The radiological characteristics, tertiary lymphoid structures, and survival status associated with EGFR mutation in patients with subsolid nodules like stage I-II LUAD.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for the patients with subsolid nodule in early lung cancer stage is not routinely. The clinical value and impact in patients with EGFR mutation on survival outcomes is further needed to be elucidated to decide whether the application of EGFR-TKIs was appropriate in early lung adenocarcinoma (LUAD) stage appearing as subsolid nodules. MATERIALS AND METHODS: The inclusion of patients exhibiting clinical staging of IA-IIB subsolid nodules. Clinical information, computed tomography (CT) features before surgical resection and pathological characteristics including tertiary lymphoid structures of the tumors were recorded for further exploration of correlation with EGFR mutation and prognosis. RESULTS: Finally, 325 patients were enrolled into this study, with an average age of 56.8 ± 9.8 years. There are 173 patients (53.2%) harboring EGFR mutation. Logistic regression model analysis showed that female (OR = 1.944, p = 0.015), mix ground glass nodule (OR = 2.071, p = 0.003, bubble-like lucency (OR = 1.991, p = 0.003) were significant risk factors of EGFR mutations. Additionally, EGFR mutations were negatively correlated with TLS presence and density. Prognosis analysis showed that the presence of TLS was associated with better recurrence-free survival (RFS)(p = 0.03) while EGFR mutations were associated with worse RFS(p = 0.01). The RFS in patients with TLS was considerably excel those without TLS within EGFR wild type group(p = 0.018). Multivariate analyses confirmed that EGFR mutation was an independent prognostic predictor for RFS (HR = 3.205, p = 0.037). CONCLUSIONS: In early-phase LUADs, subsolid nodules with EGFR mutation had specific clinical and radiological signatures. EGFR mutation was associated with worse survival outcomes and negatively correlated with TLS, which might weaken the positive impact of TLS on prognosis. Highly attention should be paid to the use of EGFR-TKI for further treatment as agents in early LUAD patients who carrying EGFR mutation.

Clinical characteristics and therapeutic effects of checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer.

BACKGROUND: With the application of immune checkpoint inhibitors (ICIs) in cancer treatment, more and more attention has been paid to checkpoint inhibitor-related pneumonitis (CIP), which requires a better understanding of its clinical characteristics and therapeutic effects. METHODS: The clinical and imaging data of 704 patients with non-small cell lung cancer (NSCLC) who received immunotherapy were analyzed retrospectively; the clinical characteristics of CIP were summarized, and the therapeutic regimens and effects of the patients were summarized. RESULTS: 36 CIP patients were included in the research. The most common clinical symptoms were cough, shortness of breath and fever. The CT manifestations were summarized as follows: Organizing pneumonia (OP) in 14 cases (38.9%), nonspecific interstitial pneumonia (NSIP) in 14 cases (38.9%), hypersensitiviy pneumonitis(HP) in 2 cases (6.3%), diffuse alveolar damage in 1 case (3.1%) and atypical imaging manifestations in 5 cases (13.9%). 35 cases received glucocorticoid therapy, 6 patients were treated with gamma globulin and 1 patient was treated with tocilizumab. There were no deaths in CIP G1-2 patients and 7 deaths occured in CIP G3-4 patients. 4 patients were treated again with ICIs. CONCLUSION: We found that glucocorticoid 1-2 mg/kg was effective for most patients with moderate to severe CIP, and a few patients with hormone insensitivity needed early immunosuppressive therapy. A few patients can be rechallenged with ICIs, but CIP recurrence needs to be closely monitored.

Comparisons of lymphocytes profiles and inflammatory cytokines levels in blood of patients with differed severity of infection by human adenovirus type 7.

BACKGROUND: Human adenovirus (HAdV) infection outbreak causes community-acquired pneumonia. Cellular immune dysfunction and hypercytokinemia play important roles in the pathogenesis of adenovirus respiratory infection. Some soluble factors in peripheral blood can assist in judging the virus-induced disease severity. The expression levels of inflammatory cytokines differ among patients with different disease severity. However, whether and how HAdV-7 infection influences the composition of blood immune cells and serum cytokine levels in patients at different disease stages, as well as the diagnosis values of these parameters, have rarely been intensively studied. We aimed to investigate lymphocytes profiles and cytokines levels in blood of patients at different disease stages upon human adenovirus type 7 (HAdV-7) infections, and explored the diagnosis values of the investigated parameters. METHODS: Patients from two outbreaks of HAdV-7 in military of China were categorized into upper respiratory infection (URI) group, common pneumonia (CP) group and severe pneumonia (SP) group according to disease severity. Peripheral blood samples were subjected to routine laboratory tests, while flow cytometry and ELISA were used to measure the lymphocyte subsets and cytokines in blood, respectively. The receiver operating characteristic (ROC) curves were performed to examine the diagnostic of these blood parameters. RESULTS: Signs of imbalanced lymphocytes composition and hypercytokinemia were observed in HAdV-7-infected patients. The percentages of CD3+ T cells and NK cells were significantly decreased along with the aggravation of the disease, particularly for NK cells and CD4+ T cells. The neutrophil to lymphocyte ratio (NLR) increased significantly in patients with more severe disease. In addition, the levels of serum CXCL10, IL-2 and TNF-α were positively correlated with disease severity, while reduced levels of IFN-γ and IL-10 were found in SP patients. Furthermore, analysis of ROC showed that multiple parameters including the percentage of blood CD3+ cells and serum CXCL10 level could predict the progression of HAdV-7 infection. CONCLUSION: Imbalance of immune state with hypercytokinemia occurred during HAdV-7 infection. The percentages of blood immune cells such as CD3+ T cells and the levels of serum cytokines such as CXCL10 showed potential diagnosis values in HAdV-7 infection.

The prognosis of different types of pleural tags based on radiologic-pathologic comparison.

OBJECTIVES: There are increasing numbers of studies of pleural tags (PTs). The purpose of this case series was to classify the PTs in patients with peripheral pulmonary adenocarcinoma based on radiologic-pathologic comparison and to study the prognosis. METHODS: The clinical, imaging, pathological and prognostic data of 161 patients with peripheral pulmonary adenocarcinoma in three hospitals were analyzed retrospectively. We classified PTs using computed tomography (CT) for pathologic comparison. RESULTS: According to the relationship between tumors and pleural on CT images, PTs were classified into four types: type 1, one or more linear pleural tag; type 2, one or more linear pleural tag with soft tissue component at the pleural end; type 3, one soft tissue cord-like pleural tag; type 4, directly abutting the visceral pleura, pulling or pushing the visceral pleura. In these PTs, the incidence of visceral pleural invasion (VPI) was high in type 2 (46.88%) and type 3 (56.41%) of PTs. Our prognostic analysis showed that micropapillary or solid histological subtype (HR = 5.766, 95% CI: 1.435-23.159, P = 0.014) and type 3 of PTs (HR = 11.058, 95% CI: 1.349-90.623, P = 0.025) were two independent risk factors for tumor progression. CONCLUSIONS: PT is a risk factor for poor prognosis in patients with peripheral pulmonary adenocarcinoma, the presence of which on CT images can remind us to provide patients with a more reasonable treatment.

Significance of differential expression profiles of ABC transporters in azole susceptibility between Cryptococcus gattii VGI and VGII strains.

Azoles were used as the primary antifungal agents to treat the Cryptococcus gattii infection. Evidence showed that subtypes of C. gattii respond differently to azoles, but the mechanism is largely elusive. In this study, we aimed to find the mechanisms of differences in azole drug susceptibility in different subtypes of C. gattii. Eight clinical strains of C. gattii were collected for molecular typing, multilocus sequence typing (MLST) analysis, and antifungal susceptibility testing. Based on drug susceptibility differences, the RNA sequencing data were analyzed to find candidate azole drug susceptibility genes, and qPCR validation was performed. Five VGI subtypes and three VGII subtypes were identified among the eight strains of C. gattii. The clinical isolates showed high genetic diversity, and seven sequence types (STs) were identified. The geometric mean (GM) of minimum inhibitory concentration (MIC) for fluconazole, voriconazole, and itraconazole of VGI subtype was significantly lower than that of VGII subtype, and genes related to transporter activities were differentially expressed between VGI and VGII strains. The results of the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs (differential expressed genes) were found to be enriched in multiple ABC transporters. We further performed qPCR to quantify the expression level of seven ABC transporters. We found that ABC transporters ATM1, MDR1, PDR5, PDR5-3, and PXA2 were expressed significantly higher in VGII strains than in VGI strains. Our work revealed four novel ABC transporters, ATM1, PDR5, PDR5-3, and PXA2, promising candidate targets regulating azole susceptibility in C. gattii strains. LAY SUMMARY: Azoles were used as the primary antifungal agents for treating Cryptococuss gattii infection. Since subtypes of C. gattii respond differently to azoles. We analyzed mRNA expression profiles of different subtypes and identified four ABC transporters that could be potential genes regulating azole sensitivity.

Consolidation radiographic morphology can be an indicator of the pathological basis and prognosis of partially solid nodules.

BACKGROUND: Part-solid nodules (PSNs) have gradually shifted to defining special clinical subtypes. Commonly, the solid portions of PSNs show various radiological morphologies, of which the corresponding pathological basis and prognosis are unclear. We conducted a radiological-pathological evaluation to determine the histopathologic basis of different consolidation radiographic morphologies related to prognosis. MATERIALS AND METHODS: A cohort of 275 patients with a surgical pathological diagnosis of lung adenocarcinoma were enrolled. Preoperative computed tomography (CT) images of the PSNs were recorded and assessed. A panel of 103 patients with complete pathological specimens was selected to examine the radiological-pathological associations, and follow-up was performed to identify the prognosis. RESULTS: Of the 275 patients, punctate consolidation was observed radiologically in 43/275 (15.7%), stripe consolidation in 68/275 (24.7%), and irregular consolidation in 164/275 (59.6%) patients. The radiological morphology of the solid components was significantly associated with the histopathological subtypes (P < 0.001). Visual punctate solid components on CT correlated with tertiary lymphoid structures, stripe solid components on CT correlated with fibrotic scar, and irregular solid components on CT correlated with invasion. PSNs with regular consolidation had a better prognosis than those with irregular consolidation. CONCLUSION: Radiological morphology of solid components in PSNs can indicate the pathological basis and is valuable for prognosis. In particular, irregular solid components in PSNs usually indicate serious invasive growth, which should be taken with caution during assessment.

Gene, virulence and related regulatory mechanisms in Cryptococcus gattii.

Cryptococcus gattii is a kind of basidiomycetous yeast, which grows in human and animal hosts. C. gattii has four distinct genomes, VGI/AFLP4, VGII/AFLP6, VGIII/AFLP5, and VGIV/AFLP7. The virulence of C. gattii is closely associated with genotype and related stress-signaling pathways, but the pathogenic mechanism of C. gattii has not been fully identified. With the development of genomics and transcriptomics, the relationship among genes, regulatory mechanisms, virulence, and treatment is gradually being recognized. In this review, to better understand how C. gattii causes disease and to characterize hypervirulent C. gattii strains, we summarize the current understanding of C. gattii genotypes, phenotypes, virulence, and the regulatory mechanisms.

Radiographic features and prognosis of early- and late-onset non-small cell lung cancer immune checkpoint inhibitor-related pneumonitis.

BACKGROUND: Immunotherapy is becoming a standard of care for non-small cell lung cancer (NSCLC). Checkpoint inhibitor-associated pneumonia (CIP) is a rare and potentially life-threatening event that can occur at any time during tumor immunotherapy. However, there may be differences in the radiological patterns and prognosis of CIP during different periods. This study aimed to investigate the radiographic features and prognosis of early- and late-onset immune-related pneumonitis. METHODS: We retrospectively analyzed the clinical data of 677 NSCLC patients receiving immunotherapy to identify 32 patients with CIP, analyzed the clinical and radiographic data, and summarized the radiological features and prognosis of early- and late-onset CIP. RESULTS: CIP had an incidence of 4.7%, a median onset time of 10 weeks, and a mortality of 28.1%. Among these, CIP included 14 early-onset cases, where grade ≥ 3 CIP accounted for 92.9%, main radiographic pattern was organizing pneumonia (OP)-like pattern, and mortality was 50.0%. We also identified 18 late-onset CIPs, where grade ≥ 3 CIP accounted for 50.0%, main radiographic pattern was nonspecific interstitial pneumonia (NSIP)-like pattern, and mortality was 11.1%. The overall survival rate of the early-onset group was significantly lower than that of the late-onset group (P < 0.05). CONCLUSION: Early-onset CIP cases were higher in the Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade and mainly presented with an OP-like radiographic pattern; whereas, late-onset CIP cases were lower in CTCAE grade and mainly presented with an NSIP-like radiographic pattern. Finally, the prognosis of the early-onset CIP group was poorer than that of the late-onset CIP group. We believe that this study will be helpful for clinicians for making early diagnosis and deciding treatment modalities for patients with CIP.

Pulmonary mucosa-associated lymphoid tissue lymphoma: CT findings and pathological basis.

BACKGROUND: Pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) is the most frequent subset of primary pulmonary lymphoma. This study aimed to identify radiologic characteristics of pulmonary MALToma based on computed tomography (CT) observations and pathologic features, and further investigate its prognosis. METHODS: Sixty-six patients (55.4 ± 10.9 years; 51.5% male) diagnosed as pulmonary MALToma by pathology were retrospectively enrolled. According to distributions and features of lesions shown on CT, patients were divided into three patterns, including single nodular/mass, multiple nodular/mass, and pneumonia-like consolidative. RESULTS: Variety of the location and extent of the lymphomatous infiltration accounted for different characteristics demonstrated at CT. The pneumonia-like consolidative pattern was the most frequent pattern observed in 42 patients (63.6%), followed by single nodular/mass (21.2%) and multiple nodular/mass (15.2%). CT features included air bronchogram (72.7%), well-marginated halo sign (53.0%), coarse spiculate with different lengths (72.7%), angiogram sign (77.1% of 35 patients), peribronchovascular thickening (48.5%), irregular cavitation (16.7%) and pulmonary cyst (7.6%). The estimated 5-year cumulative overall survival rate of pulmonary MALToma was 100.0%. CONCLUSIONS: Pulmonary MALToma demonstrates several characteristics at CT. Identification of the significant pulmonary abnormalities of this indolent disease entity might be helpful for early diagnosis and optimal treatment.

Exosomal miRNA profiling before and after surgery revealed potential diagnostic and prognostic markers for lung adenocarcinoma.

Exosome is a crucial manner for cancer cell to cell communication and circulating exosomes sever as promising diagnostic and prognostic markers for various types of diseases. A predominant type of cargo of exosome is small RNAs, especially miRNAs. Here, we profiled plasma exosomal miRNAs of six lung adenocarcinoma patients before and after surgery, as well as six healthy individuals as normal control. Our profiling revealed 38 upregulated and 37 downregulated exosomal miRNAs in the plasma of lung adenocarcinoma patients. Additionally, we found that most upregulated miRNAs were increased in the lung adenocarcinoma samples of TCGA database. We further evaluated the correlation between the upregulated exosomal miRNAs and overall survival with Kaplan-Meier survival analysis using online databases. Our results suggested that exosomal miR-151a-5p, miR-10b-5p, miR-192-5p, miR-106b-3p, and miR-484 are potential prognostic markers for lung adenocarcinoma. Importantly, we validated candidate miRNAs in lung adenocarcinoma patients before and after surgery as well as in healthy controls and found that miR-484 was significantly increased in the plasma of lung adenocarcinoma patients and strikingly decreased post-surgery. Hence, we provided novel information on lung adenocarcinoma-derived exosomal miRNA and potential non-invasive diagnostic and prognostic markers for lung adenocarcinoma.

Comparative study of imaging and pathology of primary mucinous adenocarcinoma with different imaging manifestations.

BACKGROUND: Pulmonary mucinous adenocarcinoma is a special type of lung cancer. Its imaging manifestations are diverse, which brings challenges to clinical diagnosis. However, its formation mechanism is unclear. OBJECTIVE: The objective of this study is to analyse the relevant mechanisms of the formation of pulmonary mucinous adenocarcinoma by observing its different imaging and pathological manifestations. DATA AND METHODS: Retrospective analysis was conducted on imaging manifestations and pathological data of 103 patients with pulmonary mucinous adenocarcinoma confirmed intraoperatively or pathologically. RESULTS: Forty-three patients had pulmonary mucinous adenocarcinoma with a solitary nodule/mass, 41 patients with localized pneumonia and 19 patients with diffuse pneumonia. Their CT manifestations included 'falling snowflake sign', ground-glass opacity close to the heart, vacuous signs/honeycombing and withered tree branches. Under the microscope, all the three types of pulmonary mucinous adenocarcinoma had visibly formed mucus lakes but were made of tumour cells with totally different shapes, which included the goblet-like shape (tall column-like shape) and quasi-circular shape. Tall column-shaped tumour cells were negative or weakly positive for thyroid transcription factor-1 (TTF-1) and strongly positive for ALK mutation, whereas quasi-circular tumour cells were positive for TTF-1 and less positive for ALK mutation. CONCLUSION: The different imaging manifestations of mucinous adenocarcinoma are possibly due to the different amounts or viscosity of mucus produced, and the mechanisms of its formation may include (1) tumour cells in different shapes have different abilities to produce mucus; (2) tumours in different stages produce different amounts or viscosity of mucus; and (3) the TTF-1 and ALK genes affect the production of mucus.

Immune-related adverse events in non-small cell lung cancer: Occurrence, mechanisms and therapeutic strategies.

The emergence of immune checkpoint inhibitors (ICIs) has heralded a transformative era in the therapeutic landscape of non-small cell lung cancer (NSCLC). While ICIs have demonstrated clinical efficacy in a portion of patients with NSCLC, these treatments concurrently precipitate a spectrum of immune-related adverse events (irAEs), encompassing mild to severe manifestations, collectively posing a risk of significant organ damage. Consequently, there exists an imperative to augment our comprehension of the pathophysiological underpinnings of irAEs and to formulate more efficacious preventive and ameliorative strategies. In this comprehensive review, we delineate the clinical presentation of organ-specific irAEs in patients with NSCLC and provide an in-depth analysis of recent advancements in understanding the mechanisms driving ICI-induced toxicity. Furthermore, we discuss potential strategies and targets for ameliorating these irAEs. Ultimately, this review aims to furnish valuable insights to guide further research endeavours in the context of irAEs in NSCLC patients.

Indirubin-3'-monoxime exhibits potent antiviral and anti-inflammatory effects against human adenoviruses in vitro and in vivo.

Human adenovirus (HAdV) infection is a major cause of respiratory disease, yet no antiviral drugs have been approved for its treatment. Herein, we evaluated the antiviral and anti-inflammatory effects of cyclin-dependent protein kinase (CDK) inhibitor indirubin-3'-monoxime (IM) against HAdV infection in cells and a transgenic mouse model. After evaluating its cytotoxicity, cytopathic effect reduction, antiviral replication kinetics, and viral yield reduction assays were performed to assess the anti-HAdV activity of IM. Quantitative real-time polymerase chain reaction (qPCR), quantitative reverse transcription PCR (qRT-PCR), and western blotting were used to assess the effects of IM on HAdV DNA replication, transcription, and protein expression, respectively. IM significantly inhibited HAdV DNA replication as well as E1A and Hexon transcription, in addition to significantly suppressing the phosphorylation of the RNA polymerase II C-terminal domain (CTD). IM mitigated body weight loss, reduced viral burden, and lung injury, decreasing cytokine and chemokine secretion to a greater extent than cidofovir. Altogether, IM inhibits HAdV replication by downregulating CTD phosphorylation to suppress viral infection and corresponding innate immune reactions as a promising therapeutic agent.

Computed tomography (CT) characteristics and pathologic basis of ciliated muconodular papillary tumors of the lung.

Background: Ciliated muconodular papillary tumor (CMPT) is a rare pulmonary tumor with papillary architecture. Most studies have focused on the clinicopathological features of CMPT, while computed tomography (CT) characteristics have rarely been systematically described. Methods: A cohort of 27 patients with surgically resected CMPT were identified. Clinical and demographic features were recorded. Preoperative CT images of the CMPTs and the corresponding histopathological basis were also retrospectively analyzed. Results: All of the tumors appeared as solitary nodules. Pure ground glass, part-solid nodules and solid nodules were detected in 2/27 (7.4%), 17/27 (63.0%), and 8/27 (29.6%) patients, respectively. Twenty-one tumors (77.8%) were located in the lower lobe. The average tumor size was 1.21±0.74 (range, 0.44-3.46) cm. Eighteen (66.7%) of the 27 patients had tumors with well-defined margins and lobulated contours. Fifteen patients (55.6%) had air bronchograms in the tumor, and 19 patients (70.4%) had air-containing space. There were two patients whose tumor size was enlarged and accompanied by an increase in solid components, and one patient simply had an increase in tumor size at the preoperative follow-up duration. Notably, one patient with solid tumor components was finally diagnosed with CMPT accompanied by adenocarcinoma. Conclusions: CMPTs of the lung mostly manifest as solitary, lobulated, well-defined tumors with air-containing spaces on CT and often occur in the periphery of the pulmonary lower lobe. When CT findings meet these criteria, the possibility of CMPT should be considered. Additionally, CMPT can coexist with adenocarcinoma. Further investigation will contribute significantly to the biological properties of CMPT and its relationship to the potential for malignant transformation.

The Relationship between the Outdoor School Violence Distribution and the Outdoor Campus Environment: An Empirical Study from China.

It is widely believed that outdoor environmental design contributes to outdoor violence prevention. To enhance the effectiveness of environmental design, the intrinsic link between the outdoor school violence distribution (OSVD) and the outdoor campus environment (OCE) should be fully considered. For this purpose, this study investigated boarding school L, located in southern Zhejiang Province of China, through a questionnaire and Spatial Syntax theory. Based on the questionnaire marker method (N = 338, 50.59% female), the OSVD was mapped using the kernel density estimation in ArcGIS, including four types of teacher-student conflict: verbal bullying, physical conflict, and external intrusion. The spatial analysis of the OCE (spatial configuration and spatial visibility) then was generated by the DepthmapX, involving four spatial attributes such as integration, mean depth, connectivity, and visibility connectivity. Statistical analysis results indicated the correlation between the OSVD and both the spatial configuration and spatial visibility of the OCE. For the different violence types, there were differences in the impact relationships, with integration being a significant predictor of teacher-student conflict and physical conflict (p < 0.01) and a general predictor of verbal bullying (p < 0.05), while mean depth was a significant predictor of physical conflict (p < 0.01), but not recommended as a predictor of external intrusion. This study explores and predicts the relationship between the OSVD and the OCE, providing guidance and evidence for school violence prevention environmental design. It is a novel attempt, but still challenging and requires more research to refine.

PIWI-interacting RNAs in cancer: Biogenesis, function, and clinical significance.

PIWI-interacting RNAs (piRNAs) are a less-studied class of small non-coding RNAs approximately 24-31 nucleotides in length. They express in germline and somatic cells and form complexes with PIWI proteins to exert regulatory effects. New studies show that piRNAs are aberrantly expressed in various cancers. In this review, we focus on those piRNAs that are associated with cancer hallmarks such as proliferation, invasion, and chemoresistance and discuss their potential as biomarkers for cancer diagnosis and prognosis.

HMMR associates with immune infiltrates and acts as a prognostic biomaker in lung adenocarcinoma.

BACKGROUND: To explore the expression of hyaluronan mediated motility receptor (HMMR) in lung adenocarcinoma (LUAD) and its relationship with clinicopathological features and tumor-infiltrating is not clear. METHODS: The expression of HMMR in Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA)-LUAD. TCGA was employed to examine the relationship between the clinicopathological characteristics and HMMR expression and the LUAD patients' prognosis. Tumor Immune Estimation Resource (TIMER)database was employed to analyze the relationship between immune infiltration and HMMR. Gene Set Enrichment Analysis was explored through gene enrichment. Gene Expression Omnibus (GEO) data and our hospital data were utilized to confirm the findings. RESULTS: The expression level of HMMR in lung adenocarcinoma tissue and cells was greater than that in the normal group, which was linked to clinical stage, smoking history, and recurrence, and could increase the progression or recurrence of LUAD. Patients in the pathological grade had a significant expression of HMMR in moderately differentiated LUAD tissues. In addition, HMMR has an impact on LUAD patients' overall survival rate [P = 9.5e-06; hazard ratio (HR) = 2]. The level of HMMR expression in LUAD was significantly linked to neutrophils, CD8+T, and CD4+T cells. TMB analysis showed that HMMR could also affect the tumor microenvironment in LUAD. HMMR might be employed as an independent predictive biomarker of LUAD, according to a multivariate COX regression analysis. The findings of GSEA analysis showed that the samples with high HMMR expression levels were rich in cell cycle, cell metabolism, and DNA replication. The analysis results of GSE31210 data are basically consistent with those of TCGA-LUAD. CONCLUSIONS: It is suggested that HMMR has an effect on the occurrence and development of lung adenocarcinoma. Besides, HMMR is also linked to the level of immune infiltration of neutrophils, CD8+T cells, and CD4+T cells and LUAD patients' prognosis. HMMR was suggested to be utilized as a biomarker or therapeutic target to judge the prognosis and immune infiltration of LUAD.

Tertiary lymphoid structures in lung adenocarcinoma: characteristics and related factors.

OBJECTIVE: Tertiary lymphoid structures (TLSs) are found in a variety of malignancies and affect the growth of tumors, but few studies have addressed their role in lung adenocarcinoma (LAC). We aimed to evaluate clinical features associated with TLSs in patients with LAC. METHODS AND MATERIALS: A collection of resected pulmonary nodules in patients with LAC was retrospectively analyzed. TLSs were quantified by their number per square millimeter tumor area (density) and by the degree of lymphocyte aggregation (maturity) in each case. The correlation between TLS density and maturity and clinical features was calculated. RESULTS: A total of 243 patients were selected, of whom 219 exhibited TLSs. The occurrence of TLSs was correlated with computed tomography (CT) features as follows: pure ground-glass nodules (pGGNs) (n = 43) was associated with a lower occurrence rate than part-solid nodules (PSNs) (n = 112) and solid nodules (SNs) were (n = 88) (p = 0.037). TLS density was correlated with age and CT features. Poisson regression showed higher TLS density in PSNs and SNs than in pGGNs (incidence rate ratio [IRR]: 3.137; 95% confidence interval [CI]: 1.35-7.27; p = 0.008 and IRR: 2.44; 95% CI: 1.02-5.85; p = 0.046, respectively). In addition, TLS density was higher in patients aged under 60 years than in those aged over 60 years (IRR: 0.605; 95% CI: 0.4-0.92; p = 0.018). The maturity of TLSs was higher in patients with higher tumor stages (p = 0.026). CONCLUSIONS: We demonstrated distinct profiles of TLSs in early LAC and their correlations with CT features, age, and tumor stages, which could help understand tumor progression and management.

Mining whole-lung information by artificial intelligence for predicting EGFR genotype and targeted therapy response in lung cancer: a multicohort study.

BACKGROUND: Epidermal growth factor receptor (EGFR) genotype is crucial for treatment decision making in lung cancer, but it can be affected by tumour heterogeneity and invasive biopsy during gene sequencing. Importantly, not all patients with an EGFR mutation have good prognosis with EGFR-tyrosine kinase inhibitors (TKIs), indicating the necessity of stratifying for EGFR-mutant genotype. In this study, we proposed a fully automated artificial intelligence system (FAIS) that mines whole-lung information from CT images to predict EGFR genotype and prognosis with EGFR-TKI treatment. METHODS: We included 18 232 patients with lung cancer with CT imaging and EGFR gene sequencing from nine cohorts in China and the USA, including a prospective cohort in an Asian population (n=891) and The Cancer Imaging Archive cohort in a White population. These cohorts were divided into thick CT group and thin CT group. The FAIS was built for predicting EGFR genotype and progression-free survival of patients receiving EGFR-TKIs, and it was evaluated by area under the curve (AUC) and Kaplan-Meier analysis. We further built two tumour-based deep learning models as comparison with the FAIS, and we explored the value of combining FAIS and clinical factors (the FAIS-C model). Additionally, we included 891 patients with 56-panel next-generation sequencing and 87 patients with RNA sequencing data to explore the biological mechanisms of FAIS. FINDINGS: FAIS achieved AUCs ranging from 0·748 to 0·813 in the six retrospective and prospective testing cohorts, outperforming the commonly used tumour-based deep learning model. Genotype predicted by the FAIS-C model was significantly associated with prognosis to EGFR-TKIs treatment (log-rank p<0·05), an important complement to gene sequencing. Moreover, we found 29 prognostic deep learning features in FAIS that were able to identify patients with an EGFR mutation at high risk of TKI resistance. These features showed strong associations with multiple genotypes (p<0·05, t test or Wilcoxon test) and gene pathways linked to drug resistance and cancer progression mechanisms. INTERPRETATION: FAIS provides a non-invasive method to detect EGFR genotype and identify patients with an EGFR mutation at high risk of TKI resistance. The superior performance of FAIS over tumour-based deep learning methods suggests that genotype and prognostic information could be obtained from the whole lung instead of only tumour tissues. FUNDING: National Natural Science Foundation of China.

Cryptococcosis caused by cryptococcus gattii: 2 case reports and literature review.

Cryptococcosis caused by Cryptococcus gattii, is a life threatening fungal infection with recently increasing prevalence. C. gattii is a species complex comprising multiple independent species. However, many biological characteristics and clinical features of cryptococcosis due to C. gattii are relatively less well defined. In this paper, we identify two cases of C. gattii infection, and laboratory findings of genotype VGI and VGII in two groups of apparently immunocompetent Chinese individuals respectively. Upon detailed review of all 35 cases of C. gattii infections, it was observed that C. gattii can cause debilitating illness in both immunocompetent and immunocompromised individuals. Cryptococcosis due to C. gattii is a serious systemic fungal infection, with pulmonary central nervous system tropism. Epidemiologically, C. gattii infection is not only restricted in tropical and subtropical regions, but also in other geographical settings.