From pixels to patient care: deep learning-enabled pathomics signature offers precise outcome predictions for immunotherapy in esophageal squamous cell cancer.

BACKGROUND: Immunotherapy has significantly improved survival of esophageal squamous cell cancer (ESCC) patients, however the clinical benefit was limited to only a small portion of patients. This study aimed to perform a deep learning signature based on H&E-stained pathological specimens to accurately predict the clinical benefit of PD-1 inhibitors in ESCC patients. METHODS: ESCC patients receiving PD-1 inhibitors from Shandong Cancer Hospital were included. WSI images of H&E-stained histological specimens of included patients were collected, and randomly divided into training (70%) and validation (30%) sets. The labels of images were defined by the progression-free survival (PFS) with the interval of 4 months. The pretrained ViT model was used for patch-level model training, and all patches were projected into probabilities after linear classifier. Then the most predictive patches were passed to RNN for final patient-level prediction to construct ESCC-pathomics signature (ESCC-PS). Accuracy rate and survival analysis were performed to evaluate the performance of ViT-RNN survival model in validation cohort. RESULTS: 163 ESCC patients receiving PD-1 inhibitors were included for model training. There were 486,188 patches of 1024*1024 pixels from 324 WSI images of H&E-stained histological specimens after image pre-processing. There were 120 patients with 227 images in training cohort and 43 patients with 97 images in validation cohort, with balanced baseline characteristics between two groups. The ESCC-PS achieved an accuracy of 84.5% in the validation cohort, and could distinguish patients into three risk groups with the median PFS of 2.6, 4.5 and 12.9 months (P < 0.001). The multivariate cox analysis revealed ESCC-PS could act as an independent predictor of survival from PD-1 inhibitors (P < 0.001). A combined signature incorporating ESCC-PS and expression of PD-L1 shows significantly improved accuracy in outcome prediction of PD-1 inhibitors compared to ESCC-PS and PD-L1 anlone, with the area under curve value of 0.904, 0.924, 0.610 for 6-month PFS and C-index of 0.814, 0.806, 0.601, respectively. CONCLUSIONS: The outcome supervised pathomics signature based on deep learning has the potential to enable superior prognostic stratification of ESCC patients receiving PD-1 inhibitors, which convert the images pixels to an effective and labour-saving tool to optimize clinical management of ESCC patients.

Fabrication Methods of Continuous Pure Metal-Organic Framework Membranes and Films: A Review.

Metal-organic frameworks (MOFs) have drawn intensive attention as a class of highly porous, crystalline materials with significant potential in various applications due to their tunable porosity, large internal surface areas, and high crystallinity. This paper comprehensively reviews the fabrication methods of pure MOF membranes and films, including in situ solvothermal synthesis, secondary growth, electrochemical deposition, counter diffusion growth, liquid phase epitaxy and solvent-free synthesis in the category of different MOF families with specific metal species, including Zn-based, Cu-based, Zr-based, Al-based, Ni-based, and Ti-based MOFs.

Outcome-Supervised Deep Learning on Pathologic Whole Slide Images for Survival Prediction of Immunotherapy in Patients with Non-Small Cell Lung Cancer.

Although programmed death-(ligand) 1 (PD-(L)1) inhibitors are marked by durable efficacy in patients with non-small cell lung cancer (NSCLC), approximately 60% of the patients still suffer from recurrence and metastasis after PD-(L)1 inhibitor treatment. To accurately predict the response to PD-(L)1 inhibitors, we presented a deep learning model using a Vision Transformer (ViT) network based on hematoxylin and eosin (H&E)-stained specimens of patients with NSCLC. Two independent cohorts of patients with NSCLC receiving PD-(L)1 inhibitors from Shandong Cancer Hospital and Institute and Shandong Provincial Hospital were enrolled for model training and external validation, respectively. Whole slide images (WSIs) of H&E-stained histologic specimens were obtained from these patients and patched into 1024 × 1024 pixels. The patch-level model was trained based on ViT to identify the predictive patches, and patch-level probability distribution was performed. Then, we trained a patient-level survival model based on the ViT-Recursive Neural Network framework and externally validated it in the Shandong Provincial Hospital cohort. A total of 291 WSIs of H&E-stained histologic specimens from 198 patients with NSCLC in Shandong Cancer Hospital and 62 WSIs from 30 patients with NSCLC in Shandong Provincial Hospital were included in the model training and validation. The model achieved an accuracy of 88.6% in the internal validation cohort and 81% in the external validation cohort. The survival model also remained a statistically independent predictor of survival from PD-(L)1 inhibitors. In conclusion, the outcome-supervised ViT-Recursive Neural Network survival model based on pathologic WSIs could be used to predict immunotherapy efficacy in patients with NSCLC.

Impact of nab-paclitaxel plus PD-1/PD-L1 inhibitor on chemorefractory relapsed small-cell lung cancer.

Background: The present study evaluated the efficacy and safety of nab-paclitaxel (nab-PTX) with a concurrent PD-1/PD-L1 inhibitor in patients with refractory relapsed small-cell lung cancer (SCLC). Patients & methods: We retrospectively analyzed 240 patients with refractory relapsed SCLC: 40 patients were treated with nab-PTX plus PD-1/PD-L1 inhibitor, and 200 received traditional chemotherapy. Results: Median progression-free survival in the nab-PTX plus PD-1/PD-L1 inhibitor and traditional chemotherapy groups was 3.6 and 2.5 months (p = 0.0021), respectively. The median overall survival was 8.0 and 5.2 months (p = 0.0002), respectively. No new safety issues were identified. Conclusion: Nab-PTX plus PD-1/PD-L1 inhibitor significantly improved survival in patients with refractory relapsed SCLC compared with traditional chemotherapy.

Most patients with refractory relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival rates. This study analyzed the clinical outcomes and safety profiles of patients treated with nab-paclitaxel (nab-PTX) plus PD-1/PD-L1 inhibitor compared with patients treated with conventional chemotherapy. Notably, treatment with nab-paclitaxel and PD-1/PD-L1 inhibitor was associated with more favorable clinical outcomes, including better overall response and disease control rates, as well as longer overall survival and progression-free survival. In terms of side effect profiles, the two groups were balanced and had a similar incidence of grade ≥3 adverse events, including depleted blood cells and hair loss. To the best of our knowledge, we are the first to report the use of nab-PTX plus PD-1/PD-L1 inhibitor in the treatment of refractory relapsed SCLC. In addition, nab-PTX plus PD-1/PD-L1 inhibitor showed more effective antitumor activity in patients with secondary tumors in the liver, further confirming that nab-PTX plus PD-1/PD-L1 inhibitor is effective for patients with refractory relapsed SCLC.

Inactivation of Ihh in Sp7-Expressing Cells Inhibits Osteoblast Proliferation, Differentiation, and Bone Formation, Resulting in a Dwarfism Phenotype with Severe Skeletal Dysplasia in Mice.

Indian hedgehog (Ihh) is an indispensable paracrine factor for proper tissue patterning, skeletogenesis, and cellular proliferation. Recent genetic studies have revealed critical roles of chondrocyte-derived Ihh in regulating chondrocyte proliferation, hypertrophy and cartilage ossification. However, the functions of Sp7-expressing cell-derived Ihh in osteoblast differentiation and bone formation remain unclear. Sp7 is an essential transcription factor for osteoblast differentiation. In the current study, we generated Sp7-iCre; Ihhfl/fl mice, in which the Ihh gene was specifically deleted in Sp7-expressing cells to investigate the roles of Ihh. Ihh ablation in Sp7-expressing cells resulted in a dwarfism phenotype with severe skeletal dysplasia and lethality at birth, but with normal joint segmentation. Sp7-iCre; Ihhfl/fl mice had fewer osteoblasts, almost no cortical and trabecular bones, smaller skulls, and wider cranial sutures. Additionally, the levels of osteogenesis- and angiogenesis-related genes, and of major bone matrix protein genes were significantly reduced. These results demonstrated that Ihh regulates bone formation in Sp7-expressing cells. Ihh deficiency in primary osteoblasts cultured in vitro inhibited their proliferation, differentiation, and mineralization ability, and reduced the expression of osteogenesis-related genes. Moreover, the deletion of Ihh also attenuated the Bmp2/Smad/Runx2 pathway in E18.5 tibial and primary osteoblasts. The activity of primary osteoblasts in mutant mice was rescued after treatment with rhBMP2. In summary, our data revealed that Ihh in Sp7-expressing cells plays an indispensable role in osteoblast differentiation, mineralization, and embryonic osteogenesis, further implicated that its pro-osteogenic role may be mediated through the canonical Bmp2/Smad/Runx2 pathway.

Gait Analysis of Bilateral Knee Osteoarthritis and Its Correlation with Western Ontario and McMaster University Osteoarthritis Index Assessment.

Background and objectives: Objective, accurate, and intuitive evaluation of knee joint function in patients with knee osteoarthritis (KOA) is important. This study aimed to clarify the gait characteristics of patients with bilateral KOA and their correlation with Western Ontario and McMaster University Osteoarthritis Index (WOMAC). Materials and Methods: 20 patients with bilateral KOA and 20 conditionally matched healthy individuals were enrolled in the experimental and control groups, respectively. Footscan and CODA motion gait analysis systems were used to analyse the gait parameters. Gait spatiotemporal parameters and knee joint motion parameters were collected. Weight-bearing balance and walking stability were assessed using discrete trends of relevant gait indicators. Patients in the experimental group were evaluated using WOMAC. Pearson's correlation analysis was performed on the gait data and WOMAC score data of the experimental group. Results: Velocity, cadence, step length, and stride length of the experimental group were significantly lower than those of the control group (p < 0.01). Step time and gait cycle were significantly greater in the experimental group than in the control group (p < 0.01). Total stance and double-stance times of the experimental group were significantly greater than those of the control group (p < 0.01), whereas the single-stance time was shorter than that of the control group (p < 0.01). The range of motion and maximum flexion angle in the experimental group were significantly lower than those in the control group (p < 0.01), and the minimum angle of knee extension was greater than that in the control group (p < 0.01). The discrete trend of weight-bearing balance and walking stability gait index in the experimental group was greater than that in the control group. The WOMAC score and gait analysis were significantly correlated (p < 0.05). Conclusions: The gait function of patients with KOA is significantly worse than that of normal people. The WOMAC scale and gait analysis can be used to assess KOA severity from different perspectives with good consistency.

Vibrational Approach to the Dynamics and Structure of Protein Amyloids.

Amyloid diseases, including neurodegenerative diseases such as Alzheimer's and Parkinson's, are linked to a poorly understood progression of protein misfolding and aggregation events that culminate in tissue-selective deposition and human pathology. Elucidation of the mechanistic details of protein aggregation and the structural features of the aggregates is critical for a comprehensive understanding of the mechanisms of protein oligomerization and fibrillization. Vibrational spectroscopies, such as Fourier transform infrared (FTIR) and Raman, are powerful tools that are sensitive to the secondary structure of proteins and have been widely used to investigate protein misfolding and aggregation. We address the application of the vibrational approaches in recent studies of conformational dynamics and structural characteristics of protein oligomers and amyloid fibrils. In particular, introduction of isotope labelled carbonyl into a peptide backbone, and incorporation of the extrinsic unnatural amino acids with vibrational moieties on the side chain, have greatly expanded the ability of vibrational spectroscopy to obtain site-specific structural and dynamic information. The applications of these methods in recent studies of protein aggregation are also reviewed.

How Does Masculinity Play a Protective Role for Gay Men? The Mediation Effect of Mindfulness Between Gender Role and Mental Distress.

Masculinity is validated as a protective factor in mental health for gay population. However, potential mediators between masculinity and mental health remain unclear. Mindfulness, as one of the individual's traits has been proved to play an essential role on mental health. Yet the correlation between mindfulness and masculinity has barely been examined, and whether mindfulness could serve as a key mediator to explain the protective effect masculinity bringing to mental health for gay men remains unknown. To test this hypothesis, we recruited 210 gay men in China to conduct online questionnaires containing scales of FFMQ, BSRI, DASS-21 and demographic features. Based on mediation analysis, we found among gay men, mindfulness significantly mediates the negative relationship between masculinity and stress (SIE (standardized indirect effect) = -.20, 95% CI [-.28 -.11]), anxiety (SIE = -.17, 95% CI [-.26 -.09]) and depression (SIE = -.20, 95% CI [-.29 -.11]). Furthermore, by decomposing sub-dimensions of mindfulness, we found both "describing" and "acting with awareness" exhibit significant mediation effects between masculinity and mental distress. We further found "being analytical", one key sub-dimension of masculinity, positively correlates with mindful describing (r = .369, p < .001). Our results indicate that trait mindfulness serves as a core mediator between masculinity and mental health, the key trait in masculinity (being analytical) closely connects with the essential element of mindfulness (describing) and low in masculinity might undermine gay men's abilities of acting with awareness (staying focused). Our findings may also shed light on developing gay men-aimed mindfulness-based clinical interventions.

[Meta-analysis of autologous bone grafts and bone substitute for the treatment of tibial plateau fractures].

OBJECTIVE: To explore clinical efficacy of autologous bone grafts and bone substitute for the treatment of tibial plateau fractures by Meta analysis. METHODS: Controlled clinical studies on autogenous bone transplantation and bone substitutes in treating tibial plateau fractures published on PubMed,Web of Science,CNKI,Wanfang and other databases from January 2005 to August 2022 were searched by computer. Literature screening and data extraction were performed according to randomized controlled trial(RCT),and the quality of RCT were evaluated by using intervention meta-analysis criteria in Cochrane manual. Meta-analysis of joint depression,secondary collapse rate of articular surface,blood loss,operative time and infection rate between two methods were performed by Rev Man 5.3 software. RESULTS: Seven RCT studies (424 patients) were included,296 patients in bone replacement group and 128 patients in autograft group. Operative time [MD=-16.79,95%CI(-25.72,-7.85),P=0.000 2] and blood loss[MD=-70.49,95%CI(-79.34,-61.65),P<0.000 01] between two groups had statistically differences,while joint depression[MD=-0.17,95%CI(-0.91,0.58),P=0.66],secondary collapse rate of joint surface[RR=-0.74, 95%CI(0.35,1.57),P=0.43],infection rate [RR=1.21,95%CI(0.31,4.70),P=0.78] between two groups had no differences. CONCLUSION: The effects of bone substitute and autograft for the treatment of tibial plateau fracture have similar effects in terms of joint depression,secondary articular surface collapse rate and infection rate. However,compared with autologous bone transplantation,bone replacement could reduce blood loss and shorten operation time.

A CNN model for early detection of pepper Phytophthora blight using multispectral imaging, integrating spectral and textural information.

BACKGROUND: Pepper Phytophthora blight is a devastating disease during the growth process of peppers, significantly affecting their yield and quality. Accurate, rapid, and non-destructive early detection of pepper Phytophthora blight is of great importance for pepper production management. This study investigated the possibility of using multispectral imaging combined with machine learning to detect Phytophthora blight in peppers. Peppers were divided into two groups: one group was inoculated with Phytophthora blight, and the other was left untreated as a control. Multispectral images were collected at 0-h samples before inoculation and at 48, 60, 72, and 84 h after inoculation. The supporting software of the multispectral imaging system was used to extract spectral features from 19 wavelengths, and textural features were extracted using a gray-level co-occurrence matrix (GLCM) and a local binary pattern (LBP). The principal component analysis (PCA), successive projection algorithm (SPA), and genetic algorithm (GA) were used for feature selection from the extracted spectral and textural features. Two classification models were established based on effective single spectral features and significant spectral textural fusion features: a partial least squares discriminant analysis (PLS_DA) and one-dimensional convolutional neural network (1D-CNN). A two-dimensional convolutional neural network (2D-CNN) was constructed based on five principal component (PC) coefficients extracted from the spectral data using PCA, weighted, and summed with 19-channel multispectral images to create new PC images. RESULTS: The results indicated that the models using PCA for feature selection exhibit relatively stable classification performance. The accuracy of PLS-DA and 1D-CNN based on single spectral features is 82.6% and 83.3%, respectively, at the 48h mark. In contrast, the accuracy of PLS-DA and 1D-CNN based on spectral texture fusion reached 85.9% and 91.3%, respectively, at the same 48h mark. The accuracy of the 2D-CNN based on 5 PC images is 82%. CONCLUSIONS: The research indicates that Phytophthora blight infection can be detected 48 h after inoculation (36 h before visible symptoms). This study provides an effective method for the early detection of Phytophthora blight in peppers.

Effect of longitudinal changes of cachexia on the efficacy and toxicity of immune checkpoint inhibitors in esophageal squamous cell cancer (ESCC) patients.

PURPOSE: Immune checkpoint inhibitors (ICIs) have enhanced survival in advanced esophageal squamous cell cancer (ESCC) patients, but their efficacy varies. Cachexia, characterized by muscle loss and significant weight loss, might influence ICI response. This study examines the relationship between cachexia's longitudinal changes and ICI outcomes in ESCC patients. METHODS: ESCC patients undergoing at least two ICI cycles from 2017 to 2021 were studied. Cachexia's baseline and evolving patterns during ICI treatment were observed. Kaplan-Meier and Cox regression analyses were used to assess cachexia's effect on ICI efficacy. Chi-square tests were used to determine cachexia's link to immune-related adverse effects (irAEs). RESULTS: Two hundred seventy-eight ICI-treated patients had a median progression-free survival (PFS) of 5.78 months and overall survival (OS) of 8.3 months. Pretreatment cachexia led to worse outcomes: PFS 7.87 versus 5.3 months, time to progression (TTP) 10.9 versus 6.1 months, and OS 14.3 versus 9.2 months. Irreversible cachexia showed the poorest results. Cachexia's changes weren't associated with irAEs. CONCLUSION: Baseline and evolving cachexia significantly impact ICI efficacy in ESCC patients. Continuous cachexia monitoring during ICI therapy is crucial for optimal ESCC management.

TSP-1 increases autophagy level in cartilage by upregulating HSP27 which delays progression of osteoarthritis.

This study aimed to determine whether Thrombospondin-1 (TSP-1) can be used as a biomarker to diagnose early osteoarthritis (OA) and whether it has a chondroprotective effect against OA. We examined TSP-1 expression in cartilage, synovial fluid, and serum at different time points after anterior cruciate ligament transection (ACLT) surgery in rats. Subsequently, TSP-1 was overexpressed or silenced to detect its effects on extracellular matrix (ECM) homeostasis, autophagy level, proliferation and apoptosis in chondrocytes. Adenovirus encoding TSP-1 was injected into the knee joints of ACLT rats to test its effect against OA. Combined with proteomic analysis, the molecular mechanism of TSP-1 in cartilage degeneration was explored. Intra-articular injection of an adenovirus carrying the TSP-1 sequence showed chondroprotective effects against OA. Moreover, TSP-1 expression decreases with OA progression and can effectively promote cartilage proliferation, inhibit apoptosis, and helps to sustain the balance between ECM anabolism and catabolism. Overexpression of TSP-1 also can increase autophagy by upregulating Heat Shock Protein 27 (HSP27, hspb1), thereby enhancing its effect as a stimulator of autophagy. TSP-1 is a hopeful strategy for OA treatment.

Efficacy and safety of anti-programmed death-1 antibody-based combination therapy in advanced or metastatic gastric or gastroesophageal junction cancer in Chinese patients: A real-world study.

PURPOSE: Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. METHODS: In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed. RESULTS: In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. CONCLUSIONS: Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.

Development and Validation of Nomograms for Predicting Pneumonia in Patients with COVID-19 and Lung Cancer.

Background: COVID-19 has spread worldwide, becoming a global threat to public health and can lead to complications, especially pneumonia, which can be life-threatening. However, in lung cancer patients, the prediction of pneumonia and severe pneumonia has not been studied. We aimed to develop effective models to assess pneumonia after SARS-CoV-2 infection in lung cancer patients to guide COVID-19 management. Methods: We retrospectively recruited 621 lung cancer patients diagnosed with COVID-19 via SARS-CoV-2 RT-PCR analysis in two medical centers and divided into training and validation group, respectively. Univariate and multivariate logistic regression analysis were used to identify independent risk factors of all-grade pneumonia and ≥ grade 2 pneumonia in the training group. Nomograms were established based on independent predictors and verified in the validation group. C-index, ROC curves, calibration curve, and DCA were used to evaluate the nomograms. Subgroup analyses in immunotherapy or thoracic radiotherapy patients were then conducted. Results: Among 621 lung cancer patients infected with SARS-CoV-2, 203 (32.7%) developed pneumonia, and 66 (10.6%) were ≥ grade 2. Multivariate logistic regression analysis showed that diabetes, thoracic radiotherapy, low platelet and low albumin at diagnosis of COVID-19 were significantly associated with all-grade pneumonia. The C-indices of the prediction nomograms in the training group and validation group were 0.702 and 0.673, respectively. Independent predictors of ≥ grade 2 pneumonia were age, KPS, thoracic radiotherapy, platelet and albumin at COVID 19 diagnosis, with C-indices of 0.811 and 0.799 in the training and validation groups. In the thoracic radiotherapy subgroup, 40.8% and 11% patients developed all-grade and ≥grade 2 pneumonia, respectively. The rates in the immunotherapy subgroup were 31.3% and 6.6%, respectively. Conclusion: We developed nomograms predicting the probability of pneumonia in lung cancer patients infected with SARS-CoV-2. The models showed good performance and can be used in the clinical management of COVID-19 in lung cancer patients. Higher-risk patients should be managed with enhanced protective measures and appropriate intervention.

Pulmonary sarcoidosis-like reactions induced by sintilimab in esophageal cancer: A case report.

RATIONALE: Esophageal cancer is one of the deadliest cancers in the world, with high incidence and mortality rates ranking among the top ten in China. The efficacy of conventional treatments is limited and often accompanied by severe adverse reactions, which results in unsatisfactory outcomes. The mechanism of immune checkpoint inhibitors (ICIs) is to activate cytotoxic T cells to kill tumor cells expressing tumor antigens. The application of ICIs has profoundly changed the mode of cancer treatment. However, the use of ICIs also induces a series of adverse reactions similar to autoimmune reactions, called immune-related adverse events (irAEs). Some ICIs can cause manifestations similar to those in the development of sarcoidosis, which are called sarcoidosis-like reactions or granulomatosis. PATIENT CONCERNS: We report a 50-year-old Chinese male patient. DIAGNOSES: The patient had been diagnosed with advanced esophageal squamous cell carcinoma , and was confirmed to have pulmonary sarcoidosis-like reactions associated with sintilimab, a human programmed cell death protein 1 (PD-1) inhibitor. INTERVENTIONS: The patient was administered corticosteroid treatment. OUTCOMES: After receiving steroid treatment, the patient's systemic and pulmonary symptoms improved rapidly. To our knowledge, this is the first report of pulmonary sarcoidosis-like reaction in a patient with esophageal squamous cell carcinoma. The patient then continued to receive 1 year of follow-up antitumor treatment after the appearance of lung pulmonary sarcoidosis-like reactions. The prognosis was good and the patient's condition is currently stable. LESSONS: The diagnosis of ICI-induced sarcoidosis often requires comprehensive evaluation through clinical, pathological, and radiological assessment. A subset of patients with sarcoidosis-like reactions may not require treatment unless there is organ dysfunction or severe clinical symptoms, and these reactions generally respond well to treatment. The occurrence of sarcoidosis-like reactions after immunotherapy is positively correlated with the long-term prognosis of cancer patients. However, this hypothesis requires larger prospective studies for validation.

Comparison of the Incidence Rate of Radiation Pneumonitis Observed in Patients with Advanced Lung Adenocarcinoma Treated with Simultaneous Thoracic Radiotherapy and 1G/2G/3G EGFR-TKIs.

Purpose: The present study aimed to evaluate the incidence rate of radiation pneumonitis (RP) in patients with advanced lung adenocarcinoma treated with first-generation (1G), second-generation (2G), or third-generation (3G) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with thoracic radiotherapy (TRT). Patients and Methods: Patients with advanced lung adenocarcinoma simultaneously treated with 1G/2G/3G EGFR-TKIs and TRT between 2015-2021 at Shandong Cancer Hospital and Institute were screened. The incidence rate of clinical and imaging RP was compared between the three groups. Results: A total of 200 patients treated with EGFR-TKIs were enrolled in this study, including 100 patients who were treated with 1G EGFR-TKIs, 50 patients who were treated with 2G EGFR-TKIs, and 50 patients who were treated with 3G EGFR-TKIs (patients matched in a 2:1:1 ratio for tumor characteristics). The overall incidence of clinical RP in the 1G, 2G, and 3G EGFR-TKI groups were 29%, 48%, and 28% (p=0.043), respectively, and that of imaging RP were 33%, 58%, and 36% (p=0.010), respectively. The incidence of RP with a clinical grade ≥3 in the three groups were 14%, 28%, and 12% (p=0.055), respectively, and that with an imaging grade ≥3 in the three groups were 11%, 32%, and 10% (p=0.002), respectively. The incidence of clinical RP was higher in the CFRT group than in the SBRT group, with an overall clinical grade of 38% vs 10% (p<0.001) and imaging grade of 46% vs 10% (p<0.001), respectively. In the multivariate analysis, only GTV volume was an independent predictive factor for all risks of clinical and imaging RP. V20 and grouping of 1G/2G/3G EGFR-TKIs were other independent predictive factors for the risk factors of RP for imaging grades. Conclusion: Compared with 2G EGFR-TKIs combined with TRT, 1G or 3G EGFR-TKIs combined with TRT achieved a lower incidence of RP.

Integrated multi-dimensional deep neural network model improves prognosis prediction of advanced NSCLC patients receiving bevacizumab.

Background: The addition of bevacizumab was found to be associated with prolonged survival whether in combination with chemotherapy, tyrosine kinase inhibitors or immune checkpoint inhibitors in the treatment landscape of advanced non-small cell lung cancer (NSCLC) patients. However, the biomarkers for efficacy of bevacizumab were still largely unknown. This study aimed to develop a deep learning model to provide individual assessment of survival in advanced NSCLC patients receiving bevacizumab. Methods: All data were retrospectively collected from a cohort of 272 radiological and pathological proven advanced non-squamous NSCLC patients. A novel multi-dimensional deep neural network (DNN) models were trained based on clinicopathological, inflammatory and radiomics features using DeepSurv and N-MTLR algorithm. And concordance index (C-index) and bier score was used to demonstrate the discriminatory and predictive capacity of the model. Results: The integration of clinicopathologic, inflammatory and radiomics features representation was performed using DeepSurv and N-MTLR with the C-index of 0.712 and 0.701 in testing cohort. And Cox proportional hazard (CPH) and random survival forest (RSF) models were also developed after data pre-processing and feature selection with the C-index of 0.665 and 0.679 respectively. DeepSurv prognostic model, indicated with best performance, was used for individual prognosis prediction. And patients divided in high-risk group were significantly associated with inferior PFS (median PFS: 5.4 vs 13.1 months, P<0.0001) and OS (median OS: 16.4 vs 21.3 months, P<0.0001). Conclusions: The integration of clinicopathologic, inflammatory and radiomics features representation based on DeepSurv model exhibited superior predictive accuracy as non-invasive method to assist in patients counseling and guidance of optimal treatment strategies.

Effectiveness of antibiotics loaded bone cement in primary total knee arthroplasty: A systematic review and meta-analysis.

INTRODUCTION: The application of antibiotics loaded bone cement (ALBC) in the revision of failed total knee arthroplasty (TKA) has been widely accepted to reduce risk of peri-prosthetic infection. However, the prophylactic use of ALBC in primary TKA remains controversial. This study was aimed to identify the prophylactic effect on peri-prosthetic infection and safety of ALBC in primary TKA. HYPOTHESIS: The application of ALBC could reduce the risk of peri-prosthetic infection in primary TKA. MATERIALS AND METHODS: Electronic platforms including PubMed, EMBASE, and CENTRAL were retrieved to identify studies comparing outcomes of prophylactic ALBC and plain cement in primary TKA. For outcomes reported as dichotomous variable and continuous variable, risk ratio (RR) and weighted mean difference (WMD) as well as their 95% confidence intervals (95% CI) were selected as the effect sizes for pooling. While for those outcomes reported the adjusted effect sizes such as odds ratio (OR, derived from multivariate logistic regression), and hazard ratio (HR, derived from multivariate COX proportional hazard model), the reported effect sizes were selected for pooling. RESULTS: A total of 17 studies with 2,074,844 patients (1,093,920 in ALBC group and 980,924 in plain cement group) were eligible for final inclusion. No significant difference was found between ALBC and plain cement groups both for the unadjusted (RR=1.02, 95% CI: 0.86∼1.21, p=0.832) and adjusted (OR=0.94, 95% CI: 0.76∼1.17, p=0.596) peri-prosthetic infection rate. ALBC application was related to significantly increased length of hospital stay (WMD=0.13, 95% CI: 0.10∼0.17, p<0.001). There was no significance on the difference of operation related adverse events between two groups (RR=1.31, 95% CI: 0.68∼2.52, p=0.420). Significantly increased risks of acute renal failure and readmission, and temporarily increased ototoxicity in ALBC group were reported in one of the primary study. DISCUSSION: There is no sufficient evidence supporting decreased peri-prosthetic infection rate with ALBC application in primary TKA. What's more, it must be taken into consideration about the safety and added cost of additional impregnated antibiotics. LEVEL OF EVIDENCE: III; meta-analysis.

Zinc finger protein 521 attenuates osteoarthritis via the histone deacetylases 4 in the nucleus.

To determine whether zinc finger protein 521 (Zfp521) has a chondroprotective effect by maintaining extracellular matrix (ECM) homeostasis to attenuate osteoarthritis (OA). In chondrocytes, Zfp521 was overexpressed or silenced to detect its effects on proliferation, apoptosis, and ECM homeostasis. Adenovirus encoding Zfp521 was injected into the knee joints of anterior cruciate ligament transection rats to test its efficacy against OA. Combined with proteomic analysis, the molecular mechanism of Zfp521 in cartilage degeneration was further explored. An intra-articular injection of adenovirus carrying a Zfp521 sequence showed a chondroprotective effect against OA. The molecular mechanism around Zfp521 was classified at the molecular, cellular, histological, and functional levels. It was reported that Zfp521 could effectively promote cartilage proliferation, inhibit apoptosis, and maintain the balance of anabolism and catabolism of ECM. Moreover, it was confirmed that Zfp521 exerted its effect better by upregulating histone deacetylases 4 (HDAC4) in the nucleus and was significantly weakened in the absence of HDAC4 in the nucleus. Overall, Zfp521 better exerts its efficacy against OA by increasing the HDAC4 content in the nucleus, making it a promising strategy for OA treatment.

α2-macroglobulin-rich serum as a master inhibitor of inflammatory factors attenuates cartilage degeneration in a mini pig model of osteoarthritis induced by "idealized" anterior cruciate ligament reconstruction.

Post-traumatic osteoarthritis is a special type of osteoarthritis and a common disease, with few effective treatments available. α2-Macroglobulin (α2M) is important to chondral protection in post-traumatic osteoarthritis. However, its injection into xenogeneic joint cavities involves safety hazards, limiting clinical applications. Exploring serum α2M-enriching strategies and the therapeutic effect and mechanism of α2M-rich serum (α2MRS) autologous joint injection to treat post-traumatic osteoarthritis has significant value. In the present study, a unique filtration process was used to obtain α2MRS from human and mini pig serum. We evaluated the potential of α2MRS in protecting against post-surgery cartilage degeneration. We identify the potential of α2MRS in reducing the expression of inflammatory cytokines and factors that hasten cartilage degeneration in post-operative conditions leading to post-traumatic osteoarthritis. The potential of α2MRS was analyzed in interleukin-1ß induced human chondrocytes and mini pig models. In the chondrocyte model, α2MRS significantly promoted human chondrocyte proliferation and reduced apoptosis and chondrocyte catabolic cytokine gene transcription and secretion. The anterior cruciate ligament autograft reconstruction model of mini pigs was randomized into groups, operated on, and injected with α2MRS or saline. The results showed that α2MRS injection significantly suppressed the levels of inflammatory factors, improved gait, and showed significantly lower cartilage degeneration than the groups that did not receive α2MRS injections. This study highlights the chondroprotective effects of α2MRS, elucidated its potential applications against cartilage degeneration, and could provide a basis for the clinical translation of α2MRS.