Search

Abstract In our previous phase II T1219 trial for advanced biliary tract cancer (ABTC), the combination of nivolumab with modified gemcitabine and S-1 exhibited promising efficacy, while the programmed-death-ligand-1 (PD-L1) expression did not predict chemoimmunotherapy efficacy. Lymphocyte-activation-gene-3 (LAG-3), a negative immune checkpoint, is frequently co-expressed with PD-L1. This study assessed the predictive value of LAG-3 expression in ABTC patients who received chemoimmunotherapy. We analyzed 44 formalin-fixed ABTC samples using immunohistochemical staining for PD-L1 and LAG-3 and correlated them with the clinical efficacy of chemoimmunotherapy. Digital spatial profiling was conducted in selected regions of interest to examine immune cell infiltration and checkpoint expression in six cases. Three public BTC datasets were used for analysis: TCGA-CHOL, GSE32225, and GSE132305. LAG-3 positivity was observed in 38.6% of the ABTC samples and was significantly correlated with PD-L1 positivity (P < 0.001). The objective response rate (ORR) was significantly higher in LAG-3-positive tumors than in LAG-3-negative tumors (70.6% vs. 33.3%, P = 0.029). The LAG-3 expression level was associated with an increased ORR (33%, 58%, and 100% for LAG-3 < 1%, 1–9%, and ≥ 10%, respectively; P = 0.018) and a deeper therapeutic response (20.1%, 38.6%, and 57.6% for the same respective groups; P = 0.04). LAG-3 expression is positively correlated with the expression of numerous immune checkpoints. Enrichment of CD8+ T cells was observed in LAG-3-positive BTC, indicating that LAG-3 expression may serve as a biomarker for identifying immune-inflamed tumors and predicting the therapeutic response to chemoimmunotherapy in ABTC.

Background: Neuroendocrine carcinomas (NECs) are classified by the World Health Organization as poorly differentiated, aggressive Grade 3 tumors with high proliferative indices and frequent lung involvement. While initial treatment for advanced NEC typically involves etoposide and platinum-based therapies, standardized options for subsequent lines of treatment are lacking. This study evaluates the efficacy and outcomes of various second-line treatments for NECs following progression after initial therapy. Materials and Methods: A retrospective cohort study was conducted at Taipei Veterans General Hospital, Taiwan, from January 2016 to June 2023. The study included patients aged 18 years or older diagnosed with extrapulmonary NEC who had progressed following initial platinum and etoposide therapy. Treatment response and survival outcomes were assessed. Results: The study analyzed 34 patients across four treatment regimens: 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI), 5-fluorouracil, leucovorin, and irinotecan, 5-fluorouracil, leucovorin, and Nivolumab + Ipilimumab. The FOLFOXIRI regimen demonstrated the highest objective response rate of 33.3% and a disease control rate of 66.7%, compared to the other groups, with a median progression-free survival of 4.1 months and median overall survival of 9.7 months. Conclusion: The FOLFOXIRI regimen shows potential as an effective second-line treatment for patients with extrapulmonary NEC who have progressed after first-line therapy with platinum/etoposide.

Patients with advanced intrahepatic cholangiocarcinoma (iCCA) have a poor prognosis. Recent advances in molecular profiling offer hope by enabling targeted treatment for those with specific mutations, potentially increasing survival rates. Pemigatinib targets fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements, providing a promising avenue for treatment. Here, we report the case of a 70-year-old woman diagnosed with advanced iCCA, characterized by FGFR2-Bicaudal family RNA binding protein 1 (BICC1) fusion, who received pemigatinib therapy. Despite adverse effects including mucositis and nail changes, she continued treatment following dose adjustments for over 18 months. This report highlights the importance of dose optimization in maintaining patients on therapy and preventing treatment discontinuation. Real-world patients are often more fragile than those in clinical trials, necessitating tailored dose adjustments. However, the literature on alternative dose modifications remains limited. This case represents the longest documented successful treatment of advanced iCCA with pemigatinib in Taiwan, emphasizing the potential efficacy of pemigatinib treatment in a real-world setting.

Background Cholangiocarcinoma is a challenging malignancy with limited responses to conventional therapies, particularly immune checkpoint inhibitor therapy. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) are key components of the tumor microenvironment (TME) and have been implicated in the immune response to cancer. However, the role and difference of TLSs and TILs in patients with cholangiocarcinoma remains unclear. This study elucidates their contributions to the TME.Methods We examined 16 tumor samples from a single-arm, phase II trial of nivolumab plus modified gemcitabine and S-1 and various datasets. Immunohistochemistry and RNA sequencing were employed to assess TLSs and TILs presence and activity. Differential gene expression and signature of immune cell composition were examined by GeoMx Digital Spatial Profiler and Cancer Transcriptome Altas analysis.Results TLS-positive (N=7) patients demonstrated significantly better immunotherapy outcomes compared with TLS-negative (N=9) patients, including higher objective response rates (71% vs 0%) and disease control rates (100% vs 67%). The presence of TLSs correlated with improved progression-free and overall survival (p=0.03). TLSs were associated with “inflamed” tumors characterized by substantial immune infiltration, particularly involving T and B cells. Gene expression analyses identified significant upregulation of B cell-related genes in TLSs. Additionally, TLSs exhibited higher properties of memory B cells and myeloid dendritic cells but lower levels of innate immune cells compared with TILs. T cells within TLSs showed elevated expression of precursor-exhausted-related genes and lower cytotoxicity signature. Furthermore, TILs in TLS-positive tumors had higher levels of exhaustion signatures compared with TILs in TLS-negative tumors. Clinical data corroborated these findings, with higher PD-L1 and LAG-3 expression in TLS-positive tumors.Conclusion Our findings revealed that TILs in TLS-positive tumors have more exhausted T cell signature and PD-1 and LAG-3 protein expression in CCA which support our clinical finding. TLSs can predict favorable immunotherapy responses in patients with cholangiocarcinoma, highlighting their potential as a biomarker and therapeutic target to enhance treatment efficacy.

Objective: The current study aimed to investigate the basic principles and clinical applications, including the selection of proper candidates, follow-up strategies, and radiation protection issues relating to peptide receptor radionuclide therapy (PRRT). Data Sources and Study Selection: We searched various scientific databases using specific keywords. Results: Due to the overexpression of somatostatin receptors in neuroendocrine tumors (NETs), PRRT is currently considered an important therapeutic modality for the management of NETs. Conclusion: PRRT incorporates the systemic administration of a tumor-targeting radiolabeled peptide to patients with tumors, allowing for more precise delivery of radiation doses to tumor sites while sparing normal tissues.

Abstract Background International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib’s cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV. Methods A 3-state partitioned survival model was employed to assess ivosidenib’s cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib’s cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios. Results Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib’s cost and utility values on estimate uncertainty. Conclusions At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50–60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.

Background: The Taiwan Oncology Society (TOS) and the Taiwan Society of Pathology (TSP) have collaborated to present a joint position paper on the molecular tumor boards (MTBs) within the medical institutions of Taiwan. Materials and Methods: To raise awareness of MTBs among health-care professionals, policymakers, and the public, a total of 20 experts from TOS and TSP formulated a joint consensus statement through a voting process. Results: The joint statement proposes key recommendations: (1) MTB discussions encompass diverse molecular analyses including next-generation sequencing (NGS), RNA sequencing, whole-exon sequencing, and whole-genomic sequencing addressing relevant genomic changes, tumor mutation burden, microsatellite instability, and specific biomarkers for certain cancers. (2) MTB meetings should involve multidisciplinary participants who receive regular updates on NGS-related clinical trials. (3) Prioritize discussing cases with unique clinical needs, gene alterations lacking treatments, untreatable neoplasms, or oncogenes unresponsive to targeted therapies. (4) Base MTB discussions on comprehensive patient data, including genetics, pathology, timing of specimen collection, and NGS outcomes. (5) MTBs offer treatment recommendations: standard therapies, off-label use, clinical trials, genetic counseling, and multidisciplinary reviews. (6) MTB effectiveness can be gauged by member composition, case reviews, treatment suggestions, and patient outcomes. Encourage government incentives for MTB engagement. Conclusion: The primary aim of this initiative is to promote the advancement of precision oncology in Taiwan.

Background: Patients with locally advanced esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemoradiotherapy (nCRT) may not always receive resection despite the possible achievement of a pathologic complete response (pCR) being associated with superior survival benefit. We aimed to compare outcomes among ESCC patients with or without pCR and those refusing surgery. Methods: In total, 111 medically operable, non-cervical ESCC patients after the same protocol of nCRT (platinum/5-fluorouracil plus radiation 50Gy) were prospectively enrolled between 2011 and 2021. Eighty-three of them underwent esophagectomy comprising pCR (n = 32) and non-pCR (n = 51), while 28 operable patients declined surgery (refusal-of-surgery group). Predictors and survival data were analyzed. Results: In terms of esophagectomy, 38.5% (32/83) patients achieved pCR. The pCR group exhibited better pretreatment performance status than the non-pCR group (adjusted odds ratio: 0.11, 95% confidence interval: 0.03–0.58; p = 0.01). Among pCR, non-pCR, and refusal-of-surgery groups, the 5-year overall survival (OS) rates were 56%, 29% and 50% (p = 0.08) and progression-free survival (PFS) rates were 52%, 28% and 36% (p = 0.07) respectively. The pCR group had significantly better OS and PFS than the non-PCR group (adjusted hazard ratio: 2.33 and 1.93, p = 0.02 and 0.049 respectively) but not the refusal-of-surgery group. Conclusion: Better pretreatment performance status is associated with higher chance of pCR. Consistent with previous studies, we found attainment of pCR confers the best OS and PFS. Suboptimal OS in the refusal-of-surgery group reflects some of them would have residual disease in addition to complete remission. Further studies are needed to identify prognostic factors of pCR to select candidates who could validly decline esophagectomy.

Immunotherapy with immune checkpoint inhibitors (ICIs) is beneficial in treating tumors with high microsatellite instability or DNA mismatch repair deficiency (dMMR) tumors. However, the ideal therapy for patients with advanced dMMR cancer after the failure of the first ICI regimen remains unclear. This case report describes a patient with dMMR ascending colon cancer who later developed endometrial cancer. The patient underwent a sequence of immunotherapies, starting with pembrolizumab, followed by a combination of ipilimumab and nivolumab and finally single-agent nivolumab. This sequence led to a prolonged period of disease control exceeding 20 months. The case highlights the potential benefits of dual checkpoint inhibition and sequential ICI regimens in managing advanced dMMR tumors even after first-line ICI failure; this combination is a promising strategy to explore in future research.

Abstract Epithelial‐mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G‐proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in RAB31 expression in the oxaliplatin‐resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight RAB31's powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta‐databases, RAB31 RNA levels were continually detected in colorectal tissue arrays. Additionally, RAB31 protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. RAB31 expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial‐type marker CDH1 was suppressed in RAB31 overexpression models, whereas the expression of the mesenchymal‐type markers SNAI1 and SNAI2 increased. Notably, RAB31‐induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that RAB31/AGR2 axis‐mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that RAB31 alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.

Objective: The current study aimed to investigate the issues in contemporary management strategies that focus on small pancreatic neuroendocrine tumors (PNETs). Data Sources and Study Selection: We searched various scientific databases using specific keywords. Results: Surveillance-only strategies were considered for selected patients. The exact cut-off value of small neuroendocrine tumors for surveillance-only strategies needs to be verified with additional high-level evidence. Conclusion: There is no consensus on the size and treatment strategy for small PNETs currently. Patients with small nonfunctioning PNETs require individualized recommendations for surgery versus active surveillance based on tumor size, radiographic characteristics, and patient characteristics, such as age and comorbidities and also patient references.

Abstract Background The prognosis of unfavorable cancer of unknown primary is extremely poor. This is the first report to compared the treatment results between generations of CUP and examined prognostic factors. Methods This retrospective single‐center cohort study enrolled 68 patients with newly diagnosed unfavorable cancer of unknown primary at Taipei Veteran General Hospital from 2017 to 2020 as study cohort and 167 patients from 2000 to 2009 as historical cohort. Results The median overall survival was 4.3 months in the study cohort (95% CI, 2.7–6.2 months) and 4.5 months in the historical cohort (95% CI, 3.0–5.5 months; p = 0.858). Eleven patients in the study cohort received immunotherapy. The disease control rates were 45%. Multivariate analysis showed that an Eastern Cooperative Oncology Group score > 1 and a C‐reactive protein level > 1 correlated with poor survival. A new prognostic stratification model was constructed by using Eastern Cooperative Oncology Group score and C‐reactive protein values. The good‐, intermediate‐, and poor‐risk groups had distinct median overall survival of 18.3, 7.0 and 1.2 months, respectively (area under the curve, 0.817; p < 0.001). Conclusion The outcome of unfavorable cancer of unknown primary has not changed much over the last 20 years. The application of a new prognostic stratification model can further stratify unfavorable cancer of unknown primary.

Abstract Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pathways mediated by regorafenib. We established a transcriptomic database for regorafenib-treated CCA cells using expression microarray chips. Our data indicate that regorafenib inhibits yes-associated protein 1 (YAP1) activity in various CCA cells. In addition, we demonstrated that YAP1 regulates epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin and SNAI2. We further examined YAP1 activity, phosphorylation status, and expression levels of YAP1 downstream target genes in the regorafenib model. We found that regorafenib dramatically suppressed these events in CCA cells. Moreover, in vivo results revealed that regorafenib could significantly inhibit lung foci formation and tumorigenicity. Most importantly, regorafenib and amphiregulin (AREG) neutralize antibody exhibited synergistic effects against CCA cells. In a clinical setting, patients with high YAP1 and EMT expression had a worse survival rate than patients with low YAP1, and EMT expression did. In addition, we found that YAP1 upregulated the downstream target amphiregulin in CCA. Our findings suggest that AREG neutralizing antibody antibodies combined with regorafenib can reverse the CCA metastatic phenotype and EMT in vitro and in vivo. These findings provide novel therapeutic strategies to combat the metastasis of CCA.

Abstract Background Vascular endothelial growth factor (VEGF) plays a role in the tumor microenvironment. Sorafenib, which inhibits the VEGF pathway, has an immune-modulation function but lacks substantial clinical data. This study aims to explore the efficacy of anti-PD-1 combined sorafenib in advanced hepatocellular carcinoma (HCC). Methods HCC patients who underwent anti-PD-1 treatment at Taipei Veterans General Hospital (Taipei, Taiwan) between January 2016 and February 2019 were reviewed. The efficacy was compared between groups after propensity-score matching. Results There were 173 HCC patients receiving anti-PD-1. After excluding unsuitable cases, 140 patients were analyzed, of which 58 received combination therapy and 82 received anti-PD-1 alone. The combination therapy had a trend of higher CR rate (8.6% vs. 4.9%, ns.), ORR (22.4% vs. 19.5%, ns.) and significantly higher DCR (69.0% vs. 37.8%, p 10, > 50 and > 66%), the higher the ORR (70, 80 and 92%) and CR rates (30, 35 and 58%) were achieved at day 28. Conclusions This is the first study to demonstrate the combination of anti-PD-1 and sorafenib had better efficacy and survival benefit. A prospective randomized study is needed to confirm this finding.

Purpose: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs’ therapeutic efficacies through tumor microenvironment alteration. Results: We analyzed whether CX-5461 enhances ICIs’ effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-β secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens. Conclusions: Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones.

Pancreatic neuroendocrine carcinoma (panNEC) is a rare disease. The rearrangements of neurotrophic tropomyosin receptor kinase (NTRK) genes are oncogenic. And in the existed literatures, the prevalence of NTRK3 was only 0.1% in neuroendocrine tumors. NTRK inhibitor was approved for refractory and recurrence NTRK fusion-positive solid tumors did not respond to standard treatment. We described a patient with panNEC who was confirmed to have ETV6-NTRK3 fusion gene by liquid biopsy. The patient initially responded well to entrectinib, a first-generation NTRK inhibitor, but developed resistance with two acquired NTRK3-G623R and NTRK3-G623E mutations detected by a second liquid biopsy. Kirsten rat sarcoma vial oncogene (KRAS) K117N mutation was found initially but became undetectable after resistance. This was the first report demonstrating the novel agent, entrectinib, used for the NTRK3-fusion gene found by the liquid biopsy in panNEC. Our report provides evidence of not only the effectiveness but also the acquired resistance of entrectinib. Also, we highlighted the potential role of genomic sequencing after entrectinib failure. Furthermore, liquid biopsy should be considered if acquiring tissue from the patient is challenging. Further studies regarding NTRK inhibitors in panNEC were needed.

Objective Diagnosis of SLE is based on clinical manifestations but is heterogeneous in early onset. Hence, we aimed to evaluate the feature of the immunoprofiling in patients with SLE and apply it to develop an immune signature algorithm for supporting SLE diagnosis.Methods We enrolled 13 newly diagnosed patients with SLE and 9 healthy controls (HCs) followed by analysing their immunoprofilings within their peripheral blood mononuclear cells (PBMCs) through flow cytometry. The immunoprofiling from the patients with SLE and HCs were ranked and formed an immune signature score. Besides, we enrolled four patients with SLE and monitored the changes in their immunoprofilings after immunosuppressant treatment.Results Among 93 immune cell subsets, 29 differed significantly between patients with SLE and HCs, and lower dendritic and natural killer cell percentages and a higher CD8+ T-cell percentage were identified in patients with SLE. In an investigation of immune-tolerant-related cell subsets, higher concentrations of CD8+ regulatory natural killer T cells, programmed cell death 1 (PD-1)+ T cells, and lower concentrations of programmed cell death ligand 1 (PD-L1)+ PBMCs were observed in the SLE group. The immune signature score from patients with SLE was significantly different from that from the HCs. After treatment, the disease activity of the four patients were tended to stable and percentages of PD-L1+ monocytes, PD-1+ CD4 T and CD8 T cells in patients with SLE exhibited positively and negatively correlation with the SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) score, which might associate with the remission of SLE.Conclusions The comparison of immunprofiling between patients with SLE and HCs exhibited a distinct pattern. This difference and its application to immune signature algorithm shed light on the studies of SLE pathogenesis and immune-based diagnostic tool development in the future.

Cholangiocarcinoma (CCA) is the second most common primary liver malignancy and carries a dismal prognosis due to difficulties in achieving an optimal resection, and poor response to current standard-of-care systemic therapies. We previously devised a CTLA4-PD-L1 DNA cancer vaccine (DNA vaccine) and demonstrated its therapeutic effects on reducing tumor growth in a thioacetamide (TAA)-induced rat intrahepatic CCA (iCCA) model. Here, we developed a CTLA4-PD-L1 chimeric protein vaccine (Protein vaccine), and examined its effects in the rat iCCA model. In a therapeutic setting, iCCA-bearing rats received either DNA plus Protein vaccines or Protein vaccine alone, resulting in increased PD-L1 and CTLA-4 antibody titers, and reduced iCCA tumor burden as verified by animal positron emission tomography (PET) scans. Treating iCCA-bearing rats with Protein vaccine alone led to the increase of CTAL4 antibody titers that correlated with the decrease of tumor SUV ratio, indicating regressed tumor burden, along with increased CD8 and granzyme A (GZMA) expression, and decreased PD-L1 expression on tumor cells. In a preventive setting, DNA or Protein vaccines were injected in rats before the induction of iCCA by TAA. Protein vaccines induced a more sustained PD-L1 and CTLA-4 antibody titers compared with DNA vaccines, and was more potent in preventing iCCA tumorigenesis. Correspondingly, Protein vaccines, but not DNA vaccines, downregulated PD-L1 gene expression and hindered the carcinogenesis of iCCA. Taken together, the CTLA4-PD-L1 chimeric protein vaccine may function both as a therapeutic cancer vaccine and as a preventive cancer vaccine in the TAA-induced iCCA rat model.

Intelligent machinery fault diagnosis is one of the key technologies for the transformation and competitiveness of traditional factories. Complex production environments make it difficult to maintain good prediction performance using traditional methods. This paper proposes a deep convolutional neural network combined with an adaptive environmental noise method to achieve robust fault classification. The proposed method uses six-dimensional physical signals for data fusion and feature fusion, extracts obvious features and enhances subtle features, and uses continuous wavelets and Gramian angular fields to transform signals with different physical and frequency characteristics into time–frequency maps and two-dimensional images. The fusion technology of different signals can provide comprehensive features for fault prediction, improving upon the blind spots of traditional methods to extract features, and then perform prediction and classification through deep convolutional neural networks. In the experiment, the tool failure classification of the dental milling machine is used as a verification case. The results show that the prediction accuracy of the proposed method is nearly 100%, much better than other comparison methods. In addition, white noise was added in the experiment to verify the noise immunity of the model. The results show that the accuracy of the proposed method is 99%, which is better than other comparison methods in terms of accuracy and robustness, proving the effectiveness of the proposed method for fault diagnosis and classification.

Abstract Background Due to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade. In this study, we established a screening model to discover novel prognostic biomarkers in HCC patients. Methods Candidate biomarkers were screened by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analyses of five HCC normal (N)/tumor (T) paired tissues and preliminarily verified them through several in silico database analyses. Expression levels and functional roles of candidate biomarkers were respectively evaluated by immunohistochemical staining in N/T paired tissue (n = 120) and MTS, colony formation, and transwell migration/invasion assays in HCC cell lines. Associations of clinicopathological features and prognoses with candidate biomarkers in HCC patients were analyzed from GEO and TCGA datasets and our recruited cohort. Results We found that the transmembrane P24 trafficking protein 9 (TMED9) protein was elevated in HCC tissues according to a global proteomic analysis. Higher messenger (m)RNA and protein levels of TMED9 were observed in HCC tissues compared to normal liver tissues or pre-neoplastic lesions. The TMED9 mRNA expression level was significantly associated with an advanced stage and a poor prognosis of overall survival (OS, p = 0.00084) in HCC patients. Moreover, the TMED9 protein expression level was positively correlated with vascular invasion (p = 0.026), OS (p = 0.044), and disease-free survival (p = 0.015) in our recruited Taiwanese cohort. In vitro, manipulation of TMED9 expression in HCC cells significantly affected cell migratory, invasive, proliferative, and colony-forming abilities. Conclusions Ours is the first work to identify an oncogenic role of TMED9 in HCC cells and may provide insights into the application of TMED9 as a novel predictor of clinical outcomes and a potential therapeutic target in patients with HCC.

Exposure to alkylating agents and radiation may cause damage and apoptosis in cancer cells. Meanwhile, this exposure involves resistance and leads to metabolic reprogramming to benefit cancer cells. At present, the detailed mechanism is still unclear. Based on the profiles of several transcriptomes, we found that the activity of phospholipase D (PLD) and the production of specific metabolites are related to these events. Comparing several particular inhibitors, we determined that phospholipase D1 (PLD1) plays a dominant role over other PLD members. Using the existing metabolomics platform, we demonstrated that lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) are the most critical metabolites, and are highly dependent on aldolase A (ALDOA). We further demonstrated that ALDOA could modulate total PLD enzyme activity and phosphatidic acid products. Particularly after exposure to alkylating agents and radiation, the proliferation of lung cancer cells, autophagy, and DNA repair capabilities are enhanced. The above phenotypes are closely related to the performance of the ALDOA/PLD1 axis. Moreover, we found that ALDOA inhibited PLD2 activity and enzyme function through direct protein–protein interaction (PPI) with PLD2 to enhance PLD1 and additional carcinogenic features. Most importantly, the combination of ALDOA and PLD1 can be used as an independent prognostic factor and is correlated with several clinical parameters in lung cancer. These findings indicate that, based on the PPI status between ALDOA and PLD2, a combination of radiation and/or alkylating agents with regulating ALDOA-PLD1 may be considered as a new lung cancer treatment option.

Background: ARID1A is a key component of the SWI/SNF chromatin remodeling complex, which has been identified in various cancers. Loss of ARID1A expression is correlated with poor prognosis in gastric cancer (GC); however, the clinical relevance of ARID1A mutations in GC has not yet been reported. Materials and Methods: A total of 518 GC patients receiving gastrectomy were enrolled. The analysis of 13 mutations of the ARID1A gene using mass spectrometric single-nucleotide polymorphism genotyping technology was conducted. The clinicopathological features of GC with and without ARID1A mutations were compared. Results: Among the 518 GC patients, 59 (11.4%) had ARID1A mutations. For diffuse-type GC, patients with ARID1A-mutated tumors were older and had fewer poorly differentiated tumors, fewer incidence of Epstein–Barr virus infection, a higher likelihood of ARID1A expression loss, more microsatellite instability-high tumors, a lower prevalence of peritoneal recurrence, and better survival rates than those with ARID1A nonmutant tumors. For intestinal-type GC, patients with ARID1A-mutant tumors had more PI3K/AKT pathway genetic mutations than patients with ARID1A nonmutant tumors. Multivariate analysis showed that ARID1A mutations are an independent prognostic factor in diffuse-type GC. Conclusion: ARID1A mutations are associated with a better prognosis in diffuse-type GC.

Abstract Background Liposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use. This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions. Results The T½z for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188Re-liposome. 188Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response. Conclusion This phase 0 exploratory IND study shows that nanocarrier 188Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial. Trial registration Taiwan FDA MA1101G0 (Jan 31, 2012).

BackgroundTo date, few reports have investigated genetic alterations and clinicopathological features in cardia and noncardia gastric cancer (GC).MethodsIn total, 435 GC patients receiving curative surgery were included. The clinicopathological features, recurrence patterns, prognoses and genetic alterations were compared between cardia and noncardia GC patients.ResultsAmong the 435 enrolled patients, 47 (10.8%) had cardia GC. Compared with noncardia GC, cardia GC was associated with more intestinal-type tumors and similar initial recurrence patterns and 5-year overall survival (OS; 50.8% vs. 50.5%, P = 0.480) and disease-free survival (DFS; 48.6% vs. 48.9%, P = 0.392) rates. For both intestinal-type GC and diffuse-type GC, the clinicopathological features and 5-year OS and DFS rates were not significantly different between the cardia and noncardia GC patients. Multivariable analysis showed that cardia GC was not an independent prognostic factor. Compared with noncardia GC, cardia GC was associated with increased PIK3CA amplification than in patients with intestinal-type GC and was associated with increased HER2 expression in patients with diffuse-type GC.ConclusionsCardia GC is not an independent prognostic factor. In cardia GC patients with intestinal-type GC, PIK3CA amplification was more common, and in those with diffuse-type GC, HER2 expression was more common. Targeted therapy may be beneficial for these patient subgroups.

P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) plays a crucial role in determining response against medications, including cancer therapeutics. It is now well established that p-glycoprotein acts as an ATP dependent pump that pumps out small molecules from cells. Ample evidence exist that show p-glycoprotein expression levels correlate with drug efficacy, which suggests the rationale for developing p-glycoprotein inhibitors for treatment against cancer. Preclinical and clinical studies have investigated this possibility, but mostly were limited by substantial toxicities. Repurposing FDA-approved drugs that have p-glycoprotein inhibition activities is therefore a potential alternative approach. In this review, we searched the Drugbank Database (https://www.drugbank.ca/drugs) and identified 98 FDA-approved small molecules that possess p-glycoprotein inhibition properties. Focusing on the small molecules approved with indications against non-cancer diseases, we query the scientific literature for studies that specifically investigate these therapeutics as cancer treatment. In light of this analysis, potential development opportunities will then be thoroughly investigated for future efforts in repositioning of non-cancer p-glycoprotein inhibitors in single use or in combination therapy for clinical oncology treatment.

Background Immunotherapy with immune checkpoint inhibitor (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC). However, whether ICIs would have the risk of hepatitis B virus (HBV) reactivation and the necessary of nucleos(t)ide analogs (NUCs) prophylaxis are still unclear. We aimed to investigate the role of NUCs prophylaxis in HBV-infected patients who underwent ICIs treatment.Methods The study was a retrospective prospective design to review and follow-up consecutive 62 patients with chronic hepatitis B or resolved HBV infection who had received ICIs treatment for the unresectable HCC. Of them, 60 patients with documented baseline serum HBV DNA value were classified into three categories according to the baseline HBV viral load and the status of antiviral therapy before ICI treatment. The clinical status, including tumor response, viral kinetics and liver function, was recorded and investigated.Results No HBV reactivation occurred in the 35 patients with HBV DNA ≤100 IU/mL on NUCs therapy. Of the 19 patients with HBV DNA >100 IU/mL who started NUCs simultaneously with ICI treatment, none encountered HBV reactivation during the immunotherapy. Of the six HBV patients without NUCs treatment, three had a greater than 1 log decrease in HBV viral load, and one maintained his serum HBV DNA in undetectable status during ICI treatment. Eventually, one out of six experienced HBV reactivation after 9 weeks of ICI treatment.Conclusion No patients on antiviral therapy developed HBV reactivation, and one out of six not receiving antiviral therapy had HBV reactivation. HBV viral load higher than 100 IU/mL is safe and not a contraindication for ICI treatment for HCC, if NUCs can be coadministrated.

Background Immunological checkpoint blockade is effective in treating various malignancies. Identifying predictive biomarkers to assist patient selection for immunotherapy has become a priority in both clinical and research settings.Methods Mutations in patients who responded to immunotherapy were identified through next-generation sequencing. Relationships among protein kinase, DNA-activated, catalytic polypeptide (PRKDC) mutations, mutation load and microsatellite instability (MSI) were analyzed using datasets from The Cancer Genome Atlas. These relationships were validated by conducting an in vitro study and by using tissue samples from 34 patients with gastric cancer. The CT26 animal model was used to evaluate the role of PRKDC as a predictive biomarker and the efficacy of the DNA-PK inhibitor.Results From the published literature, we found that among patients whose tumors harbored PRKDC mutations, 75%, 53.8%, and 50% of those with lung cancer, melanoma, and renal cell carcinoma, respectively, responded to immunotherapy. Most of these mutations were truncating and located in functional domains or in a destabilizing PRKDC protein structure. Additional analysis showed that a PRKDC mutation was significantly associated with a high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer. Patients with gastric cancer or colon cancer harboring PRKDC mutations were also highly associated with MSI-high status. Finally, we found that knockout PRKDC or DNA-PK inhibitor (PRKDC encodes the catalytic subunit of DNA-dependent protein kinase) enhanced the efficacy of the anti-programmed cell death protein one pathway monoclonal antibody in the CT26 animal model.Conclusions PRKDC is not only a predictive biomarker but also a drug target for immune checkpoint inhibitors.

Fine particulate matter (PM2.5) has an adverse effect on reproductive function, in particular causing reduced male reproductive function, but relatively few studies have directly targeted its effects on female reproduction. To investigate the effects of PM2.5 exposure on female reproduction, we exposed female mice to PM2.5 by intratracheal instillation for 28 days, and evaluated apoptosis of ovarian granulosa cells and oocytes and the quality embryos after insemination. Our results showed increased numbers of apoptotic granulosa cells and oocytes after exposure to elevated concentrations of PM2.5, which had adverse effects on female fertility via compromising embryo development and quality. We conclude that PM2.5 induced apoptosis of ovarian granulosa cells and oocytes leading to disrupted embryo development and female fertility in mice. Keywords: PM2.5, Ovary, Embryo, Oocyte, Mice

Hypercalcemia caused by parathyroid carcinoma is an extremely rare malignancy, with resulting higher morbidity and mortality, and remains a difficult challenge for clinicians. We herein have demonstrated the case of a 74-year-old woman with metastatic parathyroid carcinoma, complicated with refractory hypercalcemia both at initial presentation and during disease progression. Initially, her calcium level responded poorly to conventional medical treatments such as hydration, loop diuretics, and bisphosphonates; her hypercalcemia was only resolved after en bloc resection of parathyroid tumor as well as metastasectomy. However, her disease progressed and her hypercalcemia showed only a transient response to cinacalcet in the setting of worsening hyperparathyroidism. Ultimately, the addition of denosumab appeared to provide effective and durable treatment benefits. Keywords: Parathyroid carcinoma, Hyperparathyroidism, Hypercalcemia

Abstract Overexpression of ALDH is associated with cancer stem-like features and poor cancer prognosis. High ALDH activity has been observed in cancer stem-like cells. There are a total of 19 human ALDH isoforms, all of which are associated with reducing oxidative stress and protecting cells from damage. However, it is unknown whether all ALDHs are associated with poor cancer prognosis and which ones play a significant role in cancer progression. In this study, we used RNA sequencing data from The Cancer Genome Atlas (TCGA) to evaluate the differential expression of 19 ALDH isoforms in 5 common human cancers. The 19 ALDH genes were analyzed with an integrating meta-analysis of cancer prognosis. Genotyping and next-generation RNA sequencing for 30 pairwise samples of head and neck squamous cell carcinoma were performed and compared with the TCGA cohort. The analysis showed that each ALDH isoform had a specific differential expression pattern, most of which were related to prognosis in human cancer. A lower expression of ALDH2 in the tumor was observed, which was independent from the ALDH2 rs671 SNP variant and the expression of other mitochondria-associated protein coding genes. This study provides new insight into the association between ALDH expression and cancer prognosis.

The data presented in this article are related to the research article entitled âSynthesis and Characterization of Boron Fenbufen and its F-18 Labeled Homolog for Boron Neutron Capture Therapy of COX-2 Overexpressed Cholangiocarcinomaâ. The contents of the data article include 1) the set up for performing in vitro binding assay, 2) 1H-, 13C- and 19F-NMR of compounds described in main text, 3) HPLC chromatogram of the fluorination mixtures, 4) data of in vitro stability test, cell survival assay, western blot and PCR analysis, 5) the modules for fixing the two CCA rats for BNCT, and 6) bar diagram for tumor reduction using [18F]FDG-PET 24Â h post treatment with BNCT. Keywords: Setup, NMR spectra, Coupling constant, Binding, Survival

Abstract Background RAB GTPases are important in the regulation of membrane trafficking and cell movement. Recently, exocytic RABs have received increasing attention in cancer research. However, the functional roles of exocytic RABs in colorectal carcinogenesis remain to be elucidated. Methods Immunohistochemistry analysis of a microarray containing 215 colorectal adenocarcinoma tissues was used to identify the association between exocytic RABs and patient prognosis. Complementary functional RAB3C overexpression and knockdown experiments were performed. The molecular mechanism of RAB3C in inducing colon cancer cell metastasis was determined. Results High RAB3C expression in patients was found to be significantly associated with advanced pathological stage, distant metastasis and poor prognosis. Multivariate analyses showed that high RAB3C expression was an independent prognostic marker in overall (P = 0.001) and disease-free survival (P

Abstract Background As life expectancy continues to increase around the world, the use of minimally invasive surgery (MIS) could be beneficial for octogenarian and older gastric cancer patients. Methods A total of 359 gastric cancer patients who underwent curative surgery between March 2011 and March 2015 were enrolled; 80 of these patients (22.2%) were octogenarians and older. Surgical approaches included MIS (50 laparoscopic and 65 robotic) and open surgery (n = 244). Surgical outcomes of MIS and open surgery in octogenarian and older patients were compared with younger patients. Results Among octogenarian and older patients, relative to open surgery (n = 53), MIS (n = 27) was associated with less operative blood loss, a shorter postoperative hospital stay and similar rates of surgical complications and mortality. For MIS (n = 115), octogenarian and older patients exhibited similar postoperative outcomes to those of younger patients. For open surgery (n = 244), relative to younger patients, octogenarian and older patients experienced longer postoperative hospital stays, a higher rate of wound infection and a higher incidence of pneumonia. Conclusions MIS for gastric cancer is beneficial and can be performed safely in octogenarian and older patients.

Abstract Objective Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although the predictive tool is still unknown. Methods This study aimed to develop a novel gene panel by selecting DNA damage response (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) databank and validating them in previously reported cohorts. This association between DDR gene mutations and tumor mutation burden or microsatellite status was analysed from The Cancer Genome Atlas (TCGA) databank. Furthermore, we made the gene panel clinically accessible and predicted the response in clinical patients receiving ICIs by using cell‐free DNA. Results The top 20 mutated DDR genes in various cancers (total 37 genes) were taken from the COSMIC databank, and the DDR genes found to individually predict a response rate > 50% in Van Allen's cohort were selected (Science, 350, 2015 and 207). Eighteen DDR genes were selected as the gene panel. The prevalence and predicted response rate were validated in the other three reported cohorts. Tumor mutational burden‐high was positively associated with mutations of the 18 DDR genes for most cancers. We used cell‐free DNA to test the DDR gene panel and validated by our patients receiving ICIs. This DDR gene panel accounted for approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients with a mutated gene panel receiving ICIs. Conclusion This gene panel is a novel and reliable tool for predicting the response to ICIs in cancer patients and guides the appropriate administration of ICIs in clinical practice.

Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and the cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the library of integrated network-based cellular signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy.

Abstract Background Head and neck squamous cell carcinoma (HNSCC) represents a unique and major health concern worldwide. Significant increases in glucose uptake and aerobic glycolysis have been observed in HNSCC cells. Glucose transporters (GLUTs) represent a major hub in the glycolysis pathway, with GLUT4 having the highest glucose affinity. However, GLUT4’s role in HNSCC has not been fully appreciated. Methods An in silico analysis was performed in HNSCC cohorts to identify the most significant glucose transporter associated with HNSCC patient prognosis. An immunohistochemical analysis of a tissue microarray with samples from 90 HNSCC patients was used to determine the association of GLUT4 with prognosis. Complementary functional expression and knockdown studies of GLUT4 were performed to investigate whether GLUT4 plays a role in HNSCC cell migration and invasion in vitro and in vivo. The detailed molecular mechanism of the function of GLUT4 in inducing HNSCC cell metastasis was determined. Results Our clinicopathologic analysis showed that increased GLUT4 expression in oral squamous cell carcinoma patients was significantly associated with a poor overall survival (OS, P = 0.035) and recurrence-free survival (RFS, P = 0.001). Furthermore, the ectopic overexpression of GLUT4 in cell lines with low endogenous GLUT4 expression resulted in a significant increase in migratory ability both in vitro and in vivo, whereas the reverse phenotype was observed in GLUT4-silenced cells. Utilizing a GLUT4 overexpression model, we performed gene expression microarray and Ingenuity Pathway Analysis (IPA) to determine that the transcription factor tripartite motif-containing 24 (TRIM24) was the main downstream regulator of GLUT4. In addition, DDX58 was confirmed to be the downstream target of TRIM24, whose downregulation is essential for the migratory phenotype induced by GLUT4–TRIM24 activation in HNSCC cells. Conclusions Here, we identified altered glucose metabolism in the progression of HNSCC and showed that it could be partially attributed to the novel link between GLUT4 and TRIM24. This novel signaling axis may be used for the prognosis and therapeutic treatment of HNSCC in the future.

Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy.

Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although their predictive tools have not yet completely developed. Here, we aimed to exam the role of 70-gene chromosomal instability signature (CIN70) in cancers, and its association with previous predictors, tumor mutation burden (TMB), and microsatellite instability (MSI), for patients undergoing ICIs, as well as the possible predictive value for ICIs. We examined the association of CIN70 with TMB and MSI, as well as the impact of these biomarkers on the survival of 33 cancer cohorts from The Cancer Genome Atlas (TCGA) databank. The predictive value of the ICIs of CIN70 in previously published reports was also validated. Using the TCGA dataset, CIN70 scores were frequently (either positively or negatively) associated with TMB, but were only significantly associated with MSI status in three types of cancer. In addition, our current study showed that all TMB, MSI, and CIN70 had their own prognostic values for survival in patients with various cancers, and that they could be cancer type-specific. In two validation cohorts (melanoma by Hugo et al. and urothelial cancer by Snyder et al.), no significant difference of CIN70 scores was found between responders and non-responders (p-value = 0.226 and 0.108, respectively). In addition, no overall survival difference was noted between patients with a high CIN70 and those with a low CIN70 (p-value = 0.106 and 0.222, respectively). In conclusion, the current study, through a comprehensive bioinformatics analysis, demonstrated a correlation between CIN70 and TMB, but CIN70 is not the predictor for cancer patients undergoing ICIs. Future prospective studies are warranted to validate these findings.

Cholangiocarcinoma (CCA) is a malignant tumor with aggressive biological behavior. Immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and antiprogrammed death 1 (PD-1) are critical immune-checkpoint molecules that repress T-cell activation. The DNA vaccine potential against CTLA4 and PD-1 in CCA is unknown. We used a thioacetamide (TAA)-induced intrahepatic cholangiocarcinoma (iCCA) rat model to investigate the DNA vaccine potential against CTLA4, PD-1, and PD-L1. We detected PD-L1 expression in CCA and CD8+ T-cell infiltration during CCA progression in rats. We validated antibody production, carcinogenesis, and CD8+ T-cell infiltration in rats receiving DNA vaccination against PD-1, PD-L1, or CTLA4. In our TAA-induced iCCA rat model, the expression of PD-L1 and the infiltration of CD8+ T cells increased as in rat CCA tumorigenesis. PD-1 antibodies in rats were not increased after receiving PD-1 DNA vaccination, and CCA tumor growth was not suppressed. However, in rats receiving PD-L1–CTLA4 DNA vaccination, CCA tumor growth was inhibited, and the antibodies of PD-L1 and CTLA4 were produced. Furthermore, the number of CD8+ T cells was enhanced after PD-L1–CTLA4 DNA vaccination. DNA vaccination targeting CTLA4–PD-L1 triggered the production of specific antibodies and suppressed tumor growth in TAA-induced iCCA rats.

Dental laboratories require manpower resources for manufacturing prostheses and inventory management. In this paper, we developed an automated inventory management system for dental laboratories to improve the production efficiency. A sensing system was developed based on the framework of Internet of things to collect the information of cobalt-chromium disks both in the storage room and manufacturing area, and an expert system was developed to automatically conduct inventory management based on the established rules. The proposed system can reduce the time of recording data and also assist the manager in configuring and managing material orders. The experimental results showed that a large amount of working time is reduced, resulting in the benefits of saving money and improving efficiency in dental manufacturing.

Cholangiocarcinoma (CCA) has been identified as a highly malignant cancer that can be transformed from epithelial cells of the bile duct, including intrahepatic, perihilar and extrahepatic. High-resolution imaging tools (abdominal ultrasound, computed tomography and percutaneous transhepatic cholangial drainage) are recruited for diagnosis. However, the lack of early diagnostic biomarkers and treatment evaluation can lead to serious outcomes and poor prognosis (i.e., CA19-9, MUC5AC). In recent years, scientists have established a large number of omics profiles to reveal underlying mechanisms and networks (i.e., IL-6/STAT3, NOTCH). With these results, we achieved several genomic alteration events (i.e., TP53mut, KRASmut) and epigenetic modifications (i.e., DNA methylation, histone modification) in CCA cells and clinical patients. Moreover, we reviewed candidate gene (such as NF-kB, YAP1) that drive gene transcription factors and canonical pathways through transcriptomics profiles (including microarrays and next-generation sequencing). In addition, the proteomics database also indicates which molecules and their directly binding status could trigger dysfunction signatures in tumorigenesis (carbohydrate antigen 19-9, mucins). Most importantly, we collected metabolomics datasets and pivotal metabolites. These results reflect the pharmacotherapeutic options and evaluate pharmacokinetic/pharmacodynamics in vitro and in vivo. We reversed the panels and selected many potentially small compounds from the connectivity map and L1000CDS2 system. In this paper, we summarize the prognostic value of each candidate gene and correlate this information with clinical events in CCA. This review can serve as a reference for further research to clearly investigate the complex characteristics of CCA, which may lead to better prognosis, drug repurposing and treatment strategies.

The classification of pathological tumor-node-metastasis (pTNM) staging of gastric cancer was revised in the 8th American Joint Committee on Cancer (AJCC) edition. The major revision was the separation of pN3a and pN3b in the pTNM staging. The current study evaluated the prognostic impact of this change.A total of 1,517 patients who underwent curative surgery for gastric cancer with a retrieved lymph node number ≥15 at our institution from January 1995 to December 2011 were enrolled. Survival was compared for the disease classified according to both the 7th and 8th editions.After separation of pN3a and pN3b in the pTNM stage definition, the 8th edition still provides significant survival differences between each stage. The multivariate analysis demonstrated that the pTNM stage in both the 7th and 8th editions was an independent prognostic factors of overall survival and disease-free survival. The 8th edition has a better homogeneity than the 7th edition with a significantly higher likelihood ratio chi-square test. Regarding the OS and DFS, the time-dependent receiver operating characteristic (ROC) curves of the two staging systems are almost overlapping, indicating that the prognostic performance is comparable between the two staging systems.Both the 7th and 8th edition-based stages are independent prognostic factors for gastric cancer. The 8th edition has a better homogeneity than the 7th edition; the 8th edition provides discriminant survival differences among each pTNM stage that are comparable to those in the 7th edition.

Axin-1, a negative regulator of Wnt signaling, is a versatile scaffold protein involved in centrosome separation and spindle assembly in mitosis, but its function in mammalian oogenesis remains unknown. Here we examined the localization and function of Axin-1 during meiotic maturation in mouse oocytes. Immunofluorescence analysis showed that Axin-1 was localized around the spindle. Knockdown of the Axin1 gene by microinjection of specific short interfering (si)RNA into the oocyte cytoplasm resulted in severely defective spindles, misaligned chromosomes, failure of first polar body (PB1) extrusion, and impaired pronuclear formation. However, supplementing the culture medium with the Wnt pathway activator LiCl improved spindle morphology and pronuclear formation. Downregulation of Axin1 gene expression also impaired the spindle pole localization of γ-tubulin/Nek9 and resulted in retention of the spindle assembly checkpoint protein BubR1 at kinetochores after 8.5 h of culture. Our results suggest that Axin-1 is critical for spindle organization and cell cycle progression during meiotic maturation in mouse oocytes.

Adenosquamous carcinoma (ASC) is a rare disease involving various organs, yet there are no large-scale population-based comparative studies on ASC among different organs.The incidence and overall survival of ASC among various organs in cases diagnosed in Taiwan from January 1, 2003 to December 31, 2010 were calculated and compared using data from the Taiwan Cancer Registry (TCR). The various organs were classified and divided into three different systems: the female reproductive, respiratory, and alimentary systems. Survival analysis were also compared among 30,850 patients diagnosed as ASC, adenocarcinoma (AC) or squamous cell carcinoma (SCC) in organs with frequent ASC.During the study period, a total of 576 ASC cases were diagnosed in Taiwan. The most common primary system was respiratory (73.8%), followed by alimentary (16.2%) and female reproductive (10%). The overall survival were significantly higher for cases involving the female reproductive system, followed by the respiratory and alimentary systems (P = 0.016). The median overall survival were worse in males than females for cases involving the respiratory system (22.4 vs. 31.8 months, P = 0.044). Multivariate analysis showed that age ≧ 65, more advanced T and N categories were independent unfavorable prognostic factors of overall survival in ASC. ASC histology is an independent unfavorable prognostic factor compared with AC and SCC.ASC at an old age and more advanced T and N categories were found to be associated with a poor prognosis.

The multiple cellular targets affected by proteasome inhibition implicate a potential role for bortezomib, a first-in-class proteasome inhibitor, in enhancing antitumor activities in hematologic malignancies. Here, we examined the antitumor activity and drug targets of bortezomib in leukemia cells. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis assays and associated molecular events assessed by Western Blot. Gene silencing was performed by small interference RNA. Drug was tested in vivo in xenograft models of human leukemia cell lines and in primary leukemia cells. Clinical samples were assessed by immunohistochemical staining. Bortezomib differentially induced apoptosis in leukemia cells that was independent of its proteasome inhibition. Cancerous inhibitor of protein phosphatase 2A, a cellular inhibitor of protein phosphatase 2A, mediated the apoptotic effect of bortezomib. Bortezomib increased protein phosphatase 2A activity in sensitive leukemia cells (HL-60 and KG-1), but not in resistant cells (MOLT-3 and K562). Bortezomib’s downregulation of cancerous inhibitor of protein phosphatase 2A and phospho-Akt correlated with its drug sensitivity. Furthermore, cancerous inhibitor of protein phosphatase 2A negatively regulated protein phosphatase 2A activity. Ectopic expression of CIP2A up-regulated phospho-Akt and protected HL-60 cells from bortezomib-induced apoptosis, whereas silencing CIP2A overcame the resistance to bortezomib-induced apoptosis in MOLT3 and K562 cells. Importantly, bortezomib exerted in vivo antitumor activity in HL-60 xenografted tumors and induced cell death in some primary leukemic cells. Cancerous inhibitor of protein phosphatase 2A was expressed in leukemic blasts from bone marrow samples. Cancerous inhibitor of protein phosphatase 2A plays a major role in mediating bortezomib-induced apoptosis in leukemia cells.

Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Currently, only sorafenib is approved by the FDA for advanced HCC treatment; therefore, there is an urgent need to discover candidate therapeutic drugs for HCC. We hypothesized that if a drug signature could reverse, at least in part, the gene expression signature of HCC, it might have the potential to inhibit HCC-related pathways and thereby treat HCC. To test this hypothesis, we first built an integrative platform, the "Encyclopedia of Hepatocellular Carcinoma genes Online 2", dubbed EHCO2, to systematically collect, organize and compare the publicly available data from HCC studies. The resulting collection includes a total of 4,020 genes. To systematically query the Connectivity Map (CMap), which includes 6,100 drug-mediated expression profiles, we further designed various gene signature selection and enrichment methods, including a randomization technique, majority vote, and clique analysis. Subsequently, 28 out of 50 prioritized drugs, including tanespimycin, trichostatin A, thioguanosine, and several anti-psychotic drugs with anti-tumor activities, were validated via MTT cell viability assays and clonogenic assays in HCC cell lines. To accelerate their future clinical use, possibly through drug-repurposing, we selected two well-established drugs to test in mice, chlorpromazine and trifluoperazine. Both drugs inhibited orthotopic liver tumor growth. In conclusion, we successfully discovered and validated existing drugs for potential HCC therapeutic use with the pipeline of Connectivity Map analysis and lab verification, thereby suggesting the usefulness of this procedure to accelerate drug repurposing for HCC treatment.