Multi-sequence generative adversarial network: better generation for enhanced magnetic resonance imaging images.

Introduction: MRI is one of the commonly used diagnostic methods in clinical practice, especially in brain diseases. There are many sequences in MRI, but T1CE images can only be obtained by using contrast agents. Many patients (such as cancer patients) must undergo alignment of multiple MRI sequences for diagnosis, especially the contrast-enhanced magnetic resonance sequence. However, some patients such as pregnant women, children, etc. find it difficult to use contrast agents to obtain enhanced sequences, and contrast agents have many adverse reactions, which can pose a significant risk. With the continuous development of deep learning, the emergence of generative adversarial networks makes it possible to extract features from one type of image to generate another type of image. Methods: We propose a generative adversarial network model with multimodal inputs and end-to-end decoding based on the pix2pix model. For the pix2pix model, we used four evaluation metrics: NMSE, RMSE, SSIM, and PNSR to assess the effectiveness of our generated model. Results: Through statistical analysis, we compared our proposed new model with pix2pix and found significant differences between the two. Our model outperformed pix2pix, with higher SSIM and PNSR, lower NMSE and RMSE. We also found that the input of T1W images and T2W images had better effects than other combinations, providing new ideas for subsequent work on generating magnetic resonance enhancement sequence images. By using our model, it is possible to generate magnetic resonance enhanced sequence images based on magnetic resonance non-enhanced sequence images. Discussion: This has significant implications as it can greatly reduce the use of contrast agents to protect populations such as pregnant women and children who are contraindicated for contrast agents. Additionally, contrast agents are relatively expensive, and this generation method may bring about substantial economic benefits.

Association of the Advanced Lung Cancer Inflammation Index (ALI) and Gustave Roussy Immune (GRIm) score with immune checkpoint inhibitor efficacy in patients with gastrointestinal and lung cancer.

OBJECTIVE: This study aimed to conduct a comprehensive analysis, evaluating the prognostic significance of the baseline Advanced Lung Cancer Inflammation Index (ALI) and Gustave Roussy Immune (GRIm) Score in patients undergoing immune checkpoint inhibitor (ICI) therapy. METHODS: A comprehensive search was performed across various databases, including PubMed, the Cochrane Library, EMBASE, and Google Scholar, until October 21, 2023, to compile relevant articles for analysis. The investigation encompassed diverse clinical outcomes, including overall survival (OS) and progression-free survival (PFS). RESULTS: This analysis included a total of 15 articles, comprising 19 studies involving 3335 patients. Among the 19 studies, nine studies focused on NSCLC, and six studies were conducted on HCC. Pooled results revealed that patients with elevated ALI levels experienced prolonged OS (HR: 0.51, 95% CI: 0.37-0.70, p < 0.001) and extended PFS (HR: 0.61, 95% CI: 0.52-0.72, p < 0.001). Furthermore, a GRIm score > 1 was associated with reduced OS (HR: 2.07, 95% CI: 1.47-2.92, p < 0.001) and diminished PFS (HR: 1.78, 95% CI: 1.35-2.34, p < 0.001) in cancer patients receiving ICIs. Subgroup analysis indicated that ALI cutoff values of 18 exhibited enhanced predictive potential. Additionally, for HCC patients, those with HCC-GRIm score > 2 showed a substantially decreased risk of mortality compared to individuals with HCC-GRIm score ≤ 2 (HR: 2.63, 95% CI: 1.89-3.65, p < 0.001). CONCLUSION: The ALI and GRIm score served as dependable prognostic indicators for patients undergoing ICI therapy in the context of cancer treatment.

Diagnostic value of procalcitonin in patients with periprosthetic joint infection: a diagnostic meta-analysis.

Background: The success rate of periprosthetic joint infection (PJI) treatment is still low. Early diagnosis is the key to successful treatment. Therefore, it is necessary to find a biomarker with high sensitivity and specificity. The diagnostic value of serum procalcitonin (PCT) for PJI was systematically evaluated to provide the theoretical basis for clinical diagnosis and treatment in this study. Methods: We searched the Web of Science, Embase, Cochrane Library, and PubMed for studies that evaluated the diagnostic value of serum PCT for PJI (from the inception of each database until September 2020). Two authors independently screened the literature according to the inclusion and exclusion criteria. The quality of each selected literature was evaluated by using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) tool. RevMan 5.3 software was used for the quality evaluation. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were merged by using Meta-DiSc 1.4 software. The area under the curve (AUC) and Q index were calculated after the summary receiver operating characteristic (SROC) was generated. We also performed subgroup analysis. Results: A total of 621 patients were enrolled in the nine studies. The pooled sensitivity of serum PCT for PJI diagnosis was 0.441 [95% confidence interval (CI), 0.384-0.500], the pooled specificity was 0.852 (95% CI, 0.811-0.888), the pooled PLR was 2.271 (95% CI, 1.808-2.853), the pooled NLR was 0.713 (95% CI, 0.646-0.786), and the pooled DOR was 5.756 (95% CI, 3.673-9.026). The area under SROC (the pooled AUC) was 0.76 (0.72-0.79). Q index was 0.6948. Conclusion: This study showed that PCT detection of PJI had poor diagnostic accuracy. Hence, the serum PCT is not suitable as a serum marker for PJI diagnosis.

Integrated metabolomics revealed the photothermal therapy of melanoma by Mo2C nanosheets: toward rehabilitated homeostasis in metabolome combined lipidome.

Melanoma, the most aggressive and life-threatening form of skin cancer, lacks innovative therapeutic approaches and deeper bioinformation. In this study, we developed a photothermal therapy (PTT) based on Mo2C nanosheets to eliminate melanoma while utilizing integrated metabolomics to investigate the metabolic shift of metabolome combined lipidome during PTT at the molecular level. Our results demonstrated that 1 mg ml-1 Mo2C nanosheets could efficiently convert laser energy into heat with a strong and stable photothermal effect (74 ± 0.9 °C within 7 cycles). Furthermore, Mo2C-based PTT led to a rapid decrease in melanoma volume (from 3.299 to 0 cm2) on the sixth day, indicating the effective elimination of melanoma. Subsequent integrated metabolomics analysis revealed significant changes in aqueous metabolites (including organic acids, amino acids, fatty acids, and amines) and lipid classes (including phospholipids, lysophospholipids, and sphingolipids), suggesting that melanoma caused substantial fluctuations in both metabolome and lipidome, while Mo2C-based PTT helped improve amino acid metabolism-related biological events (such as tryptophan metabolism) impaired by melanoma. These findings suggest that Mo2C nanosheets hold significant potential as an effective therapeutic agent for skin tumors, such as melanoma. Moreover, through exploring multidimensional bioinformation, integrated metabolomics technology provides novel insights for studying the metabolic effects of tumors, monitoring the correction of metabolic abnormalities by Mo2C nanosheet therapy, and evaluating the therapeutic effect on tumors.

Bone Healing and Clinical Outcome Following Medial Opening-wedge High Tibial Osteotomy Using Wedge-Shaped Cancellous Allograft.

OBJECTIVE: Medial opening-wedge high tibial osteotomy (MOWHTO) is considered to be an effective treatment for symptomatic knee osteoarthritis (KOA) of isolated the medial compartment with varus alignment of the lower extremity. However, the choice of material to fill the void remains controversial. This study aims to evaluate the bone union of the osteotomy gap using a novel wedge-shaped cancellous allograft after MOWHTO and its effect on clinical outcomes. METHODS: All patients who underwent MOWHTO using a novel wedge-shaped cancellous allograft combined with TomoFix locking compression plate (LCP) fixation between January 2016 and July 2020 were enrolled. The radiographic parameters including hip-knee-ankle angle (HKAA), medial proximal tibial angle (MPTA), femorotibial angle (FTA) and posterior tibial slope angle (PTSA) were measured between pre-operative and post-operative radiographs. Knee Society score (KSS) and range of motion (ROM) were assessed preoperatively and at last follow-up. Patients included in this study were divided into two groups according to the correction angle: small correction group (< 10°; SC group) and large correction group (≥ 10°; LC group). The modified Radiographic Union score for tibial fractures (mRUST) was used to assess the difference in bone healing between the two groups at 1, 3, 6, and 12 months postoperatively and at the final follow-up. A paired student's t test was conducted for comparison of differences of the relevant data pre-operatively and post-operatively. RESULTS: A total of 82 patients (88 knees) were included in this study. The HKAA, MPTA, FTA and PTSA increased from -6.4° ± 3.0°, 85.1° ± 2.6°, 180.1° ± 3.2° and 7.7° ± 4.4° preoperatively to 1.2° ± 4.3° (p < 0.001), 94.4° ± 3.3° (p < 0.001), 171.0° ± 2.8° and 11.8° ± 5.8° (p < 0.001) immediately postoperatively, respectively. However, no significant statistic difference was found in above-mentioned parameters at last follow-up compared to immediate postoperative data (p > 0.05). All patients in this study achieved good bone healing at the final follow-up and no significant differences in mRUST scores were seen between the SC group and LC group. The KSS-Knee score and KSS-Function score improved significantly from 55.4 ± 3.7 and 63.3 ± 4.6 preoperatively to 86.4 ± 2.8 (p < 0.001) and 89.6 ± 2.9 (p < 0.001) at last follow-up, respectively. Nevertheless, there was no significant difference in ROM between pre-operation and last follow-up (p > 0.05). CONCLUSION: For MOWHTO, the wedge-shaped cancellous allograft was a reliable choice for providing good bone healing and clinical outcomes.

Proteomic Study on Multi-Organ Metastases of Human Ovarian Clear Cell Carcinoma Cell Line in a Xenograft Mouse Model Based on a Novel Sequence-Specific Analysis Strategy.

BACKGROUND: To investigate the gene regulation of tumor cells in the process of different organ metastasis on a xenograft mouse model and screen the genes involved in the organ-target metastasis of tumor cells. METHODS: A multi-organ metastasis model was constructed with a human ovarian clear cell carcinoma cell line (ES-2) based on a severe immunodeficiency mouse strain (NCG). Differentially expressed tumor proteins among multi-organ metastases were successfully characterized by microliter liquid chromatography-high-resolution mass spectrometry, sequence-specific data analysis and multivariate statistical data analysis. Liver metastases were selected as typical for subsequent bioinformatic analysis. Selected liver metastasis-specific genes in ES-2 cells were validated by sequence-specific quantitation including high resolution-multiple reaction monitoring quantification at protein level and quantitative real-time polymerase chain reaction at mRNA level. RESULTS: From the mass spectrometry data, a total of 4503 human proteins were identified using the sequence-specific data analysis strategy. Of them, 158 proteins were selected as specifically regulated genes in liver metastases for subsequent bioinformatics studies. Based on Ingenuity Pathway Analysis (IPA) pathway analysis and sequence-specific quantitation, Ferritin light chain (FTL), lactate dehydrogenase A (LDHA) and long-chain-fatty-acid-CoA ligase 1 (ACSL1) were finally validated as specifically upregulated proteins in liver metastases. CONCLUSIONS: Our work provides a new approach to analyze gene regulation in tumor metastasis in xenograft mouse model. In presence of a large number of mouse protein interference, we validated the up-regulation of human ACSL1, FTL and LDHA in ES-2 liver metastases, which reflects the adaptive regulation of tumor cells to the liver microenvironment through metabolic reprogramming.

The Prognostic Value of the GNRI in Patients with Stomach Cancer Undergoing Surgery.

Malnutrition often induces an adverse prognosis in cancer surgery patients. The elderly nutrition risk index (GNRI) is an example of the objective indicators of nutrition-related risks. We performed a meta-analysis to thoroughly examine the evidence for the GNRI in predicting the outcomes of patients undergoing stomach cancer surgery. Eligible articles were retrieved using PubMed, the Cochrane Library, EMBASE, and Google Scholar by 24 October 2022. The clinical outcomes were overall survival (OS), cancer-specific survival (CSS), and post-operative complications. A total of 11 articles with 5593 patients were included in this meta-analysis. The combined forest plot showed that for every unit increase in the preoperative GNRI score in patients with stomach cancer, their postoperative mortality was reduced by 5.6% (HR: 0.944; 95% CI: 0.933−0.956, p < 0.001). The pooled results also demonstrated that a low GNRI was correlated with poor OS (HR: 2.052; 95% CI: 1.726−2.440, p < 0.001) and CSS (HR: 1.684; 95% CI: 1.249−2.270, p = 0.001) in patients who underwent stomach cancer surgery. Postoperative complications were more likely to occur in patients with a low GNRI, as opposed to those with a high GNRI (OR: 1.768; 95% CI: 1.445−2.163, p < 0.001). There was no evidence of significant heterogeneity, and the sensitivity analysis supported the stability and dependability of the above results. the GNRI is a valuable predictor of long-term outcomes and complications in stomach cancer patients undergoing surgery.

CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy.

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.

Predictors and complications of blood transfusion in rheumatoid arthritis patients undergoing total joint arthroplasty.

PURPOSE: Our research investigated predictors of postoperative blood transfusion rate following total joint arthroplasty (TJA) in patients with rheumatoid arthritis (RA) and evaluated the incidence of complications in the transfusion group and non-transfusion group. METHODS: The authors retrospectively analyzed risk factors among 320 RA patients who underwent elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) from January 2010 to December 2018. Demographic characteristics, laboratory results, medication history, and surgical protocol were gathered from electronic medical records. Univariable and multivariable logistic regression analyses were conducted to measure the impact of relevant variables on the need for transfusions. In addition, we compared the incidence of complications associated with transfusion. RESULTS: The cohort comprised 320 RA patients, aged 57.4 ± 12.0 years, of whom 137 required postoperative blood transfusions and 183 did not. BMI, type of surgery, duration of surgery, disease activity score 28 (DAS28-CRP), tranexamic acid (TXA) administration, and preoperative hemoglobin (Hb) were all risk factors for transfusion after adjusting for the planned procedure. CONCLUSION: Previously published predictors, such as BMI, low preoperative hemoglobin, duration of surgery, procedure type (THA), were also identified in our analysis. Moreover, TXA administration and the DAS28-CRP showed the potential to influence risk. The incidence of postoperative complications was increased in patients who received blood transfusions compared to non-transfusion group. Our findings could help to identify RA patient population requiring blood transfusions, to ensure the necessary steps are adopted to limit blood loss and improve blood management strategies. Key Points • The risk factors for blood transfusion in rheumatoid arthritis patients undergoing total joint arthroplasty were BMI, the type of surgery, duration of surgery, TXA administration, DAS28-CRP, and preoperative hemoglobin. • The incidence of postoperative complications was increased in patients who received blood transfusions compared to non-transfusion group.

Research Status and Hotspots of Chronic Osteomyelitis: A Bibliometric and Visualized Analysis.

OBJECTIVE: The treatment of chronic osteomyelitis (COM) is extremely challenging for physicians and patients. It is of great significance to explore the research status, development trend and future research hotspots in the field of COM to promote the development of this field. This study is aimed to explore the global research status of COM and predict its future research hotspots based on bibliometric and visualized analysis. METHODS: Web of Science core collection database was used to search the related literature of COM from 1994 to 2020. All data were imported into Microsoft Excel 2019 for collation. Additionally, the literature quality of countries, authors, journals, and institutions is evaluated. The VOS viewer software was used for conducting co-analysis, co-citation analysis, and keyword co-occurrence analysis of literature to analyze the global status and predict the future hotspots of the COM field. RESULTS: A total of 726 articles were retrieved in this study. The number of global publications shows a trend of wave growth, but the increase is not significant. It is expected that the number of COM articles will remain at more than 50 per year in the next decade. The COM literature published in the United States (Publications = 160, H index = 37, average citations per item = 28.63) is of the highest quality. Girschick HJ (Publications = 16, H index = 14, average citations per item = 52.25) is the most contributed scholar in the field of COM. UNIV IOWA (Publications = 15, H index = 11, average citations per item = 57.27) and UNIV WURZBURG (Publications = 18, H index = 15, average citations per item = 47.5) are influential institutions in the field of COM. The results of co-occurrence analysis show that the field of COM can be roughly divided into the following five modules: COM surgical research, COM basic research, COM diagnosis-related research, chronic recurrent multifocal osteomyelitis (CRMO)-related research, risk factors of COM. Risk factors of COM are the module with the highest concentration of hot words. CONCLUSION: COM-related research will continue to develop further in the next decade. The diagnosis research and risk factors of COM are the most popular research modules in recent years. Some controversial or troubled issues including the efficacy of perforator flap and fascia flap covering soft tissue, searching exclusive detection methods for the diagnosis of COM and bisphosphonates and biological agents in the treatment of CRMO may lead to the development of the COM field.

The potential performance of serum albumin to globulin ratio, albumin and globulin in the diagnosis of periprosthetic joint infection and prediction of reinfection following reimplantation.

BACKGROUND: This study was conducted to evaluate the performance of serum albumin (ALB), globulin (GLO), and albumin to globulin ratio (AGR) in the diagnosis of PJI and prediction of reinfection following reimplantation in PJI patients who underwent two-stage revision. METHODS: We perform a retrospective data collection on identified patients who underwent revision arthroplasties in our institution from January 2010 to January 2020. A total of 241 patients were stratified into: group A (PJI), group B (aseptic loosening). Fifty-five patients who underwent two-stage revision in group A were assigned to group C. Group C was stratified into subgroup 1 (reinfection) and subgroup 2 (non-reinfection). Receiver operating characteristic curves were used to evaluate the utility of serum markers for diagnosing PJI and predicting reinfection following reimplantation. RESULTS: In the diagnosis of PJI, there were significant differences in the levels of ALB, GLO, and AGR between groups A and group B (P < 0.05). The AUC value of serum AGR (0.851) was similar to ESR (0.841) and CRP (0.866) (all p > 0.05). The AUC values of serum ALB and GLO were 0.757 and 0.753, respectively. As for predicting reinfection following reimplantation, the serum ALB in the non-reinfection group was higher than that in the reinfection group (p = 0.041). The AUC value of serum ALB was 0.7. CONCLUSION: AGR was promising adjunct marker for the diagnosis of PJI, similar to CRP and ESR. ALB and GLO have an acceptable value for the diagnosis of PJI. ALB may be expected to be a kind of effective marker for predicting reinfection following reimplantation.

A systematic review and meta-analysis comparing complications following total hip arthroplasty for systemic lupus erythematosus versus for non-systemic lupus erythematosus.

BACKGROUND: Osteonecrosis of the femoral head is one of the most severe complications in systemic lupus erythematosus (SLE) patients. Total hip arthroplasty (THA) is an effective treatment for femoral head necrosis. However, there is no consensus on the specific effect of THA on SLE patients. The objective of the present study was to review the current evidence regarding rates of THA complications and postoperative function in systemic lupus erythematosus. METHODS: Two independent reviewers searched PubMed, Cochrane Library, and EMBASE from January 1, 2000, to December 29, 2021. The primary outcomes were postoperative complications, including deep vein thrombosis (DVT), hematoma, wound infection, dislocation, periprosthetic fracture, revision, mortality. RESULTS: A total of 179 articles yielded 28 studies eligible for inclusion with 10 studies used for meta-analysis. This study found a statistically significant difference in DVT, dislocation, wound infection, periprosthetic fracture, and revision. CONCLUSIONS: This meta-analysis shows that SLE patients with THA are at an increased risk of DVT, wound infection, dislocation, periprosthetic fracture, revision, periprosthetic joint infection, following THA in comparison with non-SLE patients with THA. There was no adequate evidence to support the notion that the risk of seroma or hematoma following THA is increased in SLE. Also, there was no significant difference in HHS scores between SLE patients and non-SLE patients after THA.

Diagnostic accuracy of calprotectin in periprosthetic joint infection: a diagnostic meta-analysis.

BACKGROUND: Periprosthetic joint infection (PJI) is considered to be one of the most challenging complications of joint replacement, which remains unpredictable. As a simple and emerging biomarker, calprotectin (CLP) has been considered to be useful in ruling out PJI in recent years. The purpose of this study was to investigate the accuracy and sensitivity of CLP in the diagnosis of PJI. METHODS: We searched and screened the publications from PubMed, Web of Science, EMBASE, and Cochrane Library from database establishment to June 2021. Subsequently, Stata version 16.0 software was used to combine the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), operating characteristic curve, and area under the curve (AUC). Heterogeneity across articles was evaluated by the I2 statistics. Finally, sources of heterogeneity were detected by subgroup analysis based on study design, detection method, sample size, and cutoff values. RESULTS: A total of 7 studies were included in our study, comprising 525 patients. The pooled sensitivity, specificity, PLR, and NLR of CLP for PJI diagnosis were 0.94(95% CI 0.87-0.98), 0.93(95% CI 0.87-0.96), 13.65(95% CI 6.89-27.08), and 0.06(95% CI 0.02-0.15), respectively, while the DOR and AUC were 222.33(95% CI 52.52-941.11) and 0.98 (95% CI 0.96-0.99), respectively. CONCLUSION: Synovial CLP is a reliable biomarker and can be used as a diagnostic criterion for PJI in the future. However, the uncertainty resulting from the poor study numbers and sample sizes limit our ability to definitely draw conclusions on the basis of our study.

Study of arthroscopic superior capsule reconstruction in the treatment of irreparable rotator cuff tears.

Background: The objective of this study was to investigate the clinical outcome and radiographic findings after arthroscopic superior capsule reconstruction (ASCR) with a new augmented autograft technique for irreparable rotator cuff tears. Methods: Between 2018 and 2020, 11 patients whose shoulders had irreparable rotator cuff tears underwent ASCR using a fascia lata weaving mesh. Physical examination, radiography, and magnetic resonance imaging (MRI) were performed before surgery and the average follow-up was 20 months (18-24 months) after surgery. Clinical outcome scores were recorded. Results: Average clinical outcome scores improved significantly at the final follow-up, with 94.7 points scored on the American Shoulder and Elbow Surgeons scale (range, 85-100 points) and 34.5 points on the University of California, Los Angeles scale (33-35 points) (P < 0.05). Mean active elevation increased significantly from 30.1° to 150° (P < 0.05) and external rotation increased from 30° to 59.2° (P < 0.05). The acromiohumeral distance (AHD) increased from 3.9 ± 0.6 mm preoperatively to 10.1 ± 0.7 mm postoperatively (P < 0.05). No patient had graft tear or tendon retear during follow-up. Conclusions: ASCR with a new augmented autograft can restore the function of the shoulder joint with irreparable rotator cuff tears. Our results suggest that this reconstruction technique can help obtain good clinical and radiographic outcomes, which can provide a reliable method for the treatment of irreparable rotator cuff tears. Level of Evidence: Level IV, therapeutic case series.

Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding of and inability to accurately capture high-risk CRC patients who are most likely to recur. We aimed to improve high-risk classification by identifying biological pathways associated with outcome in adjuvant stage II/III CRC. METHODS AND FINDINGS: We included 1062 patients with stage III or high-risk stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT trial, and performed expression profiling to identify a prognostic signature. Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines were used to further validate the prognostic biology. Our retrospective analysis of the adjuvant AVANT trial uncovered a prognostic signature capturing three biological functions-stromal, proliferative and immune-that outperformed the Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like Oncotype Dx in an independent cohort. Importantly, within the immune component, high granzyme B (GZMB) expression had a significant prognostic impact while other individual T-effector genes were less or not prognostic. In addition, we found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic in a T cell independent fashion. A limitation of our study is that these results, although robust and derived from a large dataset, still need to be clinically validated in a prospective study. CONCLUSIONS: This work furthers our understanding of the underlying biology that propagates stage II/III CRC disease progression and provides scientific rationale for future high-risk stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable high-risk CRC. Our results also shed light on an alternative GZMB source with context-specific implications on the disease's unique biology.

Impact of intraoperative medial collateral ligament injury on outcomes after total knee arthroplasty: a meta-analysis and systematic review.

BACKGROUND: As an uncommon but severe complication, medial collateral ligament (MCL) injury in total knee arthroplasty (TKA) may be significantly under-recognized. We aimed to determine whether MCL injury influences postoperative outcomes of patients undergoing TKA. METHODS: Two independent reviewers searched PubMed, Cochrane Library, and EMBASE from their inception to July 1, 2021. The main outcomes were postoperative function, and secondary outcomes included the incidences of revision and complications. RESULTS: A total of 403 articles yielded 15 studies eligible for inclusion with 10 studies used for meta-analysis. This study found that there was a statistically significant difference in postoperative functional scores, range of motion (ROM), complications, and revision rates, with adverse outcomes occurring more commonly in patients with MCL injury. CONCLUSIONS: This meta-analysis highlights the complexity of MCL injury during TKA and shows the impact on postoperative function, joint mobility, complications, and revision. Surgeons need to prevent and put more emphasis on MCL injury during TKA.

Impact of Anti-HER2 Treatments Combined With Atezolizumab on the Tumor Immune Microenvironment in Early or Metastatic Breast Cancer: Results From a Phase Ib Study.

BACKGROUND: Despite advances, there continues to be unmet need in breast cancer. Combining anti-programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-cell-dependent cytolytic antitumor activity. METHODS: This open-label, phase Ib study evaluated the safety of atezolizumab-based combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2-positive (HER2+) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early-breast cancer (eBC) "window of opportunity" study, patients with operable HER2+ locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers. RESULTS: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components' individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8+ T-cell infiltration increased from baseline in HER2+ eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or T-DM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion. CONCLUSION: Atezolizumab with antibody-dependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2+ eBC tumors more than those with mBC tumors.

Reliability of circulating fibrinogen in the diagnosis of prosthesis-related infections: a systematic review and meta-analysis.

BACKGROUND: Fibrinogen (FIB) has recently been used as a biomarker to diagnose periprosthetic joint infection (PJI), but its reliability is still questionable. The aim of this study was to investigate the accuracy of FIB in the diagnosis of PJI after joint replacement. METHODS: We searched for literatures published in PubMed, EMBASE, and the Cochrane Library from the time of database inception to September 2020 and screened the studies according to the inclusion criteria. Then, we calculated the diagnostic parameters of FIB, including the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), area under the curve (AUC), and diagnostic odds ratio (DOR). In addition, we implemented subgroup analyses to identify the sources of heterogeneity. RESULTS: Seven studies including 1341 patients were selected in our meta-analysis. The pooled sensitivity, specificity, PLR, NLR, and DOR of FIB for PJI diagnosis were 0.78 (95% confidence interval [CI], 0.73-0.82), 0.83 (95% CI, 0.81-0.86), 4.60 (95% CI, 3.30-6.42), 0.24 (95% CI, 0.18-0.34), and 20.13 (95% CI, 14.80-27.36), respectively, while the AUC was 0.896. CONCLUSION: The present study indicated that FIB was a reliable detection method and might be introduced into the diagnostic criteria for PJI. However, more robust studies are still needed to confirm the current findings, because most of the included studies were retrospective and had small sample sizes.

Enrichment of circulating tumor-derived extracellular vesicles from human plasma.

Extracellular vesicles (EVs) are gaining considerable traction within the liquid biopsy arena, as carriers of information from cells in distant sites that may not be accessible for biopsy. Therefore, there is a need to develop methods to enrich for specific EV subtypes, based on their cells of origin. Here we describe the development of an automated method to enrich tumor-derived EVs from plasma using the CellSearch technology compared to Total EVs isolated using differential ultracentrifugation (DUC). We use a modified CellSearch protocol to enrich EpCAM+ EVs from the plasma of patients with non-small cell lung carcinoma (NSCLC) and triple negative breast cancer (TNBC). As a test case, we examined PD-L1, an immune checkpoint ligand known to be expressed in some tumor tissues, to demonstrate enrichment for EpCAM+ EVs. For this purpose, we developed two custom immunoassays utilizing the Simoa HD-1 analyzer (Quanterix) to detect PD-L1 in EVs and interrogate specific EV populations from human plasma. PD-L1 was present in Total EVs from the plasma of healthy individuals and cancer patients, since it is also expressed on several immune cells. However, EpCAM+ EVs were only detectable from the plasma of cancer patients, suggesting these are tumor-derived EVs. As low as 250 µL of plasma could be used to reliably detect PD-L1 from patient-derived EpCAM+ EVs. In summary, this report demonstrates the development of a robust tumor-derived EV enrichment method from human blood. Furthermore, this proof-of-concept study is extendable to other known cancer-specific proteins expressed on EVs exuded from tumors.

Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade.

The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti-PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy. SIGNIFICANCE: The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency-approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.This article is highlighted in the In This Issue feature, p. 1.