Enhancing regional control in p16-negative oropharyngeal cancer: A propensity score-matched analysis of upfront neck dissection and definitive chemoradiotherapy.

BACKGROUND: The presence of p16 and neck disease is important predictors of prognosis for oropharyngeal squamous cell carcinoma (OPSCC). Patients who are p16-negative and have clinically node-positive (cN+) disease generally have worse oncologic outcomes. This study aimed to investigate whether upfront neck dissection (UFND) could provide potential benefits for patients with cN+ p16-negative OPSCC. METHODS: Through this retrospective study, 76 patients with cN+ p16-negative OPSCC were analyzed, those who received either definite concurrent chemoradiotherapy (CCRT group) or UFND followed by chemoradiotherapy (UFND group). The primary endpoints were regional recurrence-free survival (RRFS), disease-specific survival (DSS), and overall survival (OS). Factors associated with survival were evaluated by univariate and multivariate analysis. Survival between the two groups was compared by propensity score-matched analysis. RESULTS: Matched 23 patients in each group through propensity analysis, the UFND group showed a significantly better 5-year RRFS (94.1% vs 61.0%, p = 0.011) compared to the CCRT group. Univariate analysis revealed that UFND was the sole factor associated with regional control (hazard ratio [HR] = 0.110; 95% CI, 0.014-0.879; p = 0.037). Furthermore, the study found that the CCRT group was associated with a higher dose of radiotherapy and exhibited a significantly higher risk of mortality due to pneumonia. CONCLUSION: The study indicated that UFND followed by CCRT may be a potential treatment option for patients with cN+ p16-negative OPSCC, as it can reduce the risk of regional recurrence. Additionally, the study highlights that definite CCRT is connected to a larger dose of radiotherapy and a higher risk of fatal pneumonia. These findings could be beneficial in informing clinical decision-making and improving treatment outcomes for patients with OPSCC.

Profiles of Cough and Associated Risk Factors in Nonhospitalized Individuals With SARS-CoV-2 Omicron Variant Infection: Cross-Sectional Online Survey in China.

BACKGROUND: Cough is a common symptom during and after COVID-19 infection; however, few studies have described the cough profiles of COVID-19. OBJECTIVE: The aim of this study was to investigate the prevalence, severity, and associated risk factors of severe and persistent cough in individuals with COVID-19 during the latest wave of the Omicron variant in China. METHODS: In this nationwide cross-sectional study, we collected information of the characteristics of cough from individuals with infection of the SARS-CoV-2 Omicron variant using an online questionnaire sent between December 31, 2022, and January 11, 2023. RESULTS: There were 11,718 (n=7978, 68.1% female) nonhospitalized responders, with a median age of 37 (IQR 30-47) years who responded at a median of 16 (IQR 12-20) days from infection onset to the time of the survey. Cough was the most common symptom, occurring in 91.7% of participants, followed by fever, fatigue, and nasal congestion (68.8%-87.4%). The median cough visual analog scale (VAS) score was 70 (IQR 50-80) mm. Being female (odds ratio [OR] 1.31, 95% CI 1.20-1.43), having a COVID-19 vaccination history (OR 1.71, 95% CI 1.37-2.12), current smoking (OR 0.48, 95% CI 0.41-0.58), chronic cough (OR 2.04, 95% CI 1.69-2.45), coronary heart disease (OR 1.71, 95% CI 1.17-2.52), asthma (OR 1.22, 95% CI 1.02-1.46), and gastroesophageal reflux disease (GERD) (OR 1.21, 95% CI 1.01-1.45) were independent factors for severe cough (VAS>70, 37.4%). Among all respondents, 35.0% indicated having a productive cough, which was associated with risk factors of being female (OR 1.44, 95% CI 1.31-1.57), having asthma (OR 1.84, 95% CI 1.52-2.22), chronic cough (OR 1.44, 95% CI 1.19-1.74), and GERD (OR 1.22, 95% CI 1.01-1.47). Persistent cough (>3 weeks) occurred in 13.0% of individuals, which was associated with the risk factors of having diabetes (OR 2.24, 95% CI 1.30-3.85), asthma (OR 1.70, 95% CI 1.11-2.62), and chronic cough (OR 1.97, 95% CI 1.32-2.94). CONCLUSIONS: Cough is the most common symptom in nonhospitalized individuals with Omicron SARS-CoV-2 variant infection. Being female, having asthma, chronic cough, GERD, coronary heart disease, diabetes, and a COVID-19 vaccination history emerged as independent factors associated with severe cough, productive cough, and persistent cough.

A machine learning-based radiomics model for prediction of tumor mutation burden in gastric cancer.

Purpose: To evaluate the potential of machine learning (ML)-based radiomics approach for predicting tumor mutation burden (TMB) in gastric cancer (GC). Methods: The contrast enhanced CT (CECT) images with corresponding clinical information of 256 GC patients were retrospectively collected. Patients were separated into training set (n = 180) and validation set (n = 76). A total of 3,390 radiomics features were extracted from three phases images of CECT. The least absolute shrinkage and selection operator (LASSO) model was used for feature screening. Seven machine learning (ML) algorithms were employed to find the optimal classifier. The predictive ability of radiomics model (RM) was evaluated with receiver operating characteristic. The correlation between RM and TMB values was evaluated using Spearman's correlation coefficient. The explainability of RM was assessed by the Shapley Additive explanations (SHAP) method. Results: Logistic regression algorithm was chosen for model construction. The RM showed good predictive ability of TMB status with AUCs of 0.89 [95% confidence interval (CI): 0.85-0.94] and 0.86 (95% CI: 0.74-0.98) in the training and validation sets. The correlation analysis revealed a good correlation between RM and TMB levels (correlation coefficient: 0.62, p < 0.001). The RM also showed favorable and stable predictive accuracy within the cutoff value range 6-16 mut/Mb in both sets. Conclusion: The ML-based RM offered a promising image biomarker for predicting TMB status in GC patients.

Dynamic changes in macrophage subtypes during lung cancer progression and metastasis at single-cell resolution.

Background: Lung cancer remains a major global health challenge. Macrophages (Macs) are one important component of tumor microenvironments (TMEs); however, their prognostic relevance to lung cancer is currently unknown due to the complexity of their phenotypes. Methods: In the present study, reanalysis and atlas reconstruction of downloaded single-cell RNA sequencing (scRNAseq) data were used to systematically compare the component and transcriptional changes in Mac subtypes across different stages of lung cancer. Results: We found that with the progression of lung cancer, the proportion of alveolar macrophages (aMacs) gradually decreased, while the proportions of Macs and monocytes (Monos) gradually increased, suggesting a chemotaxis process followed by a Mono-Mac differentiation process. Meanwhile, through ligand-receptor (LR) screening, we identified 9 Mac-specific interactions that were enriched during the progression and metastasis of lung cancer, which could potential promote M2 polarization or the infiltration of M2 Macs. Moreover, we found that the expression of SPP1 in Macs increased with lung cancer progression, and identified 9 genes that were correlated with the expression of SPP1 in Macs, which might also contribute to the immunosuppression process in lung cancer. Conclusions: Our results revealed detailed changes in Macs at different stages of lung cancer progression and metastasis and provided potential therapeutic targets that could be used in future lung cancer treatments.

NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1.

Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4ΔL12_16) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4ΔL12_16 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4ΔL12_16 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4ΔL12_16 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy.

The value of machine learning based radiomics model in preoperative detection of perineural invasion in gastric cancer: a two-center study.

Purpose: To establish and validate a machine learning based radiomics model for detection of perineural invasion (PNI) in gastric cancer (GC). Methods: This retrospective study included a total of 955 patients with GC selected from two centers; they were separated into training (n=603), internal testing (n=259), and external testing (n=93) sets. Radiomic features were derived from three phases of contrast-enhanced computed tomography (CECT) scan images. Seven machine learning (ML) algorithms including least absolute shrinkage and selection operator (LASSO), naïve Bayes (NB), k-nearest neighbor (KNN), decision tree (DT), logistic regression (LR), random forest (RF), eXtreme gradient boosting (XGBoost) and support vector machine (SVM) were trained for development of optimal radiomics signature. A combined model was constructed by aggregating the radiomic signatures and important clinicopathological characteristics. The predictive ability of the radiomic model was then assessed with receiver operating characteristic (ROC) and calibration curve analyses in all three sets. Results: The PNI rates for the training, internal testing, and external testing sets were 22.1, 22.8, and 36.6%, respectively. LASSO algorithm was selected for signature establishment. The radiomics signature, consisting of 8 robust features, revealed good discrimination accuracy for the PNI in all three sets (training set: AUC = 0.86; internal testing set: AUC = 0.82; external testing set: AUC = 0.78). The risk of PNI was significantly associated with higher radiomics scores. A combined model that integrated radiomics and T stage demonstrated enhanced accuracy and excellent calibration in all three sets (training set: AUC = 0.89; internal testing set: AUC = 0.84; external testing set: AUC = 0.82). Conclusion: The suggested radiomics model exhibited satisfactory prediction performance for the PNI in GC.

Boron Neutron Capture Therapy Followed by Image-Guided Intensity-Modulated Radiotherapy for Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

BACKGROUND: This trial investigated the efficacy and safety of salvage boron neutron capture therapy (BNCT) combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for recurrent head and neck cancer after prior radiotherapy (RT). METHODS: BNCT was administered using an intravenous boronophenylalanine-fructose complex (500 mg/kg) in a single fraction; multifractionated IG-IMRT was administered 28 days after BNCT. For BNCT, the mucosa served as the dose-limiting organ. For IG-IMRT, the clinical target volume (CTV) and the planning target volume (PTV) were generated according to the post-BNCT gross tumor volume (GTV) with chosen margins. RESULTS: This trial enrolled 14 patients, and 12 patients received combined treatment. The median BNCT average dose for the GTV was 21.6 Gy-Eq, and the median IG-IMRT dose for the PTV was 46.8 Gy/26 fractions. After a median (range) follow-up period of 11.8 (3.6 to 53.2) months, five patients had a complete response and four had a partial response. One patient had grade 4 laryngeal edema; another patient had a grade 4 hemorrhage. Most tumor progression occurred within or adjacent to the CTV. The 1-year overall survival and local progression-free survival rates were 56% and 21%, respectively. CONCLUSION: Despite the high response rate (64%) of this trial, there was a high incidence of in-field and marginal failure with this approach. Future studies combining BNCT with modalities other than radiation may be tried.

Anti-VEGF Therapy Possibly Extends Survival in Patients With Colorectal Brain Metastasis by Protecting Patients From Neurologic Disability.

BACKGROUND: Colorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM. METHODS: A total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non-anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal. RESULTS: Patients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis. CONCLUSIONS: Anti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.

Survival analyses of different treatment modalities and clinical stage for hypopharyngeal carcinoma.

Objective: We investigated the effects of different treatment modalities and clinical stage for hypopharyngeal carcinoma (HPC) patients. Methods: Between February 2004 and December 2012, 167 HPC patients were reviewed. We calculated overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis failure-free survival (DMFFS) using the Kaplan-Meier method and compared various survival outcomes between definitive chemoradiotherapy (CRT) and surgery-based therapy (SBT). Results: There were no significant differences in baseline characteristics between SBT (n = 102) and definitive CRT (n = 65) groups. The 5-year rates of OS (59.7% vs. 24.0%, p < 0.0001) and PFS (49.9% vs. 22.6%, p = 0.0002) were significantly better in patients who received SBT than in those who received definitive CRT. The SBT group also obtained better LFFS (p < 0.0001), RFFS (p = 0.0479), and DMFFS (p = 0.0110). We did similar analyses by different T-classification (T1-2, T3, and T4) and found that SBT had better OS (p < 0.0001 and p = 0.0020), PFS (p < 0.0001 and p = 0.0513), LFFS (p = 0.0002 and p = 0.0075), RFFS (p = 0.1949 and p = 0.0826), and DMFFS (p = 0.0248 and p = 0.0436) in the T4 and T1-2 subgroups but similar OS (p = 0.9598), PFS (p = 0.5052), RFFS (p = 0.9648), and DMFFS (p = 0.8239) in T3 patients. Analyses by different overall stages revealed no differences between definitive CRT and SBT for stage III patients but significantly better results for stage IV patients who received SBT. Conclusions: SBT can obtain significant survival benefits when compared with definitive CRT for the whole cohort of patients. Definitive CRT has similar survival outcomes compared with SBT only for T3 tumors or overall stage III disease.

Radiomic features derived from pretherapeutic MRI predict chemoradiation response in locally advanced rectal cancer.

BACKGROUND: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant concurrent chemoradiotherapy (CRT) followed by surgical excision. Current evidence suggests a favorable prognosis for those with pathological complete response (pCR), and surgery may be spared for them. We trained and validated regression models for CRT response prediction with selected radiomic features extracted from pretreatment magnetic resonance (MR) images to recruit potential candidates for this watch-and-wait strategy. METHODS: We retrospectively enrolled patients with LARC who underwent pre-CRT MR imaging between 2010 and 2019. Pathological complete response in surgical specimens after CRT was defined as the ground truth. Quantitative features derived from both unfiltered and filtered images were extracted from manually segmented region of interests on T2-weighted images and selected using variance threshold, univariate statistical tests, and cross-validation least absolute shrinkage and selection operator (Lasso) regression. Finally, a regression model using selected features with high coefficients was optimized and evaluated. Model performance was measured by classification accuracies and area under the receiver operating characteristic (AUROC). RESULTS: We extracted 1223 radiomic features from each MRI study of 133 enrolled patients. After tumor excision, 34 (26 %) of 133 patients had pCR in resected specimens. When 25 image-derived features were selected from univariate analysis, classification AUROC was 0.86 and 0.79 with the addition of six clinical features on the hold-out internal validation dataset. When 11 image-derived features were used, the optimized linear regression model had an AUROC value of 0.79 and 0.65 with the addition of six clinical features on the hold-out dataset. Among the radiomic features, texture features including gray level variance, strength, and cluster prominence had the highest coefficient by Lasso regression. CONCLUSION: Radiomic features derived from pretreatment MR images demonstrated promising efficacy in predicting pCR after CRT. However, radiomic features combined with clinical features did not result in remarkable improvement in model performance.

Development of a tumor control probability model for boron neutron capture therapy of head and neck cancer.

The tumor control probability (TCP) model has been used for estimating the response of the radiation (photon) therapy for a given treatment dose (distribution). In Taiwan, boron neutron capture therapy (BNCT) is still at the stage of the clinical trials without standard dose prescription. In this study, universal survival curve (USC) model was selected as the TCP model for BNCT. The tumor response and dose distribution from protocol I of the clinical trial of the recurrent head and neck (H&N) cancer conducted by Taipei Veterans General Hospital and National Tsing Hua University were used to verify the TCP model established in this study. The results showed that, using the USC model as a biological model of dose conversion, the TCP calculated by the generalized Equivalent Uniform Dose (gEUD)-based TCP model can be used to well correlate the relationship between the tumor response and dose distribution of the patients of recurrent H&N cancer. The result shows that 25% and 60% of TCP correspond to partial response and complete response of H&N cancer, respectively. This study also indicated that, when BNCT was used to treat recurrent H&N cancer, the minimum dose was an important factor on the efficacy of the treatment. Minimum dose of 18 Gy-w corresponds to at least 60% of TCP.

The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China): Protocol of a prospective multicenter observational study.

BACKGROUND: Bronchiectasis is a highly heterogeneous chronic airway disease with marked geographic and ethnic variations. Most influential cohort studies to date have been performed in Europe and USA, which serve as the examples for developing a cohort study in China where there is a high burden of bronchiectasis. The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China) is designed to: (1) describe the clinical characteristics and natural history of bronchiectasis in China and identify the differences of bronchiectasis between the western countries and China; (2) identify the risk factors associated with disease progression in Chinese population; (3) elucidate the phenotype and endotype of bronchiectasis by integrating the genome, microbiome, proteome, and transcriptome with detailed clinical data; (4) facilitate large randomized controlled trials in China. METHODS: The BE-China is an ongoing prospective, longitudinal, multi-center, observational cohort study aiming to recruit a minimum of 10,000 patients, which was initiated in January 2020 in China. Comprehensive data, including medical history, aetiological testing, lung function, microbiological profiles, radiological scores, comorbidities, mental status, and quality of life (QoL), will be collected at baseline. Patients will be followed up annually for up to 10 years to record longitudinal data on outcomes, treatment patterns and QoL. Biospecimens, if possible, will be collected and stored at - 80 °C for further research. Up to October 2021, the BE-China has enrolled 3758 patients, and collected 666 blood samples and 196 sputum samples from 91 medical centers. The study protocol has been approved by the Shanghai Pulmonary Hospital ethics committee, and all collaborating centers have received approvals from their local ethics committee. All patients will be required to provide written informed consent to their participation. CONCLUSIONS: Findings of the BE-China will be crucial to reveal the clinical characteristics and natural history of bronchiectasis and facilitate evidence-based clinical practice in China. Trial registration Registration Number in ClinicalTrials.gov: NCT03643653.

Treatment outcomes of cetuximab-containing regimen in locoregional recurrent and distant metastatic head and neck squamous cell carcinoma.

BACKGROUND: Recurrent/ metastatic squamous cell carcinoma of head and neck (R/M SCCNH) is still a difficult-to-treat disease with poor clinical outcomes and limited treatment choices. In view of locoregional recurrent versus distant metastatic SCCHN, the therapeutic efficacy of cetuximab-containing regimen and relevant prognostic factors for these two groups may be different. Thus, the aim of this study was to explore the treatment outcomes of cetuximab-containing regimen in locoregional recurrent and distant metastatic SCCHN groups, and to identify clinical factors correlated with better survival outcomes. METHODS: From 2016 to 2020, patients with R/M SCCHN who received cetuximab-containing regimen in our institute were enrolled in this study. Clinical outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated in both locoregional recurrence and distant metastasis groups. Exploratory analysis were conducted to investigate major clinical features associated with better outcomes. RESULTS: A total of 107 patients with locoregional recurrent SCCHN (N = 66) and distant metastatic SCCNH (N = 41) who received cetuximab-containing regimen were enrolled in this retrospective study. Patients with oral cavity cancer and patients with disease recurrence within 6 months after radiation therapy were significantly increased in locoregional recurrence group. The median OS (15.6 vs. 9.7 months, P = 0.004) and PFS (5.8 months vs. 4.2 months, P = 0.008) were longer in locoregional recurrence group than in distant metastasis group. In multivariate analysis of clinical features, locoregional recurrence was still an important risk factor associated with better OS (Hazzard ratio (HR) 0.64, p = 0.06) and PFS (HR 0.67, p = 0.075). In addition, a trend of favorable disease control rate (DCR; 62.5% vs. 45.0%, p = 0.056) was noted in locoregional recurrence group. In locoregional recurrence group, prior salvage surgery was associated with longer OS (HR = 0.24, P = 0.008) and PFS (HR = 0.30, P = 0.005). CONCLUSION: SCCHN with locoregional recurrence is associated with better disease control and survival outcomes comparing to distant metastatic SCCHN when treated with cetuximab-containing regimen. Salvage surgery for locoregional recurrence may further improves clinical outcome.

Multifunctional nanoprobes combined with radiotherapy and hypoxia-activated therapy synergistically improve antitumor efficacy.

The presence of hypoxia in tumors is characteristic of most solid tumors and it promotes not only tumor angiogenesis but also tumor cell invasion and metastasis. It also results in resistance of tumor tissue to radiation, leading to poor outcomes of tumor radiotherapy. Therefore, to address this conundrum, highly selective gold nanoclusters were prepared as fluorescent imaging agents and radiosensitizers and then loaded with tumor hypoxia-activated prodrugs to prepare nanoprobes which synergistically improved the anti-tumor efficacy by combining radiotherapy and hypoxia-activated therapy. The designed nanoprobes have ultra-small size, high selectivity for integrin αvß3 receptor-positive tumor cells and tumor neovascular endothelial cells, and excellent fluorescence imaging performance. The experimental procedures were carried out in vitro and in vivo to demonstrate that the developed nanoprobes have a high level of biocompatibility, efficient radiosensitization effect, and anti-tumor efficacy at cell and tissue levels. The combined application of radiotherapy and hypoxia-activated therapy can overcome the radiation resistance caused by tumor hypoxia, compensate for the limitations of single radiotherapy, inhibit tumor growth, improve the efficacy of tumor radiotherapy, and provide new possibilities for the development of more precise and effective treatment strategies.

The effect of Mitomycin-C in neoadjuvant concurrent chemoradiotherapy for rectal cancer.

BACKGROUND: Neoadjuvant concurrent chemoradiotherapy (nCCRT) followed by total mesorectal excision has become the standard of care for advanced rectal cancer, but the most effective regimen of chemotherapeutic agents has not yet been determined. The purpose of this study is to determine the effect of Mitomycin-C (MMC) in nCCRT for rectal cancer. METHODS: From 2000 to 2017, patients with rectal adenocarcinoma who received nCCRT followed by radical surgery were enrolled in our study. The patients were retrospectively separated into two groups according to nCCRT regimens (with or without MMC). Other factors related to cancer down-staging after nCCRT, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: One hundred ninety-five patients received radiotherapy (RT) + MMC + oral tegafur-uracil (UFUR), and 191 patients received RT + UFUR without MMC as neoadjuvant CCRT. Adding MMC might increase the down-staging rate (odds ratio [OR] = 1.520, p = 0.058), and down-staging had significant effect to improve OS (OR = 1.726, p = 0.002) and DFS (OR = 2.185, p < 0.001). The OS and DFS were improved in patients who received MMC, although this result did not reach a statistically significant difference. There was a higher incidence of low-grade toxicities in the MMC group, especially neutropenia, genitourinary side effects, and dermatological side effects ( p < 0.001). CONCLUSION: Adding MMC to the regimen of nCCRT for rectal adenocarcinoma is shown to increase tumor down-staging rate and improve disease-free and OS, although these benefits come at the cost of increased low-grade toxicities. Prospective randomized studies are needed to explore the role of MMC in nCCRT for rectal cancer.

A multiphase contrast-enhanced CT radiomics model for prediction of human epidermal growth factor receptor 2 status in advanced gastric cancer.

Background: Accurate evaluation of human epidermal growth factor receptor 2 (HER2) status is of great importance for appropriate management of advanced gastric cancer (AGC) patients. This study aims to develop and validate a CT-based radiomics model for prediction of HER2 overexpression in AGC. Materials and Methods: Seven hundred and forty-five consecutive AGC patients (median age, 59 years; interquartile range, 52-66 years; 515 male and 230 female) were enrolled and separated into training set (n = 521) and testing set (n = 224) in this retrospective study. Radiomics features were extracted from three phases images of contrast-enhanced CT scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator method. Univariable and multivariable logistical regression analysis were used to establish predictive model with independent risk factors of HER2 overexpression. The predictive performance of radiomics model was assessed in the training and testing sets. Results: The positive rate of HER2 was 15.9% and 13.8% in the training set and testing set, respectively. The positive rate of HER2 in intestinal-type GC was significantly higher than that in diffuse-type GC. The radiomics signature comprised eight robust features demonstrated good discrimination ability for HER2 overexpression in the training set (AUC = 0.84) and the testing set (AUC = 0.78). A radiomics-based model that incorporated radiomics signature and pathological type showed good discrimination and calibration in the training (AUC = 0.85) and testing (AUC = 0.84) sets. Conclusion: The proposed radiomics model showed favorable accuracy for prediction of HER2 overexpression in AGC.

Reprogramming alternative macrophage polarization by GATM-mediated endogenous creatine synthesis: A potential target for HDM-induced asthma treatment.

Cellular energy metabolism plays a crucial role in the regulation of macrophage polarization and in the execution of immune functions. A recent study showed that Slc6a8-mediated creatine uptake from exogenous supplementation modulates macrophage polarization, yet little is known about the role of the de novo creatine de novobiosynthesis pathway in macrophage polarization. Here, we observed that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, was upregulated in alternative (M2) polarized macrophages, and was dependent on the transcriptional factor STAT6, whereas GATM expression was suppressed in the classical polarized (M1) macrophage. Next, we revealed that exogenous creatine supplementation enhanced IL-4-induced M2 polarization, confirming recent work. Furthermore, we revealed that genetic ablation of GATM did not affect expression of M1 marker genes (Nos2, IL1b, IL12b) or the production of nitric oxide in both peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs). By contrast, expression levels of M2 markers (Arg1, Mrc1, Ccl17 and Retnla) were lower following GATM deletion. Moreover, we found that deletion of GATM in resident alveolar macrophages (AMs) significantly blocked M2 polarization but with no obvious effect on the number of cells in knockout mice. Lastly, an upregulation of GATM was found in lung tissue and bronchoalveolar lavage fluid macrophages from HDM-induced asthmatic mice. Our study uncovers a previously uncharacterized role for the de novo creatine biosynthesis enzyme GATM in M2 macrophage polarization, which may be involved in the pathogenesis of related inflammatory diseases such as an T helper 2 (Th2)-associated allergic asthma.

A Rare Case of Post-Primary Tuberculosis Which Was Pathologically Diagnosed as Lipoid Pneumonia.

Case Presentation: The patient was a middle-aged housewife who had been using the household spray for a long time, and the main symptoms were cough and sputum production. Chest CT showed lobar ground-glass opacities (GGOs) with small patchy consolidation in the right middle lobe (RML), specifically, lung tissue pathology showed a large number of foamy cells and scattered multinucleated giant cells. The patient received empirical anti-infective treatment, but no clinical improvement was observed. Laboratory tests, including smears and cultures of sputum, blood and bronchoalveolar lavage fluid (BALF), did not provide clear evidence for pathogenic microorganisms. Therefore, the presumptive diagnosis was exogenous LP (ExLP). After 28 days of prednisone treatment, her symptoms improved, but 2 months later, she presented with a worsening cough, and the GGOs had progressed into lobar consolidation. Transbronchial lung biopsy (TBLB) culture showed mycobacterium tuberculosis (MTB), and lung tissue pathology showed granulomatous inflammation. After anti-tuberculosis treatment, the consolidation in the right middle lobe was gradually absorbed, along with a considerable symptom improvement. The final diagnosis of the patient was MTB infection with an endogenous lipoid pneumonia (EnLP)-like presentation. Conclusion: The current case highlights that the MTB infection should be considered when pathology shows LP accompanied by scattered multinucleated giant cells.

Airway acidification impaired host defense against Pseudomonas aeruginosa infection by promoting type 1 interferon ß response.

Airway microenvironment played an important role in the progression of chronic respiratory disease. Here we showed that standardized pondus hydrogenii (pH) of exhaled breath condensate (EBC) of bronchiectasis patients was significantly lower than that of controls and was significantly correlated with bronchiectasis severity index (BSI) scores and disease prognosis. EBC pH was lower in severe patients than that in mild and moderate patients. Besides, acidic microenvironment deteriorated Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection in mice models. Mechanistically, acidic microenvironment increased P. aeruginosa outer membrane vesicles (PA_OMVs) released and boosted it induced the activation of interferon regulatory factor3 (IRF3)-interferonß (IFN-ß) signalling pathway, ultimately compromised the anti-bacteria immunity. Targeted knockout of IRF3 or type 1 interferon receptor (IFNAR1) alleviated lung damage and lethality of mice after P. aeruginosa infection that aggravated by acidic microenvironment. Together, these findings identified airway acidification impaired host resistance to P. aeruginosa infection by enhancing it induced the activation of IRF3-IFN-ß signalling pathway. Standardized EBC pH may be a useful biomarker of disease severity and a potential therapeutic target for the refractory P. aeruginosa infection. The study also provided one more reference parameter for drug selection and new drug discovery for bronchiectasis.