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Abstract Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-β-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients’ responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches.

Abstract Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

Abstract Background Myasthenia gravis (MG) is the most common paraneoplastic disorder associated with thymic neoplasms. MG can develop after thymectomy, and this condition is referred to post-thymectomy myasthenia gravis (PTMG). Diffuse panbronchiolitis (DPB), is a rare form of bronchiolitis and is largely restricted to East Asia, has been reported in association with thymic neoplasms. Only three cases of combined MG and DPB have been reported in the literature. Case presentation A 45-year-old Taiwanese woman presented to our hospital with productive cough, rhinorrhea, anosmia, ear fullness, shortness of breath, and weight loss. She had a history of thymoma, and she underwent thymectomy with adjuvant radiotherapy 7 years ago. Chest computed tomography scan revealed diffuse bronchitis and bronchiolitis. DPB was confirmed after video-assisted thoracoscopic surgery lung biopsy, and repeated sputum cultures grew Pseudomonas aeruginosa. She has been on long-term oral azithromycin therapy thereafter. Intravenous antipseudomonal antibiotics, inhaled amikacin, as well as oral levofloxacin were administered. Three months after DPB diagnosis, she developed ptosis, muscle weakness, and hypercapnia requiring the use of noninvasive positive pressure ventilation. MG was diagnosed based on the acetylcholine receptor antibody and repetitive stimulation test results. Her muscle weakness gradually improved after pyridostigmine and corticosteroid therapies. Oral corticosteroids could be tapered off ten months after the diagnosis of MG. She is currently maintained on azithromycin, pyridostigmine, and inhaled amikacin therapies, with intravenous antibiotics administered occasionally during hospitalizations for respiratory infections. Conclusions To our knowledge, this might be the first case report of sequential development of DPB followed by PTMG. The coexistence of these two disorders poses a therapeutic challenge for balancing infection control for DPB and immunosuppressant therapies for MG.

The anti-programmed death-ligand 1 (PD-L1) antibody is a standard therapy for advanced hepatocellular carcinoma (HCC). Tumor expression of PD-L1 can be induced upon stimulus. Because cyclin-dependent kinase 9 (CDK9) inhibition reduces the expression of inducible proteins, we explored the influence of CDK9 inhibition on PD-L1 expression in HCC cells. We found that PD-L1 expression was low in HCC cells; however, IFN-γ treatment increased this expression. CDK9 inhibitors AZD4573 and atuveciclib reduced the IFN-γ induced PD-L1 expression in a dose-dependent manner. CDK9 knockdown yielded similar results, but CDK9 overexpression reversed the influence of the CDK9 inhibitors. In the orthotopic mouse model, mice treated with a CDK9 inhibitor and an anti-PD-L1 antibody had significantly smaller tumors and exhibited longer survival than mice treated with either agent. In conclusion, CDK9 inhibition could reduce the expression of PD-L1 in HCC cells. Using both CDK9 inhibitors and anti-PD-L1 antibodies is more effective than using either agent alone.

Abstract Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in advanced esophageal squamous cell carcinoma (ESCC). Heterogeneous responses to ICIs have been reported previously. Here, we describe a patient with advanced ESCC exhibiting a response to durvalumab plus tremelimumab for more than 6 months except primary resistant esophageal tumor. The esophageal tumor had higher regulatory T cells, neutrophils, and mast cells scores estimated by NanoString platform than hepatic tumor. The immunohistochemistry study confirmed higher expression levels of Foxp3, and myeloperoxidase (MPO) in the esophageal tumor. The different immune contextures may underlie the heterogeneous responses to ICI combination in this ESCC patient.

Abstract Objective In lung cancer patients, most deaths are caused by the distant dissemination of cancer cells. Epithelial–mesenchymal transition (EMT) and collective cell migration are distinct and important mechanisms involved in cancer invasion and metastasis. Additionally, microRNA dysregulation contributes significantly to cancer progression. In this study, we aimed to explore the function of miR‐503 in cancer metastasis. Methods Molecular manipulations (silencing or overexpression) were performed to investigate the biological functions of miR‐503 including migration and invasion. Reorganization of cytoskeleton was assessed using immunofluorescence and the relationship between miR‐503 and downstream protein tyrosine kinase 7 (PTK7) was assessed using quantitative real‐time PCR, immunoblotting, and reporter assays. The tail vein metastatic animal experiments were performed. Results Herein, we demonstrated that the downregulation of miR‐503 confers an invasive phenotype in lung cancer cells and provided in vivo evidence that miR‐503 significantly inhibits metastasis. We found that miR‐503 inversely regulates EMT, identified PTK7 as a novel miR‐503 target, and showed the functional effects of miR‐503 on cell migration and invasion were restored upon reconstitution of PTK7 expression. As PTK7 is a Wnt/planar cell polarity protein crucial for collective cell movement, these results implicated miR‐503 in both EMT and collective migration. However, the expression of PTK7 did not influence EMT induction, suggesting that miR‐503 regulates EMT through mechanisms other than PTK7 inhibition. Furthermore, we discovered that PTK7 mechanistically activates focal adhesion kinase (FAK) and paxillin, thereby controlling the reorganization of the cortical actin cytoskeleton. Conclusion Collectively, miR‐503 is capable of governing EMT and PTK7/FAK signaling independently to control the invasion and dissemination of lung cancer cells, indicating that miR‐503 represents a pleiotropic regulator of cancer metastasis and hence a potential therapeutic target for lung cancer.

Determining the exact type of epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation in lung cancer has become important. We found that not all ex20ins mutations reported by cobas EGFR test v2 could be validated by Sanger sequencing even using surgical specimens with high tumor contents. This study aimed to validate the ex20ins results reported by the cobas test and to determine whether there were clinicopathological factors associated with aberrant cobas ex20ins report. In total, 123 cobas-reported cases with ex20ins were retrospectively collected and validated by Sanger sequencing and Idylla assay. Clinicopathological features between ex20ins cobas+/Sanger+ group (n = 71) and cobas+/Sanger- group (n = 52) were compared. The Idylla assay detected ex20ins in 82.6% of cobas+/Sanger+ cases but only in 4.9% of cobas+/Sanger- cases. The cobas+/Sanger- group was significantly associated with higher tumor contents, poorly differentiated patterns, tumor necrosis, and a lower internal control cycle threshold value reported by the Idylla which suggesting the presence of increased EGFR gene copy numbers. EGFR fluorescence in situ hybridization (FISH) revealed the majority of cobas+/Sanger- group had EGFR high copy number gain (16%) or amplification (76%) according to the Colorado criteria. Among cases reported to have concomitant classic EGFR and ex20ins mutations by the cobas, the classic EGFR mutations were all detected by Sanger sequencing and Idylla, while the ex20ins mutations were undetected by Sanger sequencing (0%) or rarely reported by Idylla assay (3%). FISH revealed high EGFR copy number gain (17.9%) and amplification (79.5%) in cases reported having concomitant classic EGFR and ex20ins mutations by the cobas. This study demonstrated an unusually high frequency of EGFR amplification in cases with aberrant cobas ex20ins report which could not be validated by Sanger sequencing or Idylla assay. Ex20ins reported by the cobas test should be validated using other methods especially those reported having concomitant ex20ins and classic EGFR mutations.

Abstract Introduction According to current International Association for the Study of Lung Cancer guideline, physicians may first use plasma cell‐free DNA (cfDNA) methods to identify epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)‐resistant mechanisms (liquid rebiopsy) for lung cancer. Tissue rebiopsy is recommended if the plasma result is negative. However, this approach has not been evaluated prospectively using next‐generation sequencing (NGS). Methods We prospectively enrolled patients with lung cancer with first‐line EGFR‐TKI resistance who underwent tissue rebiopsy. The rebiopsied tissues and cfDNA were sequenced using targeted NGS, ACTDrug®+, and ACTMonitor®Lung simultaneously. The clinicopathological characteristics and treatment outcomes were analyzed. Results Totally, 86 patients were enrolled. Twenty‐six (30%) underwent tissue biopsy but the specimens were inadequate for NGS. Among the 60 patients with paired tissue and liquid rebiopsies, two‐thirds (40/60) may still be targetable. T790M mutations were found in 29, including 14 (48%) only from tissue and 5 (17%) only from cfDNA. Twenty‐four of them were treated with osimertinib, and progression‐free survival was longer in patients without detectable T790M in cfDNA than in patients with detectable T790M in cfDNA (p = 0.02). For the 31 T790M‐negative patients, there were six with mesenchymal–epithelial transition factor (MET) amplifications, four with ERBB2 amplifications, and one with CCDC6‐RET fusion. One with MET amplification and one with ERBB2 amplification responded to subsequent MET and ERBB2 targeting agents respectively. Conclusions NGS after EGFR‐TKI resistance may detect targetable drivers besides T790M. To do either liquid or tissue NGS only could miss patients with T790M. To do tissue and liquid NGS in parallel after EGFR‐TKI resistance may find more patients with targetable cancers.

Abstract Background The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer adopts new criteria for tumor size, and for determining pTis, pT1a(mi), and pT1a. The latter is based on the size of stromal invasion. It is quite challenging for lung pathologists. Methods All patients who had undergone surgical resection for pulmonary adenocarcinoma (ADC) at Chung Shan Medical University Hospital between January 2014 and April 2018 were reviewed, and restaged according to the eighth AJCC staging system. The clinical characteristics and survival of patients with tumor stage 0 (pTis), I or II were analyzed. Results In total, 376 patients were analyzed. None of the pTis, pT1a(mi), or pT1a tumors recurred during the follow‐up period up to 5 years, but pT1b, pT1c, pT2a, and pT2b tumors all had a few tumor recurrences (p

Background: Ultrasound-guided core biopsy (USCB) is a minimally invasive sampling procedure which may help to confirm the diagnoses of the thyroid tumors with indeterminate results of ultrasound-guided fine-needle aspiration (USFNA). Although with potential advantages, the working protocol of introducing USCB in the routine practice has not been established yet. This study aims to evaluate the efficacy of USCB when it is included in the clinical workflow of assessing the thyroid tumors with indeterminate USFNA results after a long-term follow up. Methods: Between 2009 and 2016, consecutive patients receiving thyroid USFNA were reviewed retrospectively in the tertiary referral hospital. The patients, who finally received USCB for their thyroid tumors after repeated indeterminate USFNA results, were recruited. The important sonographic features in facilitating specific diagnoses by USCB, differentiating malignancy from benignity, and confirming origins of thyroid tumors were analyzed and the role of USCB was investigated. Results: Thirty-nine patients met the inclusion criteria were analyzed. The specific diagnoses were confirmed in 23 patients (59%) by USCB. Taller than wide, ill-defined margin and hypoechogenicity helped in differentiating malignant tumors and the latter two features were pertinent to the success of applying USCB for specific diagnosis. No sonographic features were able to differentiate the thyroid malignancy from extra-thyroid origins exclusively. Thyroid USCB facilitated clinical decision making in 37 of the 39 patients (94.9%) with indeterminate USFNA results. Conclusion: The USCB is a cost-effective sampling procedure for confirming the diagnosis of indeterminate thyroid tumors and their clinical management, especially for those malignancies from extra-thyroid origins.

IntroductionThe MET exon 14 skipping (METex14) mutation is an important oncogenic driver in lung cancer. We performed a retrospective analysis of clinical data from lung cancer patients with the METex14 mutation to analyze their survival outcomes and associated prognostic factors.MethodsA one-step reverse transcription-polymerase chain reaction to examine the presence of the METex14 mutation was performed using RNA samples from 1374 lung cancer patients with no detected EGFR and ALK mutations. Pathological features and immunohistochemistry (IHC) results for c-MET were analyzed in patients with METex14-positive tumors.ResultsMETex14 was identified in 69 patients with lung cancer, including 53 adenocarcinoma (ADC) and 16 non-ADC patients. In comparison with patients without the METex14 mutation, lung cancer patients harboring the METex14 mutation were generally elderly individuals, never-smokers, and had poor performance scores. A higher frequency of METex14 mutations was detected in pulmonary sarcomatoid carcinoma (PSC) patients (24.3%, n = 9/37). However, stage IV PSC patients with or without the METex14 mutations showed similarly poor overall survival (OS) (p = 0.429). For all 36 METex14-positive lung ADCs, multivariate analysis showed several poor prognostic factors, including strong c-MET IHC staining (p = 0.006), initial brain metastasis (p = 0.005), and administration of only supportive care (p < 0.001). After excluding seven patients who received only supportive care, we further analyzed 29 stage IV lung ADC patients with METex14 mutations who received anti-cancer treatment. Multivariate analysis showed that pemetrexed treatment (p = 0.003), lung radiotherapy (p = 0.020), initial brain metastasis (p = 0.005), and strong c-MET IHC staining (p = 0.012) were independent prognostic factors for OS in these patients.ConclusionsA higher frequency of METex14 mutations was detected in PSC patients. Stage IV PSC patients with or without the METex14 mutations had similarly poor overall survival. Pemetrexed-based chemotherapy, strong c-MET ICH staining, initial brain metastasis, and lung radiotherapy, may help predict survival outcomes in patients with advanced lung ADCs harboring the METex14 mutation.

Objectives: A definitive diagnosis of pulmonary sarcomatoid carcinoma cannot be made with small biopsies. In clinical practice, a diagnosis of advanced non-small-cell lung cancer with spindle cell and/or giant cell carcinoma (NSCLCsg), or possible sarcomatoid carcinoma, is acceptable. Therefore, we aimed to investigate the treatment patterns and outcomes of advanced NSCLCsg. Materials and methods: Between 01 January 2012 and 01 April 2021, patients with pathologically proven advanced NSCLCsg were enrolled. The choice of treatment was based on clinician discretion. Results: In all, 101 patients with advanced NSCLCsg were enrolled. In total, 77 (76.2%) patients received at least one line of systemic therapy; 44 patients (43.1%) had received platinum doublet chemotherapy; 27 (26.7%) patients had been treated with targeted therapies; and 23 patients (22.8%) had been given an immune checkpoint inhibitor (ICI). The median overall survival (OS) was 6.3 months [95% confidence interval (CI): 3.6–9.0 months]. Excluding patients without systemic therapy, patients who had received an ICI had better OS (median: 18.2 months) than those who had not (median 3.8 months, log-rank test p = 0.002). No significant difference in OS was detected between patients who had or had not received platinum doublet chemotherapy (log-rank test p = 0.279), or targeted therapy (log-rank test p = 0.416). Having received any systemic therapy [hazard ratio (HR): 0.33, 95% CI: 0.18–0.61, p

Summary: Background: Preoperative differentiation of follicular thyroid carcinoma (FTC) from follicular adenoma (FA) remains an unsolved puzzle. Patients sometimes undergo unnecessary lobectomy for histology confirmation inevitably. Objective: In this retrospective study, we propose new gray-scale ultrasonographic (US) features that may help to differentiate FTC from FA. Method: Medical charts and US images of follicular thyroid neoplasms were collected prospectively. Gray-scale US features including conventional parameters adding tubercle-in-nodule and trabecular formation were recorded. Results: The histopathologic diagnosis was FA in 139 and FTC in 49 patients. In patients with FTC, minimally invasive follicular carcinoma (MIFC) was seen in 36 patients and widely invasive follicular carcinoma (WIFC) in 13. The incidences of calcifications (p

ObjectivesThe choice of resection method for geriatric patients with early-stage non-small cell lung cancer (NSCLC) remains contentious. This study aimed to evaluate survival and perioperative outcomes after thoracoscopic lobectomy resection (LR) or sublobar resection (SR) in patients aged ≥75 years with pathologic stage (pStage) I NSCLC.Materials and MethodsWe retrospectively examined 258 consecutive patients aged ≥75 years with pStage I NSCLC who underwent thoracoscopic tumor resection at our institute from 2011 to 2018. Propensity score matching (PSM) analysis identified 60 patients in each group for comparison of survival-related parameters, including disease-free survival (DFS), lung cancer-specific overall survival (OS), and non-lung cancer-specific OS, using the Kaplan-Meier analysis.ResultsLR and SR were performed in 84 (32.6%) and 174 (67.4%) patients aged ≥75 years, respectively. The LR group had younger patients, better performance status, larger tumor sizes, and deeper tumor location than the SR group. Multivariate studies showed that the resection method was not a prognostic factor for OS. The two PSM-matched groups were not significantly different with respect to lung cancer-specific OS (p = 0.116), non-lung cancer-specific OS (p = 0.408), and DFS (p = 0.597). SR helped achieve better perioperative outcomes than LR, including fewer postoperative complications (10.0% vs. 28.3%, p = 0.011), shorter operative times (p < 0.001), decreased blood loss (p = 0.026), and shorter chest tube duration (p = 0.010) and hospital stays (p = 0.035).ConclusionsThoracoscopic SR may provide similar oncological outcomes to LR, but may be a safer and more feasible surgical method for geriatric patients with pStage I NSCLC.

The clinicopathological presentation of early-stage lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations has been seldom studied. Our study enrolled patients with stage I and II lung adenocarcinoma between January 2014 and December 2017 at the National Taiwan University Hospital. Clinicopathological features and prognosis were retrospectively reviewed and analyzed depending on EGFR mutation status. EGFR mutations were detected in 622 (60%) out of 1034 patients. Compared to the group without EGFR mutations, the group with EGFR mutations had more patients above 65 years of age (p < 0.001), more non-lepidic histological subtypes (p < 0.001), higher CEA levels (p = 0.044), higher grade of pleural (p = 0.02) and lymphovascular (p = 0.001) invasion, higher histological grade (p < 0.001), and a more advanced pathological stage (p = 0.022). In multivariate analysis, there was no significant difference in PFS or OS between the EGFR mutant and wild-type groups. In subtype analysis, the tumors with an L858R mutation had a more lepidic predominant histological type (p = 0.019) and less lymphovascular invasion (p = 0.011). No significant differences in PFS or OS were detected between the exon 19 deletion and L858R mutation groups. In early-stage lung adenocarcinoma, EGFR mutation may be considered as a treatment response predictor for tyrosine kinase inhibitors, instead of a predictor of clinical prognosis.

Background: As the overall survival of patients with cancer continues to improve, the incidence of second primary malignancies seems to be increasing. Previous studies have shown controversial results regarding the survival of patients with primary lung cancer with previous extrapulmonary malignancies. This study aimed to determine the clinical picture and outcomes of this particular subgroup of patients.Materials and Methods: We included 2,408 patients who underwent pulmonary resection for primary lung cancer at our institute between January 1, 2011 and December 30, 2017 in this retrospective study. Medical records were extracted and clinicopathological parameters and postoperative prognoses were compared between patients with lung cancer with and without previous extrapulmonary malignancies.Results: There were 200 (8.3%) patients with previous extrapulmonary malignancies. Breast cancer (30.5%), gastrointestinal cancer (17%), and thyroid cancer (9%) were the most common previous extrapulmonary malignancies. Age, sex, a family history of lung cancer, and preoperative carcinoembryonic antigen levels were significantly different between the two groups. Patients with previous breast or thyroid cancer had significantly better overall survival than those without previous malignancies. Conversely, patients with other previous extrapulmonary malignancies had significantly poorer overall survival (p < 0.001). The interval between the two cancer diagnoses did not significantly correlate with clinical outcome.Conclusion: Although overall survival was lower in patients with previous extrapulmonary malignancies, previous breast or thyroid cancer did not increase mortality. Our findings may help surgeons to predict prognosis in this subgroup of patients with primary lung cancer.

ObjectivesDifferentiating thyroid nodules with a cytological diagnosis of follicular neoplasm remains an issue. The goal of this study was to determine whether ultrasonographic (US) findings obtained preoperatively from the computer-aided detection (CAD) system are sufficient to further stratify the risk of malignancy for this diagnostic cytological category.MethodsFrom September 2016 to September 2018 in our hospital, patients diagnosed with Bethesda category IV (follicular neoplasm or suspicion of follicular neoplasm) thyroid nodules and underwent surgical excisions were include in the study. Quantification and analysis of tumor features were performed using CAD software. The US findings of the region of interest, including index of composition, margin, echogenicity, texture, echogenic dots indicative of calcifications, tall and wide orientation, and margin were calculated into computerized values. The nodules were further classified into American Thyroid Association (ATA) and American College of Radiology Thyroid Imaging Reporting & Data System (TI-RADS) categories.Results92 (10.1%) of 913 patients were diagnosed with Bethesda category IV thyroid nodules. In 65 patients, the histological type of the nodule was identified. The quantitative features between patients with benign and malignant conditions differed significantly. The presence of heterogeneous echotexture, blurred margins, or irregular margins was shown to have the highest diagnostic value. The risks of malignancy for nodules classified as having very low to intermediate suspicion ATA, non-ATA, and high suspicion ATA patterns were 9%, 35.7%, and 51.7%, respectively. Meanwhile, the risks of malignancy were 12.5%, 26.1%, and 53.8% for nodules classified as TIRADS 3, 4, and 5, respectively. When compared to human observers, among whom poor agreement was noticeable, the CAD software has shown a higher average accuracy.ConclusionsFor patients with nodules diagnosed as Bethesda category IV, the software-based characterizations of US features, along with the associated ATA patterns and TIRADS system, were shown helpful in the risk stratification of malignancy.

Esophageal cancer (EC) is a deadly cancer that frequently develops multiple primary cancers (MPCs). However, the risk biomarkers of MPC in EC have hardly been investigated. We retrospectively enrolled 920 subjects with primary EC and analyzed the possible risk factors as well as MPC single-nucleotide polymorphisms (SNPs) from blood DNA. A total of 184 subjects (20.0%) were confirmed to have MPC, 59 (32.8%) had synchronous MPC, and 128 (69.6%) had head and neck cancer. Elderly EC patients have an increased risk of having gastrointestinal cancer (Odds ratio, OR[95% CI]=6.70 [1.49–30.19], p=0.013) and a reduced risk of developing HNC (OR[95% CI]=0.44 [0.24–0.81], p=0.008). MPC risk was also associated with betel nut chewing (OR[95% CI]=1.63, 1.14–2.32], p=0.008), the A allele of ALDH2:rs671 (p=0.074 and 0.030 for GA and AA, respectively), the CC genotype in CISH:rs2239751 (OR[95% CI]=1.99 [1.2–3.32], p=0.008), and the G allele of ERCC5:rs17655 (p=0.001 and 0.090 for GC and CC, respectively). ADH1B:rs1229984 also correlated with MPC risk (p=0.117). Patients carrying four risk SNPs had a 40-fold risk of MPC (OR[95% CI]=40.25 [6.77–239.50], p

The 2021 WHO classification proposed a pattern-based grading system for early-stage invasive non-mucinous lung adenocarcinoma. Lung adenocarcinomas with high-grade patterns have poorer outcomes than those with lepidic-predominant patterns. This study aimed to establish genetic prognostic signatures by comparing differences in gene expression profiles between low- and high-grade adenocarcinomas. Twenty-six (9 low- and 17 high-grade adenocarcinomas) patients with histologically “near-pure” patterns (predominant pattern comprising >70% of tumor areas) were selected retrospectively. Using RNA sequencing, gene expression profiles between the low- and high-grade groups were analyzed, and genes with significantly different expression levels between these two groups were selected for genetic prognostic signatures. In total, 196 significant candidate genes (164 upregulated and 32 upregulated in the high- and low-grade groups, respectively) were identified. After intersection with The Cancer Genome Atlas–Lung Adenocarcinoma prognostic genes, three genes, exonuclease 1 (EXO1), family with sequence similarity 83, member A (FAM83A), and disks large-associated protein 5 (DLGAP5), were identified as prognostic gene signatures. Two independent cohorts were used for validation, and the areas under the time-dependent receiver operating characteristic were 0.784 and 0.703 in the GSE31210 and GSE30219 cohorts, respectively. Our result showed the feasibility and accuracy of this novel three-gene prognostic signature for predicting the clinical outcomes of lung adenocarcinoma.

Background/Purpose: Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) are uncommon salivary gland tumors comprising proliferation of basaloid cells. Nuclear β-catenin expression and mutations in its encoding gene (CTNNB1) are reported to be specific to BCA. PIK3CA mutations are only found in BCAC not in BCA. However, in previous studies the number of cases was relatively small. The present study analyzed 44 cases of basal cell neoplasms to identify the CTNNB1 and PIK3CA mutation profiles in this rare salivary gland tumor. Methods: The basic clinical features and detailed histological patterns of 41 BCA and three BCAC cases were analyzed. All basal cell neoplasms and a tissue microarray of adenoid cystic carcinoma (AdCC) were tested for β-catenin immunohistochemistry. CTNNB1, PIK3CA, and CYLD mutations were detected by PCR and Sanger sequencing in each case. Results: Nuclear β-catenin expression was present in 97.6% of BCA and 66.7% of BCAC cases but not in AdCC cases. CTNNB1 mutations were found in 60% of BCA but not in BCAC. None of the tested cases had PIK3CA mutations. CTNNB1 mutation trended to be more common in those cases having a predominant tubular or tubulotrabecular patterns (p = 0.059). Conclusion: β-catenin immunohistochemistry is very useful for the differential diagnosis between BCA/BCAC and AdCC. CTNNB1 mutations are common in BCA, especially those with tubular or tubulotrabecular patterns. Keywords: Basal cell adenoma, CTNNB1, Beta catenin, Salivary glands

A kinesin family member 5b (KIF5B)-MET proto-oncogene, receptor tyrosine kinase (MET) rearrangement was reported in patients with lung adenocarcinoma but its oncogenic function was not fully evaluated. We used one-step reverse transcription-polymerase chain reaction for RNA samples to screen for the KIF5B-MET fusion in 206 lung adenocarcinoma and 28 pulmonary sarcomatoid carcinoma patients. Genomic breakpoints of KIF5B-MET were determined by targeted next-generation sequencing. Soft agar colony formation assays, proliferation assays, and a xenograft mouse model were used to investigate its oncogenic activity. In addition, specific MET inhibitors were administered to evaluate their anti-tumor activities. A KIF5B-MET fusion variant in a patient with a mixed-type adenocarcinoma and sarcomatoid tumor was identified, and another case was found in a pulmonary sarcomatoid carcinoma patient. Both cases carried the same chimeric gene, a fusion between exons 1–24 of KIF5B and exons 15–21 of MET. KIF5B-MET-overexpressing cells exhibited significantly increased proliferation and colony-forming ability. Xenograft tumors harboring the fusion gene demonstrated significantly elevated tumor growth. Ectopic expression of the fusion gene stimulated the phosphorylation of KIF5B-MET as well as downstream STAT3, AKT, and ERK1/2 signaling pathways. The MET inhibitors significantly repressed cell proliferation; phosphorylation of downstream STAT3, AKT, and ERK1/2; and xenograft tumorigenicity. In conclusion, the KIF5B-MET variant was demonstrated to have an oncogenic function in cancer cells. These findings have immediate clinical implications for the targeted therapy of subgroups of non-small cell lung cancer patients.

Pleurodesis with biomaterial membrane is an emerging treatment method for pneumothorax. However, the ideal one for the common disease is still under debate. Methods: We investigate the Poly-ε-caprolactone (PCL) membrane pleurodesis by using New Zealand White rabbits, which was sacrificed for examination one month later. Moreover, inflammation and fibrosis scoring were done under microscopic evaluation, as well as Western blot analysis in vitro and in vivo. Results: Gross evaluation of pleurodesis score revealed that dense PCL membrane produced moderate pleural adhesion, while porous PCL membrane exhibited significantly higher pleurodesis scores. Conclusion: PCL membrane induced significant degree of adhesion, both within the abdomen and chest of the rabbits. The porous PCL membrane produces more intensive adhesion than dense one. Fibronectin plays an important role in the process of pleurodesis. Further study is required for the clinical application of the promising material.

Esophageal squamous cell carcinoma (ESCC) is a deadly disease for which no effective targeted therapeutic agent has been approved. Both AXL and c-MET have been reported to be independent prognostic factors for ESCC. Thus, inhibitors of AXL/c-MET might have great potential as targeted therapy for ESCC. In the current study, we evaluated the therapeutic potential of the AXL/c-MET selective inhibitors, R428 and cabozantinib, in cell and mouse xenograft models. We demonstrated that both R428 and cabozantinib significantly inhibited the growth of CE81T and KYSE-70 ESCC cells and showed by wound-healing assay that they both inhibited ESCC cell migration. In the animal model, ESCC xenograft models were established by injecting KYSE-70 cells with Matrigel into the upper back region of NOD-SCID male mice followed by treatment with vehicle control, R428 (50 mg/kg/day), cisplatin (1.0 mg/kg), or cabozantinib (30 mg/kg/day) for the indicated number of days. R428 alone significantly inhibited ESCC tumor growth compared to the vehicle; however, no synergistic effect with cisplatin was observed. Notably, the dramatic efficacy of cabozantinib alone was observed in the mouse xenograft model. Collectively, our study demonstrated that both cabozantinib and R428 inhibit ESCC growth in cell and xenograft models. The results reveal the great potential of using cabozantinib for targeted therapy of ESCC.

Primary hepatic capillary hemangioma in adults is very rare. Here, we report a case of hepatic capillary hemangioma in a 71-year-old woman. She had abnormal liver function tests, and abdominal sonography revealed a 2-cm nodular lesion and fatty liver. Computed tomography scan revealed a hypervascular tumor. During 2 years’ follow-up, the hepatic tumor enlarged to 3 cm in diameter. Serological tests showed no evidence of chronic viral hepatitis or increased level of alpha-fetoprotein. In fear of hepatocellular carcinoma, she received atypical hepatectomy. Microscopically, the tumor turned out to be a capillary hemangioma in a background of steatohepatitis. We searched the literature, and only six similar cases were found. We made a brief review of this rare disease entity and described its clinicopathological features.

Kayexalate (sodium polystyrene sulfonate) is a cation-exchange resin used to treat patients with hyperkalemia. Concomitant administration of kayexalate and sorbitol may induce gastrointestinal injury, which is potentially lethal. However, this well-documented complication is often underrecognized both clinically and pathologically. We propose a typical case along with colonoscopic photos and microscopic pictures. Additionally, we also present a review of the literature on this rare drug-induced side effect.

Intravascular large B cell lymphoma (IVLBCL) is a rare variant of diffuse large B cell lymphoma. We reported the clinical and immunohistochemical characteristics of 10 cases of IVLBCL from Taiwan between 1995 and 2008. Methods: Clinical data were reviewed and immunoperoxidase stains were performed with antibodies against CD20, CD10, Bcl-6, MUM1, and CD5. Results: There were eight males and two females with a median age of 59 years. Patients presented with dyspnea (5/10), fever (7/10), splenomegaly (5/10), and bone marrow involvement (8/10). Anemia (9/10), thrombocytopenia (6/10), and elevated serum lactate dehydrogenase or ferritin levels (8/10) were also common. Nine cases were CD20+CD10−Bcl-6−, similar to non-germinal center B cells. Six out of seven patients survived after chemotherapy, but three cases with thrombocytopenia that precluded chemotherapy died within 2 months. Conclusion: Our cases of IVLBCL had a non-germinal center B origin and belonged to the Asian variant of this disease. The liver, spleen, and bone marrow, but rarely the skin or brain, were involved. Thrombocytopenia is a major risk factor for mortality in these cases.

Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of the liver typically with a slow but progressive course. We report the clinical and immunohistochemical characteristics of six cases from our institution between 1993 and 2008. Methods: We searched the files of the Department of Pathology in National Taiwan University Hospital from January 1993 to December 2008 and found six cases of primary HEH. The clinical data were reviewed. The microscopic findings of each case were listed and analyzed. Confirmational immunoperoxidase stains were performed with antibodies against two endothelial markers (CD31 and CD34) and one epithelial marker (AE1/AE3 or cytokeratin). Results: There were five female patients and one male patient with HEH, and the mean age was 45.3 years (range, 25–86 years). Most patients were asymptomatic and one third of cases presented as right costal or abdominal pain. Anemia was the most common laboratory abnormality. Liver failure developed at the advanced diffuse stage. Imaging studies revealed three different patterns as single nodular, multiple nodular, or diffuse types, reflecting different stages of disease and clinical symptoms. Microscopic findings included intracytoplasmic vascular lumen formation (100%), sinusoidal spreading (100%), vessel obliteration (66.7%), necrosis (66.7%), and cellular pleomorphism (16.7%). All cases expressed endothelial markers of CD31 and CD34, reflecting their vascular nature. Two patients received surgical treatment including partial liver resection and liver transplantation. Tumor recurrence developed 8 and 17 months later, respectively. Conclusion: HEH showed insidious growth and frequent multicentricity, making early diagnosis and tumor resection difficult. Definite diagnosis totally relies on pathologic study. Tumor progression to hepatic failure is slow. Liver transplantation is currently the most prevalent treatment modality for HEH, but experience in Taiwan is limited due to the rarity of this disease.

Pancreatic serous cystadenomas account for 1–2% of all exocrine pancreatic tumors, and endocrine tumors account for 1–2% of all pancreatic neoplasms. The combination of pancreatic serous cystadenoma and endocrine tumor is even rarer. Here, we report two cases of combined pancreatic serous adenoma and endocrine tumor. One was a 64-year-old woman with serous cystadenoma and pancreatic endocrine tumor. The other case was a 28-year-old woman with von Hippel–Lindau disease with combined pancreatic serous oligocystic adenoma and well-differentiated malignant endocrine carcinoma. Reviewing the literature, we found 15 similar cases that showed two different age distributions and clinical presentations. Careful examination of benign serous cystadenoma should be kept in mind during clinical practice, to rule out the possibility of combined malignant endocrine tumor. In addition, von Hippel–Lindau disease should also be suspected when a young adult presents with combination of pancreatic serous cystadenoma and endocrine tumor.

PURPOSE:To investigate the association between genetic polymorphisms of growth factor-related genes and prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS:A total of 334 ESCC patients with advanced tumor stages (stages IIB, III and IV) were enrolled in the study. The genotypes of 14 candidate single nucleotide polymorphisms (SNPs) involved in growth factor-related functions were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes, and were correlated with the clinical outcome of patients. Serum levels of growth factors were examined by enzyme-linked immunosorbent assay (ELISA). RESULTS:The genetic polymorphisms of EGF:rs4444903, EGF:rs2237051 and VEGF:rs2010963 showed significant associations with overall survival (OS) of advanced ESCC patients (A/A+ A/G vs. GG, [HR = 0.77, 95% CI = 0.60-0.99, P = 0.039 for rs4444903; A/G+ G/G vs. A/A, [HR = 0.74, 95% CI = 0.58-0.95, P = 0.019 for rs2237051; G/G+G/C vs. C/C, [HR] inves = 0.69, 95% CI = 0.50-0.95, P = 0.023 for rs2010963). EGFR:rs2227983 and 3 SNPs of PIK3CA also showed borderline significant correlation with OS of advanced ESCC patients (P = 0.058 for rs2227983; P = 0.069, 0.091 and 0.067 for rs6443624, rs7651265 and rs7621329 of PIK3CA respectively). According to cumulative effect analysis of multiple SNPs, patients carrying 4 unfavorable genotypes exhibited more than a 3-fold increased risk of mortality. Finally, both EGF and VEGF expression levels significantly associated with patient mortality. CONCLUSION:The genetic variants and expression levels of EGF and VEGF can serve as prognostic predictors in patients with advanced ESCC, and thus provide more information for optimizing personalized therapies for patients with ESCC.