Eles, a copper ion carrier, served as a control for administration of TTM, a copper ion chelator. One week after treatment, the swelling of mouse paw was observed, and the clinical scoring of the arthritis in mice was evaluated once a week. Paw mechanical pain detection was performed and photographs were taken to observe the severity of paw swelling before the mice were sacrificed. Catwalk gait analysis system was used to evaluate the gait changes in mice. HE and saffron O solid green staining were used to evaluate pathomorphologic changes in the mice knee joints and paws. Immunostaining techniques were used to detect the protein expression of MMP3, CD31, and VEGF in the mice paws. Luminex technology was used to detect alterations in the serum inflammatory factors. Results:Compared with the Ctrl group, in the PBS and Eles groups, the joints were red, swollen and deformed; the arthritis clinical scores were significantly higher; the bone destruction, synovial hyperplasia and inflammatory cell infiltration and pathological changes in the joint tissues were obvious; the expression levels of inflammatory factors, such as serum MCP-1, IL-1 β, IL-9, and IFN- γ, were significantly higher while the expression level of IL-10 was significantly lower. Simultaneously, the expression of CD31 and VEGF factors was significantly enhanced. Compared with the PBS group, in the TTM group, the joint swelling and deformation were significantly improved, the arthritis clinical score was reduced, and the joint bone destruction, inflammatory cell infiltration and synovial hyperplasia were alleviated, and the levels of serum MCP-1, IL-1 β, IL-9 and IFN- γ were significantly decreased while the level of anti-inflammatory factor IL-10 was increased. There was no significant difference in the expression of MMP-3, CD31 or VEGF factors between the CTRL group and the TTM group. Conclusion:TTM can block synovial inflammation, angiogenesis, and bone destruction multiple times by simultaneously targeting multiple inflammatory factors, VEGF factors, and bone destruction mediators, thereby alleviating the pathological damage to the joint tissues induced by CIA in RA mice.

Objective:To investigate the therapeutic effects of the copper chelator ammonium tetrathiomolybdate (TTM) on rheumatoid arthritis (RA) in a mouse model.Methods:Twenty-four male dilution brown non-Agoutia/1 mice were randomly divided into 4 groups: a blank control group (Ctrl group, n=6), a collagen-induced arthritis (CIA) + phosphate buffer saline (PBS) treatment group (PBS group, n=6), a CIA+TTM treatment group (TTM group, n=6), and a CIA+Elesclomol treatment group (Eles group, n=6). Eles, a copper ion carrier, served as a control for administration of TTM, a copper ion chelator. One week after treatment, the swelling of mouse paw was observed, and the clinical scoring of the arthritis in mice was evaluated once a week. Paw mechanical pain detection was performed and photographs were taken to observe the severity of paw swelling before the mice were sacrificed. Catwalk gait analysis system was used to evaluate the gait changes in mice. HE and saffron O solid green staining were used to evaluate pathomorphologic changes in the mice knee joints and paws. Immunostaining techniques were used to detect the protein expression of MMP3, CD31, and VEGF in the mice paws. Luminex technology was used to detect alterations in the serum inflammatory factors. Results:Compared with the Ctrl group, in the PBS and Eles groups, the joints were red, swollen and deformed; the arthritis clinical scores were significantly higher; the bone destruction, synovial hyperplasia and inflammatory cell infiltration and pathological changes in the joint tissues were obvious; the expression levels of inflammatory factors, such as serum MCP-1, IL-1 β, IL-9, and IFN- γ, were significantly higher while the expression level of IL-10 was significantly lower. Simultaneously, the expression of CD31 and VEGF factors was significantly enhanced. Compared with the PBS group, in the TTM group, the joint swelling and deformation were significantly improved, the arthritis clinical score was reduced, and the joint bone destruction, inflammatory cell infiltration and synovial hyperplasia were alleviated, and the levels of serum MCP-1, IL-1 β, IL-9 and IFN- γ were significantly decreased while the level of anti-inflammatory factor IL-10 was increased. There was no significant difference in the expression of MMP-3, CD31 or VEGF factors between the CTRL group and the TTM group. Conclusion:TTM can block synovial inflammation, angiogenesis, and bone destruction multiple times by simultaneously targeting multiple inflammatory factors, VEGF factors, and bone destruction mediators, thereby alleviating the pathological damage to the joint tissues induced by CIA in RA mice.

OBJECTIVE: To evaluate the value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for assessing disease activity in patients with rheumatoid arthritis (RA) treated with tofacitinib. METHODS: This retrospective study was conducted among 98 RA patients in active stage treated with tofacitinib in Third Xiangya Hospital and 100 healthy control subjects from the Health Management Center of the hospital from 2019 to 2021. We collected blood samples from all the participants for measurement of erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and other blood parameters 1 month before and 6 months after tofacitinib treatment. We further evaluated PLR and NLR before and after tofacitinib treatment in the RA patients, and analyzed their correlations with RA disease activity. RESULTS: PLR and NLR increased significantly in RA patients as compared with the healthy controls. In the RA patients, PLR and NLR were positively correlated with the levels of hs- CRP, ESR, IL- 6, Disease Activity Score of 28 joints-ESR (DAS28-ESR), anti-cyclic citrullinated peptide (CCP), and rheumatoid factor (RF) before and after tofacitinib treatment. Tofacitinib treatment for 6 months significantly decreased hs-CRP, ESR, IL-6, CCP, RF and DAS28-ESR levels in the RA patients. CONCLUSION NLR and PLR can be useful biomarkers for assessing disease activity in RA patients treated with tofacitinib.
Humans ; Neutrophils ; Retrospective Studies ; C-Reactive Protein/analysis* ; Interleukin-6/metabolism* ; Arthritis, Rheumatoid ; Lymphocytes

Objective:To investigate the risk factors affecting the completion of postoperative adjuvant chemotherapy in elderly patients with progressive gastric cancer.Methods:Clinicopathological data of patients diagnosed with gastric adenocarcinoma and treated with radical surgery at our hospital between January 2017 and December 2018 were retrospectively collected, and 96 patients were finally included in the study according to the inclusion and exclusion criteria.Patients were divided into a completed chemotherapy group and an uncompleted chemotherapy group depending on whether they had completed 6 cycles of adjuvant chemotherapy after surgery.The optimal cut-off value was derived from the receiver operating characteristic(ROC)curve, and the Youden Index was calculated.Relevant factors that might affect the completion of postoperative adjuvant chemotherapy in elderly patients with progressive gastric cancer were included in univariate and multivariate Logistic regression analyses to identify independent risk factors affecting the completion of postoperative adjuvant chemotherapy in gastric cancer patients.The Kaplan-Meier(K-M)method was used to plot the survival curves for the groups, and the log-rank test was used to compare the survival rates between the groups.Results:A total of 96 patients, aged 60-89 years, with a mean age of(70.3±7.0)years, were included.Sixteen patients completed postoperative adjuvant chemotherapy, while 80 patients did not.The following analysis was performed on clinicopathological data of patients in the two groups.Univariate Logistic regression analysis showed that patient age ≥70 years( OR=8.135, 95% CI: 1.735-38.153, P=0.008)or a preoperative prognostic nutritional index(PNI)score <49.5( OR=4.765, 95% CI: 1.549-14.656, P=0.006)affected the completion of postoperative adjuvant chemotherapy.The risk factors that might affect the completion of postoperative adjuvant chemotherapy in elderly gastric cancer patients were analyzed using multivariate Logistic regression and the results showed that age ≥70 years( OR=9.815, 95% CI: 1.947-49.485, P=0.006)and a preoperative PNI score <49.5( OR=5.895, 95% CI: 1.711-20.305, P=0.005)were independent risk factors hindering the completion of postoperative adjuvant chemotherapy. Conclusions:Age ≥70 years and PNI<49.5 are independent risk factors for the completion of postoperative adjuvant chemotherapy.Failure to complete postoperative adjuvant chemotherapy is associated with a poor prognosis.PNI is a valid predictor for whether postoperative adjuvant chemotherapy will be completed and helps to screen chemotherapy patients who need nutritional intervention.

Objective:To analyze the interim clinical efficacy of laparoscopic and open distal gastrectomy for gastric cancer in elderly patients.Methods:The prospective randomized controlled study was conducted. The clinicopathological data of 102 patients aged ≥65 years who underwent distal gastrectomy for gastric cancer in the Nanfang Hospital of Southern Medical University from September 2014 to May 2018 were collected. After excluding 6 patients, 96 patients were finally included. Based on random number table, patients were allocated into two groups. Patients undergoing laparoscopic distal gastrectomy were allocated into laparoscopic group, and patients undergoing open distal gastrectomy were allocated into open group, respectively. Obser-vation indicators: (1) grouping situations of the enrolled patients; (2) intraoperative situations; (3) postoperative situations; (4) follow-up. Follow-up using outpatient examination and telephone interview was conducted to detect complications in the postoperative 30 days up to July 2018. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the t test. Measurement data with skewed distribution were represented as M( P25, P75) or M(range), and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was analyzed using the chi-square test. Comparison of ordinal data was analyzed using the non-parameter Mann-Whitney U test. Results:(1) Grouping situations of the enrolled patients: a total of 96 patients were selected for eligibility. There were 66 males and 30 females, aged from 65 to 85 years, with a median age of 69 years. There were 49 of 96 patients in the laparoscopic group and 47 patients in the open group. (2) Intraoperative situations: patients in the two groups underwent distal gastrectomy successfully with D 2 lymphadenectomy, without intra-operative conversion to laparotomy. The volume of intraoperative blood loss and surgical incision length were 50 mL(50 mL,100 mL) and (7.1±1.7)cm for the laparoscopic group, respectively, versus 100 mL(100 mL,200 mL) and (19.1±1.7)cm for the open group, showing significant differences between the two groups ( Z=?3.779, t=?34.880, P<0.05) . (3) Postoperative situations: the number of lymph node dissected, time to postoperative initial out-of-bed activities, time to postoperative first flatus, time to postoperative first liquid food intake, time to postoperative first semi-liquid food intake, time to drainage tube removal, duration of postoperative hospital stay were 49(35,62), 1.9 days(1.3 days,2.9 days), 2.6 days(2.2 days,2.9 days), 3.4 days(2.7days,4.0 days), 5.9 days(4.7 days,7.7 days), 4.9 days(3.5 days,6.8 days), 7.7 days(6.7 days,8.9 days) for the laparoscopic group, respectively, versus 40(27,51), 2.5 days (1.8 days,3.3 days), 2.6 days(2.2 days,2.9 days), 3.9 days(2.9 days,5.7 days), 4.9 days(3.9 days, 5.9 days), 6.3 days(4.7 days,8.9 days), 8.7 days(6.9 days,11.7 days), showing significant differences between the two groups ( Z=?2.354, ?2.210, ?2.743, ?2.474, ?2.906, ?2.503, ?2.359, P<0.05). (4) Follow-up: patients in the two groups received 30 days of follow-up. During the follow-up, 8 patients in the laparoscopic group had postoperative complications, including 1 case with Clavien-Dindo grade Ⅰ complications, 7 cases with Clavien-Dindo grade Ⅱ complications, and no patient with Clavien-Dindo grade Ⅲ complications. Thirteen patients in the open group had postoperative complications, including 2 cases with Clavien-Dindo grade Ⅰ complications, 10 cases with Clavien-Dindo grade Ⅱ complications, and 1 case with Clavien-Dindo grade Ⅲ complications. There was no significant difference in the above indicators between the two groups ( χ2=1.135, 1.973, 1.054, P>0.05). The overall complication rate was 16.3%(8/49) and 27.7%(13/47) for the laparoscopic group and open group, respectively, showing no significant difference between the two groups ( χ2=1.803, 99.7% confidence interval as ?∞ to 2.4%, P>0.05). The upper limit of 99.7% confidence interval was less than non-inferiority level of 15%, interim analysis of which showed that the complication rate of the laparoscopic group was non-inferior to the open group. Conclusion:For elderly patients undergoing laparoscopic or open distal gastrectomy for gastric cancer, laparoscopic surgery does not increase intraoperative or postoperative complications, and has advantages of minimally invasiveness, fine operation, quicker recovery, and shorter hospital stay. Registry: this study was registered at clinicaltrials.gov in United States, with the registry number of NCT02246153.

Conversion therapy is adopted to achieve radical cure for patients with originally unresectable but potentially resectable late stage gastric cancer, who obtain partial or complete remission after systemic chemotherapy, to acquire relatively longer postoperative survival and recurrence-free survival. Some of the previous researches on conversion therapy for originally unresectable gastric cancer suggest that high chemotherapy response rate, high pathological response rate and R0 resection rate are associated with favorable prognosis. And the efficacy of patients with lymphatic metastasis is better than that of those with peritoneal metastasis. The protocol of conversional chemotherapy varies and so does its efficacy according to different reports. Latest clinical researches indicate that initially unresectable gastric cancer gained higher remission rate and better chance of R0 operation and consequently prolonged survival from paclitaxel based triplet chemotherapy. However, not all originally unresectable gastric cancer can benefit from conversion therapy due to the high heterogeneity of its biological behavior. Regarding the enormous number of originally unresectable gastric cancer patients, it will be a research hot spot in the field of surgical oncology, on screening criteria to select cases suitable for conversion. Exploration on conversion therapy for gastric cancer is still at initial stage, and reports that have been published are mostly single-centered with limited sample, lacking of sufficient evidence on its feasibility, safety and efficacy. Expert consensus on conversion indication, case selection, chemotherapy regimen, efficacy assessment and resection range is absent. So it is in urgent need for higher level clinical evidence to support and guide this practice. Such goal can never be achieved without joint efforts of all parties to carry out clinical trial to modify the practice of conversion therapy for late stage gastric cancer, and determine the proper selection of suitable candidates for conversion therapy, eventually to offer optimal strategy for originally unresectable gastric cancer patients. Thus, this article focuses on reviewing research progress of conversion therapy for originally unresectable late stage gastric cancer.

OBJECTIVETo evaluate the feasibility and safety of intracorporeal Roux-en-Y esophagojejunostomy via the transoral anvil(OrVil) by mini-laparotomy anastomosis during laparoscopic total gastrectomy (LTG) for gastric cancer.

METHODSFrom March 2010 to December 2016, 414 consecutive gastric adenocarcinoma patients underwent either intracorporeal Roux-en-Y esophagojejunostomy (n=43) via the OrVil or extracorporeal circular anastomosis (n=371) via auxiliary incision during LTG. After generating propensity scores with six covariates, including gender, age, body mass index (BMI), neoadjuvant chemotherapy, tumor location, and tumor size, 43 patients undergoing OrVil method (OrVil group) were matched with 43 patients undergoing extracorporeal circular anastomosis approach (extracorporeal anastomosis group). Operation-associated parameters and safety were compared between the two groups.

RESULTSBoth groups were balanced regarding baseline variables (all P > 0.05). The total operative time [(235.6±49.8) minutes vs. (221.1±46.5) minutes, t=1.397, P=0.166] and anvil insertion time [(10.0±3.2) minutes vs. (10.6±4.5) minutes, t=-0.671, P=0.504] were not significantly different between the two group, whereas the duration of reconstruction and the mean length of minilaparotomy [(48.3±12.0) minutes vs. (55.9±12.3) minutes, t=-2.899, P=0.005; (5.6±0.6) cm vs. (8.1±2.2) cm, t=-7.118, P=0.001] in the OrVil group were significantly shorter. The number of retrieved lymph nodes, mean blood loss and proximal resection margin were not significantly different between two groups (all P > 0.05). As a whole, OrVil group had advantages over extracorporeal anastomosis group during the postoperative recovery course. The time to liquid intake [(3.7±1.8) days vs. (6.2±7.2) days, t=-2.236, P=0.030], time to fluid diet [(4.8±2.3) days vs. (7.2±7.1) days, t=-2.013, P=0.048], and time to semi-fluid diet [(6.7±2.9) days vs. (10.2±9.6) days, t=-2.245, P=0.029] were significantly shorter in the OrVil group. The first ambulatory time, time to first flatus and length of hospital stay were not significantly different between two groups(all P>0.05). The morbidity of intraoperative complication [7.0%(3/43) vs. 4.7%(2/43), χ²=0.000, P=1.000] and postoperative complication [30.2%(13/43) vs. 20.9%(9/43), χ²=1.484, P=0.223], and even the distribution of severity (χ²=0.013, P=0.990) between the two groups were not significantly different. The incidence of anastomotic leakage (AL) was 9.3% (4/43) and 18.6% (8/43) in the OrVil group and extracorporeal anastomosis group respectively without significant difference (χ²=1.550, P=0.213). Multivariate analysis showed that the OrVil anastomosis was not a risk factor of AL(HR=0.663, 95%CI:0.120-3.674, P=0.638).

CONCLUSIONSIntracorporeal esophagojejunostomy using the OrVil system is more minimally invasive and convenient to operate without increasing the risk of operation-related complication. Thus it may be a potential safe approach to optimize the reconstruction for LTG.

Anastomosis, Surgical ; Gastrectomy ; methods ; Humans ; Laparoscopy ; Laparotomy ; Postoperative Complications ; Propensity Score ; Retrospective Studies ; Stomach Neoplasms ; surgery ; Treatment Outcome

Advanced gastric cancer (AGC) has a high recurrence rate (especially peritoneal relapse) and a poor prognosis. Systematic chemotherapy or targeted therapy have not been able to significantly reduce the major cause of an unfavorable prognosis, namely the high peritoneal AGC recurrence rate post-surgery. Further studies concerning the application of hyperthermic intraperitoneal chemotherapy (HIPEC) post curative surgery for AGC patients, namely the prophylactic HIPEC (P-HIPEC), have involved a prophylactic approach to prevent peritoneal relapse following curative gastrectomy in high-risk patients. Theoretically, breaking the "plasma-peritoneal barrier" increases cytotoxic chemotherapy activity via a synergistic hyperthermic effect; therefore, HIPEC can eradicate free cancer cells and micro-metastasis within the peritoneal cavity intraoperatively or soon after curative gastrectomy to reduce peritoneal recurrence. Many clinical trials have shown that P-HIPEC can reduce peritoneal recurrence and improve prognosis of AGC patients. However, some studies applying HIPEC at an early stage have revealed a high rate of complications that limited generalizability. This procedure has been increasingly adopted, given the complication rate has now been reduced and safety has been proven. Recently, for assessing the important role of HIPEC, many high-quality prospective randomized controlled clinical trials have been conducted to further investigate the best guidance for P-HIPEC and to demonstrate its effectiveness and safety with a higher grade of evidence. With theory development, the technique, equipment, and management of HIPEC and the role of P-HIPEC for AGC continues to evolve. This study summarizes the progress of P-HIPEC for high-risk AGC patients.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Chemotherapy, Cancer, Regional Perfusion ; Combined Modality Therapy ; Humans ; Hyperthermia, Induced ; Neoplasm Recurrence, Local ; Peritoneal Neoplasms ; drug therapy ; Randomized Controlled Trials as Topic ; Stomach Neoplasms ; drug therapy

OBJECTIVETo summarize the treatment status of gastric gastrointestinal stromal tumor (GIST) in Shandong province,by analyzing the clinicopathological features and prognostic factors.

METHODSClinicopathological and follow-up data of 1 165 patients with gastric GIST between January 2000 and December 2013 from 23 tertiary referral hospitals in Shandong Province were collected to establish a database. The risk stratification of all cases was performed according to the National Institutes of Health(NIH) criteria proposed in 2008. Kaplan-Meier method was used to calculate the survival rate. Log-rank test and Cox regression model were used for univariate and multivariate prognostic analyses.

RESULTSAmong 1 165 cases of gastric GIST, 557 were male and 608 were female. The median age of onset was 60 (range 15-89) years. Primary tumors were located in the gastric fundus and cardia in 623 cases(53.5%), gastric body in 346 cases(29.7%), gastric antrum in 196 cases(16.8%). All the cases underwent resection of tumors, including endoscopic resection (n=106), local resection (n=589), subtotal gastrectomy(n=399), and total gastrectomy(n=72). Based on the NIH risk stratification, there were 256 cases (22.0%) at very low risk, 435 (37.3%) at low risk, 251 cases (21.5%) at intermediate risk, and 223 cases (19.1%) at high risk. A total of 1 116 cases(95.8%) were followed up and the median follow-up period was 40 (range, 1-60) months. During the period, 337 patients relapsed and the median time to recurrence was 34 (range 1-60) months. The 1-, 3-, and 5-year survival rates were 98.6%, 86.1% and 73.4%, respectively. The 5-year survival rates of patients at very low, low, intermediate, and high risk were 93.1%, 85.8%, 63.0% and 42.3% respectively, with a statistically significant difference (P=0.000). Multivariate analysis showed that primary tumor site (RR=0.580, 95%CI:0.402-0.835), tumor size (RR=0.450, 95%CI:0.266-0.760), intraoperative tumor rupture(RR=0.557, 95%CI:0.336-0.924), risk classification (RR=0.309, 95%CI:0.164-0.580) and the use of imatinib after surgery (RR=1.993, 95%CI:1.350-2.922) were independent prognostic factors.

CONCLUSIONSThe choice of surgical procedure for gastric GIST patients should be based on tumor size. All the routine procedures including endoscopic resection, local excision, subtotal gastrectomy and total gastrectomy can obtain satisfactory curative outcomes. NIH classification has a high value for the prediction of prognosis. Primary tumor site, tumor size, intraoperative tumor rupture, risk stratification and postoperative use of imatinib are independent prognostic factors in gastric GIST patients.

OBJECTIVETo introduce the application and clinical effect of self-made liver fixing device in laparoscopic radical gastrectomy.

METHODSClinical data of 469 patients underwent laparoscopic radical gastrectomy in Nanfang Hospital, Southern Medical University from March 2014 to January 2017 were analyzed retrospectively. In laparoscopic radical gastrectomy, self-made liver fixing device was used to expose surgical field covered by hepatic lobe in gastric lesser curvature and hepatic flexure of colon. Manufacture of the self-made liver fixing device: appropriate length of the catheter was cut according to the size of liver; the lotus suture needle with a thread was put through two catheters to connect them. Then the prepared liver fixing device was sent into abdominal cavity through a 12-mm Trocar hole with needle holder and was fixed on the free hepatic lateral hepatogastric ligament with hemo-lock. Finally the application effect of the liver fixing device was evaluated by reviewing the surgical videos.

RESULTSA mean time of 40.3 seconds was required to complete liver fixing by using the self-made liver fixing device in laparoscopic radical gastrectomy and liver did not slip down in all the cases. Liver secondary manual fixing by assistants was 2 times averagely. Three cases had mild liver injury.

CONCLUSIONThe self-made liver fixing device in laparoscopic radical gastrectomy is easy to operate and can effectively expose sufficient surgical field, with high security and convenient materials.