Comprehensive Genomic and Transcriptomic Analysis of Sclerosing Pneumocytoma.

Sclerosing pneumocytoma is a rare and distinct lung neoplasm whose histogenesis and molecular alterations are the subject of ongoing research. Our recent study revealed that AKT1 internal tandem duplications (ITD), point mutations, and short indels were present in almost all tested sclerosing pneumocytomas, suggesting that AKT1 mutations are a major driving oncogenic event in this tumor. Although the pathogenic role of AKT1 point mutations is well established, the significance of AKT1 ITD in oncogenesis remains largely unexplored. We conducted comprehensive genomic and transcriptomic analyses of sclerosing pneumocytoma to address this knowledge gap. RNA-sequencing data from 23 tumors and whole-exome sequencing data from 44 tumors were used to obtain insights into their genetic and transcriptomic profiles. Our analysis revealed a high degree of genetic and transcriptomic similarity between tumors carrying AKT1 ITD and those with AKT1 point mutations. Mutational signature analysis revealed COSMIC signatures 1 and 5 as the prevailing signatures of sclerosing pneumocytoma, associated with the spontaneous deamination of 5-methylcytosine and an unknown etiology, respectively. RNA-sequencing data analysis revealed that the sclerosing pneumocytoma gene expression profile is characterized by activation of the PI3K/AKT/mTOR pathway, which exhibits significant similarity between tumors harboring AKT1 ITD and those with AKT1 point mutations. Notably, an upregulation of SOX9, a transcription factor known for its involvement in fetal lung development, was observed in sclerosing pneumocytoma. Specifically, SOX9 expression was prominent in the round cell component, whereas it was relatively lower in the surface cell component of the tumor. To the best of our knowledge, this is the first comprehensive investigation of the genomic and transcriptomic characteristics of sclerosing pneumocytoma. Results of the present study provide insights into the molecular attributes of sclerosing pneumocytoma and a basis for future studies of this enigmatic tumor.

Dual-specificity phosphatases 22-deficient T cells contribute to the pathogenesis of ankylosing spondylitis.

BACKGROUND: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS). METHODS: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice. RESULTS: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral T cells were significantly higher in AS group than those of healthy controls (all p < 0.05), while DUSP22 (also named JKAP) mRNA levels were significantly lower in AS group than healthy controls (p < 0.001). The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in T cells were positively correlated with mRNA levels of tumor necrosis factor-α (TNF-α), whereas DUSP22 was inversely correlated (all p < 0.05). In addition, inverse correlations of DUSP22 gene expression in peripheral T cells with C-reactive protein, erythrocyte sedimentation rate, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were observed (all p < 0.05). More importantly, aged DUSP22 knockout mice spontaneously developed syndesmophyte formation, which was accompanied by an increase of TNF-α+, interleukin-17A+, and interferon-γ+ CD3+ T cells. CONCLUSIONS: DUSP22 may play a crucial role in the pathogenesis and regulation of disease activity of AS.

Constant p.L424H Mutation in GTF2I in Micronodular Thymomas With Lymphoid Stroma: Evidence Supporting Close Relationship With Type A and AB Thymomas.

Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I.

Genomic Profiling With Large-Scale Next-Generation Sequencing Panels Distinguishes Separate Primary Lung Adenocarcinomas From Intrapulmonary Metastases.

The distinction between different separate primary lung cancers (SPLCs) and intrapulmonary metastases (IPMs) is a challenging but clinically significant issue. Histopathology-based classification is the current practice; however, it is subjective and affected by interobserver variability. Recently, next-generation sequencing (NGS) panels have been used in lung cancer diagnostics. This study aimed to investigate the value of large-scale NGS panels for distinguishing between SPLCs and IPMs. A total of 32 patients with 69 lung adenocarcinomas were included. Comprehensive histopathologic assessments of multiple pulmonary adenocarcinomas were performed independently by 3 pathologists. The consensus of histopathologic classification was determined by a majority vote. Genomic analysis was performed using an amplicon-based large-scale NGS panel, targeting single-nucleotide variants and short insertions and deletions in 409 genes. Tumor pairs were classified as SPLCs or IPMs according to a predefined molecular classification algorithm. Using NGS and our molecular classification algorithm, 97.6% of the tumor pairs can be unambiguously classified as SPLCs or IPMs. The molecular classification was predictive of postoperative clinical outcomes in terms of overall survival (P = .015) and recurrence-free interval (P = .0012). There was a moderate interobserver agreement regarding histopathologic classification (κ = 0.524 at the tumor pair level). The concordance between histopathologic and molecular classification was 100% in cases where pathologists reached a complete agreement but only 53.3% where they did not. This study showed that large-scale NGS panels are a powerful modality that can help distinguish SPLCs from IPMs in patients with multiple lung adenocarcinomas and objectively provide accurate risk stratification.

Nuclear expression of AFF2 C-terminus is a sensitive and specific ancillary marker for DEK::AFF2 carcinoma of the sinonasal tract.

DEK::AFF2 carcinoma of the sinonasal tract is an emerging entity. The tumor is typically characterized by papillary proliferation of non-keratinizing squamous epithelial cells with monotonous cytologic features, which may mimic other sinonasal tumors. The confirmation of this gene fusion has thus far relied solely on next-generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). This current study aimed to validate an immunohistochemical assay for AFF2 C-terminus as an ancillary marker. We first analyzed publicly available RNA sequencing data of sinonasal tumors from the national center for biotechnology information (NCBI) sequence read archive and identified 3 DEK::AFF2 carcinomas out of 28 sinonasal tumors. The gene expression of AFF2 was significantly higher in the fusion-positive cases compared to the wild-type tumors (p < 0.001), while DEK was not. We then optimized an immunohistochemical assay with an anti-AFF2 C-terminus antibody for ancillary diagnosis. Seventeen DEK::AFF2 carcinomas, including 11 cases with predominantly low-grade morphology and one showing glandular differentiation, as well as 78 DEK FISH-negative sinonasal tumors were evaluated by AFF2 immunohistochemistry (IHC). Sixteen of the 17 DEK::AFF2 carcinomas showed nuclear AFF2 expression in ≥30% of tumor cells, including one decalcified case that failed FISH and RT-PCR confirmation. The one case that was negative for AFF2 IHC in the tumor cells also lacked expression in the internal positive control. It was thus considered a failure of the IHC rather than a truly negative case and was excluded from the statistical analysis. All DEK FISH-negative sinonasal tumors were negative for nuclear AFF2 expression. The nuclear expression of AFF2 IHC showed 100% sensitivity and specificity for DEK::AFF2 carcinoma. Accordingly, AFF2 IHC is a highly sensitive and specific ancillary marker that distinguishes DEK-AFF2 carcinoma from the other sinonasal tumors with overlapping morphological features and may be an especially useful alternative for decalcified specimens.

Treatment Patterns and Outcomes in Patients with Esophageal Cancer: An Analysis of a Multidisciplinary Tumor Board Database.

BACKGROUND: Multidisciplinary management strategies are standard in esophageal cancer. Based on a multidisciplinary tumor board (MTB) database in a high-volume center, we aimed to evaluate real-world treatment patterns and patient outcomes in patients with esophageal cancer. In addition, we determined the impact of MTB discussions on patient prognosis. METHODS: Patients diagnosed with esophageal cancer between 2010 and 2019 were retrospectively reviewed. The pattern of treatment modalities and overall survival (OS) of patients with limited, locally advanced, and advanced/metastatic disease were reported. RESULTS: Data from 1132 patients, including 247 patients with limited esophageal cancer, 606 patients with locally advanced esophageal cancer, and 279 patients with advanced/metastatic esophageal cancer were included. Upfront surgery was the most common (56.3%) treatment modality for patients with limited esophageal cancer, while treatment for locally advanced esophageal cancer included upfront surgery (19.1%), neoadjuvant chemoradiotherapy (44.9%), and definitive chemoradiotherapy (36.0%); however, 27.9% of patients undergoing neoadjuvant chemoradiotherapy did not receive planned esophagectomy. Definitive chemoradiotherapy was mainly used for patients with locally advanced and advanced/metastatic disease, but had an incompletion rate of 22.0% and 33.7%, respectively. Regarding survival, the 5-year OS rates were 56.4%, 26.3%, and 5.1% in patients with limited, locally advanced, and advanced/metastatic disease, respectively. Additionally, patients whose clinical management was discussed in the MTB had a significantly better 5-year OS rate than the other patients (27.3% vs. 20.5%, p < 0.001). CONCLUSIONS: We report the real-world data of treatment patterns and patient outcomes in patients with esophageal cancer with respect to multidisciplinary management, and demonstrate the positive impact of MTB discussions on patient prognosis.

A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasis.

BACKGROUND: Metastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial-mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities are commonly correlated with tumor aggressiveness. However, the conclusive mechanisms indicating specific centrosomal proteins participated in tumor progression and metastasis remain largely unknown. METHODS: The expression levels of centriolar/centrosomal genes in various types of cancers were first examined by in silico analysis of the data derived from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and European Bioinformatics Institute (EBI) datasets. The expression of STIL (SCL/TAL1-interrupting locus) protein in clinical specimens was further assessed by Immunohistochemistry (IHC) analysis and the oncogenic roles of STIL in tumorigenesis were analyzed using in vitro and in vivo assays, including cell migration, invasion, xenograft tumor formation, and metastasis assays. The transcriptome differences between low- and high-STIL expression cells were analyzed by RNA-seq to uncover candidate genes involved in oncogenic pathways. The quantitative polymerase chain reaction (qPCR) and reporter assays were performed to confirm the results. The chromatin immunoprecipitation (ChIP)-qPCR assay was applied to demonstrate the binding of transcriptional factors to the promoter. RESULTS: The expression of STIL shows the most significant increase in lung and various other types of cancers, and is highly associated with patients' survival rate. Depletion of STIL inhibits tumor growth and metastasis. Interestingly, excess STIL activates the EMT pathway, and subsequently enhances cancer cell migration and invasion. Importantly, we reveal an unexpected role of STIL in tumor metastasis. A subset of STIL translocate into nucleus and associate with FOXM1 (Forkhead box protein M1) to promote tumor metastasis and stemness via FOXM1-mediated downstream target genes. Furthermore, we demonstrate that hypoxia-inducible factor 1α (HIF1α) directly binds to the STIL promoter and upregulates STIL expression under hypoxic condition. CONCLUSIONS: Our findings indicate that STIL promotes tumor metastasis through the HIF1α-STIL-FOXM1 axis, and highlight the importance of STIL as a promising therapeutic target for lung cancer treatment.

Economic Analysis of Exclusionary EGFR Test Versus Up-Front NGS for Lung Adenocarcinoma in High EGFR Mutation Prevalence Areas.

BACKGROUND: This study sought to determine whether exclusionary EGFR mutation testing followed by next-generation sequencing (NGS) is a cost-efficient and timely strategy in areas with high prevalence rates of EGFR mutation. METHODS: We developed a decision tree model to compare exclusionary EGFR testing followed by NGS and up-front NGS. Patients entered the model upon diagnosis of metastatic lung adenocarcinoma. Gene alterations with FDA-approved targeted therapies included EGFR, ALK, ROS1, BRAF, RET, MET, NTRK, and KRAS. Model outcomes were testing-related costs; time-to-test results; monetary loss, taking both costs and time into consideration; and percentage of patients who could be treated by FDA-approved therapies. Stacked 1-way and 3-way sensitivity analyses were performed. RESULTS: Exclusionary EGFR testing incurred testing-related costs of US $1,387 per patient, a savings of US $1,091 compared with the costs of up-front NGS. The time-to-test results for exclusionary EGFR testing and up-front NGS were 13.0 and 13.6 days, respectively. Exclusionary EGFR testing resulted in a savings of US $1,116 in terms of net monetary loss, without a reduction of patients identified with FDA-approved therapies. The EGFR mutation rate and NGS cost had the greatest impact on minimizing monetary loss. Given that the tissue-based NGS turnaround time was shortened to 7 days, up-front NGS testing would become the best strategy if its price could be reduced to US $568 in Taiwan. CONCLUSIONS: In areas with high prevalence rates of EGFR mutation, exclusionary EGFR testing followed by NGS, rather than up-front NGS, is currently a cost-efficient strategy for metastatic lung adenocarcinoma.

Integrative analyses of noncoding RNAs reveal the potential mechanisms augmenting tumor malignancy in lung adenocarcinoma.

Precise noncoding RNA (ncRNA)-based network prediction is necessary to reveal ncRNA functions and pathological mechanisms. Here, we established a systemic pipeline to identify prognostic ncRNAs, predict their functions and explore their pathological mechanisms in lung adenocarcinoma (LUAD). After in silico and experimental validation based on evaluations of prognostic value in multiple LUAD cohorts, we selected the PTTG3P pseudogene from among other prognostic ncRNAs (MIR497HG, HSP078, TBX5-AS1, LOC100506990 and C14orf64) for mechanistic studies. PTTG3P upregulation in LUAD cells shortens the metaphase to anaphase transition in mitosis, increases cell viability after cisplatin or paclitaxel treatment, facilitates tumor growth that leads to poor survival in orthotopic lung models, and is associated with a poor survival rate in LUAD patients in the TCGA cohort who received chemotherapy. Mechanistically, PTTG3P acts as an ncRNA that interacts with the transcription factor FOXM1 to regulate the transcriptional activation of the mitotic checkpoint kinase BUB1B, which augments tumor growth and chemoresistance and leads to poor outcomes for LUAD patients. Overall, we established a systematic strategy to uncover prognostic ncRNAs with functional prediction methods suitable for pan-cancer studies. Moreover, we revealed that PTTG3P, due to its upregulation of the PTTG3P/FOXM1/BUB1B axis, could be a therapeutic target for LUAD patients.

[Experience Providing Psychological Care to an HIV-Positive Patient With SARS-CoV-2 Infection].

Infectious diseases are often stigmatized and criminalized because of the way they are transmitted. An experience providing care to a 37-year-old patient with human immunodeficiency virus (HIV) infection who was admitted to a medical center's quarantine ward in July 2021 due to SARS-CoV-2 infection is described in this article. This patient lived with his mother, who was later diagnosed with COVID-19 as well. He was worried about his mother's health condition and, meanwhile, feared that information about his diseases and person would be exposed by the media. These stressors led to increased feelings of shame and anxiety and to situational low self-esteem. Several interventions were provided, including education regarding the importance of personal hygiene and of maintaining combination antiretroviral therapy (cART) to bolster immune system functions. During the isolation period, the nurses most regularly interacted with the patient directly. Thus, we worked to build the nurse-patient relationship by listening to the patient's worries, guaranteeing his privacy would not be compromised, and guiding him to express his emotions to reduce anxiety and enhance confidence. This experience demonstrated the importance of providing psychological care to COVID-19/HIV co-infected patients. We suggest that the government and media distribute correct and neutral information to destigmatize communicable diseases and to foster a friendlier healthcare environment.

Alveolar adenoma and coexisting atypical adenomatous hyperplasia: a case report and literature review.

Alveolar adenoma is a rare tumour of the lung. It is typically found in asymptomatic adults as a peripheral or subplerual nodule on imaging examination. Microscopically, the tumour is composed of admixture of epithelial and mesenchymal component in variable sized cystic or alveolar structures. The tumour shows a benign nature. There have been no reported recurrences or metastases. Malignant transformation of alveolar adenoma and coexisting with lung carcinoma have been rarely described. In this article, we report a case of an alveolar adenoma and coexisting atypical adenomatous hyperplasia. This case, contributing to the limited numbers of cases described to date, illustrates the importance of awareness on the possibility of alveolar adenoma being associated with lung carcinoma and its precursor lesions especially when diagnosed by small biopsy specimens.

Clinicopathological Significance of Pathologic Complete Lymph Node Regression After Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Pathologic complete lymph node regression (LNR), where the lymph nodes show evidence of neoadjuvant treatment effect but have no viable residual tumor cells, is sometimes observed following neoadjuvant treatments and has been shown to be prognostic; conflicting results exist in the current literature. METHODS: Patients who received neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for squamous carcinoma (ESCC) were retrospectively reviewed and classified according to their LNR score; 0: N(-) with no evidence of tumor involvement or regression; 1: N(-) with evidence of complete regression; 2: N(+) with < 50% viable tumor; and 3: N(+) with > 50% viable tumor. RESULTS: In total, 136 patients, comprising 73, 25, 16, and 22 patients with LNR scores of 0, 1, 2, or 3, respectively, were included. Pathologic complete LNR (LNR 1) was significantly associated with lower risks of lymphovascular invasion (0%, p < 0.001) and perineural invasion (4%, p = 0.038), and a higher rate of pathologic complete response in the primary tumor (76%, p < 0.001). The 5-year overall survival rates were 42.1%, 52.8%, and 8.0% in patients with an LNR score of 0, 1, and 2/3, respectively (p < 0.001). There was no significant difference between patients with LNR scores of 0 and 1 in overall survival (p = 0.454), disease-free survival (p = 0.501), and cumulative incidence of recurrences (hazard ratio 0.84, 95% confidence interval 0.432-1.623, p = 0.601). CONCLUSIONS: Pathologic complete LNR could be an indicator of nCRT sensitivity and can be regarded as a good prognostic factor in patients with ESCC. In the survival curve analysis that included patients with lymph node regression (LNR) scores of 0 (blue), 1 (red), and 2/3 (green), we found that patients with pathologic complete LNR (LNR 1), which suggests prior positive nodal involvement, had similar outcomes as those without evidence of prior tumor involvement in lymph node (LNR0).

Active surveillance or early resection for ground-glass nodules that need preoperative localization.

INTRODUCTION: Few studies have investigated the impact of active surveillance on pathological outcome ground-glass nodules (GGNs). We focused on GGNs that needed preoperative localization before resection and compared the pathological results between GGNs that underwent early resection or active surveillance. METHODS: We retrospectively reviewed data of resected GGNs between January 2017 and December 2018. GGNs were classified by early resection (Group A) and active surveillance (Group B). Group B was subclassified as no (Group B1) and with (Group B2) growth, and intergroup comparison of pathological results was undertaken. RESULTS: In total, 509 GGNs (124, 275, and 110 in Groups A, B1, and B2, respectively) were included. Malignancy (primary lung cancer) ratios were 68% and 72% in Groups A and B (p = .312) and 65% and 92% in Groups B1 and B2, respectively (p < .001). The ratios of invasive carcinoma were 21.4%, 9.6%, and 35.6% in Groups A, B1, and B2, respectively. Predictors for invasive carcinoma included history of lung cancer, GGN size ≥ 10 mm, solid size ≥ 6 mm, and GGN growth. CONCLUSIONS: The pathological findings were similar for GGNs in the early resection and active surveillance groups. However, rates of malignancy and invasive carcinoma increased in the group that manifested growth during active surveillance.

Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: a potential role in severe COVID-19.

BACKGROUND: Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2. RESULTS: In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2. CONCLUSIONS: These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.

Ciliated muconodular papillary tumor/bronchiolar adenoma of the lung.

Ciliated muconodular papillary tumor (CMPT) is an uncommon tumor of the lung, usually detected incidentally in the peripheral lung fields on computed tomography. It is most commonly diagnosed in patients between the sixth and last decades of life. The canonical microscopic feature is a tripartite mixture of ciliated columnar, mucous, and basal cells with papillary architecture. However, studies have shown wide morphological variations in this tumor, such as a lack of ciliated columnar or mucous cells and flat instead of papillary architecture. Hence, a new umbrella term, bronchiolar adenoma (BA), has been proposed to encompass all tumors comprising a uniform layer of basal cells underneath the luminal epithelium displaying bronchiolar differentiation. Recent molecular studies on CMPT/BA discovered a high frequency of driver gene alterations, including mutations in the BRAF, EGFR, AKT1, KRAS, and HRAS genes, as well as ALK gene rearrangements. The tumor follows an indolent clinical course, as no recurrences or metastases have been reported in patients who underwent surgical resection. In this article we review the clinical, radiological, and pathological features, and molecular characteristics of CMPTs/BAs.

Complete and durable response to immune checkpoint inhibitor in a patient with refractory and metastatic hepatoblastoma.

We herein report the case of a girl with PRETEXT III hepatoblastoma (HB) developing recurrent lung metastases despite multiple chemotherapy regimens, aggressive tumor excision, multiple lung metastasectomies, and autologous peripheral blood stem cell transplantation. High tumor mutation burden (TMB) was identified through targeted next-generation sequencing, and pembrolizumab was administered post-operatively as a last resort. A complete and sustained response to the immune checkpoint inhibitor was achieved for 22 months. Although the majority of HB have a low TMB, immune checkpoint inhibitor therapy may be useful for patients with refractory HBs with a high TMB.

Gene Expression Profile in Primary Tumor Is Associated with Brain-Tropism of Metastasis from Lung Adenocarcinoma.

Lung adenocarcinoma has a strong propensity to metastasize to the brain. The brain metastases are difficult to treat and can cause significant morbidity and mortality. Identifying patients with increased risk of developing brain metastasis can assist medical decision-making, facilitating a closer surveillance or justifying a preventive treatment. We analyzed 27 lung adenocarcinoma patients who received a primary lung tumor resection and developed metastases within 5 years after the surgery. Among these patients, 16 developed brain metastases and 11 developed non-brain metastases only. We performed targeted DNA sequencing, RNA sequencing and immunohistochemistry to characterize the difference between the primary tumors. We also compared our findings to the published data of brain-tropic and non-brain-tropic lung adenocarcinoma cell lines. The results demonstrated that the targeted tumor DNA sequencing did not reveal a significant difference between the groups, but the RNA sequencing identified 390 differentially expressed genes. A gene expression signature including CDKN2A could identify 100% of brain-metastasizing tumors with a 91% specificity. However, when compared to the differentially expressed genes between brain-tropic and non-brain-tropic lung cancer cell lines, a different set of genes was shared between the patient data and the cell line data, which include many genes implicated in the cancer-glia/neuron interaction. Our findings indicate that it is possible to identify lung adenocarcinoma patients at the highest risk for brain metastasis by analyzing the primary tumor. Further investigation is required to elucidate the mechanism behind these associations and to identify potential treatment targets.

Human Costars Family Protein ABRACL Modulates Actin Dynamics and Cell Migration and Associates with Tumorigenic Growth.

Regulation of cellular actin dynamics is pivotal in driving cell motility. During cancer development, cells migrate to invade and spread; therefore, dysregulation of actin regulators is often associated with cancer progression. Here we report the role of ABRACL, a human homolog of the Dictyostelium actin regulator Costars, in migration and tumorigenic growth of cancer cells. We found a correlation between ABRACL expression and the migratory ability of cancer cells. Cell staining revealed the colocalization of ABRACL and F-actin signals at the leading edge of migrating cells. Analysis of the relative F-/G-actin contents in cells lacking or overexpressing ABRACL suggested that ABRACL promotes cellular actin distribution to the polymerized fraction. Physical interaction between ABRACL and cofilin was supported by immunofluorescence staining and proximity ligation. Additionally, ABRACL hindered cofilin-simulated pyrene F-actin fluorescence decay in vitro, indicating a functional interplay. Lastly, analysis on a colorectal cancer cohort demonstrated that high ABRACL expression was associated with distant metastasis, and further exploration showed that depletion of ABRACL expression in colon cancer cells resulted in reduced cell proliferation and tumorigenic growth. Together, results suggest that ABRACL modulates actin dynamics through its interaction with cofilin and thereby regulates cancer cell migration and participates in cancer pathogenesis.

AKT1 internal tandem duplications and point mutations are the genetic hallmarks of sclerosing pneumocytoma.

Sclerosing pneumocytoma is a unique benign neoplasm of the lungs. The molecular alterations in sclerosing pneumocytoma are not well understood. In a previous whole-exome sequencing study, recurrent AKT1 point mutation was observed in about half of the cases of sclerosing pneumocytoma. However, in the remaining half, cancer-related mutations have still not been identified. In this study, we first analyzed the raw sequence data from the previous whole-exome sequencing study (PRJNA297066 cohort). Using Genomon-ITDetector, a special software for detection of internal tandem duplications, we identified recurrent internal tandem duplications in the AKT1 gene in 22 of the 44 tumor samples (50%). All the cases positive for AKT1 internal tandem duplications lacked AKT1 point mutations. Next, we performed targeted next-generation sequencing in an independent cohort of sclerosing pneumocytoma from our hospital (VGH-TPE cohort), and again identified recurrent AKT1 internal tandem duplications in 20 of the 40 (50%) tumor samples analyzed. The internal tandem duplications resulted in duplications of 7 to 16 amino acids in a narrow region of the Pleckstrin homology domain of the AKT1 protein. This region contains the interaction interface between the Pleckstrin homology and kinase domains, which is known to play a critical role in the activation of the AKT1 protein. Moreover, we found that AKT1 internal tandem duplications were mutually exclusive of other forms of AKT1 mutations, including point mutations and short indels. Taking all forms of AKT1 mutations together, we detected AKT1 mutations in almost all the sclerosing pneumocytomas in our study (PRJNA297066 cohort: 41 out of 44 cases, 93%; VGH-TPE cohort: 40 out of 40 cases, 100%). Our results suggest that AKT1 mutation is the genetic hallmark of sclerosing pneumocytoma. These results would help in better understanding of the pathogenesis of sclerosing pneumocytoma.

CT-Guided Core Biopsy for Peripheral Sub-solid Pulmonary Nodules to Predict Predominant Histological and Aggressive Subtypes of Lung Adenocarcinoma.

BACKGROUND: Adenocarcinoma is the most common type of lung cancer, and pre-operative biopsy plays an important role to determine its major subtypes. As proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) in 2011, the predominant histological subtype of adenocarcinoma is an indicator of outcomes and recurrence rate. However, the value of CT-guided core biopsy in predicting the predominant subtype and detecting the presence of an aggressive subtype of adenocarcinoma, peripheral sub-solid nodule, has less been discussed. METHODS: We retrospectively reviewed 318 consecutive peripheral sub-solid nodules that underwent percutaneous CT-guided lung biopsy and surgical resection, between October 2015 and December 2018 and were diagnosed as adenocarcinoma with histological subtype. The subtyping results from biopsy and surgical pathology were compared to evaluate the concordance rate. RESULTS: The overall concordance rate between biopsy and surgical pathology in determining the predominant histological subtype was 64%. Better concordance was found in small tumors (≤ 2 cm), in predicting either predominant histology (χ2 = 7.091, P = 0.008) or high grade adenocarcinoma, micropapillary and/or solid subtype, MIP-SOL (χ2 = 22.301, P < 0.001). The analysis of ground glass opacity (GGO) component (C/T ratio) obtained significantly higher accuracy in the pure GGO group than in the other two groups in predicting predominant histology or high grade adenocarcinoma (χ2 = 17.560, P < 0.001 and χ2 = 61.938, P < 0.001, respectively). CONCLUSIONS: CT-guided core biopsies provide additional value in predicting the histological subtype of lung adenocarcinoma after surgical resection, especially in small tumors (≤ 2 cm) or an initially pure GGO group.