In the implementation of laparoscopic D 3 radical resection of right colon cancer, the principle of tumor-free and complete mesenteric excision should be strictly followed. The whole lesion and lymph drainage area should be removed, and precise anatomy along the Toldt space should be performed to ensure sufficient incisional margin and complete lymph node dissection. Using 4K laparoscopy, the ultra-high definition picture is presented on the super large screen, which is more conducive to the surgeons to distinguish the anatomical plane and conduct accurate anatomy.

Lateral lymph node metastasis (LLNM) is one of the major causes for post-operative local recurrence of middle and low rectal cancer. At present, there are still controversies on the diagnosis and treatment of LLNM. The radiological assessment of LLNM generally relies on morphological criteria such as the size or shape of the node or the response to therapy, in which the diagnostic accuracy of MRI is superior to that of other imaging techniques. Neoadjuvant chemoradiotherapy could not achieve good local control for suspicious LLNM. Lateral lymph node dissection (LLND) can reduce tumor local recurrence significantly, but the clinical value of LLND in survival and quality of life of patients has been questioned. 4K laparoscope can decrease the incidence of perioperative complications and urinary and sexual dysfunction to a certain extent. Thus, selective LLND should be undertaken to patients with suspicious LLNM after neoadjuvant chemoradiotherapy, in order to reduce tumor local recurrence and improve the prognosis of patients. The authors elaborate on diagnosis and treatment including surgery or chemoradiotherapy of LLNM in 4K laparoscopic surgery for middle and low rectal cancer combined with their own experiences.

Lateral lymph node metastasis (LLNM) is the main metastatic mode and the major cause of locoregional recurrence of mid-low rectal cancer. Single chemoradiotherapy cannot achieve good local control for LLNM, while the argument against performing lateral lymph node dissection (LLND) is the increased rate of urinary and sexual dysfunction after surgery. Ultra-high definition surgical field and delicate resolution by 4K laparoscopic surgical system will be helpful to achieve good tumor clearance and function preservation by identification and exposure of the important anatomic structures such as pelvic autonomic nerve and internal iliac vessels. Therefore, selective LLND can reduce local recurrence rates, particularly in the pelvic sidewall. LLND with autonomic nerve preservation by 4K laparoscopic system is expected to further decrease the risk of perioperative complications and urinary and sexual dysfunction in appropriate patients with neoadjuvant chemoradiotherapy.

Objective:To explore the effect of standardized surgical treatment and multidisciplinary treatment strategy on the treatment outcomes of gastric cancer patients.Methods:A single-center cohort study was carried out. Clinicopathological and long-term follow up data of primary gastric cancer patients were retrieved from the database of Surgical Gastric Cancer Patient Registry (SGCPR) in West China Hospital of Sichuan University. Finally, 4516 gastric cancer patients were included and were divided into three groups according to time periods (period 1 group: exploration stage of standardized surgical treatment, 2000 to 2006, 967 cases; period 2 group: application stage of standardized surgical treatment, 2007 to 2012, 1962 cases; period 3 group: optimization stage of standardized surgical treatment and application stage of multidisciplinary treatment strategy, 2013 to 2016, 1587 cases). Differences in clinical data, pathologic features, and prognosis were compared among 3 period groups. Follow-up information was updated to January 1, 2020. The overall follow-up rate was 88.9% (4016/4516) and median follow-up duration was 51.58 months. Survival curve was drawn by Kaplan-Meire method and compared with log-rank test. Univariate and multivariate analyses were performed by Cox proportional hazards model.Results:There were significant differences among period 1, period 2 and period 3 groups in the rates of D2/D2+ lymphadenectomy [14.4%(139/967) vs. 47.2%(927/1962) vs. 75.4%(1197/1587), χ 2=907.210, P<0.001], in the ratio of proximal gastrectomy [19.8%(191/967) vs. 16.6%(325/1962) vs. 8.2%(130/1587), χ 2=100.020, P<0.001], and in the median intraoperative blood loss (300 ml vs. 100 ml vs. 100 ml, H=1126.500, P<0.001). Besides, the increasing trend and significant difference were also observed in the median number of examined lymph nodes among period 1, period 2 and period 3 groups (14 vs. 26 vs. 30, H=987.100, P<0.001). Survival analysis showed that the 5-year overall survival rate was 55.3% in period 1, 55.2% in period 2 and 62.8% in period 3, and significant difference existed between period 3 and period 1 ( P=0.004). The Cox proportional hazards model analysis showed that treatment period (period 3, HR=0.820, 95%CI: 0.708 to 0.950, P=0.008), postoperative chemotherapy (HR=0.696, 95%CI: 0.631 to 0.768, P<0.001) and mid-low gastric cancer (HR=0.884, 95%CI: 0.804 to 0.973, P=0.011) were good prognostic factors. Whereas old age (≥65 years, HR=1.189, 95%CI: 1.084 to 1.303, P<0.001), palliative resection (R1/R2, HR=1.538,95%CI: 1.333 to 1.776, P<0.001), large tumor size (≥5 cm, HR=1.377, 95%CI: 1.239 to 1.529, P<0.001), macroscopic type III to IV (HR=1.165, 95%CI: 1.063 to 1.277, P<0.001) and TNM stage II to IV(II/I: HR=1.801,95% CI:1.500~2.162, P<0.001;III/I: HR=3.588, 95% CI: 3.028~4.251, P<0.001; IV/I: HR=6.114, 95% CI: 4.973~7.516, P<0.001) were independent prognostic risk factors. Conclusion:Through the implementation of standardized surgical treatment technology and multidisciplinary treatment model, the quality of surgery treatment and overall survival increase, and prognosis of gastric cancer patients has been improved.

Objective:To explore the effect of standardized surgical treatment and multidisciplinary treatment strategy on the treatment outcomes of gastric cancer patients.Methods:A single-center cohort study was carried out. Clinicopathological and long-term follow up data of primary gastric cancer patients were retrieved from the database of Surgical Gastric Cancer Patient Registry (SGCPR) in West China Hospital of Sichuan University. Finally, 4516 gastric cancer patients were included and were divided into three groups according to time periods (period 1 group: exploration stage of standardized surgical treatment, 2000 to 2006, 967 cases; period 2 group: application stage of standardized surgical treatment, 2007 to 2012, 1962 cases; period 3 group: optimization stage of standardized surgical treatment and application stage of multidisciplinary treatment strategy, 2013 to 2016, 1587 cases). Differences in clinical data, pathologic features, and prognosis were compared among 3 period groups. Follow-up information was updated to January 1, 2020. The overall follow-up rate was 88.9% (4016/4516) and median follow-up duration was 51.58 months. Survival curve was drawn by Kaplan-Meire method and compared with log-rank test. Univariate and multivariate analyses were performed by Cox proportional hazards model.Results:There were significant differences among period 1, period 2 and period 3 groups in the rates of D2/D2+ lymphadenectomy [14.4%(139/967) vs. 47.2%(927/1962) vs. 75.4%(1197/1587), χ 2=907.210, P<0.001], in the ratio of proximal gastrectomy [19.8%(191/967) vs. 16.6%(325/1962) vs. 8.2%(130/1587), χ 2=100.020, P<0.001], and in the median intraoperative blood loss (300 ml vs. 100 ml vs. 100 ml, H=1126.500, P<0.001). Besides, the increasing trend and significant difference were also observed in the median number of examined lymph nodes among period 1, period 2 and period 3 groups (14 vs. 26 vs. 30, H=987.100, P<0.001). Survival analysis showed that the 5-year overall survival rate was 55.3% in period 1, 55.2% in period 2 and 62.8% in period 3, and significant difference existed between period 3 and period 1 ( P=0.004). The Cox proportional hazards model analysis showed that treatment period (period 3, HR=0.820, 95%CI: 0.708 to 0.950, P=0.008), postoperative chemotherapy (HR=0.696, 95%CI: 0.631 to 0.768, P<0.001) and mid-low gastric cancer (HR=0.884, 95%CI: 0.804 to 0.973, P=0.011) were good prognostic factors. Whereas old age (≥65 years, HR=1.189, 95%CI: 1.084 to 1.303, P<0.001), palliative resection (R1/R2, HR=1.538,95%CI: 1.333 to 1.776, P<0.001), large tumor size (≥5 cm, HR=1.377, 95%CI: 1.239 to 1.529, P<0.001), macroscopic type III to IV (HR=1.165, 95%CI: 1.063 to 1.277, P<0.001) and TNM stage II to IV(II/I: HR=1.801,95% CI:1.500~2.162, P<0.001;III/I: HR=3.588, 95% CI: 3.028~4.251, P<0.001; IV/I: HR=6.114, 95% CI: 4.973~7.516, P<0.001) were independent prognostic risk factors. Conclusion:Through the implementation of standardized surgical treatment technology and multidisciplinary treatment model, the quality of surgery treatment and overall survival increase, and prognosis of gastric cancer patients has been improved.

OBJECTIVE: To compare the long-term survival outcomes of Siewert II adenocarcinoma of esophagogastric junction (AEG) between transthoracic (TT) approach and transabdominal (TA) approach. METHODS: The databases of Gastrointestinal Surgery Department and Thoracic Surgery Department in West China Hospital of Sichuan University from 2006 to 2014 were integrated. Patients of Siewert II AEG who underwent resection were retrospectively collected. INCLUSION CRITERIA: (1) adenocarcinoma confirmed by gastroscopy and biopsy; (2) tumor involvement in the esophagogastric junction line; (3) tumor locating from lower 5 cm to upper 5 cm of the esophagogastric junction line, and tumor center locating from upper 1 cm to lower 2 cm of esophagogastric junction line; (4)resection performed at thoracic surgery department or gastrointestinal surgery department; (5) complete follow-up data. Patients at thoracic surgery department received trans-left thoracic, trans-right thoracic, or transabdominothoracic approach; underwent lower esophagus resection plus proximal subtotal gastrectomy; selected two-field or three-field lymph node dissection; underwent digestive tract reconstruction with esophagus-remnant stomach or esophagus-tubular remnant stomach anastomosis above or below aortic arch using hand-sewn or stapler instrument to perform anastomosis. Patients at gastrointestinal surgery department received transabdominal(transhiatal approach), or transabdominothoracic approach; underwent total gastrectomy or proximal subtotal gastrectomy; selected D1, D2 or D2 lymph node dissection; underwent digestive tract reconstruction with esophagus-single tube jejunum or esophagus-jejunal pouch Roux-en-Y anastomosis, or esophagus-remnant stomach or esophagus-tubular remnant stomach anastomosis; completed all the anastomoses with stapler instruments. The follow-up ended in January 2018. The TNM stage system of the 8th edition UICC was used for esophageal cancer staging; survival table method was applied to calculate 3-year overall survival rate and 95% cofidence interval(CI); log-rank test was used to perform survival analysis; Cox regression was applied to analyze risk factors and calculate hazard ratio (HR) and 95%CI. RESULTS: A total of 443 cases of Siewert II AEG were enrolled, including 89 cases in TT group (with 3 cases of transabdominothoracic approach) and 354 cases in TA group. Median follow-up time was 50.0 months (quartiles:26.4-70.2). The baseline data in TT and TA groups were comparable, except the length of esophageal invasion [for length <3 cm, TA group had 354 cases(100%), TT group had 44 cases (49.4%), χ²=199.23,P<0.001]. The number of harvested lymph node in thoracic surgery department and gastrointestinal surgery department were 12.0(quartiles:9.0-17.0) and 24.0(quartiles:18.0-32.5) respectively with significant difference (Z=11.29,P<0.001). The 3-year overall survival rate of TA and TT groups was 69.2%(95%CI:64.1%-73.7%) and 55.8% (95%CI:44.8%-65.4%) respectively, which was not significantly different by log-rank test (P=0.059). However, the stage III subgroup analysis showed that the survival of TA group was better [the 3-year overall survival in TA group and TT group was 78.1%(95%CI:70.5-84.0) and 46.3%(95%CI:31.0-60.3) resepectively(P=0.001)]. Multivariate Cox regression analysis revealed that the TT group had poor survival outcome (HR=2.45,95%CI:1.30-4.64, P=0.006). CONCLUSION The overall survival outcomes in the TA group are better, especially in stage III patients, which may be associated with the higher metastatic rate of abdominal lymph node and the more complete lymphadenectomy via TA approach.
Adenocarcinoma ; classification ; mortality ; pathology ; surgery ; China ; Databases, Factual ; Esophageal Neoplasms ; classification ; pathology ; surgery ; Esophagectomy ; methods ; Esophagogastric Junction ; pathology ; surgery ; Gastrectomy ; methods ; Humans ; Laparotomy ; Lymph Node Excision ; methods ; Neoplasm Staging ; Retrospective Studies ; Stomach Neoplasms ; classification ; mortality ; pathology ; surgery ; Survival Analysis ; Thoracic Surgical Procedures

Objective: To evaluate the safety and preliminary efficacy of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) with high risk factors. Methods: Data of 101 patients who were diagnosed with stage II-III rectal cancer with high risk factors and received TNT between March 2015 and January 2018 at West China Hospital of Sichuan University were analyzed retrospectively. Inclusion criteria: (1) patients were diagnosed with stage II-III rectal cancer by high-resolution MRI combined with CT and endorectal ultrasound; (2) at least one high risk factor: cT4a, cT4b, cN2, EMVI+, CRM+ and lateral lymph node+; (3) distance from tumor to anal verge was within 15 cm; (4) Eastern Collaborative Oncology Group (ECOG) performance status score was 0-1; bone marrow function, liver function and kidney function were suitable for chemoradiotherapy; (5) patients were treated with TNT strategy; (6) the follow-up data and postoperative pathological data were complete. Patients with previous rectal cancer surgery (except prophylactic colostomy), pelvic radiotherapy, and systemic chemotherapy, those with distant metastases, those without neoadjuvant radiotherapy, those receiving less than 4 cycles of neoadjuvant chemotherapy were excluded. The regimen of TNT: 3 cycles of induction CAPOX (oxaliplatin plus capecitabine) were followed by pelvic radiotherapy and concurrent CAPOX, then 3 cycles of consolidation CAPOX were delivered after radiotherapy. Total mesorectal resection (TME) or watch-and-wait strategy was selected according to the therapeutic effect and patients' wishes. Short-term efficacy, including tumor regression grade (TRG), pathological complete response (pCR), clinical complete response (cCR), postoperative complications within 30 days of surgery, and adverse events (AE) to radiotherapy and chemotherapy (measured using CTCAE 4.0) was analyzed. Results: The 101 patients included 68 males (67.3%) and 33 females (32.7%) with a median age of 54 years. The proportion of patients with cT4a, cT4b, cN2 and enlarged lateral lymph node was 13.9%, 29.7%, 56.4% and 43.6%, respectively. The mean cycle of neoadjuvant chemotherapy was 6.0±1.3. Seventy-five patients (74.3%) received at least 6 cycles of neoadjuvant chemotherapy and 100 (99.0%) completed radiotherapy. The mean cycle of induction and consolidation chemotherapy was 2.0±0.9 and 2.8±1.0 respectively. Most common grade 3 AE was leucopenia (n=13, 12.9%) and thrombocytopenia (n=7, 6.9%). Grade 3 diarrhea and radiation dermatitis were observed in 5 cases (5.0%) respectively. Grade 3 anemia and rectal pain were observed in 4 cases (4.0%) respectively. And rectal mucositis was observed in 2 cases (2.0%). Most of the AE was observed during concurrent chemoradiotherapy. No grade 4 or higher AE was observed. After TNT, 32 patients (31.7%) achieved pCR or cCR, and 62 patients (60.4%) achieved partial response (PR). Only 2 patients (2.0%) developed distant metastasis after chemoradiotherapy, while the other patients did not show disease progression. Seven patients (6.9%) with cCR refused surgery and selected watch-and-wait, while 7 patients without cCR still refused surgery. The other 87 patients (86.1%) underwent TME successfully. The mean interval from the completion of chemoradiotherapy to surgery was (20.1±8.5) weeks. The R0 resection rate was 97.7% (85/87).The morbidity of surgical complication was 16.1% (14/87), including pelvic infection or abscess in 6 cases (6.9%), anastomotic leakage in 3 (3.4%), hemorrhage in 2 (2.3%), and gastrointestinal dysfunction in 3 (3.4%). Pathological findings revealed that 24 cases (27.6%) had TRG 0, 20 (23.0%) had TRG 1, 30 (34.5%) TRG 2, and 13 (14.9%) TRG 3. Conclusion TNT is safe and has good short-term efficacy for locally advanced rectal cancer patients with high risk factors.

Objective To evaluate the safety and preliminary efficacy of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) with high risk factors. Methods Data of 101 patients who were diagnosed with stage II?III rectal cancer with high risk factors and received TNT between March 2015 and January 2018 at West China Hospital of Sichuan University were analyzed retrospectively. Inclusion criteria: (1) patients were diagnosed with stage II?III rectal cancer by high?resolution MRI combined with CT and endorectal ultrasound; (2) at least one high risk factor: cT4a, cT4b, cN2, EMVI+, CRM+and lateral lymph node+; (3) distance from tumor to anal verge was within 15 cm;(4) Eastern Collaborative Oncology Group (ECOG) performance status score was 0?1; bone marrow function, liver function and kidney function were suitable for chemoradiotherapy; (5) patients were treated with TNT strategy; (6) the follow?up data and postoperative pathological data were complete. Patients with previous rectal cancer surgery (except prophylactic colostomy), pelvic radiotherapy, and systemic chemotherapy, those with distant metastases, those without neoadjuvant radiotherapy, those receiving less than 4 cycles of neoadjuvant chemotherapy were excluded. The regimen of TNT: 3 cycles of induction CAPOX (oxaliplatin plus capecitabine) were followed by pelvic radiotherapy and concurrent CAPOX, then 3 cycles of consolidation CAPOX were delivered after radiotherapy. Total mesorectal resection (TME) or watch?and?wait strategy was selected according to the therapeutic effect and patients' wishes. Short?term efficacy, including tumor regression grade (TRG), pathological complete response (pCR), clinical complete response (cCR), postoperative complications within 30 days of surgery, and adverse events (AE) to radiotherapy and chemotherapy (measured using CTCAE 4.0) was analyzed. Results The 101 patients included 68 males (67.3%) and 33 females (32.7%) with a median age of 54 years. The proportion of patients with cT4a, cT4b, cN2 and enlarged lateral lymph node was 13.9%, 29.7%, 56.4% and 43.6%, respectively. The mean cycle of neoadjuvant chemotherapy was 6.0 ± 1.3. Seventy?five patients (74.3%) received at least 6 cycles of neoadjuvant chemotherapy and 100 (99.0%) completed radiotherapy. The mean cycle of induction and consolidation chemotherapy was 2.0 ± 0.9 and 2.8 ± 1.0 respectively. Most common grade 3 AE was leucopenia (n=13, 12.9%) and thrombocytopenia (n=7, 6.9%). Grade 3 diarrhea and radiation dermatitis were observed in 5 cases (5.0%) respectively. Grade 3 anemia and rectal pain were observed in 4 cases (4.0%) respectively. And rectal mucositis was observed in 2 cases (2.0%). Most of the AE was observed during concurrent chemoradiotherapy. No grade 4 or higher AE was observed. After TNT, 32 patients (31.7%) achieved pCR or cCR, and 62 patients (60.4%) achieved partial response (PR). Only 2 patients (2.0%) developed distant metastasis after chemoradiotherapy, while the other patients did not show disease progression. Seven patients (6.9%) with cCR refused surgery and selected watch?and?wait, while 7 patients without cCR still refused surgery. The other 87 patients (86.1%) underwent TME successfully. The mean interval from the completion of chemoradiotherapy to surgery was (20.1±8.5) weeks. The R0 resection rate was 97.7% (85/87).The morbidity of surgical complication was 16.1% (14/87), including pelvic infection or abscess in 6 cases (6.9%), anastomotic leakage in 3 (3.4%), hemorrhage in 2 (2.3%), and gastrointestinal dysfunction in 3 (3.4%). Pathological findings revealed that 24 cases (27.6%) had TRG 0, 20 (23.0%) had TRG 1, 30 (34.5%) TRG 2, and 13 (14.9%) TRG 3. Conclusion TNT is safe and has good short?term efficacy for locally advanced rectal cancer patients with high risk factors.

Objective To evaluate the safety and preliminary efficacy of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) with high risk factors. Methods Data of 101 patients who were diagnosed with stage II?III rectal cancer with high risk factors and received TNT between March 2015 and January 2018 at West China Hospital of Sichuan University were analyzed retrospectively. Inclusion criteria: (1) patients were diagnosed with stage II?III rectal cancer by high?resolution MRI combined with CT and endorectal ultrasound; (2) at least one high risk factor: cT4a, cT4b, cN2, EMVI+, CRM+and lateral lymph node+; (3) distance from tumor to anal verge was within 15 cm;(4) Eastern Collaborative Oncology Group (ECOG) performance status score was 0?1; bone marrow function, liver function and kidney function were suitable for chemoradiotherapy; (5) patients were treated with TNT strategy; (6) the follow?up data and postoperative pathological data were complete. Patients with previous rectal cancer surgery (except prophylactic colostomy), pelvic radiotherapy, and systemic chemotherapy, those with distant metastases, those without neoadjuvant radiotherapy, those receiving less than 4 cycles of neoadjuvant chemotherapy were excluded. The regimen of TNT: 3 cycles of induction CAPOX (oxaliplatin plus capecitabine) were followed by pelvic radiotherapy and concurrent CAPOX, then 3 cycles of consolidation CAPOX were delivered after radiotherapy. Total mesorectal resection (TME) or watch?and?wait strategy was selected according to the therapeutic effect and patients' wishes. Short?term efficacy, including tumor regression grade (TRG), pathological complete response (pCR), clinical complete response (cCR), postoperative complications within 30 days of surgery, and adverse events (AE) to radiotherapy and chemotherapy (measured using CTCAE 4.0) was analyzed. Results The 101 patients included 68 males (67.3%) and 33 females (32.7%) with a median age of 54 years. The proportion of patients with cT4a, cT4b, cN2 and enlarged lateral lymph node was 13.9%, 29.7%, 56.4% and 43.6%, respectively. The mean cycle of neoadjuvant chemotherapy was 6.0 ± 1.3. Seventy?five patients (74.3%) received at least 6 cycles of neoadjuvant chemotherapy and 100 (99.0%) completed radiotherapy. The mean cycle of induction and consolidation chemotherapy was 2.0 ± 0.9 and 2.8 ± 1.0 respectively. Most common grade 3 AE was leucopenia (n=13, 12.9%) and thrombocytopenia (n=7, 6.9%). Grade 3 diarrhea and radiation dermatitis were observed in 5 cases (5.0%) respectively. Grade 3 anemia and rectal pain were observed in 4 cases (4.0%) respectively. And rectal mucositis was observed in 2 cases (2.0%). Most of the AE was observed during concurrent chemoradiotherapy. No grade 4 or higher AE was observed. After TNT, 32 patients (31.7%) achieved pCR or cCR, and 62 patients (60.4%) achieved partial response (PR). Only 2 patients (2.0%) developed distant metastasis after chemoradiotherapy, while the other patients did not show disease progression. Seven patients (6.9%) with cCR refused surgery and selected watch?and?wait, while 7 patients without cCR still refused surgery. The other 87 patients (86.1%) underwent TME successfully. The mean interval from the completion of chemoradiotherapy to surgery was (20.1±8.5) weeks. The R0 resection rate was 97.7% (85/87).The morbidity of surgical complication was 16.1% (14/87), including pelvic infection or abscess in 6 cases (6.9%), anastomotic leakage in 3 (3.4%), hemorrhage in 2 (2.3%), and gastrointestinal dysfunction in 3 (3.4%). Pathological findings revealed that 24 cases (27.6%) had TRG 0, 20 (23.0%) had TRG 1, 30 (34.5%) TRG 2, and 13 (14.9%) TRG 3. Conclusion TNT is safe and has good short?term efficacy for locally advanced rectal cancer patients with high risk factors.

Objective: To observe the cellular damage of low-dose combined exposure to Hg, Pb and Cd on hippocampal neurons in rat. Methods: SH-SY5Y cells were randomly divided into 8 groups by 2×2×2 factorial design: control group, Pb exposure group, Hg exposure group, Pb+Hg exposure group, Pb+Cd exposure group, Hg+Cd exposure group and Pb+Cd+Hg exposure group. And the cell viabilities were measured. On this basis, an animal model was established. Twenty eight-week-old SD pregnant rats were randomly divided into four groups by random number table, and five in each group: the control group(distilled water), 1-fold metal mixture exposure group (1×MM, poisoning solution containing mercury chloride 0.15 mg/L, lead acetate trihydrate 25 mg/L, cadmium chloride 7.5 mg/L), 5-fold metal mixture exposure group (5×MM, poisoning solution containing mercury chloride 0.75 mg/L, lead acetate trihydrate 125.00 mg/L, cadmium chloride 37.50 mg/L), 10-fold metal mixture exposure group (10×MM, poisoning solution containing mercury chloride 1.50 mg/L, lead acetate trihydrate 250.00 mg/L, cadmium chloride 75.00 mg/L). Pregnant rats drank water until delivery. Twenty male pups were selected and exposed to these metals through breast milk until weaned. The heavy metals dose of poisoning water was adjusted, and then the weaned rats were exposed to heavy metals via drinking poisoning water until adulthood (postnatal day 83). The blood samples and brain hippocampus samples were collected to observe the ultrastructural changes of hippocampus, and to determine the levels of Hg, Pb and Cd in blood. In addition, apoptosis rate and fluorescence intensity of reactive oxygen species and intracellular free calcium concentration ([Ca²⁺]_i) in hippocampal neurons were measured. Results: Cellular factorial design analysis showed that Hg+Pb+Cd (at no observed adverse effect level, 1.0, 0.5 and 0.1 μmol/L, respectively)had a interaction on cell viability after 48 or 72 hours of combined exposure (P<0.05). The results of ultrastructure showed that mitochondria decreased, ridges and matrixes gradually dissolved in rat hippocampal neurons of 5×MM group; nuclear chromatin aggregated, more ridges and matrixes dissolved and the mitochondria also decreased in rat hippocampal neurons of 10×MM group. The concentration of Hg, Pb and Cd in the blood of 1×MM group, 5×MM group and 10×MM group were higher than those in the control group, and the differences were statistically significant (P<0.001). There was no significant difference in apoptosis rate between the 1×MM group and the control group. The apoptosis rate of 5×MM group and 10×MM group was higher than that in the control group, and the differences were statistically significant (P<0.001). There was no statistically significant difference in the fluorescence intensity of reactive oxygen species in hippocampal neurons of the 1×MM group and the control group. The fluorescence intensity of reactive oxygen species in the 5×MM group and the 10×MM group was higher than that in the control group, the difference was statistically significant (P<0.05). There was no significant difference in the fluorescence intensity of [Ca²⁺]_i between the 1×MM group and the control group. The fluorescence intensity values of [Ca²⁺]_i in the 5×MM group and the 10×MM group were higher than the control group, the differences were statistically significant (P<0.001). Conclusion Low-level combined exposure to Hg, Pb, and Cd caused synergistic neurotoxic damage, and the process may be related to the changes of neuronal apoptosis, reactive oxide species, and [Ca²⁺]_i levels.