Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3+ Regulatory T Cells via a miR-342-Dependent Mechanism.

Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3+ regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.

Differentially expressed genes associated with high metabolic tumor volume served as diagnostic markers and potential therapeutic targets for pancreatic cancer.

BACKGROUND: The lack of distinct biomarkers for pancreatic cancer is a major cause of early-stage detection difficulty. The pancreatic cancer patient group with high metabolic tumor volume (MTV), one of the values measured from positron emission tomography-a confirmatory method and standard care for pancreatic cancer, showed a poorer prognosis than those with low MTV. Therefore, MTV-associated differentially expressed genes (DEGs) may be candidates for distinctive markers for pancreatic cancer. This study aimed to evaluate the possibility of MTV-related DEGs as markers or therapeutic targets for pancreatic cancer. METHODS: Tumor tissues and their normal counterparts were obtained from patients undergoing preoperative 18F-FDG PET/CT. The tissues were classified into MTV-low and MTV-high groups (7 for each) based on the MTV2.5 value of 4.5 (MTV-low: MTV2.5 < 4.5, MTV-high: MTV2.5 ≥ 4.5). Gene expression fold change was first calculated in cancer tissue compared to its normal counter and then compared between low and high MTV groups to obtain significant DEGs. To assess the suitability of the DEGs for clinical application, the correlation of the DEGs with tumor grades and clinical outcomes was analyzed in TCGA-PAAD, a large dataset without MTV information. RESULTS: Total RNA-sequencing (MTV RNA-Seq) revealed that 44 genes were upregulated and 56 were downregulated in the high MTV group. We selected the 29 genes matching MTV RNA-seq patterns in the TCGA-PAAD dataset, a large clinical dataset without MTV information, as MTV-associated genes (MAGs). In the analysis with the TCGA dataset, MAGs were significantly associated with patient survival, treatment outcomes, TCGA-PAAD-suggested markers, and CEACAM family proteins. Some MAGs showed an inverse correlation with miRNAs and were confirmed to be differentially expressed between normal and cancerous pancreatic tissues. Overexpression of KIF11 and RCC1 and underexpression of ADCY1 and SDK1 were detected in ~ 60% of grade 2 pancreatic cancer patients and associated with ~ 60% mortality in stages I and II. CONCLUSIONS: MAGs may serve as diagnostic markers and miRNA therapeutic targets for pancreatic cancer. Among the MAGs, KIF11, RCC1, ADCY, and SDK1 may be early diagnostic markers.

Clinically conserved genomic subtypes of gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.

Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes and genomic phenotypes.

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent ß-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

Anticancer effect of locally applicable aptamer-conjugated gemcitabine-loaded atelocollagen patch in pancreatic cancer patient-derived xenograft models.

We investigated the anticancer effect of the aptamer-conjugated gemcitabine-loaded atelocollagen patch in a pancreatic cancer patient-derived xenograft (PDX) model to propose a future potential adjuvant surgical strategy during curative pancreatic resection for pancreatic cancer. A pancreatic cancer PDX model was established. Animals were grouped randomly into a no-treatment control group; treatment group treated with intraperitoneal gemcitabine injection (IP-GEM) or aptamer-conjugated gemcitabine (APT:GEM); and transplant with three kinds of patches: atelocollagen-aptamer-gemcitabine (patch I), atelocollagen-inactive aptamer-gemcitabine (patch II), and atelocollagen-gemcitabine (patch III). Tumor volumes and response were evaluated based on histological analysis by H&E staining and Immunohistochemistry (IHC) was performed. Anticancer therapy-related toxicity was evaluated by hematologic findings. The patch I group showed the most significant reduction of tumor growth rate, compared with the no-treatment group (p < 0.05). However, other treatment groups were not found to show significant reduction in tumor growth rate (0.05 < p < 0.1). There was no microscopic evidence suggesting potential toxicity, such as inflammation, nor necrotic changes in liver, lung, kidney, and spleen tissue. In addition, no leukopenia, anemia, or neutropenia was observed in the patch I group. This implantable aptamer-drug conjugate system is thought to be a new surgical strategy to augment the oncologic significance of margin-negative resection in treating pancreatic cancer in near future.

Genomic profiling of multifocal intrahepatic cholangiocarcinoma reveals intraindividual concordance of genetic alterations.

In multifocal intrahepatic cholangiocarcinoma (IHC), intrahepatic metastases (IM) represent a contraindication to surgical resection, whereas satellite nodules (SN) do not. However, no consensus criteria exist to distinguish IM from SN. The purpose of this study was to determine genetic alterations and clonal relationships in surgically resected multifocal IHC. Next-generation sequencing of 34 spatially separated IHC tumors was performed using a targeted panel of 201 cancer-associated genes. Proposed definitions in the literature were applied of SN located in the same liver segment and ≤2 cm from the primary tumor; and IM located in a different liver segment and/or >2 cm from the primary tumor. Somatic point mutations concordant across tumors from individual patients included BAP1, SMARCA4 and IDH1. Small insertions and deletions (indels) present at the same genome positions among all tumors from individuals included indels in DNA repair genes, CHEK1, ERCC5, ATR and MSH6. Copy number alterations were also similar between all tumors in each patient. In this cohort of multifocal IHC, genomic profiles were concordant across all tumors in each patient, suggesting a common progenitor cell origin, regardless of the location of tumors in the liver. The decision to perform surgery should not be based upon a perceived distinction between IM and SN.

Prognostic significance of high metabolic activity in breast cancer: PET signature in breast cancer.

High metabolic activity, reflected in increased glucose uptake, is one of the hallmarks of many cancers including breast cancer. However, not all cancers avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus, we aim to generate a genomic signature of glucose hypermetabolism in breast cancer and examine its clinical relevance. To identify genes significantly associated with glucose uptake, gene expression data were analyzed together with the standardized uptake values (SUVmax) of 18F-fluorodeoxy-glucose on positron emission tomography (PET) for 11 breast cancers. The resulting PET signature was evaluated for prognostic significance in four large independent patient cohorts (n = 5417). Potential upstream regulators accountable for the high glucose uptake were identified by gene network analysis. A PET signature of 242 genes was significantly correlated with SUVmax in breast cancer. In all four cohorts, high PET signature was significantly associated with poorer prognosis. The prognostic value of this PET signature was further supported by Cox regression analyses (hazard ratio 1.7, confidential interval 1.48-2.02; P < 0.001). The PET signature was also strongly correlated with previously established prognostic genomic signatures such as PAM50, Oncotype DX, and NKI. Gene network analyses suggested that MYC and TBX2 were the most significant upstream transcription factors in the breast cancers with high glucose uptake. A PET signature reflecting high glucose uptake is a novel independent prognostic factor in breast cancer. MYC and TBX2 are potential regulators of glucose uptake.

Different biological behaviors in left-sided pancreatic cancer according to Yonsei criteria: Proposal of a modified Yonsei criteria score.

BACKGROUND/OBJECTIVES: Our institutional experience has demonstrated that bloodless and margin-negative resection is the most potent prognostic factor in treating left-sided pancreatic cancer and we developed selection guideline. The Yonsei criteria (YC) is selection criteria for oncologically safe and effective resection of left-sided pancreatic cancer by a minimally invasive approach. In this study, we investigated whether left-sided pancreatic cancer with YC can be more individualized to predict long-term survival by using clinically and pathologically detectable parameters. METHODS: From January 2000 to December 2015, 105 patients underwent distal pancreatectomy for left-sided pancreatic cancer. The medical records of the patients were retrospectively reviewed. RESULTS: Among clinically and pathologically detectable parameters to predict tumor conditions, radiologically determined tumor size (p = 0.080) and SUVmax (p = 0.086) were identified as predictors of early tumor recurrence with marginal significance. Among them, 20% of the patients with YC were identified as having the most favoring tumor condition, with an modified YC score of 3. The patient group with the lowest mYC score was found to have a very long disease-free survival time, with a mean of 108 months, which was statistically different from those with other mYC scores (mYC score = 4, mean 47.1 months [95% CI: 27.8-69.5] vs. mYC score = 5, mean 36.7 months [95% CI: 12.7-60.7], vs. mYC score = 6, mean 10.7 months [95% CI: 3.9-17.4]). CONCLUSIONS: Modified Yonsei criteria score can predict long-term survival in resected left-sided pancreatic cancer. And patients within YC with a mYC score = 3 could have a favorable survival outcome.

The Yonsei criteria as a clinically detectable parameter for excellent prognosis in resected left-sided pancreatic cancer: outcomes of a propensity score-matched analysis.

BACKGROUND: This study aimed to identify that Yonsei criteria (YC) can be regarded as a preoperative clinical parameter to predict biological behavior of the left-sided pancreatic cancer. METHODS: Between June 2007 and December 2014, 135 patients who underwent minimally invasive (MIS) or open distal pancreatectomy for left-sided pancreatic cancer were enrolled in this study consecutively. Perioperative short-term and long-term oncologic outcomes were analyzed according to the YC retrospectively. RESULTS: Fifty-four and 81 patients did and did not meet the YC, respectively. Short-term oncologic outcomes were favorable among those meeting the YC even after propensity score matching. Patients within the YC also had better disease-free and disease-specific overall survival (p < 0.05). In analysis for receiver operating characteristic curve, area under curve of CA19-9 was satisfactory only within YC group. Multivariate analysis for disease-free survival identified the YC as a strong independent prognostic factor (p < 0.05). In preoperative clinical setting, patients' survival was clearly different based on following clinical groups, such as within YC, beyond YC, and unresectable. CONCLUSIONS: Preoperative CT-based determined YC can predict excellent short-term and long-term oncologic outcomes. YC might have a potential role as a preoperative clinical staging for left-sided pancreatic cancer. External validations of YC based on multicenter cohorts are mandatory to confirm this oncologic significance of YC.

Simultaneous enhancement of upconversion and downshifting luminescence via plasmonic structure.

We describe a metal nanodisk-insulator-metal (MIM) structure that enhances lanthanide-based upconversion (UC) and downshifting (DS) simultaneously. The structure was fabricated using a nanotransfer printing method that facilitates large-area applications of nanostructures for optoelectronic devices. The proposed MIM structure is a promising way to harness the entire solar spectrum by converting both ultraviolet and near-infrared to visible light concurrently through resonant-mode excitation. The overall photoluminescence enhancements of the UC and DS were 174- and 29-fold, respectively.

Large-scale plasma patterning of transparent graphene electrode on flexible substrates.

Graphene, a two-dimensional carbon material, has attracted significant interest for applications in flexible electronics as an alternative transparent electrode to indium tin oxide. However, it still remains a challenge to develop a simple, reproducible, and controllable fabrication technique for producing homogeneous large-scale graphene films and creating uniform patterns with desired shapes at defined positions. Here, we present a simple route to scalable fabrication of flexible transparent graphene electrodes using an oxygen plasma etching technique in a capacitively coupled plasma (CCP) system. Ascorbic acid-assisted chemical reduction enables the large-scale production of graphene with solution-based processability. Oxygen plasma in the CCP system facilitates the reproducible patterning of graphene electrodes, which allows controllable feature sizes and shapes on flexible plastic substrates. The resulting graphene electrode exhibits a high conductivity of 80 S cm(-1) and a transparency of 76% and retains excellent flexibility upon hard bending at an angle of ±175° and after repeated bending cycles. A simple LED circuit integrated on the patterned graphene film demonstrates the feasibility of graphene electrodes for use in flexible transparent electrodes.

Minimally invasive RAMPS in well-selected left-sided pancreatic cancer within Yonsei criteria: long-term (>median 3 years) oncologic outcomes.

BACKGROUND: Although minimally invasive techniques for distal pancreatectomy with or without splenectomy have been regarded as a feasible and safe treatment option for benign and borderline malignant lesions of the pancreas, the management of left-sided pancreatic cancer remains controversial. METHODS: From June 2007 to November 2010, 12 patients underwent laparoscopic or robotic radical antegrade modular pancreatosplenectomy (RAMPS) for well-selected left-sided pancreatic cancer. The Yonsei criteria for patient selection included the following conditions: (1) tumor confined to the pancreas, (2) intact fascial layer between the distal pancreas and the left adrenal gland and kidney, and (3) tumor located more than 1-2 cm from the celiac axis. We compared the clinicopathologic factors and oncologic outcomes of the minimally invasive surgery (MIS) and the conventional open surgery groups for treating left-sided pancreatic cancer. RESULTS: In the MIS group, the mean tumor size was 2.75 ± 1.32 cm, and the mean number of retrieved lymph nodes was 10.5 ± 7.14. The resection margins were confirmed to be negative for malignancy in all patients. The MIS group and open group (n = 78) were statistically different in terms of tumor size (2.8 ± 1.3 vs. 3.5 ± 1.9 cm, p = 0.05) and length of hospital stay (12.3 ± 6.8 vs. 22.4 ± 21.6 days, p = 0.002). On survival analysis, the MIS group had longer disease-free survival (DFS) and overall survival (OS) than the open group (DFS: 47.6 vs. 24.7 months, p = 0.027; OS: 60.0 vs. 30.7 months, p = 0.046). In order to overcome the heterogeneity of subjects between the MIS and the open group, we performed statically matched comparisons using the propensity score analysis and then divided the open group into two subgroups according to the Yonsei criteria. There were no significant differences in median overall survival between the MIS group and the open group that met the Yonsei criteria (60.00 vs. 60.72 months, p = 0.616). CONCLUSIONS: Minimally invasive RAMPS is not only technically feasible but also oncologically safe in cases of well-selected left-sided pancreatic cancer. Our selection criteria for minimally invasive RAMPS needs to be further validated based on additional large-volume studies.

Various retraction techniques for laparoscopic pancreaticoduodenectomy.

The laparoscopic pancreaticoduodenectomy (LPD), introduced by Gagner and Pomp in 1994, is typically done in high-volume centers due to its technical demands. Our methods aim to provide effective traction, enabling efficient surgery despite limited staffing. A retrospective analysis of 29 patients undergoing LPD by a single surgeon between September 2021 and December 2022 showed promising outcomes: median intraoperative bleeding of 425 mL, operation time of 505 minutes, and postoperative hospital stay of 10 days. With only one case requiring open conversion, our external retraction techniques demonstrate efficacy in overcoming challenges associated with manpower constraints, highlighting potential utility for surgeons in similar settings. We share LPD external retraction techniques and outcomes.

Laparoscopic pancreaticoduodenectomy and laparoscopic pancreaticoduodenectomy with robotic reconstruction: single-surgeon experience and technical notes.

Purpose: Despite the increasing number of robotic pancreaticoduodenectomies, laparoscopic pancreaticoduodenectomy (LPD) and LPD with robotic reconstruction (LPD-RR) are still valuable surgical options for minimally invasive pancreaticoduodenectomy (MIPD). This study introduces the surgical techniques, tips, and outcomes of our experience with LPD and LPD-RR. Methods: Between March 2014 and July 2021, 122 and 48 patients underwent LPD and LPD-RR respectively, at CHA Bundang Medical Center in Korea. The operative settings, procedures, and trocar placements were identical in both approaches; however, different trocars were used. We introduced our techniques of retraction methods for Kocherization and uncinate process dissection, pancreatic reconstruction, pancreatic division, and protection using the round ligament. The perioperative surgical outcomes of LPD and LPD-RR were compared. Results: Baseline demographics of patients in the LPD and LPD-RR groups were comparable, but the LPD group had older age (65.5 ± 11.6 years vs. 60.0 ± 14.1 years, p = 0.009) and lesser preoperative chemotherapy (15.6% vs. 35.4%, p = 0.008). The proportion of malignant disease was similar (LPD group, 86.1% vs. LPD-RR group, 83.3%; p = 0.759). Perioperative outcomes were also comparable, including operative time, estimated blood loss, clinically relevant postoperative pancreatic fistula (LPD group, 9.0% vs. LPD-RR group, 10.4%; p = 0.684), and major postoperative complication rates (LPD group, 14.8% vs. LPD-RR group, 6.2%; p = 0.082). Conclusion: Both LPD and LPR-RR can be safely performed by experienced surgeons with acceptable surgical outcomes. Further investigations are required to evaluate the objective benefits of robotic surgical systems in MIPD and establish widely acceptable standardized MIPD techniques.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma.

Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Clinical feasibility of curative surgery after nab-paclitaxel plus gemcitabine-cisplatin chemotherapy in patients with locally advanced cholangiocarcinoma.

BACKGROUND: This study was conducted to evaluate the clinical feasibility of nab-paclitaxel plus gemcitabine-cisplatin triplet chemotherapy in patients with locally advanced cholangiocarcinoma in real-world practice. METHODS: We retrospectively reviewed patients with locally advanced cholangiocarcinoma who were treated with nab-paclitaxel plus gemcitabine-cisplatin between October 2019 and August 2021 at a single institution. The initial diagnosis of cholangiocarcinoma was histologically confirmed. RESULTS: One hundred twenty-nine patients were included in this study. Among the patients with a measurable lesion (57.4%), the objective response rate and disease control were 60.8% and 91.9%, respectively. Seventy-seven patients (59.7%) were determined as resectable after triplet chemotherapy, but 73 (56.6%) underwent subsequent curative surgery. The major postoperative complication rate was 15.1%, and there were 2 postoperative mortalities (2.7%). There were 6 complete remission cases (8.2%) in the final pathology. The R0 resection was achieved in 67 patients (91.8%). Despite the initial locally advanced cholangiocarcinoma, a pathologic T stage of less than T2 was reported in 67 patients (91.8%). Fifty-two patients (71.2%) had no lymph node metastasis. Patients who underwent surgery after triplet chemotherapy had significantly higher 12-month overall survival (95.9% vs 76.8%; P < .001) than those treated with chemotherapy alone. CONCLUSION: Nab-paclitaxel plus gemcitabine-cisplatin chemotherapy demonstrated a down-staging effect through a high response rate, indicating that this triplet chemotherapy is feasible as induction therapy in patients with locally advanced cholangiocarcinoma.

Development of a metabolite calculator for diagnosis of pancreatic cancer.

BACKGROUND: Carbohydrate antigen (CA) 19-9 is a known pancreatic cancer (PC) biomarker, but is not commonly used for general screening due to its low sensitivity and specificity. This study aimed to develop a serum metabolites-based diagnostic calculator for detecting PC with high accuracy. METHODS: A targeted quantitative approach of direct flow injection-tandem mass spectrometry combined with liquid chromatography-tandem mass spectrometry was employed for metabolomic analysis of serum samples using an Absolute IDQ™ p180 kit. Integrated metabolomic analysis was performed on 241 pooled or individual serum samples collected from healthy donors and patients from nine disease groups, including chronic pancreatitis, PC, other cancers, and benign diseases. Orthogonal partial least squares discriminant analysis (OPLS-DA) based on characteristics of 116 serum metabolites distinguished patients with PC from those with other diseases. Sparse partial least squares discriminant analysis (SPLS-DA) was also performed, incorporating simultaneous dimension reduction and variable selection. Predictive performance between discrimination models was compared using a 2-by-2 contingency table of predicted probabilities obtained from the models and actual diagnoses. RESULTS: Predictive values obtained through OPLS-DA for accuracy, sensitivity, specificity, balanced accuracy, and area under the receiver operating characteristic curve (AUC) were 0.9825, 0.9916, 0.9870, 0.9866, and 0.9870, respectively. The number of metabolite candidates was narrowed to 76 for SPLS-DA. The SPLS-DA-obtained predictive values for accuracy, sensitivity, specificity, balanced accuracy, and AUC were 0.9773, 0.9649, 0.9832, 0.9741, and 0.9741, respectively. CONCLUSIONS: We successfully developed a 76 metabolome-based diagnostic panel for detecting PC that demonstrated high diagnostic performance in differentiating PC from other diseases.

ARID1A Mutation from Targeted Next-Generation Sequencing Predicts Primary Resistance to Gemcitabine and Cisplatin Chemotherapy in Advanced Biliary Tract Cancer.

PURPOSE: There are clinical unmet needs in predicting therapeutic response and precise strategy for the patient with advanced biliary tract cancer (BTC). We aimed to identify genomic alterations predicting therapeutic response and resistance to gemcitabine and cisplatin (Gem/Cis)-based chemotherapy in advanced BTC. MATERIALS AND METHODS: Genomic analysis of advanced BTC multi-institutional cohorts was performed using targeted panel sequencing. Genomic alterations were analyzed integrating patients' clinicopathologic data, including clinical outcomes of Gem/Cis-based therapy. Significance of genetic alterations was validated using clinical next-generation sequencing (NGS) cohorts from public repositories and drug sensitivity data from cancer cell lines. RESULTS: 193 BTC patients from three cancer centers were analyzed. Most frequent genomic alterations were TP53 (55.5%), KRAS (22.8%), ARID1A (10.4%) alterations, and ERBB2 amplification (9.8%). Among 177 patients with BTC receiving Gem/Cis-based chemotherapy, ARID1A alteration was the only independent predictive molecular marker of primary resistance showing disease progression for 1st-line chemotherapy in the multivariate regression model (odds ratio, 3.12; p=0.046). In addition, ARID1A alteration was significantly correlated with inferior progression-free survival on Gem/Cis-based chemotherapy in the overall patient population (p=0.033) and in patients with extrahepatic cholangiocarcinoma (CCA) (p=0.041). External validation using public repository NGS revealed that ARID1A mutation was a significant predictor for poor survival in BTC patients. Investigation of multi-OMICs drug sensitivity data from cancer cell lines revealed that cisplatin-resistance was exclusively observed in ARID1A mutant bile duct cancer cells. CONCLUSION: Integrative analysis with genomic alterations and clinical outcomes of the first-line Gem/Cis-based chemotherapy in advanced BTC revealed that patients with ARID1Aalterations showed a significant worse clinical outcome, especially in extrahepatic CCA. Well-designed prospective studies are mandatory to validate the predictive role of ARID1Amutation.

Clinical Significance of Glycolytic Metabolic Activity in Hepatocellular Carcinoma.

High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor survival, the strongest stem cell signature, high genomic instability, activation of EPCAM and SALL4, and low potential for benefitting from immunotherapy. Interestingly, immune cell analysis showed that regulatory T cells (Tregs) are highly enriched in high metabolic HCC tumors, suggesting that high metabolic activity of cancer cells may trigger activation or infiltration of Tregs, leading to cancer cells' evasion of anti-cancer immune cells. In summary, we identified clinically and metabolically distinct subtypes of HCC, potential biomarkers associated with these subtypes, and a potential mechanism of metabolism-mediated immune evasion by HCC cells.

MCT4 as a potential therapeutic target to augment gemcitabine chemosensitivity in resected pancreatic cancer.

BACKGROUND: Pancreatic cancer is a devastating disease with a high relapse rate, even in case of resectable pancreatic cancer. Here, we aimed to identify the prognostic significance and therapeutic options of metabolic subtypes of resectable pancreatic cancer. METHOD: Transcriptomic data were obtained from the TCGA-PAAD cohort in the The Cancer Genome Atlas (TCGA) data portal (n = 182). After integrative analysis of transcriptomic data in the discovery cohort, immunohistochemical (IHC) staining was performed in an independent cohort (n = 51) to validate the molecules of interest. Experimental testing for the molecules of interest was performed in vitro using pancreatic cancer cell line models AsPC1, BxPC3, MIA PaCa-2 and PANC-1. RESULTS: Two subtypes showing distinct gene expression patterns in the TCGA-PAAD dataset were identified. Of these, the active glucose metabolism subtype showed a significantly lower survival rate related to relapse after surgical resection. The genes SLC2A1 (GLUT1) and SLC16A3 (MCT4) were highly enriched in this subtype. The validation cohort showed a high MCT4 staining and a high relapse rate (p = 0.01). Several molecular pathways associated with aggressive tumor biology, including cell cycle regulation and Myc and mTOR downstream signaling, were highly enriched in the active glucose metabolism subtype, as well as with distinct responses to immunotherapy. MCT4 inhibition suppressed the in vitro malignant characteristics of pancreatic cancer cells and showed a synergistic effect with gemcitabine treatment. CONCLUSIONS: From our data we conclude that MCT4 may serve as a potential therapeutic target in resectable pancreatic cancer. The precision medicine strategy for resectable pancreatic cancer should be validated in a clinical setting with a prospective study design.