Rationale and design of a prospective, multicenter, cohort study on the evaluation of postoperative Venous ThromboEmbolism incidence in patients with ColoRectal Cancer (CRC-VTE trial).

Background: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication after abdominal surgery. The incidence of VTE after colorectal malignancy is higher than that after general surgery. Although more attention has been paid to the prevention of VTE, there is still a large gap between clinical practice and guideline recommendation. Methods: The Venous ThromboEmbolism incidence in patients with ColoRectal Cancer (CRC-VTE trial) will be a prospective, multicenter, cohort study to determine the current status of the incidence, diagnosis, treatment, and prevention of VTE after colorectal cancer surgery in China, as well as to further improve the level of prevention and treatment of VTE events in these fragile patients. In this study, 1,217 patients will be enrolled at 40 centers in China and evaluated on VTE events and adverse events related to VTE prevention at 5-9 and 21-28 days after surgery. The primary outcome is the incidence of VTE events during the follow-up, and secondary outcome is the incidence of adverse events associated with VTE prevention. Discussion: This study will comprehensively evaluate the incidence and prevention of VTE after colorectal cancer surgery in China, balance the relationship between VTE prevention and bleeding adverse events, and the formulate a guideline for the prevention of VTE after colorectal surgery that might suitable for national conditions. Trial Registration: Clinical trial registration number NCT04588805 (The CRC-VTE trial).

Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial).

BACKGROUND: Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain. METHODS: This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6-8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes. DISCUSSION: To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04911517. Date of registration: 23 May 2021. URL of trial registry record: https://www. CLINICALTRIALS: gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1 .

Clinical benefits of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Immunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer (mCRC) have been conducted in recent years. However, the clinical benefits, including the efficacy and safety of these treatments against mCRC, remain controversial. Hence, we conducted this meta-analysis on the clinical benefits of PD-1/PD-L1 inhibitors in patients with mCRC. METHODS: We searched online databases including MEDLINE, Embase, Cochrane Library, and Web of Science, from inception to January 4, 2021. The outcomes related to efficacy and safety were extracted and analyzed. Subgroup analyses were conducted according to the categories of dMMR-MSI-H (tumors with mismatch repair deficiency and high levels of microsatellite instability) ≥ 5% vs. dMMR-MSI-H < 5%, monotherapy vs. combination therapy, PD-1 inhibitors vs. PD-L1 inhibitors, and nivolumab vs. pembrolizumab. RESULTS: Fourteen studies including 1129 subjects were included in our systematic review. The overall complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) rates were 0.01 (95% CI 0.00-0.04), 0.04 (95% CI 0.05-0.26), 0.27 (95% CI 0.22-0.32), and 0.44 (95% CI 0.30-0.58), respectively. The overall objective response rate (ORR) and disease control rate (DCR) were 0.16 (95%CI 0.06-0.31) and 0.50 (95%CI 0.35-0.65), respectively. The overall rate of adverse events (AEs) and severe adverse responses (SAEs) were 0.84 (95% CI 0.72-0.92) and 0.30 (95% CI 0.20-0.41), respectively. The ORRs of the dMMR-MSI-H ≥ 5% and dMMR-MSI-H < 5% subgroups were 0.40 (95% CI 0.30-0.51) and 0.04 (95% CI 0.00-0.09), respectively. CONCLUSIONS: PD-1/PD-L1 inhibitors produced encouraging clinical benefits including the response rate in the treatment of dMMR-MSI-H mCRC. They actually have been influenced by the present state of mCRC therapy including pMMR-MSI-L mCRC. Nevertheless, additional multi-center prospective studies are still expected. TRIAL REGISTRATION: We have registered this study in the International Prospective Register of Systematic Reviews (PROSPERO), and the registration number is CRD42021249601 .

Baicalin suppresses the progression of Type 2 diabetes-induced liver tumor through regulating METTL3/m6A/HKDC1 axis and downstream p-JAK2/STAT1/clevaged Capase3 pathway.

BACKGROUND: Epidemiological and clinical evidence suggests that diabetes increases the risk of liver cancer. Although the co-occurrence of type 2 diabetes (T2D) and liver cancer is becoming more frequent, the underlying mechanisms remain unclear. Even though baicalin, extensively used in traditional Chinese medicine (TCM), can control T2D and inhibit liver cancer separately, minimal research is available regarding its possible effect on T2D-induced liver cancer. Thus, in the present study, we aimed to investigate the role of baicalin in T2D-induced hepatocellular cancer, and for the first time, we particularly emphasized the regulation of baicalin in genes RNA m6A in hepatocellular cancer. METHODS: Here, we constructed a cell culture model under a high concentration of glucose and a T2D-induced liver tumor model to evaluate the in vitro and in vivo role of baicalin in T2D-induced liver cancer progression. After confirming the suppressive effect of baicalin and the HKDC1 antibody on T2D-induced liver tumors, the epigenetic alterations (DNA 5mC and RNA m6A) of the baicalin-regulated HKDC1 gene were detected using MS and q-PCR. Next, the METTL3 gene-regulated m6A (2854 site) was investigated using SELECT PCR. Finally, the impact of the other three baicalin analogs (baicalein, wogonoside, and wogonin) on tumor inhibition was tested in vivo while verifying the related RNA m6A mechanism. RESULTS: The results showed that baicalin and the HKDC1 antibody suppressed T2D-induced liver tumor progression in vitro and in vivo. Furthermore, baicalin significantly inhibited the epigenetic modification (DNA 5mC and RNA m6A) of HKDC1 in HepG2 tumors, mainly targeting the RNA m6A site (2854). The m6A-related gene, METTL3, regulated the RNA m6A site (2854) of HKDC1, which was also restricted by baicalin. Moreover, the study verified that baicalin regulated the METTL3/HKDC1/JAK2/STAT1/caspase-3 pathway in liver cancer cells when exposed to a high glucose concentration. In addition, the three baicalin analogs were proven to regulate the m6A (2854 site) of HKDC1 and suppress T2D-induced liver tumors. CONCLUSIONS: The findings of this study revealed that baicalin suppressed T2D-induced liver tumor progression by regulating the METTL3/m6A/HKDC1 axis, which might support its potential application for preventing and treating T2D-induced liver cancer.

Feasibility and outcomes of ERAS protocol in elective cT4 colorectal cancer patients: results from a single-center retrospective cohort study.

BACKGROUND: Programs of Enhanced Recovery After Surgery reduces morbidity and shorten recovery in patients undergoing colorectal resections for cancer. Patients presenting with more advanced disease such as T4 cancers are frequently excluded from undergoing ERAS programs due to the difficulty in applying established protocols. The primary aim of this investigation was to evaluate the possibility of applying a validated ERAS protocol in patients undergoing colorectal resection for T4 colon and rectal cancer and to evaluate the short-term outcome. METHODS: Single-center, retrospective cohort study. All patients with a clinical diagnosis of stage T4 colorectal cancer undergoing surgery between November 2016 and January 2020 were treated following the institutional fast track protocol without exclusion. Short-term postoperative outcomes were compared to those of a control group treated with conventional care and that underwent surgical resection for T4 colorectal cancer at the same institution from January 2010 to October 2016. Data from both groups were collected retrospectively from a prospectively maintained database. RESULTS: Eighty-two patients were diagnosed with T4 cancer, 49 patients were included in the ERAS cohort and 33 in the historical conventional care cohort. Both, the mean time of tolerance to solid food diet and postoperative length of stay were significantly shorter in the ERAS group than in the control group (3.14 ± 1.76 vs 4.8 ± 1.52; p < 0.0001 and 6.93 ± 3.76 vs 9.50 ± 4.83; p = 0.0084 respectively). No differences in perioperative complications were observed. CONCLUSIONS: Results from this cohort study from a single-center registry support the thesis that the adoption of the ERAS protocol is effective and applicable in patients with colorectal cancer clinically staged T4, reducing significantly their length of stay and time of tolerance to solid food diet, without affecting surgical postoperative outcomes.

A systematic review and meta-analysis on complications of transanal total mesorectal excision.

AIM: Transanal total mesorectal excision (TaTME) is a surgical approach for treating mid to low rectal cancer as well as other colorectal diseases. Since the procedure is difficult to master, perioperative complications of TaTME should be examined precisely, especially during the early implementation phase of this procedure. The primary aim of this review was to determine a pooled morbidity and anastomotic leakage (AL) rate after TaTME surgery, and the secondary aim was to show the completeness of reporting of complications among the included studies, as well as the correlation between completeness and reported incidence of complications. METHOD: A systematic review of literature was conducted using Medline, Embase and Cochrane databases, searching for observational studies reporting on complications after TaTME. Studies published between 1 January 2010 and 15 October 2019 were included. Meta-analysis on the proportion of morbidity, AL and intraoperative complications was performed. RESULTS: Forty-one studies (2446 TaTME cases), consisting of 27 noncomparative studies and 14 comparative studies, were included, after screening 1711 possible studies. The pooled rates of overall morbidity and AL were 30.0% (95% CI 26.4%-34.0%) and 6.8% (95% CI 5.2%-8.9%), respectively. Subgroup analysis showed that the morbidity rate in studies that reported 30-day results (35.5%; 95% CI 31.8%-39.4%) was significantly higher than the rate in studies that did not define the follow-up length for complications (23.4%; 95% CI 17.8%-30.1%; p = 0.003). The rates of intraoperative urethral injury, rectal injury, vaginal injury and bladder injury were 0.3% (95% CI 0.1%-1.7%), 0.4% (95% CI 0.1%-2.2%), 0.3% (95% CI 0.1%-0.8%) and 0.3% (95% CI 0.1%-1.7%), respectively. CONCLUSION: This meta-analysis shows that pooled perioperative complication rates were within acceptable ranges. However, the significant difference in overall morbidity rate between the studies with 30-day results and the studies without a specified follow-up time, indicates a large under-reporting of complications in many studies.

Verification of data in a nationwide transanal total mesorectal excision registry in China.

BACKGROUND AND OBJECTIVES: Transanal total mesorectal excision is a surgical procedure for mid- and low rectal cancer. The Chinese TaTME Registry Collaborative is a nationwide database collecting information on patients who have undergone this procedure. METHODS: Centers were invited by the registry committee to participate in a three-part data audit project: remote audits for data completeness and deviation values, onsite source verification of data accuracy, and an online survey of the characteristics of data managers. RESULTS: Twenty-three tertiary centers participated in this project. The median case volume registered by the centers was 51 (interquartile range, 25-89). The overall data completeness for 30 verified variables was 89.1%. Eight centers achieved a high data completeness rate (>95%). The source data of eight centers were verified onsite. The overall accuracy rate was 90.4% (85.3%-97.6% across centers). Postoperative complications, mortality, and proximal/distal resection margin involvement were accurately reported in >95% of cases. The data completeness rate was higher if the data manager was a surgeon/surgical resident (94.2% vs. 84.8%, p = 0.045). CONCLUSIONS: The completeness and accuracy of the data in the Chinese TaTME Registry Collaborative are acceptable. The quality of the data is highest when entered by colorectal surgeons and residents.

Transanal Total Mesorectal Excision: Short-term Outcomes of 1283 Cases from a Nationwide Registry in China.

BACKGROUND: Transanal total mesorectal excision is a promising surgical procedure for mid to low rectal cancer. OBJECTIVE: This study aimed to determine the short-term outcomes of Chinese patients treated with transanal total mesorectal excision. DESIGN: This was an observational study using data from an online registry system. SETTING: Study participants were recruited from 40 different centers across 15 provinces in China. PATIENTS: Patients with either benign or malignant rectal disease who underwent transanal total mesorectal excision procedure and were registered in the Chinese Transanal Total Mesorectal Excision Registry Collaborative from May 2010 to November 2019 were included. INTERVENTION: Patients underwent transanal total mesorectal excision. MAIN OUTCOME MEASURES: The primary outcomes measured were the postoperative complications and pathological outcomes. RESULTS: In total, 1283 patients, comprising 888 men (69.2%) and 395 women (39.8%) with a median age of 61 (22-92) years and a median BMI of 23.6 (14.5-46.3) kg/m2, were analyzed. Among 40 participating centers, the average number of registered cases was 32.1±34.7, and 12 centers (30%) registered >40 cases in the registry. Among 849 patients with rectal cancer who underwent laparoscopic-assisted transanal total mesorectal excision, the conversion rate was 0.5% in the abdominal phase and 1.9% in the perineal phase. Three patients reported urethral injury (0.5%). The postoperative complication rate and the anastomotic leakage incidence were 18.4% and 5.8%. The quality of the total mesorectum excision specimens was found to be complete in 81.9% of patients. In addition, the positive circumferential resection margin rate was 2.8%. LIMITATIONS: The primary limitation of this registry study was the high percentage of missing data (10.8% overall), and, for some of the analyzed variables, up to 35% of the data was missing. Postoperative complications were not monitored after discharge, resulting in a lower morbidity rate than the 30-day morbidity rate reported in other studies. CONCLUSIONS: The short-term outcomes of patients who underwent transanal total mesorectal excision procedures in China were acceptable. See Video Abstract at http://links.lww.com/DCR/B414. EXCISIN TOTAL DEL MESORRECTO POR VA TRANSANAL RESULTADOS A CORTO PLAZO DE CASOS DE UN REGISTRO NACIONAL EN CHINA: ANTECEDENTES:La excisión total del mesorrecto por vía transanal es un procedimiento quirúrgico prometedor para el cáncer de recto medio y bajo.OBJETIVO:Determinar los resultados a corto plazo de los pacientes chinos tratados con escisión mesorrectal total transanal.DISEÑO:Estudio observacional con datos de un sistema de registro en línea.AJUSTE:Los participantes del estudio fueron reclutados en 40 centros diferentes en 15 provincias de China.PACIENTES:Se incluyeron pacientes con enfermedad rectal benigna o maligna que se sometieron a una cirugía de excisión total del mesorrecto por vía transanal y que se registraron en el Registro Colaborativo de Excisión Total del Mesorrecto por vía Transanal en China desde mayo de 2010 hasta noviembre de 2019.INTERVENCIÓN:Excisión total delmesorrecto por vía transanal.PRINCIPALES MEDIDAS DE RESULTADO:Complicaciones postoperatorias y resultados patológicos.RESULTADOS:Fueron analizados un total de 1.283 pacientes, que comprendían 888 hombres (69,2%) y 395 mujeres (39,8%) con una mediana de edad de 61 (22-92) años y una mediana de índice de masa corporal de 23,6 (14,5-46,3) kg / m2. Entre los 40 centros participantes, el promedio de casos registrados fue de 32,1 ± 34,7, y 12 centros (30%) inscribieron > 40 casos en el registro. Entre 849 pacientes con cáncer de recto que se sometieron a excisión total del mesorrecto pééor vía transanal asistida por laparoscopia, la tasa de conversión fue del 0,5% en la fase abdominal y del 1,9% en la fase perineal. Tres pacientes refirieron una lesión uretral (0,5%). La tasa de complicaciones posoperatorias y la incidencia de fuga anastomótica fueron del 18,4% y el 5,8%, respectivamente. La calidad de las muestras de excisión total del mesorrecto se evaluó como completa en el 81,9% de los pacientes. Además, la tasa de margen de resección circunferencial positiva fue del 2,8%.LIMITACIONES:La principal limitación del presente estudio de registros fue el alto porcentaje de datos faltantes (10,8% en general), y para algunas de las variables analizadas, faltaba hasta el 35% de los datos. Las complicaciones postoperatorias no fueron verificadas después del alta, lo que resultó en una tasa de morbilidad más baja que la tasa de morbilidad a 30 días informada en otros estudios.CONCLUSIONES:Los resultados a corto plazo de los pacientes que se sometieron al procedimiento de excisión total del mesorrecto por vía transanal en China fueron aceptables. Consulte Video Resumen en http://links.lww.com/DCR/B414. (Traducción-Dr. Xavier Delgadillo).

Opportunities and Challenges of Nanoparticles in Digestive Tumours as Anti-Angiogenic Therapies.

Digestive tumours, a common kind of malignancy worldwide, have recently led to the most tumour-related deaths. Angiogenesis, the process of forming novel blood vessels from pre-existing vessels, is involved in various physiological and pathological processes in the body. Many studies suggest that abnormal angiogenesis plays an important role in the growth, progression, and metastasis of digestive tumours. Therefore, anti-angiogenic therapy is considered a promising target for improving therapeutic efficacy. Traditional strategies such as bevacizumab and regorafenib can target and block the activity of proangiogenic factors to treat digestive tumours. However, due to resistance and some limitations, such as poor pharmacokinetics, their efficacy is not always satisfactory. In recent years, nanotechnology-based anti-angiogenic therapies have emerged as a new way to treat digestive tumours. Compared with commonly used drugs, nanoparticles show great potential in tumour targeted delivery, controlled drug release, prolonged cycle time, and increased drug bioavailability. Therefore, anti-angiogenic nanoparticles may be an effective complementary therapy to treat digestive tumours. In this review, we outline the different mechanisms of angiogenesis, the effects of nanoparticles on angiogenesis, and their biomedical applications in various kinds of digestive tumours. In addition, the opportunities and challenges are briefly discussed.

Nephroblastoma overexpressed protein (NOV) enhances 5-Fu-mediated inhibitory effect of colorectal cancer cell proliferation via JNK/AP-1/caspase-8/caspase-3 pathway.

Chemoresistance often occurs during 5-fluorouracil (5-Fu) treatment of colorectal cancer (CRC). It is significant to explore the potential strategies to sensitize colorectal cancer cells to 5-Fu treatment. We studied the sensitization of Nephroblastoma overexpressed protein (NOV) on 5-Fu treatment. NOV was overexpressed and knocked down in HT115 and RKO cells respectively. Cell proliferation experiments and related mechanism studies by RT-qPCR and Western blot were performed Subsequently. Nude mouse xenograft model was established to test the inhibitory effect of 5-FU on CRC cells in vivo. In this study, we found that NOV mRNA expression was significantly lower in tumor tissues than that in the normal tissues (P < 0.05). The cell proliferation was reduced in the HT115-NOVexp groups (P < 0.05) and increased in the RKO-NOVkd groups (P < 0.05) than that in the control groups and NC groups. The RT-PCR and Western Blot results showed that NOV inhibited the expression of activator protein (AP)-1 (P < 0.05) and promoted the expression of Caspase-8/3 (P < 0.05) in CRC cells in vitro. NOV also improved the inhibitory effect of 5-Fu on inhibiting colorectal cancer proliferation in a tumor cell xenotransplantation nude mouse model. NOV inhibited the expression of AP-1 and JUK and promoted the expression of Caspase-8/3 in cancer tissues in a tumor cell xenotransplantation nude mouse model. In summary, NOV can sensitize CRC cells towards 5-Fu-mediated inhibitory effect on cell proliferation and its sensitization may be achieved by the JNK/AP-1/Caspase-8/Caspase-3 pathway.

Screening policies, preventive measures and in-hospital infection of COVID-19 in global surgical practices.

BACKGROUND: In a surgical setting, COVID-19 patients may trigger in-hospital outbreaks and have worse postoperative outcomes. Despite these risks, there have been no consistent statements on surgical guidelines regarding the perioperative screening or management of COVID-19 patients, and we do not have objective global data that describe the current conditions surrounding this issue. This study aimed to clarify the current global surgical practice including COVID-19 screening, preventive measures and in-hospital infection under the COVID-19 pandemic, and to clarify the international gaps on infection control policies among countries worldwide. METHODS: During April 2-8, 2020, a cross-sectional online survey on surgical practice was distributed to surgeons worldwide through international surgical societies, social media and personal contacts. Main outcome and measures included preventive measures and screening policies of COVID-19 in surgical practice and centers' experiences of in-hospital COVID-19 infection. Data were analyzed by country's cumulative deaths number by April 8, 2020 (high risk, >5000; intermediate risk, 100-5000; low risk, <100). RESULTS: A total of 936 centers in 71 countries responded to the survey (high risk, 330 centers; intermediate risk, 242 centers; low risk, 364 centers). In the majority (71.9%) of the centers, local guidelines recommended preoperative testing based on symptoms or suspicious radiologic findings. Universal testing for every surgical patient was recommended in only 18.4% of the centers. In-hospital COVID-19 infection was reported from 31.5% of the centers, with higher rates in higher risk countries (high risk, 53.6%; intermediate risk, 26.4%; low risk, 14.8%; P < 0.001). Of the 295 centers that experienced in-hospital COVID-19 infection, 122 (41.4%) failed to trace it and 58 (19.7%) reported the infection originating from asymptomatic patients/staff members. Higher risk countries adopted more preventive measures including universal testing, routine testing of hospital staff and use of dedicated personal protective equipment in operation theatres, but there were remarkable discrepancies across the countries. CONCLUSIONS: This large international survey captured the global surgical practice under the COVID-19 pandemic and highlighted the insufficient preoperative screening of COVID-19 in the current surgical practice. More intensive screening programs will be necessary particularly in severely affected countries/institutions. STUDY REGISTRATION: Registered in ClinicalTrials.gov: NCT04344197.

Down-regulation of microRNA-203a suppresses IL-1ß-induced inflammation and cartilage degradation in human chondrocytes through Smad3 signaling.

Osteoarthritis (OA) is a chronic and prevalent degenerative musculoskeletal disorder, which is characterized by articular cartilage degradation and joint inflammation. MicroRNA-203a (miR-203a) has been shown to be involved in multiple pathological processes during OA, but little is known about its function in chondrocyte extracellular matrix (ECM) degradation. In the present study, we aimed to elucidate the effects of miR-203a on articular cartilage degradation and joint inflammation. We observed that the miR-203a level was significantly up-regulated in OA tissues and in an in vitro model of OA, respectively. Inhibition of miR-203a significantly alleviated the interleukin (IL)-1ß-induced inflammatory response and ECM degradation in chondrocytes. Moreover, mothers against decapentaplegic homolog 3 (Smad3), a key factor in maintaining chondrocyte homeostasis, was identified as a putative target of miR-203a in chondrocytes. More importantly, inhibition of Smad3 impaired the inhibitory effects of the miR-203a on IL-1ß-induced inflammatory response and ECM degradation. Collectively, these results demonstrated that miR-203a may contribute to articular cartilage degradation of OA by targeting Smad3, suggesting a novel therapeutic target for the treatment of OA.

MicroRNA-129-5p alleviates spinal cord injury in mice via suppressing the apoptosis and inflammatory response through HMGB1/TLR4/NF-κB pathway.

Secondary injury after spinal cord injury (SCI) is one reversible pathological change mainly involving excessive inflammatory response and neuro-apoptosis. Since in recent years, microRNAs (miRNAs) have been proposed as novel regulators of inflammation in different disease conditions. However, the role of miRNAs in the inflammatory response and apoptosis of secondary injury after SCI remains to be fully elucidated. Here, we tried to explore the influence and mechanism of miRNAs on the neuron inflammatory response and apoptosis after SCI. The expression profiles of miRNA were examined using miRNA microarray, and among the candidate miRNAs, miR-129-5p was found to be the most down-regulated miRNA in spinal tissues. Overexpression of miR-129-5p using agomir-miR-129-5p promoted injury mice functional recovery, suppressed the apoptosis and alleviated inflammatory response in spinal tissues. Using LPS-induced BV-2 cell model, we found miR-129-5p was also proved in protecting inflammatory response and cell apoptosis in vitro. High-mobility group protein B1 (HMGB1), a well-known inflammatory mediator, was found to be directly targeted by miR-129-5p and it was associated with the inhibitory effect of miR-129-5p on the activation of toll-like receptor (TLR)-4 (TLR4)/ nuclear factor-κB (NF-κB) pathway in vitro and in vivo. Further experiments revealed that the anti-apoptosis and anti-inflammatory effects of miR-129-5p were reversed by HMGB1 overexpression in BV-2 cells. Collectively, these data revealed that miR-129-5p alleviated SCI in mice via suppressing the apoptosis and inflammatory response through HMGB1//TLR4/NF-κB pathway. Our data suggest that up-regulation of miR-129-5p may be a novel therapeutic target for SCI.

The application of defunctioning stomas after low anterior resection of rectal cancer.

Defunctioning stomas are frequently used by colorectal surgeons after unsatisfactory anastomosis. The primary purpose of constructing a defunctioning stoma is to prevent an anastomotic leakage or to alleviate the detrimental consequences of it. However, the construction of defunctioning stomas is not free and is associated with adverse impacts on the patient. Stoma-related complications can develop in different stages and can impair a patient's quality of life. Furthermore, one in every four to six defunctioning stomas turns into a non-closure stoma. Since no definite indications for the creation of a defunctioning stoma are available, surgeons have to carefully weigh their benefits against their adverse effects. Thus, the precise selection of patients who should undergo the creation of a defunctioning stoma is of great importance, and an alternative method for preventing anastomotic leakage is needed.

Proposal for subclassification to select patients for hepatectomy with intermediate hepatocellular carcinoma and Child-Pugh A liver function: A double-center study from China.

Increasing evidence has shown that hepatectomy provides a longer overall survival (OS) for patients with hepatocellular carcinoma (HCC) in the intermediate stage. Unfortunately, not all patients benefit from liver resection, even if hepatectomy is feasible. This study aimed to propose a subclassification to select patients for surgical resection.OS of patients with intermediate-stage HCC who underwent hepatectomy at Beijing Friendship Hospital or Peking Union Medical College Hospital were reviewed. Patients were divided into 2 groups based on the results of survival analysis. The prognosis of these patients was compared with that in those who were treated by trans-arterial chemoembolization (TACE) in each subgroup.A total of 259 patients with intermediate-stage HCC who were initially treated by hepatectomy were included. Multivariate analysis showed that cumulative tumor size and tumor number independently affected tumor recurrence and survival time of these patients. Patients were then divided into group A (tumor size <11 cm and tumor number < 4; n = 205) and group B (tumor size ≥11 cm and tumor number ≥ 4; n = 54). Multivariate analysis showed that hepatectomy was independently associated with longer OS compared with TACE in patients in group A (hazard ratio = 0.67, 95% confidence interval = 0.49-0.90), but not in group B.Surgical management of intermediate-stage HCC should be performed with more complexity than current practice. Hepatic resection could be considered as the first-line treatment only for patients with HCC who have a cumulative tumor size of less than 11 cm and <4 tumors.

Identification of biomarkers for Barcelona Clinic Liver Cancer staging and overall survival of patients with hepatocellular carcinoma.

The aim of the current study was to identify biomarkers that correlate with the Barcelona Clinic Liver Cancer (BCLC) staging system and prognosis of patients with hepatocellular carcinoma (HCC). We downloaded 4 gene expression datasets from the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo), and screened for genes that were differentially expressed between HCC and normal liver tissues, using significance analysis of the microarray algorithm. We used a weighted gene co-expression network analysis (WGCNA) to identify hub genes that correlate with BCLC staging, functional enrichment analysis to associate hub genes with their functions, protein-protein interaction network analysis to identify interactions among hub genes, UALCAN analysis to assess gene expression levels based on tumour stage, and survival analyses to clarify the effects of hub genes on patients' overall survival (OS). We identified 50 relevant hub genes using WGCNA; among them, 13 genes (including TIGD5, C8ORF33, NUDCD1, INSB8, and STIP1) correlated with OS and BCLC staging. Significantly enriched gene ontology biological process terms included RNA processing, non-coding RNA processing and phosphodiester bond hydrolysis, and 6 genes were found to interact with 10 or more hub genes. We identified several candidate biomarkers that correlate with BCLC staging and OS of HCC. These genes might be used for prognostic assessment and selection of HCC patients for surgery, especially those with intermediate or advanced disease.

[Incidence and risk factors for anastomotic leakage after anterior resection for rectal cancer].

OBJECTIVE: To assess the incidence and independent risk factors for clinical anastomotic leakage (AL) in patients undergoing anterior resection(AR) or low anterior resection, (LAR) for rectal cancer. METHODS: This was a retrospective case-control study of 550 patients with rectal cancer who underwent AR or LAR from April 2007 to March 2017 in Beijing Friendship Hospital, Capital Medical University. The relationship between the incidence of AL and clinicopathological manifestations was analyzed by Chi-squared test and Fisher exact test, and the independent risk factors of AL were analyzed using logistic regression analysis. AL is defined as a defect (including necrosis or abscess formation) of the intestinal wall at the anastomotic site, leading to a communication between the intra- and extra-luminal compartments. AL can be divided into three grades. Grade A anastomotic leakage results in no change in the management of patients, whereas grade B leakage requires active therapeutic intervention but is manageable without re-laparotomy. Grade C anastomotic leakage requires re-laparotomy. RESULTS: AL was noted in 32(5.8%) of 550 patients with rectal cancer who underwent AR or LAR, including 15(46.9%), 4(12.5%), and 13 patients (40.6%) with Grades A, B, and C, respectively. Five patients(0.9%, 5/550) died peri-operatively. AL- and non-AL-related deaths occurred in 3 (9.4%, 3/32, all cases were Grade C) and 2 patients(0.4%, 2/518), respectively, with the two mortality rates being significant difference(P=0.002). Chi-squared test or Fisher exact test showed that the incidence of AL was associated with neoadjuvant chemoradiotherapy (P=0.011), intraoperative bleeding(≥100 ml)(χ2=11.980, P=0.001), and tension-reducing suture of anastomosis(P=0.015). The results of logistic regression analysis showed that the independent risk factors of AL were neoadjuvant chemoradiotherapy(OR=2.402, 95%CI: 1.004-5.749, P=0.049), intraoperative bleeding(≥100 ml)(OR=2.971, 95%CI: 1.269-6.957, P=0.012) and tension-reducing suture of anastomosis(OR=2.304, 95%CI: 1.008-5.263, P=0.048). CONCLUSION: The incidence of AL in patients undergoing AR for rectal cancer is 5.8%. The high-risk factors for AL are neoadjuvant chemoradiotherapy, intraoperative bleeding (≥100 ml), and tension-reducing suture of anastomosis. Patients with these three risk factors have a high risk of AL rate, and a defunctioning stoma should be performed.

Risk factors for and the prevention of acute kidney injury after abdominal surgery.

Postoperative acute kidney injury in patients undergoing abdominal surgery is not rare and often results in bad outcomes for patients. The incidence of postoperative acute kidney injury is hard to evaluate reliably due to its non-unified definitions in different studies. Risk factors for acute kidney injury specific to abdominal surgery include preoperative renal insufficiency, intraabdominal hypertension, blood transfusion, bowel preparation, perioperative dehydration, contrast agent and nephrotoxic drug use. Among these, preoperative renal insufficiency is the strongest predictor of acute kidney injury. The peri-operative management of high-risk patients should include meticulous selection of fluid solutions. Balanced crystalloid solutions and albumin are generally thought to be relatively safe, while the safety of hydroxyethyl starch solutions has been controversial. The purpose of the present review is to discuss the current knowledge regarding postoperative acute kidney injury in abdominal surgical settings to help surgeons make better decisions concerning the peri-operative management.