The m6A reader IGF2BP2 promotes esophageal cell carcinoma progression by enhancing EIF4A1 translation.

Esophageal squamous cell carcinoma (ESCC) is one of most prevalent cancers worldwide, especially in China. Lacking in depth mechanism study, effective targets and therapeutics are desperately needed in the clinic. RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. Bioinformatics analysis revealed that IGF2BPs were highly expressed in ESCC tissues and at least participated in the regulation of cell proliferation of ESCC cells. Biological researches demonstrated that IGF2BP2 promoted the cell proliferation, migration and invasion of ESCC KYSE30 and KYSE450 cells. IGF2BP2 could bind to EIF4A1 mRNA by recognition of m6A sites and enhanced translation of EIF4A1. IGF2BPs, as m6A reader, IGF2BPs were oncogenic genes in ESCC by regulating the expression of EIF4A1 through m6A sites. IGF2BP2, EIF4A1 and their targets could serve as potential biomarkers and therapeutic targets for ESCC, offering promising novel approaches for the diagnosis and treatment of ESCC.

Untimely surgery for stent-fracture-related death after transjugular intrahepatic portosystemic shunt: a case report.

Transjugular intrahepatic portosystemic shunt (TIPS) is a life-saving procedure for patients with severe portal hypertension and persistent variceal bleeding. Stent fracture is a rare and severe complication; however, its cause and mechanisms remain poorly defined. This case helps understand the factors contributing to its occurrence, complications, and subsequent poor outcomes. A 63-year-old male was presented with ruptured bare stent after a TIPS procedure. The upper edge of the bare stent was ruptured, and its fraction subsequently migrated to the entrance of the right atrium. Meanwhile, a mural thrombus was formed in the inferior vena cava. A surgery for the removal of free fracture was planned for preventing the form of pulmonary embolism. Before the surgery, the fracture was shifted to the right inferior pulmonary artery. Therefore, the surgery was canceled for further evaluation. Then, hematemesis suddenly occurred with a high possibility of variceal bleeding and/or gastric ulcer bleeding. Despite comprehensive treatments, the patient symptoms were still worsened with the development of chest tightness, shortness of breath, severe hypoxia, and heart failure. Finally, the patient succumbed to systemic multiorgan failure and death. Taken together, a ruptured unstable stent should be removed as early as the patient is hemodynamically stable, as it is difficult to balance between hemostasis therapy and anticoagulation treatment in patients with liver-cirrhosis-related severe portal hypertension. Physicians should be on high alert of the potential complications of bare stent rapture after TIPS.

Ruptured TIPS stent with a fatal consequence Unstable stent rupture is a life-threatening complication of TIPS and severely complicates the treatment of gastric ulcer bleeding. Early removal of the ruptured stent is necessary to prevent further complications.

A bibliometric analysis of research on R-loop: Landscapes, highlights and trending topics.

R-loop is a necessary intermediate in specific cellular processes. To profile the landscapes, highlights, and trending topics of R-loop, publications related to R-loop from 1976 to 2022 were downloaded and bibliometric analyses were performed by Bibliometrix in R and VOSviewer. 1428 documents (including 1092 articles and 336 reviews) were included. USA, United Kingdom, and China contributed more than one-third of the publications. The annual publication increased rapidly since 2010. The research trend of R-loop has evolved from the discovery of phenomena to the exploration of molecular mechanisms, from the elucidation of biological functions to the analysis of disease correlations. Ongoing roles of R-loop in DNA repair process was highlighted and further analyzed. This study may accelerate R-loop research by highlighting important researches, understanding the trending topic, and integrating with other areas.

Targeting HER3 or MEK overcomes acquired Trastuzumab resistance in HER2-positive gastric cancer-derived xenograft.

Acquired Trastuzumab resistance is a complicated and disastrous event for HER2-positive gastric cancer (GC). In this study, we successfully established a GC PDX model with Trastuzumab sensitivity (176P) and induced a homologous model with acquired Trastuzumab resistance (176R), then comprehensively delineated the landscape of Trastuzumab resistance mechanisms using single-cell transcriptome sequencing, as well as protein profiling and genomic variation analysis. According to multi-omics study, different gene expression profiles, rather than genetic changes, contributed to acquired Trastuzumab resistance. The mechanisms underlying acquired Trastuzumab resistance present great complexity as multiple molecules and pathways were involved, including ERBB family, MAPK, PI3K/AKT, JAK/STAT, and cell cycle pathways. Through phenotypical and molecular validation, we found that Trastuzumab combined with HER3-targeted antibody or MEK inhibitor demonstrated excellent antitumor activity and good tolerance, which may serve as promising strategies for overcoming acquired Trastuzumab resistance.

Crosstalk of Eight Types of RNA Modification Regulators Defines Tumor Microenvironments, Cancer Hallmarks, and Prognosis of Lung Adenocarcinoma.

RNA modification has become an exciting underexplored field in recent years. In lung adenocarcinoma (LUAD), m6A was the best characterized and most studied RNA modification, while knowledge about other kinds of RNA modifications in LUAD is limited. In our study, we included a total of 100 RNA modification regulators of eight types of cancer-related RNA modifications (m6A, m1A, m5C, Nm, m7G, Ψ, A-to-I, and mcm5s2U) to systematically profile their specific roles in LUAD. By gene mutation and expression analysis, we identified extensive dysregulations and complicated interactions of 100 RNA modification regulators in LUAD. Based on unsupervised clustering analysis, gene set variation analysis (GSVA), and single-sample gene-set enrichment analysis (ssGSEA), two RNA modification patterns in LUAD were defined to show distinct biological characteristics. The favorable prognostic pattern was enriched with infiltrated immune cells, including activated B cells, CD8 T cells, eosinophil cells, dendritic cells, and natural killer cells, while the unfavorable prognostic pattern was enriched with cancer hallmarks, including hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, PI3K-AKT-mTOR pathway, MYC pathway, and glycolysis pathway. We also constructed an RNA modification score (RMScore) based on five critical genes (CYP17A1, NTSR1, PITX3, KRT6A, and ANLN) to evaluate the RNA modification status of individual LUAD patients. RMScore was revealed to be related to the infiltrated immune cells and cancer hallmarks and was an independent prognostic factor in the TCGA-LUAD cohort and two external GEO-LUAD cohorts. Our study was the first to comprehensively investigate the dysregulations, crosstalk, and potential prognostic value of eight types of RNA modifications in LUAD. Our results highlighted the significance of eight types of RNA modifications in tumor microenvironments and cancer hallmarks and provided novel prognostic biomarkers and potential therapeutic targets in the management of LUAD patients in the future.

CAN017, a novel anti-HER3 antibody, exerted great potency in mouse avatars of esophageal squamous cell carcinoma with NRG1 as a biomarker.

CAN017 (AV-203), a novel anti-HER3 antibody, exerts very promising anti-tumor activities in several human tumor models. The aim of this study was to further investigated the efficacy and possible responsive biomarkers of CAN017 in esophageal squamous cell carcinoma (ESCC) with Chinese characteristics. Two separate cohorts of ESCC patient-derived xenograft (PDX) models including 24 (cohort 1 as training models, from Crown Bioscience Inc.) and 22 (cohort 2 as validating models, from Peking University Cancer Hospital) models, respectively, were used to study the efficacy and safety of CAN017, as well as the correlation of NRG1 expression to the response of CAN017. In cohort 1, all PDX models showed good tolerance to CAN017 and 8 out of 24 (33.3%) PDX models responded to CAN017 with tumor growth inhibition (TGI) ≥70% compared to controls. Furthermore, the efficacy of CAN017 was positively correlated with NRG1 expression and the response rates in cohort 1 were 73% (8/11) versus 0% (0/13) in NRG1 high and low expression models, respectively. These results were also validated in PDX models of cohort 2 indicated as the powerful anti-tumor activity of CAN017 in PDX models with NRG1 high expression. In our study, HER3-targeting therapy was first demonstrated to have potency in inhibiting ESCC tumor growth, and NRG1 served as a predictive biomarker to screen patients in future clinical trials.

Comparison of the clinical features and therapeutics of COVID-19 in cardio-cerebrovascular disease (CCVD) and non-CCVD patients.

Cardio-cerebrovascular disease (CCVD) is a major comorbidity of Coronavirus disease 2019 (COVID-19). However, the clinical characteristics and outcomes remain unclear. In this study, 102 cases of COVID-19 from January 22, 2020 to March 26, 2020 in Xixi Hospital of Hangzhou were included. Twenty cases had pre-existing CCVD. Results showed that compared with non-CCVD patients, those with CCVD are more likely to develop severe disease (15% versus 1%), and the proportion of pneumonia severity index grade IV was significantly higher (25% versus 3.6%). Computed tomography images demonstrated that the proportion of multiple lobe lesion involvement was significantly higher in the CCVD group than in the non-CCVD group (90% versus 63.4%). Compared with non-CCVD group, the levels of C-reactive protein, fibrinogen, D-dimer, and serum amyloid-A were higher, whereas the total protein and arterial partial PaO2 were lower in the CCVD group. Although no statistical difference was observed in the outcomes between groups, CCVD patients received more intensive comprehensive treatment to improve COVID-19 symptoms compared with non-CCVD patients. Integrated Chinese and Western medicine treatments have certain advantages in controlling the severe conversion rate and mortality of COVID-19. In addition, given that COVID-19 patients are usually related to coagulation disorders and thrombosis risk, the application of Chinese medicine in promoting blood circulation and removing stasis should be strengthened.

A survey of insecticide resistance-conferring mutations in multiple targets in Anopheles sinensis populations across Sichuan, China.

BACKGROUND: Sichuan province is located in the southwest of China, and was previously a malaria-endemic region. Although no indigenous malaria case has been reported since 2011, the number of imported cases is on the rise. Insecticide-based vector control has played a central role in the prevention of malaria epidemics. However, the efficacy of this strategy is gravely challenged by the development of insecticide resistance. Regular monitoring of insecticide resistance is essential to inform evidence-based vector control. Unfortunately, almost no information is currently available on the status of insecticide resistance and associated mechanisms in Anopheles sinensis, the dominant malaria vector in Sichuan. In this study, efforts were invested in detecting the presence and frequency of insecticide resistance-associated mutations in three genes that encode target proteins of several classes of commonly used insecticides. METHODS: A total of 446 adults of An. sinensis, collected from 12 locations across Sichuan province of China, were inspected for resistance-conferring mutations in three genes that respectively encode acetylcholinesterase (AChE), voltage-gated sodium channel (VGSC), and GABA receptor (RDL) by DNA Sanger sequencing. RESULTS: The G119S mutation in AChE was detected at high frequencies (0.40-0.73). The predominant ace-1 genotype was GGC/AGC (119GS) heterozygotes. Diverse variations at codon 1014 were found in VGSC, leading to three different amino acid substitutions (L1014F/C/S). The 1014F was the predominant resistance allele and was distributed in all 12 populations at varying frequencies from 0.03 to 0.86. The A296S mutation in RDL was frequently present in Sichuan, with 296SS accounting for more than 80% of individuals in six of the 12 populations. Notably, in samples collected from Chengdu (DJY) and Deyang (DYMZ), almost 30% of individuals were found to be resistant homozygotes for all three targets. CONCLUSIONS: Resistance-related mutations in three target proteins of the four main classes of insecticides were prevalent in most populations. This survey reveals a worrisome situation of multiple resistance genotypes in Sichuan malaria vector. The data strengthen the need for regular monitoring of insecticide resistance and establishing a region-customized vector intervention strategy.

A COVID-19 risk score combining chest CT radiomics and clinical characteristics to differentiate COVID-19 pneumonia from other viral pneumonias.

With the continued transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout the world, identification of highly suspected COVID-19 patients remains an urgent priority. In this study, we developed and validated COVID-19 risk scores to identify patients with COVID-19. In this study, for patient-wise analysis, three signatures, including the risk score using radiomic features only, the risk score using clinical factors only, and the risk score combining radiomic features and clinical variables, show an excellent performance in differentiating COVID-19 from other viral-induced pneumonias in the validation set. For lesion-wise analysis, the risk score using three radiomic features only also achieved an excellent AUC value. In contrast, the performance of 130 radiologists based on the chest CT images alone without the clinical characteristics included was moderate as compared to the risk scores developed. The risk scores depicting the correlation of CT radiomics and clinical factors with COVID-19 could be used to accurately identify patients with COVID-19, which would have clinically translatable diagnostic and therapeutic implications from a precision medicine perspective.

Tumor mutation score is more powerful than tumor mutation burden in predicting response to immunotherapy in non-small cell lung cancer.

Tumor mutation burden (TMB) predicts response to immunotherapy in non-small cell lung cancer (NSCLC). The current TMB evaluation is expensive and not satisfactory. Here, novel tumor mutation score (TMS) was defined as the number of genes with mutations in candidate genes and compared with TMB and PD-L1 in 240 NSCLC patients and validated in 34 NSCLC patients. Eighteen genes were significantly associated with longer progression-free survival (PFS) or better response. The number of mutated genes within 18 favorable genes were defined as TMS18. TMS18 (HR = 0.307, P < 0.001) had smaller hazard ratio and P value than TMB (HR = 0.455, P = 0.004) and PD-L1 expression (HR = 0.403, P = 0.005) in survival analysis. Moreover, TMS18 had significantly higher AUC than TMB and TMS18 combined with PD-L1 improved the accuracy. Universal cutoff of TMS18 enriched more patients with benefits. These findings were largely consistent in the validation cohort. Taken together, TMS18 was more powerful than TMB in predicting response of ICIs in NSCLC. Selective TMS was more feasible and cost-effective than unselective TMB. TMS18 combined with PD-L1 might yield better efficiency in predicting response of ICIs in NSCLC with future validation in larger cohorts.

From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression.

RC48-ADC is a novel humanized antibody specific for human epidermal growth factor receptor 2 (HER2)in conjugation with a microtubule inhibitor via a cleavable linker. This study was to evaluate the antitumor activity and mechanism of RC48-ADC in gastric cancer (GC) and explore the population that may benefit from RC48-ADC treatment. Four human GC cell lines and nine patient-derived xenograft (PDX) models were exploited to evaluate the antitumor effect of RC48-ADC or trastuzumab treatment in vitro and in vivo. The expression and phosphorylation of HER2 were assessed by immunohistochemistry (IHC) staining. Critical molecules of downstream PI3K/AKT and cell cycle and apoptosis signaling pathways were detected and quantified by immunoblotting. Combined with preliminary results of preclinical research, three patients with IHC3+, IHC2+/FISH+, and IHC2+/FISH- of HER2 were enrolled to verify the efficacy of RC48-ADC treatment in advanced GC. In vitro, RC48-ADC had superior antiproliferative effects in a dose-dependent manner on GC cells, especially on HER2-positive cells. In vivo, RC48-ADC exceeded trastuzumab in GC PDX models with HER2 expression, even in models with moderate to low expression of HER2. Further exploration of mechanism showed that RC48-ADC exerted the antitumor effect by inhibiting phosphorylation of HER2, inducing G2/M phase arrest and cell apoptosis in HER2-expressed PDX models. In clinical practice, RC48-ADC had satisfactory efficacy in HER2-positive and HER2 moderately expressed GC patients and demonstrated promising efficacy in HER2-positive patients who have progressed after anti-HER2 therapy. In conclusion, RC48-ADC exerted promising antitumor activity in HER2-positive as well as score of 2+ in IHC and ISH-negative AGC patients after progression of systematic treatment.

A Prognostic Nomogram Model Based on mRNA Expression of DNA Methylation-Driven Genes for Gastric Cancer.

PURPOSE: The exploration and interpretation of DNA methylation-driven genes might contribute to molecular classification, prognostic prediction and therapeutic choice. In this study, we built a prognostic risk model via integrating analysis of the transcriptome and methylation profile for patients with gastric cancer (GC). METHODS: The mRNA expression profiles, DNA methylation profiles and corresponding clinicopathological information of 415 GC patients were downloaded from The Cancer Genome Atlas (TCGA). Differential expression and correlation analysis were performed to identify DNA methylation-driven genes. The candidate genes were selected by univariate Cox regression analyses followed by the least absolute shrinkage and selection operator (LASSO) regression. A prognostic risk nomogram model was then built together with clinicopathological parameters. RESULTS: 5 DNA methylation-driven genes (CXCL3, F5, GNAI1, GAMT and GHR) were identified by integrated analyses and selected to construct the prognostic risk model with clinicopathological parameters. High expression and low DNA hypermethylation of F5, GNAI1, GAMT and GHR, as well as low expression and high DNA hypomethylation of CXCL3 were significantly associated with poor prognosis rates, respectively. The high-risk group showed a significantly shorter prognosis than the low-risk group in the TCGA dataset (HR = 0.212, 95% CI = 0.139-0.322, P = 2e-15). The final nomogram model showed high predictive efficiency and consistency in the training and validation group. CONCLUSION: We construct and validate a prognostic nomogram model for GC based on five DNA methylation-driven genes with high performance and stability. This nomogram model might be a powerful tool for prognosis evaluation in the clinic and also provided novel insights into the epigenetics in GC.

Clinical implications of plasma ctDNA features and dynamics in gastric cancer treated with HER2-targeted therapies.

BACKGROUND: Gastric cancer (GC) is confronted with limited options for precision medicine. Human epidermal growth factor receptor 2 (HER2) is the principal druggable target of GC, yet proper biomarkers for response/resistance prediction remain unveiled. METHODS: From 40 GC patients received HER2-targeted therapy, a total of 327 peripheral blood plasma specimens was collected including baseline and treatment time points. Circulating tumor DNA (ctDNA) was extracted and sequenced with a target panel of 425 genes. Experimental validation of resistant mutations was carried out in NIH-3T3 cell line. RESULTS: Genomic features, including ERBB2 copy number variation (CNV), total copy number load, and tumor mutation burdens (TMBs), dynamically changed along with the treatment process and correlated with disease progression. Plasma ctDNA-based diagnosis was more sensitive than conventional computed tomography scanning in 40% of investigated patients, gaining additional time for clinical management. Compared to baseline, new gene alterations were emerged in 12 patients who developed drug resistance during treatment. ERBB2 mutations potentially related to Pyrotinib resistance were identified in plasma ctDNA of one patient and functional analysis of their downstream signaling pathways was carried out in NIH-3T3 cell line. TMB exhibited more power than ERBB2 CNV in predicting treatment responses and prognosis for HER2-targeted therapy in GC patients. Interestingly, survival analysis indicated that patients harboring both HER2 (ERBB2) positivity and high TMB might gain more therapeutic benefits from immune checkpoint inhibitors instead of HER2-targeted regimens that required further studies and validations CONCLUSIONS: Our work showed that the dynamic surveillance of plasma ctDNA genomic features provided instructive information for the precision medication of GC patients.

Pyrotinib combined with CDK4/6 inhibitor in HER2-positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients.

BACKGROUND: Pyrotinib was well tolerated but its efficacy was unsatisfactory in patients with HER2-positive gastric cancer (GC) (NCT02378389). This study was to optimize the efficacy of pyrotinib. METHODS: Human GC cell lines and AVATAR mice were used to explore the refractory mechanisms of pyrotinib. A pyrotinib-combined strategy was proposed, which was validated in preclinical AVATAR mouse and in clinical patients enrolled in a phase I clinical trial (NCT03480256). RESULTS: Dysregulation of CCND1-CDK4/6-Rb axis might be the key to pyrotinib refractory. The strategy of pyrotinib combined with a CDK4/6 inhibitor SHR6390 was proposed and validated in preclinical AVATAR mouse, which was successfully verified in clinical patients. For five patients treated with pyrotinib plus SHR6390 who had available response evaluation, the best response was partial response in three patients, stable disease in one patient, and progressive disease in one patient. The progression-free survival times were 120, 200, 532, 109, and 57 days, respectively. CONCLUSIONS: This translational study suggests that pyrotinib combined with SHR6390 may serve as a promising strategy for patients with HER2-positive GC. TRIAL REGISTRATION: The ClinicalTrials.gov identifiers are NCT02378389 (https://clinicaltrials.gov/ct2/show/study/NCT02378389, registered in 11 February 2015) and NCT03480256 (https://clinicaltrials.gov/ct2/show/study/NCT03480256, registered in 8 March 2018).

Cellular heterogeneity map of diverse immune and stromal phenotypes within breast tumor microenvironment.

BACKGROUND: Cellular heterogeneity within the tumor microenvironment is essential to tumorigenesis and tumor development. A high-resolution global view of the tumor-infiltrating immune and stromal cells in breast tumors is needed. METHODS: xCell was used to create a cellular heterogeneity map of 64 cell types in 1,092 breast tumor and adjacent normal tissues. xCell digitally dissects tissue cellular heterogeneity based on gene expression. Integrated statistical analyses were then performed. RESULTS: There were noticeable differences between the cell fractions in tumor tissues and normal tissues. Tumors displayed higher proportions of immune cells, including CD4+ Tem, CD8+ naïve T cells, and CD8+ Tcm compared with normal tissues. Immune inhibitory receptors (PD1, CTLA4, LAG3 and TIM3) were co-expressed on certain subtypes of T cells in breast tumors, and PD1 and CTLA4 were both positively correlated with CD8+ Tcm and CD8+ T cells. 28 cell types were significantly associated with overall survival in univariate analysis. CD4+ Tem, CD8+ Tcm, CD8+ T-cells, CD8+ naive T-cells, and B cells were positive prognostic factors but CD4+ naive T-cells were negative prognostic factors for breast cancer patients. TDRD6 and TTK are promising T cell and B cell targets for tumor vaccines. Endothelial cells and fibroblasts were significantly less prevalent in tumor tissues; astrocytes and mesangial cells were negatively correlated with the T stage. Mesangial cells and keratinocytes were found to be favorable prognostic factors and myocytes were negative prognostic factors. Five cell types were found to be independent prognostic factors and we used these to create a reliable prognostic model for breast cancer patients. Cellular heterogeneity was discovered among different breast cancer subtypes by Her2, ER, and PR status. Tri-negative patients had the highest fraction of immune cells while luminal type patients had the lowest. The various cells may have diverse or opposing roles in the prognosis of breast cancer patients. CONCLUSIONS: We created a uniquecellular map for the diverse heterogeneity of immune and stromal phenotypes within the breast tumor microenvironment. This map may lead to potential therapeutic targets and biomarkers with prognostic utility.

Chest CT of COVID-19 in patients with a negative first RT-PCR test: Comparison with patients with a positive first RT-PCR test.

To compare clinical and imaging features between patients with an initial negative reverse-transcription-polymerase chain-reaction (RT-PCR) test and patients with an initial positive RT-PCR test. CT follow-up analysis in the negative RT-PCR group is also described.Thirty-three patients with SARS-CoV-2 infection confirmed by RT-PCR, with 216 lesions upon CT, were included. Demographic information and chest CT imaging features were collected.The average age in the whole study group was 46.9 ±â€Š11.1 years, with 18 males and 15 females. Patients in the positive RT-PCR test group were more likely to have a fever than patients in the negative RT-PCR test group (85.7% vs 50%, P < .05). Lesions in the positive group were more likely to be located in the peripheral area than lesions in the negative group (83.6% vs 68.2%, P < .05). Regarding the appearance of 216 lesions, ground-glass opacities (GGOs) with consolidation (43.2%) was the most common appearance in the negative group, followed by pure GGOs (31.8%), while in the positive group, pure GGOs (32%) and GGOs with interlobular septal thickening (32.8%) were both most frequent, and the difference between them was evident (P < .05). For the follow-up analysis, the largest short-axis of a lesion was smaller upon follow-up (median size 13.6 mm vs 14 mm), albeit by a smaller margin. Pure GGOs decreased in frequency, from 31.3% to 21.3%, while consolidation increased in frequency, from 7.5% to 12.5%.The manifestations of COVID-19 in patients with a first negative RT-PCR test and patients with a positive first RT-PCR test are different to some extent. The consolidation component may increase after follow-up.

Novel tumor mutation score versus tumor mutation burden in predicting survival after immunotherapy in pan-cancer patients from the MSK-IMPACT cohort.

BACKGROUND: Tumor mutation burden (TMB) may predict the immune checkpoint inhibitor (ICI) response. The TMB calculation includes all nonsynonymous somatic mutations, but not all mutations are favorable, and the efficiency of TMB is attenuated by including adverse mutations. Moreover, no universal cutoff value of a high TMB hinders its application in practice. METHODS: Tumor mutation score (TMS), defined as the number of genes with nonsynonymous somatic mutations, TMS55, defined as the TMS of 55 favorable prognostic genes, and TMB were calculated and compared in 1,661 advanced cancer patients treated with ICIs and 3,840 matched advanced cancer patients not treated with ICIs among ten cancer types. RESULTS: TMS55 was significantly associated with TMB. In 1,661 ICI-treated patients, 55 genes were significantly associated with prolonged overall survival (OS), and a high TMS55 (TMS55 >5) was associated with a smaller hazard ratio (HR) and P value than a high TMB (highest 20% in each histology group) in predicting OS. The C-index of TMS55 was significantly higher than that of TMB (TMS55 0.65 vs. TMB 0.54, P<0.001). Moreover, TMS55 was significantly associated with improved survival in more tumor types than TMB, especially in non-small cell lung cancer (NSCLC), melanoma, bladder cancer and colorectal cancer. In 3,840 non-ICI-treated patients, a high TMS55 and TMB predicted poor OS. CONCLUSIONS: The novel TMS55 might be better than TMB as a biomarker for patients treated with ICIs. The easy calculation and universal cutoff value of TMS55 will not be affected across platforms and is feasible in clinical settings, which may greatly promote its application in the clinic with further validation.

High-resolution computed tomography manifestations of COVID-19 infections in patients of different ages.

PURPOSE: We aimed to compare chest HRCT lung signs identified in scans of differently aged patients with COVID-19 infections. METHODS: Case data of patients diagnosed with COVID-19 infection in Hangzhou City, Zhejiang Province in China were collected, and chest HRCT signs of infected patients in four age groups (<18 years, 18-44 years, 45-59 years, ≥60 years) were compared. RESULTS: Small patchy, ground-glass opacity (GGO), and consolidations were the main HRCT signs in 98 patients with confirmed COVID-19 infections. Patients aged 45-59 years and aged ≥60 years had more bilateral lung, lung lobe, and lung field involvement, and greater lesion numbers than patients <18 years. GGO accompanied with the interlobular septa thickening or a crazy-paving pattern, consolidation, and air bronchogram sign were more common in patients aged 45-59 years, and ≥60 years, than in those aged <18 years, and aged 18-44 years. CONCLUSIONS: Chest HRCT manifestations in patients with COVID-19 are related to patient's age, and HRCT signs may be milder in younger patients.

Construction of 124I-trastuzumab for noninvasive PET imaging of HER2 expression: from patient-derived xenograft models to gastric cancer patients.

PURPOSE: Here, we sought to develop a PET radioligand based on trastuzumab labeled with 124I, 124I-trastuzumab, to evaluate its distribution, internal dosimetry, and initial PET images of HER2-positive lesions in gastric cancer (GC) patients. METHODS: In animal studies, micro-PET imaging and bio-distribution were performed to examine the specificity of 124I-trastuzumab in HER2-positive and HER2-negative mouse models. Subsequently, 124I-trastuzumab was applied in human clinic trial. Six gastric cancer patients with metastases underwent 124I-trastuzumab PET imaging, with 18F-FDG PET/CT in each to compare. RESULTS: In animal studies, PET imaging of 124I-trastuzumab showed significant higher tumor uptake than that of 124I-IgG1 in HER2-positive PDX mouse models at 24 h. The low tumor uptake of 124I-trastuzumab in HER2-negative PDX models further confirmed the specificity. In human clinical studies, 18 HER2-positive lesions and 11 HER2-negative lesions were evaluated in PET imaging analysis. The detection sensitivity of 124I-trastuzumab was 100% (18/18) at 24 h. The PET images showed significant difference in tumor uptake between HER2-positive and HER2-negative lesions at 24 h (SUVmax 7.83 ± 0.55 vs. 1.75 ± 0.29, p < 0.0001). Quite striking difference in tumor uptake was observed between 124I-trastuzumab and 18F-FDG (SUVmax 1.75 ± 0.29 vs. 6.46 ± 0.44, p < 0.0001) in HER2-negative lesions, further confirming the specific binding of 124I-trastuzumab in HER2-positive lesions. The radiation-absorbed dose was calculated to be 0.3011 ± 0.005 mSv/MBq. No toxicities or adverse effects were observed in any of the patients. CONCLUSION: The findings described here demonstrated that 124I-trastuzumab was feasible to detect HER2-positive lesions in primary and metastatic gastric cancer patients and to differentiate HER2-positive and HER2-negative lesions quantitatively.