Histologic transformation of non-small-cell lung cancer in response to tyrosine kinase inhibitors: Current knowledge of genetic changes and molecular mechanisms.

Lung cancer is the leading cause of cancer death and includes two major types: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), accounting for 85% and 15% of cases, respectively. Non-small-cell lung cancer harboring actionable driver mutations is generally treated with tyrosine kinase inhibitors (TKIs) molecularly targeting individual oncogenes. Although TKIs have greatly contributed to better clinical outcomes, acquired resistance to them inevitably occurs. Histologic or lineage transformation is a rare but well-documented off-target mechanism associated with acquired resistance, and has been identified in settings following treatment with multiple different TKIs and other drugs. It includes neuroendocrine transformation, squamous cell transformation, and epithelial-to-mesenchymal transition. Here, we review the clinicopathologic features of transformed tumors and current understanding of the key genetic alterations and biologic mechanism of lineage transformation in NSCLC, particularly TKI-triggered transformation.

Regulation of the innate immune response and gut microbiome by p53.

p53 is a key tumor suppressor mutated in half of human cancers. In recent years, p53 was shown to regulate a wide variety of functions. From the transcriptome analysis of 24 tissues of irradiated mice, we identified 553 genes markedly induced by p53. Gene Ontology (GO) enrichment analysis found that the most associated biological process was innate immunity. 16S rRNA-seq analysis revealed that Akkermansia, which has anti-inflammatory properties and is involved in the regulation of intestinal barrier integrity, was decreased in p53-knockout (p53-/- ) mice after radiation. p53-/- mice were susceptible to radiation-induced GI toxicity and had a significantly shorter survival time than p53-wild-type (p53+/+ ) mice following radiation. However, administration of antibiotics resulted in a significant improvement in survival and protection against GI toxicity. Mbl2 and Lcn2, which have antimicrobial activity, were identified to be directly transactivated by p53 and secreted by liver into the circulatory system. We also found the expression of MBL2 and LCN2 was decreased in liver cancer tissues with p53 mutations compared with those without p53 mutations. These results indicate that p53 is involved in shaping the gut microbiome through its downstream targets related to the innate immune system, thus protecting the intestinal barrier.

Clinical usefulness of hypoxia imaging colonoscopy for the objective measurement of ulcerative colitis disease activity.

BACKGROUND AND AIMS: Colonic mucosal hypoxia is associated with mucosal inflammation in ulcerative colitis (UC). We aimed to assess the clinical usefulness of hypoxia imaging colonoscopy for the evaluation of clinical, endoscopic, and histologic disease activities of UC. METHODS: This retrospective cohort study comprised 100 consecutive patients with UC who underwent hypoxia imaging colonoscopy between September 2022 and September 2023 at the University of Tsukuba Hospital. Colonic tissue oxygen saturation (StO2) was measured at the biopsy sites, and StO2 values between different disease activities were compared. Receiver-operating characteristic (ROC) analysis was used to calculate the area under the ROC curve (AUROC). RESULTS: A significant correlation was identified between rectal StO2 and the Simple Clinical Colitis Activity Index, with moderate accuracy to predict bowel urgency at a 40.5% cutoff (AUROC, .74; 95% confidence interval [CI], .62-.87). Our analysis of 490 images showed median StO2 values for Mayo endoscopic subscores 0, 1, 2, and 3 as 52% (interquartile range [IQR], 48%-56%), 47% (IQR, 43%-52%), 42% (IQR, 38.8%-47%), and 39.5% (IQR, 37.3%-41.8%), respectively. Differences for all pairs were significant. Median StO2 was 49% (IQR, 44%-54%) for Geboes scores 0 to 2, significantly higher than histologically active disease (Geboes score ≥3). At a colonic StO2 cutoff of 45.5%, AUROCs for endoscopically and histologically active diseases were .79 (95% CI, .74-.84) and .72 (95% CI, .66-.77). CONCLUSIONS: StO2 obtained by hypoxia imaging colonoscopy is useful for assessing clinical, endoscopic, and histologic activities of UC, suggesting that StO2 may be a novel and objective endoscopic measurement.

High-efficiency EGFR genotyping using cell-free DNA in bronchial washing fluid.

BACKGROUND: EGFR mutation testing is required for treatment of lung adenocarcinoma using epidermal growth factor receptor-tyrosine kinase inhibitor. However, the amounts of tumor tissue or tumor cells obtained by bronchoscopy are often insufficient. Bronchial washing fluid, obtained by lavage with saline after tumor biopsy or brushing, and the supernatant of bronchial washing fluid are thought to contain cell-free DNA that would be potentially applicable for EGFR testing. METHODS: From among patients with suspected adenocarcinoma or non-small cell lung carcinoma diagnosed from biopsy or surgical specimens at the University of Tsukuba Hospital between 2015 and 2019, cell-free DNAs from 80 specimens of supernatant of bronchial washing fluid (50 with EGFR mutation and 30 with wild type EGFR) and 8 blood serum samples were examined for EGFR mutation using droplet digital PCR. RESULTS: Among the 50 patients harboring EGFR mutation, the rate of positivity for cell-free DNA extracted from supernatant of bronchial washing fluid was 80% (40/50). In nine of the EGFR mutation-positive cases, tumor cells were not detected by either biopsy or cytology, but the mutation was detected in four cases (4/9, 44%). Comparison of the cell-free DNA mutation detection rate between supernatant of bronchial washing fluid and blood serum in six cases showed that mutations were detected from the former in all cases (6/6, 100%), but from the latter in only one case (1/6, 17%). CONCLUSIONS: Using supernatant of bronchial washing fluid samples, the detection rate of EGFR mutation was high, and EGFR mutations were detectable even when no tumor cells had been detectable by biopsy or cytology. Supernatant of bronchial washing fluid might be an effective sample source for EGFR mutation testing.

High expression of eukaryotic elongation factor 1-alpha-2 in lung adenocarcinoma is associated with poor prognosis.

Eukaryotic elongation factor 1 alpha 2 (eEF1A2) encodes an isoform of the alpha subunit of the elongation factor 1 complex and is responsible for the enzymatic delivery of aminoacyl tRNA to the ribosome. Our proteomic analysis has identified eEF1A2 as one of the proteins expressed during malignant progression from adenocarcinoma in situ (AIS) to early invasive lung adenocarcinoma. The expression level of eEF1A2 in 175 lung adenocarcinomas was examined by immunohistochemical staining in relation to patient prognosis and clinicopathological factors. Quantitative PCR analysis and fluorescence in situ hybridization (FISH) were performed to evaluate the amplification of the eEF1A2 gene. Relatively high expression of eEF1A2 was observed in invasive adenocarcinoma (39/144 cases) relative to minimally invasive adenocarcinoma (1/10 cases) or AIS (0/21 cases). Among invasive adenocarcinomas, solid-type adenocarcinoma (15/32 cases, 47%) showed higher expression than other histological subtypes (23/92, 25%). Patients with eEF1A2-positive tumors had a significantly poorer prognosis than those with eEF1A2-negative tumors. Of the five tumors that were eEF1A2-positive, two cases showed amplified genomic eEF1A2 DNA, which was confirmed by both qPCR and FISH. These findings indicate that eEF1A2 overexpression occurs in the course of malignant transformation of lung adenocarcinomas and is partly due to eEF1A2 gene amplification.

Genetic and phenotypic determinants of morphologies in 3D cultures and xenografts of lung tumor cell lines.

We previously proposed the classification of lung adenocarcinoma into two groups: the bronchial epithelial phenotype (BE phenotype) with high-level expressions of bronchial epithelial markers and actionable genetic abnormalities of tyrosine kinase receptors and the non-BE phenotype with low-level expressions of bronchial Bronchial epithelial (BE) epithelial markers and no actionable genetic abnormalities of tyrosine kinase receptors. Here, we performed a comprehensive analysis of tumor morphologies in 3D cultures and xenografts across a panel of lung cancer cell lines. First, we demonstrated that 40 lung cancer cell lines (23 BE and 17 non-BE) can be classified into three groups based on morphologies in 3D cultures on Matrigel: round (n = 31), stellate (n = 5), and grape-like (n = 4). The latter two morphologies were significantly frequent in the non-BE phenotype (1/23 BE, 8/17 non-BE, p = 0.0014), and the stellate morphology was only found in the non-BE phenotype. SMARCA4 mutations were significantly frequent in stellate-shaped cells (4/4 stellate, 4/34 non-stellate, p = 0.0001). Next, from the 40 cell lines, we successfully established 28 xenograft tumors (18 BE and 10 non-BE) in NOD/SCID mice and classified histological patterns of the xenograft tumors into three groups: solid (n = 20), small nests in desmoplasia (n = 4), and acinar/papillary (n = 4). The latter two patterns were characteristically found in the BE phenotype. The non-BE phenotype exhibited a solid pattern with significantly less content of alpha-SMA-positive fibroblasts (p = 0.0004) and collagen (p = 0.0006) than the BE phenotype. Thus, the morphology of the tumors in 3D cultures and xenografts, including stroma genesis, reflects the intrinsic properties of the cancer cell lines. Furthermore, this study serves as an excellent resource for lung adenocarcinoma cell lines, with clinically relevant information on molecular and morphological characteristics and drug sensitivity.

HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability.

BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.

Trans-homophilic interaction of CADM1 promotes organ infiltration of T-cell lymphoma by adhesion to vascular endothelium.

The initial step of organ infiltration of malignant cells is the interaction with host vascular endothelial cells, which is often mediated by specific combinations of cell adhesion molecules. Cell adhesion molecule 1 (CADM1) is overexpressed in adult T-cell leukemia/lymphoma (ATL) and provides a cell-surface diagnostic marker. CADM1 promotes the adhesion of ATL cells to vascular endothelial cells and multiple organ infiltration in mice. However, its binding partner on host cells has not yet been identified. In this study, we show that CADM1 promotes transendothelial migration of ATL cells in addition to the adhesion to vascular endothelial cells. Moreover, CADM1 enhances liver infiltration of mouse T-cell lymphoma cells, EL4, after tail vein injection, whereas a CADM1 mutant lacking adhesive activity did not. Among the known CADM1-binding proteins expressed in primary endothelial cells, only CADM1 and CADM4 could induce morphological extension of ATL cells when plated onto glass coated with these proteins. Furthermore, CADM1-mediated liver infiltration of EL4 cells was canceled in conventional and vascular endothelium-specific Cadm1 knockout mice, whereas it was not canceled in Cadm4 knockout mice. These results suggest that CADM1 on host vascular endothelial cells is required for organ infiltration of ATL and other T-cell lymphomas expressing CADM1.

Immunological characteristics of severe acute hepatitis of unknown origin in a child post SARS-CoV-2 infection.

Recent studies have reported that pediatric acute liver failure of unknown origin is immune-mediated, with CD8+ T cells playing a key role. Moreover, investigation of superantigen-mediated T-cell activation by the SARS-CoV-2 spike protein in pediatric severe acute hepatitis is needed in the context of the proposed mechanism of multisystem inflammatory syndrome in children (MIS-C). We investigated the immunological characteristics of a Japanese pediatric patient with severe acute hepatitis post SARS-CoV-2 infection. The patient demonstrated autoimmune hepatitis-like liver histology with CD8+ lymphocyte-predominant infiltration. There was Th1-type immune skewing, including remarkable peripheral CD8+ T-cell activation and a skewed T cell receptor repertoire. We also found elevated plasma levels of the anti-SARS-CoV-2 spike-specific IgG antibody, and the titer peaked after treatment, as seen with MIS-C. These findings support that immunological activation involving SARS-CoV-2 spike protein plays a crucial role in a pediatric patient with acute severe hepatitis post SARS-CoV-2 infection.

Elastin in pulmonary pathology: relevance in tumours with a lepidic or papillary appearance. A comprehensive understanding from a morphological viewpoint.

Elastin and collagen are the main components of the lung connective tissue network, and together provide the lung with elasticity and tensile strength. In pulmonary pathology, elastin staining is used to variable extents in different countries. These uses include evaluation of the pleura in staging, and the distinction of invasion from collapse of alveoli after surgery (iatrogenic collapse). In the latter, elastin staining is used to highlight distorted but pre-existing alveolar architecture from true invasion. In addition to variable levels of use and experience, the interpretation of elastin staining in some adenocarcinomas leads to interpretative differences between collapsed lepidic patterns and true papillary patterns. This review aims to summarise the existing data on the use of elastin staining in pulmonary pathology, on the basis of literature data and morphological characteristics. The effect of iatrogenic collapse and the interpretation of elastin staining in pulmonary adenocarcinomas is discussed in detail, especially for the distinction between lepidic patterns and papillary carcinoma.

Continuous cyclosporine a infusion in patients with severe Kawasaki disease.

BACKGROUND: The efficacy and safety of continuous intravenous infusion of cyclosporine A (CICsA) in patients with intravenous immunoglobulin-resistant Kawasaki disease are unclear. METHODS: Between 2010 and 2020, 83 patients with Kawasaki disease that was not responsive to intravenous immunoglobulin (total dose ≥ 4 g/kg) were enrolled. All patients were started on CICsA (3 mg/kg/day) and switched to oral cyclosporine A (CsA) (4-6 mg/kg/day). Treatment efficacy, occurrence of coronary artery lesions (CALs), and laboratory parameters were evaluated. Patients were divided into two groups according to CICsA response: the responder group (afebrile ≤24 h after CICsA without additional treatment) and the weak responder group (afebrile >24 h after CICsA requiring additional treatment). RESULTS: Fifty-five patients became afebrile within 24 and 74 h became afebrile in less than 72 h. Adverse events included hypertension in four and hyperkalemia in two patients. Thirty-nine patients were defined as responders and 44 patients as weak responders. There were no significant differences in CAL between the two groups. In weak responders, white blood cells, neutrophils, and C-reactive protein levels were higher, and albumin, immunoglobulin G, and CsA concentration were lower than in responders, indicating that weak responders had more severe inflammatory findings. However, there were no significant differences in CAL. Logistic regression analysis revealed that the response to treatment for CICsA was associated with immunoglobulin G levels at baseline and CsA concentrations the day after CICsA. CONCLUSION: Although CICsA required additional treatments in about half of the cases, a favorable clinical course was observed by using this strategy, especially for reducing CAL.

Acute Perimyocarditis in an Adolescent Japanese Male after a Booster Dose of the BNT162b2 COVID-19 Vaccine.

Perimyocarditis is a rare and serious cardiac complication following COVID-19 vaccination. Young males are most at risk after the second dose. With the introduction of the booster (third) dose, some reports have focused on the risk of perimyocarditis after a booster dose. However, no currently available report in Japan has comprehensively described this phenomenon. A healthy 14-year-old Japanese male, who had completed a two-dose primary series of the BNT162b2 (Pfizer-BioNTech) vaccine six months prior, developed fever and chest pain within 24 hours after a homologous booster dose. He was transferred to our institute because of worsening chest pain. A multiplex PCR test showed no evidence of active viral infections, including SARS-CoV-2. Electrocardiography revealed ST-segment elevation in almost all leads, suggesting pericarditis. Echocardiography showed normal systolic function. Laboratory data demonstrated C-reactive protein levels of 8.8 mg/dL and elevated cardiac damage markers (troponin T, 1.9 ng/mL; creatine phosphokinase, 1527 U/L; MB isoenzyme, 120 U/L), suggesting myocarditis. He was diagnosed with perimyocarditis associated with the booster dose, which was confirmed by cardiac magnetic resonance imaging four days after initial symptoms. Chest pain improved spontaneously along with a resolution of electrocardiographic findings and laboratory data within several days. He was discharged eight days after admission. Perimyocarditis is less frequent after a booster dose than after primary doses. In this case, the patient with booster-dose-associated perimyocarditis showed favorable clinical course without severe sequelae. The patient's clinical course was consistent with findings on previous large-scale reports on primary-dose-associated perimyocarditis and case series on booster-dose-associated perimyocarditis.

Bilateral ovarian vein thrombosis without underlying conditions: A case report.

Ovarian vein thrombosis (OVT) usually occurs on the right side in women with underlying conditions such as pelvic diseases and thrombophilia or during the postpartum period. Here, we present a patient with bilateral OVTs without underlying conditions. A 63-year-old woman without remarkable past or family histories complained of mild lower abdominal pain. Computed tomography revealed bilateral OVTs, with the right-sided thrombus nearly progressing into the inferior vena cava. The presence of symptoms and risk of thrombus extension/pulmonary embolism (PE) led us to administer an oral anticoagulant (rivaroxaban) promptly. Her symptom improved gradually and bilateral OVTs disappeared by 3 months without any evidence of PE. The present case suggests that OVT can occur in a woman without underlying conditions, and the use of an anticoagulant may be a treatment option in such a case.

Short somatic alterations at the site of copy number variation in breast cancer.

Copy number variation (CNV) is a polymorphism in the human genome involving DNA fragments larger than 1 kb. Copy number variation sites provide hotspots of somatic alterations in cancers. Herein, we examined somatic alterations at sites of CNV in DNA from 20 invasive breast cancers using a Comparative Genomic Hybridization array specifically designed to detect the genome-wide CNV status of approximately 412 000 sites. Somatic copy number alterations (CNAs) were detected in 39.9% of the CNV probes examined. The most frequently altered regions were gains of 1q21-22 (90%), 8q21-24 (85%), 1q44 (85%), and 3q11 (85%) or losses of 16q22-24 (80%). Gene ontology analyses of genes within the CNA fragments revealed that cascades related to transcription and RNA metabolism correlated significantly with human epidermal growth factor receptor 2 positivity and menopausal status. Thirteen of 20 tumors showed CNAs in more than 35% of sites examined and a high prevalence of CNAs correlated significantly with estrogen receptor (ER) negativity, higher nuclear grade (NG), and higher Ki-67 labeling index. Finally, when CNA fragments were categorized according to their size, CNAs smaller than 10 kb correlated significantly with ER positivity and lower NG, whereas CNAs exceeding 10 Mb correlated with higher NG, ER negativity, and a higher Ki-67 labeling index. Most of these findings were confirmed or supported by quantitative PCR of representative DNA fragments in 72 additional breast cancers. These results suggest that most CNAs are caused by gain or loss of large chromosomal fragments and correlate with NG and several malignant features, whereas solitary CNAs of less than 10 kb could be involved in ER-positive breast carcinogenesis.

Oxytocin receptor is a promising therapeutic target of malignant mesothelioma.

Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G-protein-coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.

Tet2 deficiency in immune cells exacerbates tumor progression by increasing angiogenesis in a lung cancer model.

Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss-of-function TET2 mutations are frequently observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2-deficient immune cells in tumor tissues. Myeloid-specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single-cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2-deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2-deficient mice relative to controls. Finally, treatment of Tet2-deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2-mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2-mutated clonal hematopoiesis.

CADM1 promotes malignant features of small-cell lung cancer by recruiting 4.1R to the plasma membrane.

Cell adhesion molecule 1 (CADM1), which mediates intercellular adhesion between epithelial cells, is shown to be highly expressed in small-cell lung cancer (SCLC) and to enhance tumorigenicity of SCLC cells in nude mice. Here, we investigated the molecular mechanism underlying the oncogenic role of CADM1 in SCLC. CADM1 promoted colony formation of SCLC cells in soft agar. Analysis of deletion and point mutants of the conserved protein-binding motifs in CADM1 revealed that the 4.1 protein-binding motif in the cytoplasmic domain is responsible for the promotion of colony formation. Among the actin-binding 4.1 proteins, 4.1R was the only protein whose localization to the plasma membrane is dependent on CADM1 expression in SCLC cells. Knockdown of 4.1R suppressed the colony formation enhanced by CADM1, suggesting that 4.1R is required for the oncogenic role of CADM1 in SCLC. In primary SCLC, CADM1 expression was correlated with membranous localization of 4.1R, as was observed in a SCLC cell line. Moreover, membranous co-localization of CADM1 and 4.1R was associated with more advanced tumor stage. These results suggest that the formation of CADM1-4.1R complex would promote malignant features of SCLC.

Imaging of children with COVID-19: experience from a tertiary children's hospital in the United States.

BACKGROUND: Imaging of novel coronavirus disease 2019 (COVID-19) has been described in adults, but children have milder forms of disease. Pediatric imaging descriptions are of asymptomatic children, raising the question of whether imaging is needed in this patient group. OBJECTIVE: To describe the utilization and imaging findings in children with COVID-19 along with the comorbidities, treatment and short-term outcomes. MATERIALS AND METHODS: We retrospectively reviewed pediatric patients who had a confirmed positive test for COVID-19 during a 2-month period. We noted symptoms and presence of imaging at presentation. Comorbidities were recorded for children with imaging. Children were categorized as having multisystem inflammatory syndrome in children (MIS-C) if they met criteria for the disorder. For children who were admitted to the hospital, we documented length of hospital stay, need for intensive care unit care/ventilator support, and treatment regimen. We evaluated all imaging for acute/chronic abnormalities including chest radiographs for interstitial or alveolar opacities, distribution/symmetry of disease, zonal predominance, and pleural abnormalities. We performed descriptive statistics and compared children with MIS-C with the cohort using a Fisher exact test. RESULTS: During the study period, 5,969 children were tested for COVID-19, with 313 (5%) testing positive. Of these, 92/313 (29%) were asymptomatic and 55/313 (18%) had imaging and were admitted to the hospital for treatment. Forty-one of 55 patients (75%) with imaging had comorbidities. Chest radiographs were the most common examination (51/55 patients, or 93%) with most demonstrating no abnormality (34/51, or 67%). Children with MIS-C were more likely to have interstitial opacities and pleural effusions. US, CT or MRI was performed in 23/55 (42%) children, 9 of whom had MIS-C. Only one chest CT was performed. CONCLUSION: In our study, most pediatric patients with COVID-19 did not require hospital admission or imaging. Most children with imaging had comorbidities but children with MIS-C were more likely to have no comorbidities. Children with imaging mostly had normal chest radiography. Advanced imaging (US, CT, MRI) was less common for the care of these children, particularly CT examination of the chest and for children without MIS-C.

Reciprocal expression of trefoil factor-1 and thyroid transcription factor-1 in lung adenocarcinomas.

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor-1 (TTF-1)/NK2 homeobox 1 (NKX2-1)-positive terminal respiratory unit (TRU) types and rarely in non-TRU types. To elucidate the molecular characteristics of the major subtypes of non-TRU-type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non-TRU types). A characteristic of non-TRU-type cell lines was the strong expression of TFF-1 (trefoil factor-1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF-1 was positive in 31 cases (13%). Expression of TFF-1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF-1 correlated with the expression of HNF4-α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF-1/NKX2-1 (P < .0001). These results indicate that TFF-1 is characteristically expressed in non-TRU-type adenocarcinomas with gastrointestinal features. The TFF-1-positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF-1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF-1 inhibited cell proliferation and soft-agar colony formation and induced apoptosis in a TFF-1-high and KRAS-mutated lung adenocarcinoma cell line. These results indicate that TFF-1 is not only a biomarker, but also a potential molecular target for non-TRU-type lung adenocarcinomas.

CADM1 suppresses c-Src activation by binding with Cbp on membrane lipid rafts and intervenes colon carcinogenesis.

Cell adhesion molecules act as tumor suppressors primarily by cell attachment activity, but additional mechanisms modifying signal transduction are suggested in some cases. Cell adhesion molecule 1 (CADM1), a membrane-spanning immunoglobulin superfamily, mediates intercellular adhesion by trans-homophilic interaction and acts as a tumor suppressor. Here, we investigated CADM1-associated proteins comprehensively using proteomic analysis of immune-precipitates of CADM1 by mass spectrometry and identified a transmembrane adaptor protein, Csk-binding protein (Cbp), known to suppress Src-mediated transformation, as a binding partner of CADM1. CADM1 localizes to detergent-resistant membrane fractions and co-immunoprecipitated with Cbp and c-Src. Suppression of CADM1 expression using siRNA reduces the amount of co-immunoprecipitated c-Src with Cbp and activates c-Src in colon cancer cells expressing both CADM1 and Cbp. On the other hand, co-replacement of CADM1 and Cbp in colon cancer cells lacking CADM1 and Cbp expression suppresses c-Src activation, wound healing and tumorigenicity in nude mice. Furthermore, expression of Cbp and CADM1 was lost in 55% and 83% of human colon cancer, respectively, preferentially in tumors with larger size and/or lymph node metastasis. CADM1 would act as a colon tumor suppressor by intervening oncogenic c-Src signaling through binding with Cbp besides its authentic cell adhesion activity.