Iron overload causes macrophages to produce a pro-inflammatory phenotype in the synovium of hemophiliac arthritis via the acetyl-p53 pathway.

AIM: Haemophiliac arthritis (HA) is caused by spontaneous intra-articular hemorrhage and repeated intra-articular hematomas, leading to iron overload, which, in turn, induces M1 macrophage polarisation and inflammatory cytokine secretion, resulting in synovitis. Here, we explored the mechanism by which iron overload in HA induces the polarisation of M1 macrophages, providing a new approach for the treatment of HA synovitis. METHODS: The synovium from the knee joints of normal amputees and patients with HA was collected. Pathological changes in the synovial tissues were analysed using hematoxylin and eosin staining. Iron tissue deposition was evaluated using the iron assay kit and Prussia Blue staining, while macrophage phenotype was determined using immunofluorescence. The levels of pro-inflammatory cytokines and p53 acetylation were determine using western blotting. An in vitro iron overload model was established by inducing THP-1 macrophages with ferric ammonium citrate, and the involvement of acetylated p53 in M1 macrophage polarisation was investigated. RESULTS: Compared to control samples, the iron content in the synovium of patients with HA was significantly increased. The protein levels of M1 macrophage markers, pro-inflammatory cytokines, and acetylated p53, were also significantly elevated in the synovial tissues of patients with HA. Similar results were observed in the in vitro iron overload model. Furthermore, the inhibition of p53 acetylation in vitro reversed these iron overload-induced effects. CONCLUSION: In patients with HA, iron overload induced synovial p53 acetylation, leading to macrophage polarisation toward the M1 phenotype and increased inflammatory cytokine secretion, resulting in synovitis. HIGHLIGHTS: Synovial iron overload is associated with changes in P53 acetylation in hemophiliac arthritis (HA). Acetylated p53, a known regulator of macrophage polarization, is highly expressed in HA synovium, suggesting a potential role in M1 polarization. HA synovial macrophages predominantly polarize into the pro-inflammatory M1 phenotype, secreting elevated levels of pro-inflammatory cytokines.

Ferroptosis: a new target for iron overload-induced hemophilic arthropathy synovitis.

Iron deposition is closely related to developing haemophilic arthropathy (HA). Studying the relationship between ferroptosis signal expression and iron overload in HA synovium facilitates understanding the pathogenesis of joint synovial hyperplasia in bloodborne arthritis and the development of new protective methods. The knee synovium was collected from HA and osteoarthritis (OA) patients, and pathological changes were analysed by HE and Prussian blue staining. Ferroptosis phenotypes were examined by immunohistochemistry and western blotting. Moreover, ferric ammonium citrate (FAC)-induced was used to construct an in vitro iron overload model to investigate the relationship between iron overload and ferroptosis in synovial fibroblasts (FLS). Furthermore, the factors influencing ferroptosis in FLS were explored. Iron deposition, cell proliferation, and vascular proliferation in the synovium of HA were more obvious. Ferroptosis in HA synovium appears to inhibit. FLS ferroptosis increased with iron accumulation, malondialdehyde (MDA) in cells, and glutathione (GSH) depletion. TNF-α plays a protective role in this process. Blocking the action of TNF-α and inducing ferroptosis significantly reduced synovial proliferation. TNF-α inhibitors combined with a ferroptosis inducer may be a new therapeutic method for HA synovitis.

Effects of an Nd:YAP laser used for root canal disinfection in pulp regenerative therapy: a pilot study.

This study aimed to compare the disinfection effects between a triple antibiotic paste and neodymium-doped yttrium aluminum perovskite (Nd:YAP) laser in pulp regenerative therapy and evaluate corresponding therapeutic effects based on apical radiographs and cone-beam computed tomography (CBCT). Sixty-six immature permanent teeth in 66 patients diagnosed with acute or chronic apical periodontitis were analyzed. All teeth were given pulp regenerative therapy. The patients were categorized into a control (triple antibiotic paste) and an experimental (Nd:YAP laser) group. Teeth in the experimental group were disinfected using an Nd:YAP laser, while those in the control group were disinfected using a triple antibiotic paste. Clinical and radiological examinations were performed every 3-6 months after treatment and followed up for 24 months. Statistical analysis was performed after clinical examination and showed that after one week of treatment, symptoms persisted in two teeth in the control group and two teeth in the experimental group. Two weeks later, the clinical symptoms disappeared in all teeth (p > 0.05). After 24 months of follow-up, the clinical symptoms recurred in two teeth in the control group and one tooth in the experimental group. On radiographic examination, 31 and 27 teeth showed continued root development, and three and two teeth showed no obvious root development in the control and experimental groups, respectively. The pulp sensibility test was positive in four teeth in both groups, with no significant difference between the two groups (p > 0.05). The results of this study suggest that endodontic irradiation with an Nd:YAP laser could be an effective alternative to triple antibiotic paste during disinfection of pulp regenerative therapy. Treatment outcomes were assessed using apical radiographs and CBCT, and no negative prognostic effects of the Nd:YAP laser on pulp regenerative therapy were found.

FGF23 and SOX9 expression in haemophilic cartilage: In vitro studies of the effects of iron.

INTRODUCTION: Clarifying the links between iron and FGF23, SOX9 expression in chondrocytes would be helpful for comprehending articular cartilage degradation pathogenesis in blood-induced arthritis and exploring new protective methods. AIM: The purpose of this study was to determine iron regulation of fibroblast growth factor 23 (FGF23) and SRY-box 9 (SOX9) in human chondrocytes, an area which is unexplored in blood-induced arthritis cartilage degradation pathogenesis. METHODS: Expression of FGF23, SOX9, MMP13 and collagen Ⅱ in articular cartilage of patients with osteoarthritis (OA) or haemophilic arthritis (HA) was determined by western blot (WB). Iron-induced FGF23 and SOX9 mRNA and protein expression in primary human normal chondrocyte cells (HUM-iCell-s018) was quantified by qRT-PCR and WB, respectively. RESULTS: We found that compared with OA patients, the expression of FGF23, MMP13 in articular cartilage of patients with HA was up-regulated, while the expression of SOX9, collagen Ⅱ was down-regulated. Iron-induced FGF23 and suppressed SOX9 expression in chondrocytes in a dose-dependent manner. CONCLUSIONS: These findings demonstrated that iron was involved in hemophilic cartilage lesion directly via changing cartilage phenotype through regulation of FGF23 and SOX9 expression in chondrocytes.

Pathological changes and expression of lysine oxidases and matrix metalloproteinases -1, -2, and -3 in ligaments of patients with haemophilic arthritis.

INTRODUCTION: Studying the pathological changes of ligaments in patients with haemophilic arthritis (HA) has important significance for guiding the release of ligaments during total knee arthroplasty (TKA) and exploring interventions to prevent ligament lesions. AIM: This study was conducted to show the pathological changes and investigate the lysine oxidase (LOX) and matrix metalloproteinase (MMP)-1, -2, and -3 levels in the ligaments of patients with HA compared with those of patients with osteoarthritis (OA). METHODS: Ligaments obtained during the TKA were stained with Masson trichrome, Verhoeff-Van Gieson and haematoxylin and eosin to show the basic pathological changes. Collagen I, elastin, LOXs and MMP-1, -2, and -3 expression levels were detected via western blot. LOX and MMP-1, -2, and -3 mRNA expression levels were analysed via quantitative real-time PCR. RESULTS: Compared with OA ligaments, HA ligaments were constructed more loosely with wider gaps, more breaks, haemocytodeposition and local hypertrophy among the fibres. LOXs and MMP mRNA expression levels were upregulated in the HA tissues, which was consistent with the western blot results. Collagen I and elastin levels were also higher in patients with HA. CONCLUSIONS: The metabolism of the ligaments in patients with HA is more complex than in those with OA, and the ligaments of patients with HA have stronger healing and destruction processes. This pathology is related to iron overload and imbalanced inflammatory factors due to repeated intra-articular bleeding.

Network pharmacology-based research on the active component and mechanism of the antihepatoma effect of Rubia cordifolia L.

Rubia cordifolia L. is widely used in Asia and its antihepatoma effect has been proved by in vitro and in vivo experiments. However, there are few studies on its specific mechanism. In the present study, the network pharmacology method was used to construct the component/target/pathway molecular regulatory network for the antihepatoma effect of Rubia cordifolia L. to explore the effective components of Rubia cordifolia L. and its potential mechanism. The chemical components of Rubia cordifolia L. were identified through literature and databases, and the components were evaluated and screened by drug likeness and pharmacokinetic characteristics (ADMET). The targets of active components were predicted according to the reverse pharmacophore matching model. The hepatic carcinoma-related genes were found in databases, and antihepatoma-related gene targets were selected through comparison. The functions of target genes and related pathways were analyzed and screened using the Database for Annotation, Visualization and Integrated Discovery, and the component/target/pathways network of antihepatoma effect of Rubia cordifolia L. was constructed using Cytoscape software. Finally, 16 active compounds were screened from Rubia cordifolia L., and 39 gene targets, including AKT1, mitogen-activated protein kinase 1, and epidermal growth factor receptor, were involved. Rubia cordifolia L. also affected the hepatitis B, phosphoinositide-3-kinase-protein kinase B, and mitogen-activated protein kinase signaling pathways. Many direct-acting tumor-related signaling pathways and indirect-acting hepatitis pathways inhibit the generation of liver cancer. The present study provided a scientific basis for further elucidating the mechanism of Rubia cordifolia L. against liver cancer.

Mini-subvastus versus medial parapatellar approach for total knee arthroplasty: a prospective randomized controlled study.

PURPOSE: Whether minimally invasive total knee arthroplasty (MIS-TKA) could offer better and faster recovery without the deviation of post-operative prosthesis position and limb alignment is still controversial. This prospective and randomized study was conducted to compare the clinical and radiological outcomes between patients who underwent the mini-subvastus approach of MIS-TKA and those who underwent the medial parapatellar approach of traditional TKA. METHODS: Fifty patients, including 50 knees, who required TKA due to osteoarthritis were randomized to the mini-subvastus group (group I) or the medial parapatellar group (group II). All patients accepted the same method of anaesthesia, equal support therapy and identical rehabilitation exercise after surgery. The evaluation system included operation time, tourniquet time, blood loss, skin incision length in flexion, straight leg raising time, the time of lower limb muscle strength up to grade 4, the time of walking with aid or without aid, the time of walking up and down the stairs, the active flexion angle, range of movement (ROM), the Knee Society Scores (KSS), visual analogue score for pain (VAS), hospital stays and radiographic outcomes. RESULTS: The mini-subvastus approach offered smaller skin incision length in flexion, but at the cost of operation time (P < 0.001). No significant difference was found in tourniquet time and blood loss. The patients in group I could achieve straight leg raising, the lower limb muscle strength up to grade 4, walking with or without aid, and walking up and down the stairs earlier (P < 0.001). The active flexion angle, ROM, VAS and KSS in group I were superior to those in group II until six months post-operatively (P < 0.001), but the differences was not apparent at 12 months post-operatively. More importantly, there was no significant difference between the two groups on radiological outcomes (P > 0.05). CONCLUSIONS: The mini-subvastus approach could offer faster recovery, less pain and shorter hospital stays without compromising the principles of proper prosthesis position and limb alignment compared with the medial parapatellar approach.

Risk Factors for Nonclosure of a Temporary Defunctioning Ileostomy Following Anterior Resection of Rectal Cancer.

BACKGROUND: In patients with colorectal cancer, a defunctioning ileostomy is commonly constructed to reduce anastomotic complications. However, many patients do not undergo a subsequent procedure to have their temporary stoma closed. OBJECTIVE: This study investigated the incidence of nonclosure of ileostomies and identified factors associated with nonclosure. DESIGN: This study is a retrospective analysis of prospectively collected data. SETTING: This study was conducted at a tertiary referral cancer hospital. PATIENTS: A total of 296 patients who received anterior resection with a defunctioning ileostomy with protective intention from 2006 to 2013 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the incidence of nonclosure of ileostomy and associated risk factors. RESULTS: Patients were followed for a median time of 29 months (range, 21-100 months). At the end of the study, 51 (17.2%) patients were left with a permanent ileostomy. The median time interval from the creation of a defunctioning ileostomy to closure was 192 days (range, 14-865 days). Multivariate analyses using a logistic regression model showed that metastatic diseases (OR, 0.179, p < 0.001), Charlson Comorbidity Index score >1 (OR, 0.268; p < 0.01), and complications from the index surgery (OR, 0.391; p = 0.013) were significant independent risk factors for failing to close a defunctioning ileostomy. LIMITATIONS: Although our study has a large patient cohort, it is limited by its retrospective nature. It is difficult to fully evaluate stoma complications after hospital discharge, and the prevalence may be underestimated. CONCLUSION: One in 6 temporary ileostomies constructed during an elective anterior resection for rectal cancer was not closed. Patients should be told before the index surgery that there is a risk of nonclosure and possible complications associated with permanent ileostomy.

Rectal cancer patients after neoadjuvant radiotherapy (30Gy/10f) with negative lymph node may not benefit from postoperative adjuvant chemotherapy: a retrospective study.

OBJECTIVE: The purpose of this study is to evaluate whether adjuvant chemotherapy could bring oncologic benefit to all patients who underwent neoadjuvant radiotherapy (30Gy/10f). METHODS: Rectal cancer patients receiving preoperative radiotherapy between July 2002 and April 2009 were retrospectively identified. RESULTS: A total of 225 patients were enrolled in this study. One hundred thirty-one patients received postoperative adjuvant chemotherapy, and 94 patients did not. The 120 ypN+ and 105 ypN- patients were divided into chemo and non-chemo groups. Two groups of patients did not show any significant difference in terms of gender, age, ypT stage, preoperative serum carcinoembryonic antigen (CEA) level, differentiation, circumferential margin (CRM), lymphovascular invasion (LVI), surgical approach, local recurrence, and distant metastasis (P > 0.05). Survival analysis showed that in ypN+ patients, the 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate in chemo group were both significantly higher than non-chemo group (P < 0.05). In ypN- patients, the 5-year OS rate and 5-year DFS rate did not show any significant difference in the two groups (P > 0.05). Subgroup analysis showed that the 5-year OS rate and 5-year DFS rate in ypT0-2 N- patients (P > 0.05) and ypT3-4 N- patients (P > 0.05) did not show any significant difference, either. CONCLUSIONS: Based on a Chinese protocol, patients with ypN- stage may not benefit from adjuvant chemotherapy, regardless of the ypT stage, while the ypN+ patients may benefit from adjuvant chemotherapy. More randomized clinical trials are needed in the future.

Subcutaneous vacuum drains reduce surgical site infection after primary closure of defunctioning ileostomy.

PURPOSE: Surgical site infection (SSI) is the most common complication after primary closure of defunctioning ileostomy. We use a subcutaneous vacuum drain (SVD) in our institution to prevent infection. This study aimed to analyze the risk factors of SSI and to assess the utility of an SVD for preventing SSI in patients undergoing primary closure of ileostomy. METHODS: Patients undergoing ileostomy closure in the Department of Colorectal Surgery, Peking University Cancer Hospital, from September 2006 to March 2013, were included in this study. The clinical features of these patients with or without a subcutaneous drain were reviewed, and the complication rate of SSI was analyzed. The primary endpoints were the incidence and risk factors of SSI, and the secondary endpoints were the rate of overall complications and their management. RESULTS: A total of 245 consecutive patients were enrolled in the study. The overall incidence of SSI was 8.6%. Eighty-five (34.7%) patients received placement of an SVD. The use of SVDs was associated with a significantly lower incidence of SSI compared with primary closure (PC) without an SVD (1.2 vs. 12.5%, p = 0.001). Multivariate analyses showed that the presence of an SVD (odds ratio (OR) 0.063, p = 0.012), total operation time >90 min (OR 4.862, p = 0.002), and postoperative complications (OR 10.576, p < 0.001) were independent risk factors of SSI. CONCLUSIONS: This study shows that an SVD is effective for reducing SSI in patients undergoing PC of ileostomy. Further randomized trials are required to confirm our findings and to compare SVDs with purse-string sutures.

[Retrospective analysis of 856 cases with stage 0 to III rectal cancer underwent curative surgery combined modality therapy].

OBJECTIVE: To investigate the survival and prognostic factors of stage 0 to III rectal cancer in 10 years. METHODS: Clinical data and follow-up of 856 rectal cancer patients with stage 0-III underwent curative surgery from January 2000 to December 2010 were retrospective analyzed. There were 470 male and 386 female patients, with a mean age of (58 ± 12) years. Kaplan-Meier method was used to analyze the overall survival and disease free survival. Log-rank test was used to compare the survival between groups. Cox regression was used to analyze the independent prognostic factors of rectal cancer. RESULTS: The patients in each stage were stage 0 with 18 cases, stage I with 209 cases, stage II with 235 cases, and stage III with 394 cases. All patients received curative surgery. There were 296 patients evaluated as cT3, cT4 and any T with N+ received preoperative radiotherapy. 5.4% patients got pathological complete response (16/296), and the recurrence rate was 4.7% (14/296). After a median time of 41.7 months (range 4.1 to 144.0 months) follow-up, the 5-year overall survival rate in stage 0 to I of was 91.0%, stage II 86.2%, and stage III 60.0%, with a significant difference (P=0.000). The cumulative local recurrence rate was 4.8% (41/856), of which 70.7% (29/41) occurred within 3 years postoperatively, 97.6% (40/41) in 5 years. The cumulative distant metastasis rate was 16.4% (140/856), of which 82.9% (129/140) occurred within 3 years postoperatively, 96.4% (135/140) in 5 years. The incidence of abnormal imaging findings was significantly higher in pulmonary than liver and other sites metastases (75.0% vs. 21.7%, χ² =25.691, P=0.000). The incidence of CEA elevation was significantly higher in liver than lung and other sites metastases (56.8% vs. 37.8%, χ² =25.691, P=0.000). Multivariable analysis showed that age (P=0.015, HR=1.385, 95% CI: 1.066 to 1.801), surgical approach (P=0.029, HR=1.337, 95% CI: 1.030 to 1.733), differentiation (P=0.000, HR=1.535, 95% CI: 1.222 to 1.928), TNM stage (P=0.000, HR=1.349, 95% CI: 1.260 to 1.444) and lymphovascular invasion (P=0.001, HR=1.715, 95% CI: 1.258 to 2.342) are the independent prognostic factors for rectal cancer. CONCLUSIONS: Age, surgical approach, differentiation, TNM stage and lymphovascular invasion are independent prognostic factors for rectal cancer. Preoperative evaluation and combined modality therapy can significant reduce the local recurrence and improve overall survival for rectal cancer patients.

MicroRNA-181a promotes tumor growth and liver metastasis in colorectal cancer by targeting the tumor suppressor WIF-1.

BACKGROUND: Given the emerging role of microRNA in tumor disease progression, we investigated the association between microRNA expression, liver metastasis and prognosis of colorectal cancer. METHODS: Colorectal cancer tissues from patients with or without liver metastases were profiled to identify differentially expressed microRNA. Expression profile was further assessed using quantitative reverse transcription PCR and in situ hybridization. Correlation between miR-181a expression, the most differentially expressed microRNA, between patients with and without liver metastasis, and its downstream target genes were investigated using qRT-PCR. Luciferase reporter assay was conducted to establish functional association between miR-181a and its target genes. Manipulation of miR-181a expression and its consequences in tumor growth and metastasis were demonstrated in various in vitro and in vivo models. RESULTS: miR-181a was revealed being the most elevated in CRC with liver metastases. miR-181a expression correlated with advanced stage, distant metastasis, and served as an independent prognostic factor of poor overall survival. Stable transfection of CRC cell lines with miR-181a promoted cell motility and invasion, as well as tumor growth and liver metastasis,while silencing its expression resulted in reduced migration and invasion. Additionally, we identified WIF-1 as direct and functional targets of miR-181a. Ectopic expression of miR-181a suppressed the epithelial markers E-cadherin and ß-catenin, while enhanced the mesenchymal markers vimentin. CONCLUSION: Our data demonstrate that miR-181a expression is associated with CRC liver metastasis and survival. miR-181a has strong tumor-promoting effects through inhibiting the expression of WIF-1, and its potential role in promoting epithelial-mesenchymal transition.

Expression of HER-2 in rectal cancers treated with preoperative radiotherapy: a potential biomarker predictive of metastasis.

BACKGROUND: Evidence suggests HER-2 overexpression may be predictive of prognosis in colorectal cancer patients, though this remains controversial. OBJECTIVES: This study was performed to assess the prognostic value of HER-2 expression in locally advanced rectal cancer patients after preoperative radiotherapy. PATIENTS AND METHODS: HER-2 expression was evaluated based on immunohistochemical (IHC) staining of resected specimens from 142 mid-to-low rectal cancer patients. Fluorescence in situ hybridization (FISH) was performed to confirm HER-2 overexpression in samples with an IHC score of 2+. Tumor regression grading (TRG) of the primary tumors was determined semiquantitatively using a tumor regression grading scheme advocated in the AJCC Cancer Staging Manual 7 edition. RESULTS: When the total staining intensity was evaluated, 106 samples (74.6%) showed barely-perceptible positivity (0-1+; HER-2--negative), 15 samples (10.6%) showed moderate positivity (2+) and 21 samples (14.8%) showed strong positivity (3+, HER-2 positive). FISH confirmed that 2 cases showing moderate HER-2 positivity (2+) overexpressed HER2. There was no significant difference between the HER-2 positive and -negative groups with respect to age, gender, TRG, TNM stage, downstaging status, lymphovascular invasion or tumor differentiation. A significant correlation was found between HER-2 overexpression and the incidence of distant metastasis (p = 0.005). Subgroup analysis revealed this correlation was not significant (p = 0.247) in the radiation-insensitive (TRG0-2) subgroup, whereas a significant correlation (p = 0.026) between HER-2 overexpression and distant metastasis was found in the radiation-resistant (TRG3) subgroup. Multivariate analysis identified ypN stage (OR = 0.473, p = 0.002)and overexpression of HER-2 (OR = 3.704, p = 0.008) as independent risk factors for distant metastasis. There was no correlation between HER-2 overexpression and disease-free survival or overall survival among the study population. LIMITATIONS: We reported that HER-2 overexpression was correlated with distant metastasis in rectal cancer patients, especially in the radiation-insensitive group. However, there are certain limitations. First, this study was limited due to the fact that the number of rectal patients enrolled was only 142, which is relatively small. Second, HER-2 expression was measured by IHC with a positive ratio around 15%, which is fairly high according to the literature. Also, we collected the tissue samples preoperatively. It would be interesting to know the HER-2 expression levels pre- and postradiotherapy, as well as their correlation with local recurrence or distant metastasis. Finally, in rectal cancer patients, there is little information published on HER-2 and its role in tumor progression and metastasis. Therefore, we are pursuing the regulatory molecule underlined. CONCLUSIONS: HER-2 is overexpressed in around 15% of rectal cancer patients who receive neoadjuvant radiotherapy. Moreover, HER-2 overexpression could be a predictive biomarker of distant metastasis in rectal cancer patients after preoperative radiotherapy, especially patients showing a poor response to neoadjuvant radiotherapy.

Dislocation Does Not Seem To Be an Absolute Factor Effecting the Short- to Medium-Term Poor Prognosis of Patients with Acetabular Posterior Wall Fracture.

Dislocation is a complication of acetabular fractures involving the posterior wall, but whether dislocation is an absolute factor impacting the short- to medium-term prognosis of the hip joint remains controversial. This study aimed to compare the short- to medium-term clinical and radiological results among patients diagnosed with an acetabular fracture involving the posterior wall, with or without dislocation.Seventy-nine patients diagnosed with an acetabular fracture involving the posterior wall were retrospectively divided into posterior dislocation and non-dislocation groups. All fractures were open reduction + internal fixation with a plate screw combination through the single Kocher-Langenbeck approach. The short- to medium-term radiographic outcomes of follow-up were evaluated using the Matta radiologic grading system, while the clinical outcomes were evaluated using the modified Merle d'Aubigné-Postel evaluation system.The mean follow-up duration for all patients was 43.90 (range 24-75) months. Both groups achieved similar short- to medium-term clinical and radiographic results. There seems to be no significant differences between the two groups regarding the short- to medium-term assessment of clinical and radiographic results and the occurrence of postoperative complications (p > 0.05).In patients with acetabular fractures involving the posterior wall, hip dislocation is probably not an absolute determinant of a poor outcome. Even with early reduction, the short- to medium-term prognosis results appear similar to those of patients without dislocation.

Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer.

Importance: Total neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown. Objectives: To evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy. Design, Setting, and Participants: This cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022. Interventions: Participants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine. Main Outcomes and Measures: The primary end point was pathologic complete response rate. Results: Of 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy. Conclusions and Relevance: This study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

The LANCET robotic system can improve surgical efficiency in total hip arthroplasty: A prospective randomized, multicenter, parallel-controlled clinical trial.

Objective: To evaluate the accuracy and safety of the LANCET robotic system, a robot arm assisted operation system for total hip arthroplasty via a multicenter clinical randomized controlled trial. Methods: A total of 116 patients were randomized into two groups: LANCET robotic arm assisted THA group (N = 58) and the conventional THA group (N = 58). General information about the patients was collected preoperatively. Operational time and bleeding were recorded during the surgery. The position of the acetabular prosthesis was evaluated by radiographs one week after surgery and compared with preoperative planning. Harris score, hip mobility, prosthesis position and angle and complications were compared between the two groups at three months postoperatively. Results: None of the 111 patients who ultimately completed the 3-month follow-up experienced adverse events such as hip dislocation and infection during follow-up. In the RAA group, 52 (92.9 %) patients were located in the Lewinnek safe zone and 49 (87.5 %) patients were located in the Callanan safe zone. In the control group were 47 (85.5 %) and 44 (80.0 %) patients, respectively. In the RAA group, 53 (94.6 %) patients had a postoperative acetabular inclination angle and 51 (91.1 %) patients had an acetabular version angle within a deviation of 5° from the preoperative plan. These numbers were significantly higher than those of the control group, which consisted of 42 (76.4 %) and 34 (61.8 %) patients respectively. There were no significant differences between the two groups of subjects in terms of general condition, intraoperative bleeding, hip mobility, and adverse complications. Conclusion: The results of this prospective randomized, multicenter, parallel-controlled clinical study demonstrated that the LANCET robotic system leads conventional THA surgery in accuracy of acetabular cup placement and does not differ from conventional THA surgery in terms of postoperative hip functional recovery and complications. The translational potential of this article: In the past, the success rate of total hip arthroplasty (THA) relied heavily on the surgeon's experience. As a result, junior doctors needed extensive training to become proficient in this technique. However, the introduction of surgical robots has significantly improved this situation. By utilizing robotic assistance, both junior and senior doctors can perform THA quickly and efficiently. This advancement is crucial for the widespread adoption of THA, as patients can now receive surgical treatment in local facilities instead of overwhelming larger hospitals and straining medical resources. Moreover, the development of surgical robots with fully independent intellectual property rights holds immense value in overcoming the limitations of high-end medical equipment. This aligns with the objectives outlined in the 14th Five Year Plan for National Science and Technology Strategy.

Prognostic role of serum AZGP1, PEDF and PRDX2 in colorectal cancer patients.

This study was designed to develop novel and better reliable serum prognostic biomarkers for colorectal cancer (CRC). A 50 sample set including CRC, adenoma and healthy control sera was used to identify the serum proteins involved in CRC carcinogenesis using serum proteomic approach. Alpha-2-glycoprotein 1, zinc-binding (AZGP1), pigment epithelium derived factor (PEDF) and peroxiredoxin 2 (PRDX2) were selected as good candidates. Two independent cohorts of 868 individuals were enrolled. The expression of selected proteins in serum from cohort 1 (n = 534) was quantified with enzyme-linked immunosorbent assays. CRC sera of this cohort (n = 405) were assigned to training and test sets, which were used to identify and verify the prognostic markers. The prognostic values of identified proteins were further validated in cohort 2 (n = 334) using quantitative reverse transcription PCR and immunohistochemical staining. Our data showed that the elevated AZGP1 and decreased PEDF and PRDX2 expressions in CRC serum and tissues were correlated with liver metastases. In the training set, higher AZGP1 and lower PEDF levels in sera were significantly associated with a poorer overall survival (OS), higher AZGP1 was also associated with a poorer disease-free survival (DFS). This association was verified in the testing set and further validated in patients in cohort 2. Patients with lower PEDF or PRDX2 levels in their CRC tissues had a significantly poorer DFS or OS than patients with high levels of these proteins in cohort 2. Univariate and multivariate analyses indicated that the prognostic performance of serum AZGP1 and PEDF was independent of other clinicopathological factors. We propose that they may serve as prognostic markers and potential therapeutic targets in CRC.

The expression of chemokine receptors CCR6, CXCR2 and CXCR4 is not organ-specific for distant metastasis in colorectal cancer: a comparative study.

AIMS: The liver and lung are the organs most commonly affected by metastasis in colorectal cancer (CRC), and the interaction of chemokines and chemokine receptors (CKRs) plays an important role in the metastatic process. The aim of this study was to investigate the organ specificity of CKRs in CRC distant metastasis. METHODS AND RESULTS: Surgical specimens of primary tumours from 46 patients with metachronous distant metastases were retrieved retrospectively (20 lung metastases; 26 liver metastases). As a control, the records of 29 patients without distant metastases were randomly retrieved from our database, and their specimens were reassessed. The expression rates of CKRs, including CCR6, CXCR2, and CXCR4, were determined by immunohistochemistry, and were compared among the groups. The expression rates of CCR6 and CXCR2 were both significantly higher in the metastasis group than in the non-metastasis group (P < 0.05), but there was no statistical difference between the lung metastasis and liver metastasis subgroups. The expression of CXCR4 was not significantly different between the metastasis and non-metastasis groups. Multivariable analysis suggested that preoperative serum carcinoembryonic antigen level, CCR6 and CXCR2 were independent factors associated with distant metastasis. CONCLUSIONS: The expression of CCR6 and CXCR2 in CRC could predict metachronous distant metastasis, but they have no organ specificity for metastasis.

Anesthetic management of a patient with preoperative R-on-T phenomenon undergoing laparoscopic-assisted sigmoid colon resection: A case report.

BACKGROUND: The R-on-T phenomenon is a malignant arrhythmia associated with potentially catastrophic consequences. It may initiate ventricular tachycardia or ventricular fibrillation, which can result in syncope or sudden cardiac death. This manifestation poses a great challenge for anesthesiologists. However, it is rarely encountered in the perioperative setting. CASE SUMMARY: We herein present a case in which the R-on-T phenomenon was incidentally revealed by 24-h Holter monitoring in a patient diagnosed with sigmoid colon cancer. Careful evaluation and treatment with mexiletine were carried out preoperatively under consultation with a cardiovascular specialist, and surgery was uneventfully performed under general anesthesia after thorough preparation. CONCLUSION: Physicians should be vigilant about this infrequent but potentially fatal arrhythmia. Our experience suggests that the anesthetic process can be greatly optimized with careful preparation.