Risk factors for posthepatectomy liver failure in patients with hepatocellular carcinoma and construction of prediction model / 中华消化外科杂志

Objective:To investigate the risk factors for posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma and construction of prediction model.Methods:The retrospective case-control study was conducted. The clinicopathological data of 116 patients with hepatocellular carcinoma who underwent hepatectomy in the First Affiliated Hospital of University of Science and Technology of China from January 2019 to January 2022 were collected. There were 99 males and 17 females, aged (59±10)years. Observation indicators: (1) occurrence of PHLF; (2) analysis of factors influencing the occurrence of PHLF; (3) construction and evaluation of prediction model for PHLF. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distri-bution were represented as M( Q1, Q3), and comparison between groups was conducted using the rank sum test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test or Fisher exact probability. The univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the Logistic regression model with forward method. The regression coefficient was used to construct the prediction model. The receiver operating characteristic curve was drawn, and the area under curve (AUC) was used to evaluate the predictive ability of prediction model. Results:(1) Occurrence of PHLF. Of the 116 patients, there were 27 cases with PHLF and 89 cases without PHLF, respectively. Of the 27 patients with PHLF, 13 cases underwent laparoscopic hepatectomy and 14 cases underwent open hepatectomy. (2) Analysis of factors influencing the occurrence of PHLF. Results of multivariate analysis showed preoperative portal vein tumor thrombus and preoperative indocyanine green retention at 15 minutes (ICG R15) ≥10% were independent risk factors influencing the occurrence of PHLF ( odds ratio=13.463, 4.702, 95% confidence interval as 3.140-57.650, 1.600-13.800, P<0.05). (3) Construction and evaluation of prediction model for PHLF. According to the multivariate analysis, preoperative portal vein tumor thrombus and preoperative ICG R15 were included to construct the prediction model for predicting the occurrence of PHLF in patients with hepatocellular carcinoma. The AUC, sensitivity, specificity of prediction model was 0.750 (95% confidence interval as 0.654-0.846, P<0.05), 0.551, 0.852, respectively. Conclusions:Preoperative portal vein tumor thrombus and preoperative ICG R15 ≥10% are independent risk factors influen-cing the occurrence of PHLF. The prediction model based on these two factors has good efficacy in predicting PHLF of patients with hepatocellular carcinoma.

Application value of donor liver autologous portal venous blood rinse in orthotopic liver trans-plantation / 中华消化外科杂志

Objective:To investigate the application value of donor liver autologous portal venous blood rinse in orthotopic liver transplantation (OLT).Methods:The retrospective cohort study was conducted. The clinicopathological data of 35 pairs of donors and recipients who underwent OLT in the First Affiliated Hospital of University of Science and Technology of China from May 2018 to June 2019 were collected. Of the 35 donors, there were 31 males and 4 females, aged (48±9)years. Of the 35 recipients, there were 25 males and 10 females, aged (47±9)years. Of the 35 recipients, 16 recipients undergoing donor liver autologous portal venous blood rinse were allocated into the portal vein group, and 19 recipients undergoing donor liver albumin water rinse were allocated into the albumin group. Observation indicators: (1) surgical situations; (2) postoperative situations; (3) follow-up. Measurement data with normal distribution were represented as Mean± SD, and compari-son between groups was analyzed using the t test. Measurement data of skewed distribution were represented as M(range). Count data were descried as absolute numbers, and comparison between groups was analyzed using the Fisher exact probability. Results:(1) Surgical situations. The anhepatic phase time and arterial blood Ca 2+ concentration within 5 minutes after reperfusion of the recipients were (52±12)minutes and (0.99±0.10)mmol/L in the portal vein group, versus (64±12)minutes and (1.05±0.07)mmol/L in the albumin group, showing significant differences in the above indicators between the two groups ( t=2.94, 2.22, P<0.05). The mean arterial pressure, arterial blood K +concentration and arterial blood pH within 5 minutes after reperfusion of the recipients were (70±24)mmHg (1 mmHg=0.133 kPa), (4.7±1.3)mmol/L and 7.27±0.06 in the portal vein group, versus (71±28)mmHg, (4.6±1.1)mmol/L and 7.30±0.07 in the albumin group, showing no significant difference in the above indicators between the two groups ( t=0.14, 0.30, 1.22, P>0.05). (2) Post-operative situations. Cases with post-reperfusion syndrome (PRS), cases with severe PRS of cardiac arrest, cases with primary graft nonfunction of the recipients were 6, 0, 2 in the portal vein group, versus 8, 1, 1 in the albumin group, showing no significant difference in the above indicators between the two groups ( P>0.05). Total bilirubin on postoperative day 7 of the recipients was (90±52)μmol/L in the portal vein group, versus (166±112)μmol/L in the albumin group, showing a significant difference between the two groups ( t=2.66, P<0.05). International normalized ratio on postoperative day 7, the highest alanine aminotransferase and aspartate aminotransferase within 7 days after operation of the recipients were 2.1±2.0, (1 952±2 813)IU/L and (3 944±6 673)IU/L in the portal vein group, versus 1.8±0.6, (1 023±1 014) IU/L and (2 005±2 910)IU/L in the albumin group, showing no significant difference in the above indicators between the two groups ( t=0.66, 1.23, 1.08, P>0.05). Recipients with hepatic artery complication and biliary complication were 1 and 2 in the portal vein group, versus 0 and 4 in the albumin group, showing no significant difference in the above indicators between the two groups ( P>0.05). There were 3 cases and 2 cases died during the perioperative period in the portal vein group and the albumin group, respectively. (3) Follow-up. Of the 35 recipients, 30 recipients were followed up for 534(range, 28?776)days after operation. During the follow-up, there were 3 patients with postoperative complications in the portal vein group including 2 cases died and 1 case recovered after sympto-matic treatment. There were 5 patients with postoperative complications in the albumin group including 1 case died and 4 cases recovered after symptomatic treatment. Up to the follow-up date, 11 patients in the portal vein group and 16 patients in the albumin group were in good condition. Conclusion:Rinse of the donor liver with autologous portal venous blood during liver transplantation can shorten the time of anhepatic phase, without increasing the occurrence of post-reperfusion syndrome, ischemia re-perfusion injury and biliary tract complications.

Progress in the diagnosis and treatment of Caroli disease / 国际外科学杂志

Caroli disease is a relatively rare genetic disease, also known as congenital intrahepatic cystic cholangiectasis, which is mainly manifested as non-obstructive segmental dilation of large, intrahepatic bile ducts, which is manifested as cysts in imaging and histopathological examination. The pathogenesis of Caroli disease is still unclear, and it is mainly believed to be related to PKHD1 gene mutation. Mutations in this gene often lead to autosomal recessive polycystic kidney disease (ARPKD), so Caroli disease is commonly associated with polycystic kidney disease. Caroli disease usually develops during adolescence and is characterized by recurrent cholangitis, which is diagnosed mainly by imaging. This article reviews the progress of diagnosis and treatment of Caroli disease by reading related literature.

Clinical efficacy of avatrombopag combined with recombinant human thrombopoietin versus avatrombopag in the treatment of severe thrombocytopenia associated with chronic liver disease / 中华消化外科杂志

Objective:To investigate the clinical efficacy of avatrombopag combined with recombinant human thrombopoietin (rhTPO) versus avatrombopag in the treatment of severe thrombocytopenia associated with chronic liver disease.Methods:The retrospective cohort study was conducted. The clinical data of 56 patients with severe thrombocytopenia associated with chronic liver disease who were admitted to the First Affiliated Hospital of University of Science and Technology of China from May 2020 to October 2021 were collected. There were 36 males and 20 females, aged from 33 to 74 years, with a median age of 54 years. Of 56 patients, 21 cases undergoing treatment of avatrombopag combined with rhTPO were allocated into the combined treatment group and 35 cases undergoing treatment of avatrombopag were allocated into the monotherapy group. Observation indicators: (1) changes of platelet after treatment; (2) adverse drug reaction. Follow-up was conducted using outpatient examination and telephone interview to detect changes of platelet and effects of treatment within 2 weeks after treatment. The follow-up was up to October 2021. 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(range), and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and compari-son between groups was analyzed using the chi-square test or Fisher exact probability. Repeated measurement data were analyzed using the repeated ANOVA. Results:(1) Changes of platelet after treatment. The platelet level within 1 to 5 days and 6 to 10 days after treatment in the combined treatment group were (35±19)×10 9/L and (73±41)×10 9/L, respectively. The above indicators of the monotherapy group were (40±30)×10 9/L and (70±51)×10 9/L, respectively. There was no significant difference in change trends of platelet before and after treatment between the two groups ( Fgroup=0.30, P>0.05). There was a significant difference in platelet count before and after treatment between the two groups ( Ftime=59.96, P<0.05). There was no interaction effect in change trends of platelet between the two groups ( Finteraction=0.40, P>0.05). The effective rates were 66.67%(14/21) in the combination therapy group and 54.29%(19/35) in the monotherapy group. There was no significant difference in the effective rate between the two groups ( χ2=0.83, P>0.05). (2) Adverse drug reaction. Cases with headache, dizziness, blood transfusion reaction, hematuria, proteinuria, fever, abdominal pain, diarrhea, dyspepsia, fatigue, nausea or peripheral tissue edema were 2, 4, 1, 2, 2, 7, 10, 6, 8, 14, 12, 5 in the combined treatment group, versus 5, 8, 1, 3, 5, 7, 19, 11,20, 19, 14, 5 in the monotherapy group, respectively. There was no significant difference in cases with headache, dizziness, blood transfusion reaction, hematuria, proteinuria between the two groups ( P>0.05), and there was no significant difference in cases with fever, abdominal pain, diarrhea, dyspepsia, fatigue, nausea, peripheral tissue edema between the two groups ( χ2=1.24, 0.23, 0.05, 1.91, 0.83, 2.04, 0.81, P>0.05). Conclusion:Both of avatrombopag combined with rhTPO and monotherapy of avatrom-bopag can be used to promote the platelet level in patients with severe thrombocytopenia associated with chronic liver disease, and avatrombopag combined with rhTPO does not provide better clinical benefits compared with monotherapy avatrombopag.

Epidemiological characteristics, diagnosis, treatment and prognosis of gallbladder cancer in China: a report of 6 159 cases / 中华消化外科杂志

Objective:To investigate the epidemiological characteristics, diagnosis, treat-ment and prognosis of gallbladder cancer in China from 2010 to 2017.Methods:The single disease retrospective registration cohort study was conducted. Based on the concept of the real world study, the clinicopathological data, from multicenter retrospective clinical data database of gallbladder cancer of Chinese Research Group of Gallbladder Cancer (CRGGC), of 6 159 patients with gallbladder cancer who were admitted to 42 hospitals from January 2010 to December 2017 were collected. Observation indicators: (1) case resources; (2) age and sex distribution; (3) diagnosis; (4) surgical treatment and prognosis; (5) multimodality therapy and prognosis. The follow-up data of the 42 hospitals were collected and analyzed by the CRGGC. The main outcome indicator was the overall survival time from date of operation for surgical patients or date of diagnosis for non-surgical patients to the end of outcome event or the last follow-up. Measurement data with normal distribu-tion were represented as Mean±SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(range), and com-parison between groups was conducted using the U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Univariate analysis was performed using the Logistic forced regression model, and variables with P<0.1 in the univariate analysis were included for multivariate analysis. Multivariate analysis was performed using the Logistic stepwise regression model. The life table method was used to calculate survival rates and the Kaplan-Meier method was used to draw survival curves. Log-rank test was used for survival analysis. Results:(1) Case resources: of the 42 hospitals, there were 35 class A of tertiary hospitals and 7 class B of tertiary hospitals, 16 hospitals with high admission of gallbladder cancer and 26 hospitals with low admission of gallbladder cancer, respectively. Geographical distribution of the 42 hospitals: there were 9 hospitals in central China, 5 hospitals in northeast China, 22 hospitals in eastern China and 6 hospitals in western China. Geographical distribution of the 6 159 patients: there were 2 154 cases(34.973%) from central China, 705 cases(11.447%) from northeast China, 1 969 cases(31.969%) from eastern China and 1 331 cases(21.611%) from western China. The total average number of cases undergoing diagnosis and treatment in hospitals of the 6 159 patients was 18.3±4.5 per year, in which the average number of cases undergoing diagnosis and treatment in hospitals of 4 974 patients(80.760%) from hospitals with high admission of gallbladder cancer was 38.8±8.9 per year and the average number of cases undergoing diagnosis and treatment in hospitals of 1 185 patients(19.240%) from hospitals with low admission of gallbladder cancer was 5.7±1.9 per year. (2) Age and sex distribution: the age of 6 159 patients diagnosed as gallbladder cancer was 64(56,71) years, in which the age of 2 247 male patients(36.483%) diagnosed as gallbladder cancer was 64(58,71)years and the age of 3 912 female patients(63.517%) diagnosed as gallbladder cancer was 63(55,71)years. The sex ratio of female to male was 1.74:1. Of 6 159 patients, 3 886 cases(63.095%) were diagnosed as gallbladder cancer at 56 to 75 years old. There was a significant difference on age at diagnosis between male and female patients ( Z=-3.99, P<0.001). (3) Diagnosis: of 6 159 patients, 2 503 cases(40.640%) were initially diagnosed as gallbladder cancer and 3 656 cases(59.360%) were initially diagnosed as non-gallbladder cancer. There were 2 110 patients(34.259%) not undergoing surgical treatment, of which 200 cases(9.479%) were initially diagnosed as gallbladder cancer and 1 910 cases(90.521%) were initially diagnosed as non-gallbladder cancer. There were 4 049 patients(65.741%) undergoing surgical treatment, of which 2 303 cases(56.878%) were initially diagnosed as gallbladder cancer and 1 746 cases(43.122%) were initial diagnosed as non-gallbladder cancer. Of the 1 746 patients who were initially diagnosed as non-gallbladder cancer, there were 774 cases(19.116%) diagnosed as gallbladder cancer during operation and 972 cases(24.006%) diagnosed as gallbladder cancer after operation. Of 6 159 patients, there were 2 521 cases(40.932%), 2 335 cases(37.912%) and 1 114 cases(18.087%) undergoing ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) examination before initial diagnosis, respec-tively, and there were 3 259 cases(52.914%), 3 172 cases(51.502%) and 4 016 cases(65.205%) undergoing serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis, respectively. One patient may underwent multiple examinations. Results of univariate analysis showed that geographical distribution of hospitals (eastern China or western China), age ≥72 years, gallbladder cancer annual admission of hospitals, whether undergoing ultrasound, CT, MRI, serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis were related factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.45, 1.98, 0.69, 0.68, 2.43, 0.41, 1.63, 0.41, 0.39, 0.42, 95% confidence interval as 1.21-1.74, 1.64-2.40, 0.59-0.80, 0.60-0.78, 2.19-2.70, 0.37-0.45, 1.43-1.86, 0.37-0.45, 0.35-0.43, 0.38-0.47, P<0.05). Results of multivariate analysis showed that geographical distribution of hospitals (eastern China or western China), sex, age ≥72 years, gallbladder cancer annual admission of hospitals and cases undergoing ultrasound, CT, serum CA19-9 examination before initially diagnosis were indepen-dent influencing factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.36, 1.42, 0.89, 0.67, 1.85, 1.56, 1.57, 0.39, 95% confidence interval as 1.13-1.64, 1.16-1.73, 0.79-0.99, 0.57-0.78, 1.60-2.14, 1.38-1.77, 1.38-1.79, 0.35-0.43, P<0.05). (4) Surgical treatment and prognosis. Of the 4 049 patients undergoing surgical treatment, there were 2 447 cases(60.435%) with complete pathological staging data and follow-up data. Cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb were 85(3.474%), 201(8.214%), 71(2.902%), 890(36.371%), 382(15.611%), 33(1.348%) and 785(32.080%), respectively. The median follow-up time and median postoperative overall survival time of the 2 447 cases were 55.75 months (95% confidence interval as 52.78-58.35) and 23.46 months (95% confidence interval as 21.23-25.71), respectively. There was a significant difference in the overall survival between cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb ( χ2=512.47, P<0.001). Of the 4 049 patients undergoing surgical treatment, there were 2 988 cases(73.796%) with resectable tumor, 177 cases(4.371%) with unresectable tumor and 884 cases(21.833%) with tumor unassessable for resectabi-lity. Of the 2 988 cases with resectable tumor, there were 2 036 cases(68.139%) undergoing radical resection, 504 cases(16.867%) undergoing non-radical resection and 448 cases(14.994%) with operation unassessable for curative effect. Of the 2 447 cases with complete pathological staging data and follow-up data who underwent surgical treatment, there were 53 cases(2.166%) with unresectable tumor, 300 cases(12.260%) with resectable tumor and receiving non-radical resection, 1 441 cases(58.888%) with resectable tumor and receiving radical resection, 653 cases(26.686%) with resectable tumor and receiving operation unassessable for curative effect. There were 733 cases not undergoing surgical treatment with complete pathological staging data and follow-up data. There was a significant difference in the overall survival between cases not undergoing surgical treatment, cases undergoing surgical treatment for unresectable tumor, cases undergoing non-radical resection for resectable tumor and cases undergoing radical resection for resectable tumor ( χ2=121.04, P<0.001). (5) Multimodality therapy and prognosis: of 6 159 patients, there were 541 cases(8.784%) under-going postoperative adjuvant chemotherapy and advanced chemotherapy, 76 cases(1.234%) under-going radiotherapy. There were 1 170 advanced gallbladder cancer (pathological staging ≥stage Ⅲa) patients undergoing radical resection, including 126 cases(10.769%) with post-operative adjuvant chemotherapy and 1 044 cases(89.231%) without postoperative adjuvant chemo-therapy. There was no significant difference in the overall survival between cases with post-operative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.23, P=0.629). There were 658 patients with pathological staging as stage Ⅲa who underwent radical resection, including 66 cases(10.030%) with postoperative adjuvant chemotherapy and 592 cases(89.970%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.05, P=0.817). There were 512 patients with pathological staging ≥stage Ⅲb who underwent radical resection, including 60 cases(11.719%) with postoperative adjuvant chemotherapy and 452 cases(88.281%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemo-therapy and cases without post-operative adjuvant chemo-therapy ( χ2=1.50, P=0.220). Conclusions:There are more women than men with gallbladder cancer in China and more than half of patients are diagnosed at the age of 56 to 75 years. Cases undergoing ultrasound, CT, serum CA19-9 examination before initial diagnosis are independent influencing factors influencing initial diagnosis of gallbladder cancer patients. Preoperative resectability evaluation can improve the therapy strategy and patient prognosis. Adjuvant chemotherapy for gallbladder cancer is not standardized and in low proportion in China.

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies and provides long-term protection against SARS-CoV-2 in rhesus macaques

Coronavirus disease 2019 (COVID-19), which is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, continues to threaten global public health. Developing a vaccine that only requires single immunization but provides long-term protection for the prevention and control of COVID-19 is important. Here, we developed an adeno-associated virus (AAV)-based vaccine expressing a stable receptor-binding domain (SRBD) protein. The vaccine requires only a single shot but provides effective neutralizing antibodies (NAbs) over 598 days in rhesus macaques (Macaca mulatta). Importantly, our results showed that the NAbs were kept in high level and long lasting against authentic wild-type SARS-CoV-2, Beta, Delta and Omicron variants using plaque reduction neutralization test. Of note, although we detected pre-existing AAV2/9 antibodies before immunization, the vaccine still induced high and effective NAbs against COVID-19 in rhesus macaques. AAV-SRBD immune serum also efficiently inhibited the binding of ACE2 with RBD in the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1/P.2 (Gamma), B.1.617.2 (Delta), B.1.617.1/3(Kappa), and C.37 (Lambda) variants. Thus, these data suggest that the vaccine has great potential to prevent the spread of SARS-CoV-2.

Multi-disciplinary team of human herpes virus-6B encephalitis after liver transplantation / 器官移植

Objective To evaluate the role of multi-disciplinary team (MDT) in improving the diagnosis and treatment of human herpes virus-6B (HHV-6B) encephalitis after liver transplantation. Methods MDT consultation was delivered for one rare case of HHV-6B encephalitis after liver transplantation to establish an effective individualized treatment regime. Results On the 16 d after liver transplantation, the patient developed headache, and suddenly presented with unresponsiveness, unconsciousness, coma complicated with involuntary limb twitching on the 18 d. Blood ammonia level was increased. Brain CT scan showed cerebral ischemic changes. Electroencephalography prompted the epileptic seizure. After MDT consultation, the possibility of nervous system infection after liver transplantation was considered, and medication therapy was given to control the epileptic seizure. Cerebrospinal fluid examination via lumbar puncture hinted increased intracranial pressure. Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) of the cerebrospinal fluid demonstrated that the patient was tested positive for HHV-6B nucleic acid, which confirmed the diagnosis of HHV-6B encephalitis. The immunosuppressant regime was adjusted, intravenous ganciclovir was given for antiviral treatment, and active interventions were delivered to prevent and treat relevant complications. Epileptic seizure disappeared after 4 d, and neurological symptoms were significantly alleviated after 2 weeks. After 4-week antiviral treatment, the patient was tested negative for virology testing, and the neurological function was restored to normal. Conclusions HHV-6B encephalitis rarely occurs after adult liver transplantation, which is primarily associated with the virus reactivation after use of immunosuppressant. MDT pattern may be employed to deepen the understanding of the patient's condition, formulate more effective individualized treatment regime, and enhance the clinical efficacy and safety.

Research progress of neoadjuvant therapy for hepatocellular carcinoma / 中华肝胆外科杂志

Primary liver cancer is one of the most common malignant tumors in the world, and it is also the main cause of cancer-related death. However, the recurrence rate after surgical resection is still high. These problems have led to the development of more neoadjuvant treatment strategies aimed at improving the prognosis and reducing the recurrence rate. Despite the lack of high-level evidence to guide treatment decisions, recent advances in local and systemic therapies, including radiotherapy and immunotherapy, raise the prospect of new approaches that may improve outcomes in hepatocellular carcinoma patients.

Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18 and SARS-CoV-2-specific IgA

The current global COVID-19 pandemic is caused by beta coronavirus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which already infected over 10 million and caused 500 thousand deaths by June 2020. Overproduction of cytokines triggered by COVID-19 infection, known as "cytokine storm", is a highly risk factor associated with disease severity. However, how COVID-19 infection induce cytokine storm is still largely unknown. Accumulating in vitro and in vivo evidence suggests that gut is also susceptible to COVID19 infection: Human intestinal organoids, an in vitro model which mimic the specific cell type and spatial structure of the intestine, were susceptible to SARS-CoV2 infection; A significant fraction of patients reported gut symptoms; Viral RNA may persist for more than 30 days and infectious virus could be isolated in fecal samples. The gastrointestinal tract is the primary site of interaction between the host immune system with symbiotic and pathogenic microorganisms. The bacteria resident in our gastrointestinal tract, known as gut microbiota, is important to maintain the homeostasis of our immune system. While imbalance of gut microbiota, or dysbiosis, is associated with multiple inflammation diseases5. It's possible that SARS-CoV-2 infection may lead to alternation of gut microbiota thus worsen the host symptom. IL-18 is a proinflammatory cytokine produced multiple enteric cells, including intestinal epithelial cells (IECs), immune cells as well as enteric nervous system, and was shown to increase in the serum of COVID-19 patients. Immunoglobin A (IgA) is mainly produced in the mucosal surfaces, in humans 40-60mg kg-1 day-1 than all other immunoglobulin isotypes combined, and at least 80% of all plasma cells are located in the intestinal lamina propria. Recent study showed that SARS-CoV-2 specific IgA in the serum is positively correlate with the disease severity in COVID-19 patients11. Here we investigated the alterations of microbiota in COVID-19 patients, and its correlation with inflammatory factor IL-18 and SARS-CoV2 specific IgA.

Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis

ABSTRACTDespite the current devastation of the COVID-19 pandemic, several recent studies have suggested that the immunosuppressive drug Tocilizumab can powerfully treating inflammatory responses that occur in this disease. Here, by employing single-cell analysis of the immune cell composition of severe-stage COVID-19 patients and these same patients in post Tocilizumab-treatment remission, we have identified a monocyte subpopulation specific to severe disease that contributes to inflammatory storms in COVID-19 patients. Although Tocilizumab treatment attenuated the strong inflammatory immune response, we found that immune cells including plasma B cells and CD8+ T cells still exhibited an intense humoral and cell-mediated anti-virus immune response in COVID-19 patients after Tocilizumab treatment. Thus, in addition to providing a rich, very high-resolution data resource about the immune cell distribution at multiple stages of the COVID-19 disease, our work both helps explain Tocilizumab’s powerful therapeutic effects and defines a large number of potential new drug targets related to inflammatory storms.Competing Interest StatementJingwen Fang is the executive officer of HanGen BiotechView Full Text

Ubiquitin-specific protease 22 is associated with poor prognosis in neuroblastoma.

BACKGROUND: Ubiquitin-specific protease 22 (USP22) alters histone ubiquitination and is considered to be an oncogenic factor involved in tumor progression. The USP22 aberrance has been implicated in several malignancies, but whether USP22 plays a role in neuroblastoma (NB) remains unclear. To the best of our knowledge, the clinicopathological significance of USP22 expression in NB has not been previously reported in the English-language medical literature. OBJECTIVES: The aim of this study was to investigate the role of USP22 and its association with potential targets in patients with NB. MATERIAL AND METHODS: The potential clinicopathological significance of USP22 expression in NB was studied using immunohistochemistry, immunohistochemical staining assessment and statistical analyses. RESULTS: Based on the immunohistochemical analysis, the USP22 protein was detected more manifestly in NB tissues than in healthy peritumoral tissue. Furthermore, an association between USP22, lymph node metastasis and NB clinical stage was observed, whereby the level of USP22 protein was higher in stage III-IV specimens than in stage I-II specimens (p < 0.05). Furthermore, tumors expressing USP22 were associated with poorer patient prognosis than the USP22-negative tumors. The multivariate Cox regression analysis suggested that the level of USP22 protein is a predictive factor for survival (p < 0.05). CONCLUSIONS: Our results indicate a significant association between USP22 level and poor prognosis in NB. Thus, USP22 represents a valuable biomarker for predicting the outcome of patients with NB.

MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways.

BACKGROUND & AIMS: Mucin 13 (MUC13) is reportedly overexpressed in human malignancies. However, the clinicopathological and biological significance of MUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of this study was to define the role of MUC13 in the progression of iCCA. METHODS: Expression levels of MUC13 in human iCCA samples were evaluated by immunohistochemistry, western blot, and real-time PCR. In vitro and in vivo experiments were used to assess the effect of MUC13 on iCCA cell growth and metastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by molecular methods. The upstream regulatory effects of MUC13 were evaluated by Luciferase and DNA methylation assays. RESULTS: MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 overexpression positively correlated with clinicopathological characteristics of iCCA, such as vascular invasion and lymph node metastasis, and was independently associated with poor survival. Results from loss-of-function and gain-of-function experiments suggested that knockdown of MUC13 attenuated, while overexpression of MUC13 enhanced, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Mechanistically, we found that the phosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, such as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, were required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with epidermal growth factor receptor (EGFR) and subsequently activated the EGFR/PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing EGFR internalization. We also found that MUC13 was directly regulated by miR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in the promoter area. CONCLUSIONS: These findings suggest that aberrant hypermethylation-induced downregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading to metastasis via activation of the EGFR/PI3K/AKT signaling pathway. LAY SUMMARY: Mucin 13 overexpression has been implicated in the development of malignancies, although its role in intrahepatic cholangiocarcinoma has not been studied. Herein, we show that mucin 13 plays a critical role in intrahepatic cholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic marker and as a treatment target.

Current situation and prospect of immunotherapy for hepatocellular carcinoma / 中华消化外科杂志

Because of high morbidity and mortality, hepatocellular carcinoma (HCC) has become a serious crisis related to the health of the whole people. There are many treatment methods for HCC. In recent years, the rise of immunotherapy has provided a new weapon for the treatment of HCC, and its practical value has been more and more recognized and concerned. The immunotherapy for HCC has experienced from the initial cytotoxic drugs and small molecule inhibitors to the present immunosuppressive checkpoint inhibitors, and the mode of promoting tumor therapy has been changed greatly. At the same time, we should pay attention to the management of immune related adverse events, improve the comprehensive treatment level of HCC through the establishment of multi-disciplinary diagnosis and treatment team, and fundamentally improve the efficacy and benefit of patients.

Research and surgical application of fluorescent contrast agents / 国际外科学杂志

In recent years,the use of fluorescent contrast agents staining to guide surgery has flourished in various fields of surgery under the concept of precision surgery,which is helpful to guide surgery and provide surgeons with actual visible fluorescence imaging.Clinically,fluorescent contrast agent can be used to display tumor's outline with high recognition degree,guide operation in real time,locate lymph node metastasis,detect small metastases,and identify important anatomical structures during the operation to avoid possible side-injury.Great progress has been made in the study of fluorescent contrast agents that can mediate surgery,including the study and surgical application development of classical fluorescent contrast agents such as indocyanine green and methylene blue,etc,as well as the discovery and clinical application of new targeted fluorescent contrast agents such as folate receptor targeting contrast agents,monoclonal antibody based fluorescent targeting contrast agents and intelligent contrast agents,etc.This paper will review the research and surgical application of fluorescent contrast agents in two aspects:classical fluorescent contrast agents and new targeted fluorescent contrast agents.

Research and surgical application of fluorescent contrast agents / 国际外科学杂志

In recent years, the use of fluorescent contrast agents staining to guide surgery has flourished in various fields of surgery under the concept of precision surgery, which is helpful to guide surgery and provide surgeons with actual visible fluorescence imaging.Clinically, fluorescent contrast agent can be used to display tumor’s outline with high recognition degree, guide operation in real time, locate lymph node metastasis, detect small metastases, and identify important anatomical structures during the operation to avoid possible side-injury. Great progress has been made in the study of fluorescent contrast agents that can mediate surgery, including the study and surgical application development of classical fluorescent contrast agents such as indocyanine green and methylene blue, etc, as well as the discovery and clinical application of new targeted fluorescent contrast agents such as folate receptor targeting contrast agents, monoclonal antibody based fluorescent targeting contrast agents and intelligent contrast agents, etc. This paper will review the research and surgical application of fluorescent contrast agents in two aspects: classical fluorescent contrast agents and new targeted fluorescent contrast agents.

Thoughts and strategies on ethical issues in clinical research of surgery / 中华消化外科杂志

Medical ethics has a long history and rich connotations.It has developed from the simple "medical morality" of ancient times to the modem medical ethics.The basic principles of medical ethics include autonomy,non-maleficence,beneficence,justice,and so on.Researchers often conduct clinical researches in the balance between achievements and ethical norms.Clinical researchers of surgery should have a deep understanding of medical ethical principles and strictly abide by medical ethics.Ethics committee should strictly perform their duties and play the role of inspection and supervision.Modem medical knowledges should be popularized throughout the society to make clinical research correctly understood.Adhering principles of ethics first,people orientation and cooperation practice,with patients' benefit as evaluation criteria,balance of surgical "Dao" and "Shu" can be achieved.

The application and prospect of fusion indocyanine green fluorescence imaging system in laparoscopic hepatectomy / 中华肝胆外科杂志

As a convenient and effective intraoperative navigation tool,fusion indocyanine green fluorescence imaging system has been gradually recognized and accepted by more surgeons.The fusion indocyanine green fluorescence imaging system helps surgeons determine the hepatic plane cutting off and tumor boundary accurately.Meanwhile,it has great advantages in detecting biliary fistula during exploration in laparoscopic hepatectomy.As an emerging technology,it has good application and promotion prospects in both anatomical hepatectomy and local resection of liver tumors.At present,fusion indocyanine green fluorescence imaging system is still under exploration in laparoscopic hepatectomy,including:the choice of time of indocyanine green injection,the choice of injection dose of indocyanine green according to different liver volume resection,there is no consensus on the choice of staining mode for indocyanine green in different types of hepatectomy.This article elucidated the method and applicative value of indocyanine green fluorescence fusion imaging guidance technology in laparoscopic hepatectomy and applicative prospects for the future systematically.

The progress of hepatocellular adenoma malignant transforming in molecule mechanism researches / 中华肝胆外科杂志

Hepatocellular adenoma is a rare type of benign tumor in the liver. It has high risk of rupture and low risk of malignant transform. Recently the incidence of hepatocellular adenoma malignant transforming has been increasing. The malignant progress of hepatocellular adenoma develop to hepatocellular carcinoma has the transition state. This course not only relyes on the CTNNB1 gene exon 3 mutations, but also depends on TERT gene promoter mutation. This article will elaborate the hepatocellular adenoma malignant transforming in molecule mechanism, pathological diagnosis and therapies.

Bacterial flora distribution and antimicrobial resistance of pyogenic liver abscess: a multicenter retrospective study (A report of 897 cases) / 中华消化外科杂志

Objective@#To investigate the bacterial flora distribution and antimicrobial resistance of patients with pyogenic liver abscess (PLA) in multi-centers of China.@*Methods@#The retrospective and descriptive study was conducted. The clinical data of 897 patients with PLA at 3 medical centers in China from October 2007 to April 2018 were collected, including 656 cases in the First Hospital of Harbin Medical University, 109 cases in Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology and 132 cases in the Eastern Hepatobiliary Surgery Hospital of Naval Military Medical University. There were 582 males and 315 females, aged (59±11)years, with a range of 6-86 years. Observation indicators: (1) bacterial flora distribution; (2) bacterial resistance. Measurement data with normal distribution were represented as Mean±SD and measurement data with skewed distribution were represented as M (range). Count data were described as absolute numbers or percentages.@*Results@#(1) Bacterial flora distribution: among 897 patients, 733 cases of Klebsiella pneumoniae, 75 cases of Escherichia coli, 11 cases of Staphylococcus aureus, 10 cases of Streptococcus viridians, 9 cases of Klebsiella pneumoniae subsp. pneumoniae, 7 cases of β-emolytic streptococcus, 6 cases of Acinetobacter baumannii, 5 cases of Streptococcus intermadius, 5 cases of Enterococcus faecium, 3 cases of Alcaligenes xylosoxidans subsp. xylosoxidans, 2 cases of Proteus mirabilis, 2 cases of Streptococcus isthmus, 2 cases of Enterobacter cloacae subsp. cloacae, 1 case of Citrobacter koseri, 1 case of Proteus vulgaris, 1 case of Pasteurella pneumotropica, 1 case of Curobacter freudii, 1 case of Enterobacter amnigenus, 1 case of Stenotrophomonas maltophilia, 1 case of Acinetobacter lwoffii, 1 case of Streptococcus salivarius, 1 case of Streptococcus bacterium, 1 case of Enterococcus avium, 1 case of Enterococcus faecalis, 1 case of Klebsiella oxytoca, and 1 case of Staphylococcus epidermidis were cultured in the pus respectively. There were 12 cases of double bacterial infection, and 2 cases of multiple bacterial infections. (2) Bacterial resistance. ① Resistance of Klebsiella pneumoniae and Escherichia coli: the drug resistance rates of Klebsiella pneumoniae to ampicillin, piperacillin, cefazolin, cefuroxime, cefotaxime, ceftriaxone, ceftazidime, cefotetan, cefepime, cefoxitin, amoxicillin/carat Retinoic acid, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, meropenem, ertapenem, gentamicin, tobramycin, amikacin, tigaricycline, ciprofloxacin, levofloxacin, and trimethoprim sulfamethoxazole were 99.79%(474/475), 4.09%(7/171), 12.18%(82/673), 7.34%(49/668), 2.34%(4/171), 1.96%(11/562), 5.85%%(10/171), 0(0/562), 0.55%(4/733), 1.42%(9/635), 0(0/733), 2.46%(18/733), 0.55%(4/733), 0.27%(2/733), 1.36%(10/733), 0.14%(1/733), 0(0/733), 0.36%(2/562), 0.95%(7/733), 0.41%(3/733), 0(0/733), 0(0/562), 1.64%(12/733), 0.95%(7/733), and 4.50%(33/733), respectively. The drug resistance rates of Escherichia coli to above antibiotics were 78.67%(59/75), 40.91%(18/44), 65.33%(49/75), 56.00%(42/75), 38.64%(17/44), 41.94%(13/31), 20.00%(15/75), 3.23%(1/31), 25.33%(19/75), 5.77%(3/52), 18.67%(14/75), 32.00%(24/75), 8.00%(6/75), 16.00%(12/75), 37.33%(28/75), 1.33%(1/75), 0(0/75), 0(0/31), 40.00%(30/75), 14.67%(11/75), 1.33%(1/75), 0(0/31), 54.67%(41/75), 37.33%(28/75), and 52.00%(39/75), respectively. ② Drug resistance of other Gram-negative bacteria: the drug resistance rates of Klebsiella pneumoniae subsp. pneumoniae to ampicillin, cefazolin, cefuroxime, ceftriaxone, ceftazidime, cefotetan, cefepime, amoxicillin/carat Retinoic acid, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, meropenem, ertapenem, gentamicin, tobramycin, amikacin, ciprofloxacin, levofloxacin, and trimethoprim sulfamethoxazole were 8/8, 0/5, 0/5, 0/1, 0/9, 0/2, 0/9, 0/8, 0/9, 0/9, 0/6, 0/9, 0/9, 0/7, 0/1, 0/9, 0/8, 0/9, 0/9, 0/9, and 0/9. The drug resistance rates of Acinetobacter baumannii to ceftriaxone, ceftazidime, cefepime, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, meropenem, gentamicin, tobramycin, amikacin, tigaricycline, ciprofloxacin, levofloxacin, and trimethoprim sulfamethoxazole were 2/6, 4/6, 3/6, 0/6, 4/6, 1/6, 2/6, 4/6, 2/6, 4/6, 4/6, 3/6, 0/6, 4/6, 2/6, and 3/6, respectively. The drug resistance rates of Alcaligenes xylosoxidans subsp. xylosoxidans to ampicillin, cefazolin, cefuroxime, ceftazidime, cefepime, amoxicillin/carat Retinoic acid, piperacillin/tazobactam, aztreonam, imipenem, gentamicin, tobramycin, amikacin, ciprofloxacin, and levofloxacin were 3/3, 3/3, 3/3, 1/3, 1/3, 1/3, 0/3, 3/3, 2/3, 3/3, 3/3, 3/3, 3/3, and 1/3. ③ Drug resistance of other Gram-positive bacteria: the drug resistance rates of Staphylococcus aureus to penicillin, ampicillin, piperacillin, cefazolin, cefuroxime, cefotaxime, ceftazidime, cefepime, cefoxitin, amoxicillin/carat Retinoic acid, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, meropenem, gentamicin, tobramycin, amikacin, tetracycline, tigaricycline, ciprofloxacin, levofloxacin, moxifloxacin, trimethoprim sulfamethoxazole, linezolid, erythromycin, clindamycin, vancomycin, teicoplanin, and rifampin were 2/6, 6/8, 4/5, 4/5, 4/5, 4/5, 4/5, 4/5, 4/5, 4/5, 4/5, 4/5, 4/5, 3/5, 2/5, 2/5, 3/8, 3/5, 3/5, 0/8, 0/8, 3/8, 3/11, 0/5, 1/8, 0/8, 0/8, 2/6, 3/3, 1/3, and 0/3. The drug resistance rates of Streptococcus viridians to penicillin, ampicillin, ceftriaxone, cefoperazone/sulbactam, gentamicin, tetracycline, ciprofloxacin, levofloxacin, moxifloxacin, linezolid, erythromycin, clindamycin, vancomycin, teicoplanin, and rifampin were 3/10, 0/8, 0/7, 0/7, 2/8, 6/10, 0/8, 0/8, 0/7, 0/5, 4/10, 6/10, 0/5, 0/5, and 0/3. The drug resistance rates of β-emolytic streptococcus to antibacterial agents were 0. ④ Drug resistance of complex bacteria. For the 12 patients with double bacterial infection, in the Klebsiella pneumoniae combined with Gram-negative bacteria, the drug resistance rates of Klebsiella pneumoniae to cefotetan, cefoxitin, ampicillin/sulbactam, meropenem, ertapenem, tobramycin, tigecycline, and trimethoprim sulfamethoxazole were 0. The drug resistance rates of Acinetobacter baumannii to ertapenem, levofloxacin, and trimethoprim sulfamethoxazole were 0. The drug resistance rates of Escherichia coli to ceftazidime, cefoxitin, amoxicillin/clavulanic acid, piperacillin/tazobactam, imipenem, meropenem, ertapenem, tobramycin, amikacin, and tigecycline were 0. Citrobacter florida was sensitive to other antibiotics than levofloxacin and trimethoprim cotrimoxazole. In the Escherichia coli combined with Gram-positive bacteria, the drug resistance rates of Escherichia coli to cefotetan, cefepime, cefoxitin, cefoperazone/sulbactam, meropenem, tobramycin, and amikacin were 0. The drug resistance rates of Enterococcus faecalis to penicillin, ampicillin, levofloxacin, moxifloxacin, linezolid, vancomycin, and teicoplanin were 0. The drug resistance rates of Enterococcus casselifavus to ampicillin, tetracycline, levofloxacin, moxifloxacin, linezolid, and erythromycin were 0. The drug resistance rates of Staphylococcus hominis subspecies to levofloxacin, moxifloxacin, linezolid, vancomycin, teicoplanin, and rifampicin were 0. The drug resistance rates of Enterococcus faecium to tetracycline, linezolid, vancomycin, and teicoplanin were 0. In the multiple bacterial infections of Klebsiella pneumoniae + Escherichia coli + Staphylococcus aureus subspecies + Pseudomonas aeruginosa + Torulopsis glabrata, the drug resistance rates of Klebsiella pneumoniae to ceftriaxone, ceftazidime, cefotetan, cefepime, cefoxitin, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, tobramycin, amikacin, and levofloxacin were 0. The drug resistance rates of Escherichia coli to ceftazidime, cefotetan, cefepime, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, and amikacin were 0. The drug resistance rates of Staphylococcus aureus subspecies to ceftriaxone, ceftazidime, cefotetan, cefepime, ampicillin/sulbactam, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, tobramycin, amikacin, tigecycline, moxifloxacin, cotrimoxazole, teicoplanin, vancomycin, linezolid, and clindamycin were 0. The drug resistance rates of Pseudomonas aeruginosa to ceftazidime, cefepime, piperacillin/tazobactam, imipenem, gentamicin, tobramycin, amikacin, ciprofloxacin, and levofloxacin were 0. The drug resistance rates of Torulopsis glabrata to 5-fluorocytosine, fluconazole, itraconazole, and voriconazole were 0. In the multiple bacterial infections of Klebsiella pneumoniae + Escherichia coli + Acinetobacter baumannii, the drug resistance rates of Klebsiella pneumoniae to cefotetan, cefepime, piperacillin/tazobactam, imipenem, ertapenem, tobramycin, ciprofloxacin, and levofloxacin were 0. The drug resistance rates of Escherichia coli to amoxicillin/clavulanic acid, piperacillin/tazobactam, imipenem, meropenem were 0. The drug resistance ratets of Acinetobacter baumannii to trimethoprim sulfamethoxazole was 0.@*Conclusions@#Klebsiella pneumoniae is the main pathogen of PLA, followed by Escherichia coli. Klebsiella pneumoniae and Escherichia coli are sensitive to meropenem and tigecycline. Klebsiella pneumoniae subsp. pneumoniae and other Gram-negative bacteria are sensitive to ertapenem. Staphylococcus aureus are sensitive to Linezolid. Antibiotics are selected after drug sensitivity test for patients.

Progress of biological characteristics of stress granules and their relationship with tumors / 肿瘤研究与临床

Eukaryotes inhibit the translation of mRNA under stress conditions and form particles-stress granules (stress granules). At present, stress granules have been proved to be related to the occurrence and development of a variety of diseases, including tumors. The production of stress granules is promoted by microenvironment such as hypoxia and hyperactive oxygen in tumor cells, while stress granules-related proteins such as G3BP1, RACK1, YB-1 and mammalian target of rapamycin (mTOR) can promote the occurrence and metastasis of tumors, but the mechanism is not yet clear. In addition, studies have linked the formation of stress granules to the survival of tumor cells during chemotherapy, and believe that stress granules play a role in the treatment of tumors by different anti-tumor drugs. This review introduces the biological characteristics of stress granules and their relationship with tumors.