Publications by authors named "Qingjiang Hu"

54 Publications

Recent developments in cancer research: Expectations for a new remedy.

Ann Gastroenterol Surg 2021 Jul 15;5(4):419-426. Epub 2021 Feb 15.

Department of Surgery and Science Kyushu University Fukuoka Japan.

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.
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http://dx.doi.org/10.1002/ags3.12440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316733PMC
July 2021

Cancer-associated Fibroblast-derived Spondin-2 Promotes Motility of Gastric Cancer Cells.

Cancer Genomics Proteomics 2021 Jul-Aug;18(4):521-529

Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan;

Background/aim: Peritoneal dissemination (PD) occurs frequently in gastric cancer (GC) and is fatal. The interactions between tumor cells and stromal cells are critical for cancer progression. Our aim was to identify a novel PD-associated gene derived from stromal cells in GC.

Materials And Methods: Among the candidate PD-associated genes identified in our previous study, we focused on spondin-2 (SPON2), an extracellular matrix-secreted protein. Clinicopathological and prognostic analyses of SPON2 mRNA expression were performed using GC datasets. Localization of SPON2 expression was assessed by immunohistochemistry. In vitro migration assay and immunofluorescence staining were also conducted using GC cell lines.

Results: SPON2 was expressed in and secreted from cancer-associated fibroblasts in GC. High expression of SPON2 in tumor tissues was correlated with PD, tumor size and poor prognosis in GC. The motility of GC cells was increased by treatment with a SPON2 recombinant protein in vitro.

Conclusion: Cancer-associated fibroblast-derived SPON2 may promote PD, in part, by facilitating GC cell motility and serve as a predictive marker for PD in GC.
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http://dx.doi.org/10.21873/cgp.20277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404736PMC
April 2021

Identification of SLC38A7 as a Prognostic Marker and Potential Therapeutic Target of Lung Squamous Cell Carcinoma.

Ann Surg 2021 09;274(3):500-507

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: No effective molecular targeted therapy has been established for SCC. We conducted a comprehensive study of SCC patients using RNA-sequencing and TCGA dataset to clarify the driver oncogene of SCC.

Method: Forty-six samples of 23 patients were totally analyzed with RNA-sequencing. We then searched for candidate-oncogenes of SCC using the TCGA database. To identify candidate oncogenes, we used the following 2 criteria: (1) the genes of interest were overexpressed in tumor tissues of SCC patients in comparison to normal tissues; and (2) using an integrated mRNA expression and DNA copy number profiling analysis using the TCGA dataset, the DNA copy number of the genes was positively correlated with the mRNA expression.

Result: We identified 188 candidate-oncogenes. Among those, the high expression of SLC38A7 was a strong prognostic marker that was significantly associated with a poor prognosis in terms of both overall survival (OS) and recurrence-free survival in the TCGA dataset (P < 0.05). Additionally, 202 resected SCC specimens were also subjected to an immunohistochemical analysis. Patients with the high expression of SLC38A7 (alternative name is sodium-coupled amino acid transporters 7) protein showed significantly shorter OS in comparison to those with the low expression of SLC38A7 protein [median OS 3.9 years (95% confidence interval, 2.4-6.4 years) vs 2.2 years (95% confidence interval, 1.9-4.1 years); log rank test: P = 0.0021].

Conclusion: SLC38A7, which is the primary lysosomal glutamine transporter required for the extracellular protein-dependent growth of cancer cells, was identified as a candidate therapeutic target of SCC.
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http://dx.doi.org/10.1097/SLA.0000000000005001DOI Listing
September 2021

The effects of ARID1A mutations on colorectal cancer and associations with PD-L1 expression by stromal cells.

Cancer Rep (Hoboken) 2021 May 27:e1420. Epub 2021 May 27.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: ARID1A is a component of the SWI/SNF complex, which controls the accessibility of proteins to DNA. ARID1A mutations are frequently observed in colorectal cancers (CRCs) and have been reported to be associated with high mutational burden and tumor PD-L1 expression in vitro.

Aim: To clarify the role of ARID1A mutation in CRC.

Method And Results: We used next generation sequencing (NGS) and immunohistochemistry on clinically obtained samples. A total of 201 CRC tissues from Niigata University and Niigata Center Hospital were processed by NGS using the CANCERPLEX panel. Immunohistochemistry for ARID1A, PD-L1, MLH1, and MSH2 was performed on 66 propensity-matched (33 microsatellite instability-high [MSI-H] and 33 microsatellite-stable [MSS]) cases among 499 cases from Kyushu University. TCGA data were downloaded from cBioPortal. NGS showed significantly more mutations in ARID1A mutated CRCs (p = 0.01), and the trend was stronger for right-sided CRCs than left-sided. TCGA data confirmed these findings (p < 0.01). BRAF V600E and ATM mutations were also found at higher frequencies. Immunohistochemistry showed that 30% of MSI-H CRCs had ARID1A loss, while this was true in only 6% of MSS CRCs. In both MSI-H and MSS, PD-L1 expression by stromal cells was enhanced in the ARID1A-mutant groups (90% vs 39% in MSI-H, 100% vs 26% in MSS).

Conclusion: We found a higher mutational burden in ARID1A-mutant CRCs, and IHC study showed that ARID1A loss was correlated with high PD-L1 expression in stromal cells regardless of MSI status. These data support the idea that mutant ARID1A is a potential biomarker for CRCs.
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http://dx.doi.org/10.1002/cnr2.1420DOI Listing
May 2021

Clinical significance of signal regulatory protein alpha (SIRPα) expression in esophageal squamous cell carcinoma.

Cancer Sci 2021 Aug 11;112(8):3018-3028. Epub 2021 Jun 11.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Signal regulatory protein alpha (SIRPα) is a type I transmembrane protein that inhibits macrophage phagocytosis of tumor cells upon interaction with CD47, and the CD47-SIRPα pathway acts as an immune checkpoint factor in cancers. This study aims to clarify the clinical significance of SIRPα expression in esophageal squamous cell carcinoma (ESCC). First, we assessed SIRPα expression using RNA sequencing data of 95 ESCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical analytic data from our cohort of 131 patients with ESCC. Next, we investigated the correlation of SIRPα expression with clinicopathological factors, patient survival, infiltration of tumor immune cells, and expression of programmed cell death-ligand 1 (PD-L1). Overall survival was significantly poorer with high SIRPα expression than with low expression in both TCGA and our patient cohort (P < .001 and P = .027, respectively). High SIRPα expression was associated with greater depth of tumor invasion (P = .0017). Expression of SIRPα was also significantly correlated with the tumor infiltration of M1 macrophages, M2 macrophages, CD8 T cells, and PD-L1 expression (P < .001, P < .001, P = .03, and P < .001, respectively). Moreover, patients with SIRPα/PD-L1 coexpression tended to have a worse prognosis than patients with expression of either protein alone or neither. Taken together, SIRPα indicates poor prognosis in ESCC, possibly through inhibiting macrophage phagocytosis of tumor cells and inducing suppression of antitumor immunity. Signal regulatory protein alpha should be considered as a potential therapeutic target in ESCC, especially if combined with PD-1-PD-L1 blockade.
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http://dx.doi.org/10.1111/cas.14971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353899PMC
August 2021

Postoperative elevation in the plasma CCL2 level is a predictive biomarker of colorectal cancer recurrence.

Surg Today 2021 Oct 2;51(10):1671-1681. Epub 2021 Apr 2.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higasi-ku, Fukuoka, Fukuoka, 812-8582, Japan.

Purpose: There is currently no adequate biomarker for predicting colorectal cancer (CRC) recurrence. Chemokine (C-C motif) ligand 2 (CCL2) induces macrophages and fibroblasts to occupy metastatic niches in distant organs. The purpose of this study was to examine CCL2 as a potential predictive biomarker for CRC recurrence.

Methods: Plasma samples (n = 402) were collected from 80 stage II/III/IV CRC cases and the relationship between CCL2 profiles and recurrence was investigated. The tumor immune response genes associated with CCL2 mRNA expression in a subgroup of 8 stage I/II CRC cases with 12 recurrent sites and The Cancer Genome Atlas database were also analyzed retrospectively.

Results: Sixteen stage II/III/IV postoperative recurrent CRC cases experienced a significant increase in plasma CCL2 levels 6 months after surgery and continuously increased even after R0-1 resection. The 6-month postoperative CCL2 levels in recurrent cases of ≥ 1 year were significantly higher than in non-recurrent cases and recurrent cases of < 1 year. The CCL2 level in the primary tumor cases significantly correlated with the cytolytic activity, thus indicating a tumor immune response from the CD163-expressing macrophages.

Conclusion: Plasma CCL2 was found to be a predictive biomarker of postoperative CRC recurrence. CCL2 in metastatic sites derives from metastatic niches that surpass the host immune response.
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http://dx.doi.org/10.1007/s00595-021-02273-xDOI Listing
October 2021

[The Efficacy of topo Ⅰ-pS10 Expression in Gastric Cancer as a Predictive Biomarker for Irinotecan Use].

Gan To Kagaku Ryoho 2021 Mar;48(3):331-335

Dept. of Surgery and Science, Graduate School of Medical Sciences, Kyushu University.

Background: Though irinotecan is commonly used for treating advanced gastric cancer, there is no predictive biomarker to date. We have studied the resistant mechanism for irinotecan and found that phosphorylation of serine 10 residue of topoisomerase Ⅰ(topo Ⅰ)is an important step for irinotecan resistance. We have developed an immunohistochemical staining-based biomarker; topo Ⅰ-pS10, for predicting irinotecan efficacy.

Purpose: The purpose of this study is to test the accuracy of topo Ⅰ-pS10 immunohistochemical staining in gastric cancer clinical samples.

Methods: In this study we performed 2 sets of tests. In the training set, we stained 79 gastric cancer clinical samples which efficacy of irinotecan was measured by succinate dehydrogenase inhibition(SDI)test. In the validation set, we used 27 gastric cancer clinical samples which irinotecan was used and the efficacy was known.

Results: Training set: From the ROC curve the cut-off point was set at 35% positive nuclei. Sixty three cases were positive with topo Ⅰ-pS10 in the nuclei. With the result of irinotecan SDI, the sensitivity was 76.6% and the positive predictive value was 92.5%. This result showed that topo Ⅰ-pS10 positive case does not respond to irinotecan. Validation set: In this set, the sensitivity was 82.4% and the positive predictive value was 82.4%.

Conclusion: topo Ⅰ-pS10 staining can be used as a predictive biomarker for irinotecan for gastric cancer patients.
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March 2021

Cytolytic activity score as a biomarker for antitumor immunity and clinical outcome in patients with gastric cancer.

Cancer Med 2021 05 26;10(9):3129-3138. Epub 2021 Mar 26.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: A simple measure of immune cytolytic activity (CYT) base on mRNA expression levels of two genes, GZMA and PRF1, was recently reported. Here, we aimed to evaluate the CYT score's potential as a measure of antitumor immunity and predictor of clinical outcome in gastric cancer (GC) patients.

Materials And Methods: We evaluated the correlations between tumor-infiltrating immune cells and the CYT score in 238 GC samples from The Cancer Genome Atlas (TCGA). Next, we investigated CYT score associations with molecular subtypes, somatic mutation load, and immune checkpoint molecules in GC samples from TCGA and Asian Cancer Research Group (ACRG). Moreover, we evaluated the clinical significance of the CYT score calculated by reverse transcription (RT)-quantitative PCR (qPCR) data in 123 GC samples and the association of the CYT score with the response to anti-PD-1 therapy in 7 GC samples from Kyushu University Hospital.

Results: The CYT score positively correlated with the proportions of tumor-infiltrating CD8+ T cells and macrophages and negatively correlated with the proportion of regulatory T cells in GC tissues. A high CYT score was associated with common immune checkpoint molecules, a high mutation, the Epstein-Barr virus subtype, and the microsatellite instability subtype in GC. Moreover, a low CYT score was a poor prognosis factor in patients with GC. Finally, the CYT score was higher in a responder to anti-PD-1 therapy compared to nonresponders.

Conclusion: The CYT score reflects antitumor immunity and predicts clinical outcome in GC patients.
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http://dx.doi.org/10.1002/cam4.3828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085935PMC
May 2021

Impact of a Long Linear Staplers on the Incidence of Stricture after Triangulating Esophagogastric Anastomosis.

Surg Laparosc Endosc Percutan Tech 2021 Jan 22;31(4):453-456. Epub 2021 Jan 22.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Various techniques have been reported for esophagogastric anastomosis to prevent anastomotic leakage. Recently, not only postoperative anastomotic leakage but also anastomotic stricture is considered important because stricture contributes to the patient's postoperative quality of life. However, the best procedure for anastomosis has not been established.

Materials And Methods: The authors divided 101 patients with thoracic or abdominal esophageal cancer who underwent cervical triangulating esophagogastric anastomosis using a linear stapler between May 2017 and May 2020 into 2 groups: surgery with a short (45 mm) linear stapler (SS group, n=59) or a long (60 mm) stapler (LS group, n=42). The frequencies of anastomotic leakage and stricture were compared between the 2 groups.

Results: The incidence of anastomotic leakage and stricture without leakage were significantly lower in the LS versus SS group (respectively: leakage: 15% vs. 0%, P=0.01; stricture: 36% vs. 7%, P=0.01). A short linear stapler and anastomotic leakage were independent risk factors for anastomotic stricture in the multivariate analysis (short stapler: odds ratio, 3.27; 95% confidence interval, 1.08-9.9; P=0.03; anastomotic leakage: odds ratio, 2.78; 95% confidence interval, 1.02-8.5; P=0.04).

Conclusion: A long linear stapler is preferable for cervical triangulating esophagogastric anastomosis.
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http://dx.doi.org/10.1097/SLE.0000000000000899DOI Listing
January 2021

Gastric glomus tumor with a preoperative diagnosis by endoscopic ultrasonography-guided fine needle aspiration: a case report.

Int Cancer Conf J 2021 Jan 15;10(1):35-40. Epub 2020 Sep 15.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan.

A gastric glomus tumor (GGT) is a rare gastric submucosal tumor that can become malignant. A preoperative diagnosis would allow for a more informed decision regarding the treatment strategy. We present the case of an asymptomatic man with a GGT that was diagnosed during a preoperative examination. Upper gastrointestinal endoscopy was performed in a 64-year-old man and revealed a submucosal tumor at the lesser curvature of the antrum of the stomach. Endoscopic ultrasonography showed a 12-mm-sized hypoechoic tumor in the second and third layers of the stomach wall. A histologic diagnosis of GGT was made using endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA). Abdominal contrast-enhanced computed tomography was performed, but the identification of the tumor was difficult owing to poor enhancement. The gradual growth of the tumor made it necessary to perform an operation. Laparoscopy and endoscopy cooperative surgery was performed without any complications. The tumor cells were immunohistochemically positive for alpha-smooth muscle actin, h-caldesmon, and collagen type IV but were negative for desmin, discovered on GIST-1, S-100 protein, cluster of differentiation 34, epithelial membrane antigen, and cytokeratin AE1/AE3. The final diagnosis was identical to the preoperative diagnosis made using EUS-FNA. EUS-FNA is a useful method for the preoperative diagnosis of small submucosal tumors, including GGTs.
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http://dx.doi.org/10.1007/s13691-020-00444-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797396PMC
January 2021

Quadruple gastrointestinal cancer with discordance of mismatch repair protein deficiency and microsatellite instability suggesting Lynch syndrome.

Int Cancer Conf J 2021 Jan 24;10(1):2-5. Epub 2020 Nov 24.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan.

A 65-year-old woman with prior personal and family histories of cancer was admitted to our hospital for quadruple cancer. Preoperative endoscopy revealed a type 0-II gastric cancer (GC; gastric body), advanced type-II colon cancer (ascending colon), and early-stage recto-sigmoid colon cancers. We diagnosed her with Lynch syndrome (LS) per Amsterdam criteria, and performed distal gastrectomy, ileocecal resection and high anterior resection. Her pathological diagnoses were GC: well-to-poorly differentiated adenocarcinoma (AD, por2 > tub2) with signet-ring cells, ypT1b SM2; ascending colon cancer: AD with focal mucin products (tub2 > muc), SS; sigmoid colon cancer: AD (tub1), M; recto-sigmoid cancer: AD (tub1 > tub2), SM. Immunohistochemical tests revealed that all cancers lacked the MLH1/PMS2 protein. However, the three colon cancers were found to have high microsatellite instability (MSI); the GC was microsatellite stable (MSS). No recurrence or other cancers were observed for 30 months after surgery without adjuvant chemotherapy. As patients with LS may also develop MSS cancers, we should check for MSI in all LS cancers for proper treatment.
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http://dx.doi.org/10.1007/s13691-020-00457-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797393PMC
January 2021

Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases.

PLoS Genet 2021 01 21;17(1):e1009113. Epub 2021 Jan 21.

Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.

A Darwinian evolutionary shift occurs early in the neutral evolution of advanced colorectal carcinoma (CRC), and copy number aberrations (CNA) are essential in the transition from adenoma to carcinoma. In light of this primary evolution, we investigated the evolutionary principles of the genome that foster postoperative recurrence of CRC. CNA and neoantigens (NAG) were compared between early primary tumors with recurrence (CRCR) and early primary tumors without recurrence (precancerous and early; PCRC). We compared CNA, single nucleotide variance (SNV), RNA sequences, and T-cell receptor (TCR) repertoire between 9 primary and 10 metastatic sites from 10 CRCR cases. We found that NAG in primary sites were fewer in CRCR than in PCRC, while the arm level CNA were significantly higher in primary sites in CRCR than in PCRC. Further, a comparison of genomic aberrations of primary and metastatic conditions revealed no significant differences in CNA. The driver mutations in recurrence were the trunk of the evolutionary phylogenic tree from primary sites to recurrence sites. Notably, PD-1 and TIM3, T cell exhaustion-related molecules of the tumor immune response, were abundantly expressed in metastatic sites compared to primary sites along with the increased number of CD8 expressing cells. The postoperative recurrence-free survival period was only significantly associated with the NAG levels and TCR repertoire diversity in metastatic sites. Therefore, CNA with diminished NAG and diverse TCR repertoire in pre-metastatic sites may determine postoperative recurrence of CRC.
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http://dx.doi.org/10.1371/journal.pgen.1009113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864431PMC
January 2021

Radiomics Texture Analysis for the Identification of Colorectal Liver Metastases Sensitive to First-Line Oxaliplatin-Based Chemotherapy.

Ann Surg Oncol 2021 Jun 16;28(6):2975-2985. Epub 2021 Jan 16.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: The aim of this study was to develop a radiomics-based prediction model for the response of colorectal liver metastases to oxaliplatin-based chemotherapy.

Methods: Forty-two consecutive patients treated with oxaliplatin-based first-line chemotherapy for colorectal liver metastasis at our institution from August 2013 to October 2019 were enrolled in this retrospective study. Overall, 126 liver metastases were chronologically divided into the training (n = 94) and validation (n = 32) cohorts. Regions of interest were manually segmented, and the best response to chemotherapy was decided based on Response Evaluation Criteria in Solid Tumors (RECIST). Patients who achieved clinical complete and partial response according to RECIST were defined as good responders. Radiomics features were extracted from the pretreatment enhanced computed tomography scans, and a radiomics score was calculated using the least absolute shrinkage and selection operator regression model in a trial cohort.

Results: The radiomics score significantly discriminated good responders in both the trial (area under the curve [AUC] 0.8512, 95% confidence interval [CI] 0.7719-0.9305; p < 0.0001) and validation (AUC 0.7792, 95% CI 0.6176-0.9407; p < 0.0001) cohorts. Multivariate analysis revealed that high radiomics scores greater than - 0.06 (odds ratio [OR] 23.803, 95% CI 8.432-80.432; p < 0.0001), clinical non-T4 (OR 6.054, 95% CI 2.164-18.394; p = 0.0005), and metachronous disease (OR 11.787, 95% CI 2.333-70.833; p = 0.0025) were independently associated with good response.

Conclusions: Radiomics signatures may be a potential biomarker for the early prediction of chemosensitivity in colorectal liver metastases. This approach may support the treatment strategy for colorectal liver metastasis.
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http://dx.doi.org/10.1245/s10434-020-09581-5DOI Listing
June 2021

New Anastomosis Technique to Prevent Anastomotic Leakage in Laparoscopic Anterior Resection for Rectal Cancer, Especially Upper Rectal Cancer.

In Vivo 2020 Nov-Dec;34(6):3533-3538

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background/aim: Anastomotic leakage (AL) is a major problem in rectal cancer surgery. To prevent AL, we developed a side-to-side anastomosis technique using a circular stapler and termed it the circular side stapling technique (CST). We herein report the method and outcome of the CST.

Patients And Methods: In this study, we analyzed 154 patients with stage 0 to III rectal cancer who underwent curative laparoscopic low anterior resection. Perioperative factors and complications were compared between the CST and usual double stapling technique (DST).

Results: The CST was performed in 110 of the 154 patients. When comparing the outcomes of patients with upper rectal cancer. AL occurred in no patients in the CST group and in three patients in the DST group (p=0.011). The CST prevented AL in all patients with upper rectal cancer.

Conclusion: The CST is a safe and useful procedure in laparoscopic anterior resection. This technique can prevent AL, especially in patients with upper rectal cancer.
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http://dx.doi.org/10.21873/invivo.12195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811646PMC
June 2021

Potential association of LOXL1 with peritoneal dissemination in gastric cancer possibly via promotion of EMT.

PLoS One 2020 23;15(10):e0241140. Epub 2020 Oct 23.

Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.

Background: Peritoneal dissemination (PD) frequently occurs in gastric cancer (GC) and is incurable. In this study, we aimed to identify novel PD-associated genes and clarify their clinical and biological significance in GC.

Materials And Methods: We identified LOXL1 as a PD-associated candidate gene by in silico analysis of GC datasets (highly disseminated peritoneal GC cell line and two freely available GC datasets, GSE15459 and TCGA). Next, we evaluated the clinical significance of LOXL1 expression using RT-qPCR and immunohistochemistry staining (IHC) in a validation cohort (Kyushu cohort). Moreover, we performed gene expression analysis, including gene set enrichment analysis (GSEA) with GSE15459 and TCGA datasets. Finally, we performed a series of in vitro experiments using GC cells.

Results: In silico analysis showed that LOXL1 was overexpressed in tumor tissues of GC patients with PD and in highly disseminated peritoneal GC cells, relative to that in the control GC patients and cells, respectively. High expression of LOXL1 was a poor prognostic factor in the TCGA dataset. Next, IHC showed that LOXL1 was highly expressed in GC cells. High LOXL1 mRNA expression was associated with poorly differentiated histological type, lymph node metastasis, and was an independent poor prognostic factor in the Kyushu validation cohort. Moreover, LOXL1 expression was positively correlated with the EMT (epithelial-mesenchymal transition) gene set in GSEA. Finally, LOXL1-overexpressing GC cells changed their morphology to a spindle-like form. LOXL1 overexpression reduced CDH1 expression; increased the expression of VIM, CDH2, SNAI2, and PLS3; and promoted the migration capacity of GC cells.

Conclusions: LOXL1 is associated with PD in GC, possibly through the induction of EMT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241140PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584171PMC
December 2020

Thoracoscopic esophagectomy in total pharyngolaryngoesophagectomy for esophageal cancer; A case series.

Ann Med Surg (Lond) 2020 Dec 12;60:9-13. Epub 2020 Oct 12.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan.

Background: Total pharyngolaryngoesophagectomy (TPLE) is associated with major complications and is extremely invasive. In 2011, our institution introduced thoracoscopic esophagectomy in the left hemi-prone position and laparoscopic reconstruction with a gastric tube in patients undergoing TPLE. Herein, we describe the use of this operative method in 26 patients, focusing on the technical aspects of the surgery.

Materials And Methods: From January 2011 to December 2018, 26 patients underwent minimally invasive TPLE with gastric tube reconstruction in our institute. The thoracoscopic procedure was performed with the patient in the semi-prone position. The patient was then moved to the supine position, and the laparoscopic procedure and pharyngolaryngectomy were started simultaneously. After pharyngolaryngectomy, microvascular anastomoses or free jejunal flap interposition were performed at the site of the gastric tube reconstruction. The data from these 26 patients were retrospectively analyzed.

Results: The median age was 66 years, and 3.8% of the patients were female. The Union for International Cancer Control stages of esophageal cancer were 0 ( = 2), I ( = 4), II ( = 7), III ( = 8), and IV ( = 5). Eight patients had concomitant esophageal cancer and head and neck cancer. Reconstruction with only a narrow gastric tube was used in 16 patients, while free jejunal flap interposition was used in 10 patients. The surgical procedures resulted in minimal complications. Postoperative complications of Clavien-Dindo grade ≥1 included anastomotic leakage in two patients and pneumonia in one.

Conclusion: Thoracoscopic esophagectomy in the left hemi-prone position and laparoscopic reconstruction with a gastric tube in patients undergoing TPLE was safe and effective. The complications were improved via the development of various procedures. Further improvement is necessary before this thoracoscopic approach is established as a standard procedure for TPLE.
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http://dx.doi.org/10.1016/j.amsu.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567906PMC
December 2020

Indications for laparoscopic surgery for older rectal cancer patients with comorbidities.

Surg Today 2021 May 17;51(5):721-726. Epub 2020 Sep 17.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Purpose: Given the lack of safety studies concerning laparoscopic surgery for rectal cancer in patients ≥ 80 years old with comorbidities, we sought to investigate this in the current study.

Methods: Between 2012 and 2019, 24 patients ≥ 80 years old underwent laparoscopic surgery for rectal cancer without preoperative treatment. These patients were divided into those with [comorbidity(+) group, n = 13] and without [comorbidity(-) group, n = 11] comorbidities. The preoperative nutritional status and ASA classification, postoperative complications, time to oral diet, and length of hospital stay were evaluated in each group.

Results: In the comorbidity(+)/comorbidity(-) groups, the average age was 85.9/84.1 years old, respectively. The major comorbidities were heart disease including atrial fibrillation and valvular disorder. The average PNI and CONUT scores in the comorbidity(+)/comorbidity(-) groups were 44.7/44.2 an 3.1/2.2, respectively. Planned surgical procedures were completed in all patients. Postoperative complications occurred in 2/3 cases in the comorbidity(+)/comorbidity(-) groups, respectively, and the average time to oral diet was 3.8/3.7 days, while the average length of hospitalization after surgery was 15.2/16.5 days, respectively. In the comorbidity(+) group, there was no exacerbation of comorbidities in any cases.

Conclusion: The safety of laparoscopic surgery is acceptable among older rectal cancer patients with comorbidities.
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http://dx.doi.org/10.1007/s00595-020-02140-1DOI Listing
May 2021

A rare case of esophageal adenocarcinoma with urinary bladder metastasis.

Int Cancer Conf J 2020 Oct 18;9(4):231-234. Epub 2020 Jul 18.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan.

A 75-year-old man was admitted to our hospital for treatment of esophageal cancer (EC) in March 2017. Esophagogastroduodenoscopy revealed Barrett's esophagus and superficial, distal EC (type 0-IIc). Tumor biopsy showed esophageal adenocarcinoma. Computed tomography revealed no lymph node metastasis but did reveal a 19-mm tumor on the right side of the urinary bladder. Bladder cancer (BC) was also suspected, and the patient underwent endoscopic submucosal dissection for EC and transurethral resection of the bladder tumor. The pathological diagnosis of EC was moderately to poorly differentiated adenocarcinoma (tub2), pT1b (SM), ly0, v0. The pathological horizontal margin was negative and the vertical margin was positive. Additional esophagectomy and lymph node dissection were indicated for curability. Esophagectomy was difficult because the patient had severe cardiovascular disease, so follow-up observation was adopted. BC was classified as urothelial carcinoma Ta, ly0, v0. After 32 months, multiple tumors were found in the bladder, and BC recurrence was suspected. Transurethral resection of the bladder was performed again for seven tumors, and pathological diagnosis was poorly differentiated adenocarcinoma (tub2). The immunohistochemical features matched those of EC. We diagnosed EC metastasis in the urinary bladder. Bladder adenocarcinoma is difficult to distinguish from metastasis from other organs, especially the upper gastrointestinal tract, and cytomorphological features and appropriate clinical history are required.
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http://dx.doi.org/10.1007/s13691-020-00434-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450023PMC
October 2020

Obstructive rectal endometriosis treated by robot-assisted laparoscopic surgery: a case report.

Surg Case Rep 2020 Aug 14;6(1):211. Epub 2020 Aug 14.

Department of Surgery and Science, Kyushu University, 3-1-1 Maidashi, Fukuoka, Fukuoka, 812-8582, Japan.

Background: Rectal endometriosis is a rare disease. A definitive diagnosis prior to surgery is often difficult. We encountered a patient with rectal sub-obstructive endometriosis that was treated by robot-assisted laparoscopic low anterior resection.

Case Presentation: A 43-year-old woman visited our hospital with suspected stenosis caused by upper rectal cancer. She had a 2-year history of constipation. We were unable to confirm the diagnosis through detailed examinations, including laparoscopy. Robot-assisted laparoscopic low anterior resection with D3 lymph node dissection was performed for both diagnosis and treatment. The postoperative specimen showed a submucosal tumor. The pathological examination confirmed rectal endometriosis.

Conclusions: We herein describe a rare case of obstructive rectal endometriosis that we were unable to diagnose preoperatively. Robotic surgery was useful in this case, which involved extensive pelvic adhesion.
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http://dx.doi.org/10.1186/s40792-020-00977-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427829PMC
August 2020

The Expression Level of () mRNA in Peripheral Blood Is a Potential Biomarker for Predicting Recurrence in Breast Cancer.

Anticancer Res 2020 Jul;40(7):3733-3742

Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan

Background/aim: Programmed death-ligand 1 (PD-L1/CD274) elicits T-cell anergy, leading to immune suppression. We aimed to determine the prognostic relevance of PD-L1 expression in the blood of breast cancer (BC) patients.

Materials And Methods: We measured PD-L1 mRNA expression in blood and tumor tissues of BC patients using RT-qPCR and a dataset from The Cancer Genome Atlas, and performed a survival analysis of PD-L1 expression in the blood of 330 BC patients. Flow cytometric analysis was performed using blood cells.

Results: No statistical difference in PD-L1 expression was seen between normal controls and BC in blood or tissues. There was a significant positive correlation between the PD-L1 expression levels in blood and tissues. Decreased PD-L1 expression in blood or tissues was associated with poor recurrence-free survival. PD-L1 is mainly expressed in polymorphonuclear leukocytes.

Conclusion: Low expression of PD-L1 in the blood could serve as a biomarker of poor prognosis in BC patients.
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http://dx.doi.org/10.21873/anticanres.14362DOI Listing
July 2020

Reintroduction of nivolumab in a patient with gastric cancer after improvement of nivolumab-induced acute interstitial nephritis: a case report.

Int Cancer Conf J 2020 Jul 22;9(3):127-132. Epub 2020 May 22.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582 Japan.

Nivolumab, an anti-programmed cell death-1 (PD-1) antibody, has attracted increasing attention as a new treatment modality for gastric cancer. Herein, a case of acute kidney injury in a 66-year-old man with gastric cancer treated with nivolumab is presented. Kidney biopsy revealed severe acute interstitial nephritis and mild immunoglobulin A nephropathy. The cause of acute kidney injury was considered as acute interstitial nephritis because the main site of the lesion was the tubulointerstitium. Cessation of nivolumab and oral prednisolone administration rapidly improved the patient's renal function. Nivolumab was then restarted without worsening of renal function. To the best of the authors knowledge, this is the first case in which reintroduction of nivolumab was successfully performed in a patient with gastric cancer. Further, the relevant literature was reviewed on nivolumab-induced acute interstitial nephritis.
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http://dx.doi.org/10.1007/s13691-020-00418-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297885PMC
July 2020

Primary anorectal malignant melanoma with laparoscopic abdominoperineal resection: a case study and review of the relevant literature.

Int Cancer Conf J 2020 Jul 17;9(3):116-122. Epub 2020 Apr 17.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

ARMM is a disease with a poor prognosis. ARMM is often diagnosed at an advanced stage, and the 5-year survival rate of ARMM is < 20%. Although the number of case reports on ARMM is gradually increasing, the optimal treatment strategy for ARMM remains controversial. We report the case of an 81-year-old woman who had experienced bloody stool for 6 months before her diagnosis and who had been initially diagnosed with hemorrhoids. The pathological diagnosis of a biopsy specimen was malignant melanoma. Other examinations showed no evidence of lymph node or distant metastasis. Based on these results, laparoscopic abdominoperineal resection was performed. Three months later on her first follow-up examination, distant metastasis to the lung and liver was detected. Immunotherapy using Nivolumab was initiated to treat the recurrent disease. We reviewed the characteristics of a total of 1834 ARMM patients described in previous reports on ARMM for which the full text was available on PubMed. We experienced a case of ARMM. The prognosis of ARMM is still poor, regardless of the surgical procedure. Previous studies and our case report suggest that systemic therapy, such as immunotherapy using an anti-PD-1 ligand may be more important than reinforcement of local control for improving the prognosis of ARMM patients.
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http://dx.doi.org/10.1007/s13691-020-00401-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297936PMC
July 2020

Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer.

Oncology 2020 7;98(7):501-511. Epub 2020 May 7.

Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan,

Introduction: Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment.

Methods: PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis.

Results: PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC patients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10-4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12-6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively.

Conclusions: PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery.
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http://dx.doi.org/10.1159/000506075DOI Listing
July 2020

Postoperative C-reactive protein/albumin ratio is a biomarker of risk of recurrence and need for adjuvant chemotherapy for stage III colorectal cancer.

Int J Clin Oncol 2020 Jul 11;25(7):1318-1326. Epub 2020 Apr 11.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, Fukuoka, 812-8582, Japan.

Background: Adjuvant chemotherapy is generally recommended for patients with stage III colorectal cancer. Even with adjuvant chemotherapy, 20-30% of such patients develop recurrences; the risk factors for recurrence are currently unclear. The preoperative systemic inflammation index has been linked to poor prognoses in patients with colorectal cancer; however, the relationship between postoperative systemic inflammation index and recurrence is unclear. We aimed to evaluate the association between preoperative and postoperative systemic inflammation indexes and recurrence in patients with stage III colorectal cancer.

Methods: The following laboratory data of 133 patients with stage III colorectal cancer were analyzed: preoperative and postoperative C-reactive protein/albumin ratios (CAR); neutrophil to lymphocyte ratios (NLR); and platelet to lymphocyte ratios (PLR) and their relationships with recurrence analyzed.

Results: The optimal cutoff values for systemic inflammation indexes were determined by examining receiver operating characteristic curves. Multivariate analyses indicated that N-stage, postoperative complications, preoperative NLR, and postoperative CAR were independent predictors of recurrence-free survival (RFS). Postoperative CAR was also an independent predictor of overall survival (OS). Patients with postoperative CAR ≥ 0.035 who did not receive adjuvant chemotherapy had shorter RFS and OS than those who did. There were no significant differences in RFS and OS between patients with postoperative CAR < 0.035 who did and did not receive adjuvant chemotherapy.

Conclusions: Postoperative CAR is strongly associated with poor prognosis in patients with stage III colorectal cancer and is a useful biomarker for determining whether adjuvant chemotherapy should be administered.
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http://dx.doi.org/10.1007/s10147-020-01672-3DOI Listing
July 2020

Circulating PD-1 mRNA in Peripheral Blood is a Potential Biomarker for Predicting Survival of Breast Cancer Patients.

Ann Surg Oncol 2020 Oct 21;27(10):4035-4043. Epub 2020 Mar 21.

Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.

Background: Programmed cell death 1 (PD-1) inhibitors have shown significant therapeutic promise in various cancers. However, the clinical significance of PD-1 expression remains not fully understood. In this study, we evaluated the clinical and prognostic relevance of PD-1 expression in breast cancer (BC).

Methods: First, we analyzed PD-1 mRNA expression in BC tissues and performed a survival analysis using a dataset from The Cancer Genome Atlas. Next, we measured PD-1 mRNA expression in peripheral blood (PB) in BC patients by quantitative reverse-transcription polymerase chain reaction. We performed a survival analysis and evaluated the association between PD-1 mRNA expression in PB and the clinicopathological features of 372 BC patients who underwent curative resection. Flow cytometry (FCM) analysis was performed to identify PD-1-expressing cells in PB. Finally, we determined whether there was a correlation of PD-1 mRNA expression in PB and tumor tissue.

Results: PD-1 mRNA expression was significantly higher in tumor tissues compared with normal tissues. Decreased PD-1 mRNA expression in tumor tissue was associated with poor overall survival (OS). PD-1 mRNA expression in PB of BC patients was higher than that of healthy volunteers, and increased PD-1 mRNA expression in PB was associated with poor OS. FCM revealed that PD-1 was mostly expressed on T cells in PB, predominantly in CD4 T cells. PD-1 mRNA expression in PB was negatively correlated with PD-1 mRNA expression in tumor tissue.

Conclusion: High expression of PD-1 mRNA in preoperative PB could serve as an effective biomarker that indicates poor prognosis in BC.
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http://dx.doi.org/10.1245/s10434-020-08375-zDOI Listing
October 2020

[Appendix Cancer with Long-Term Survival after Multimodality Therapy-A Case Report].

Gan To Kagaku Ryoho 2019 Dec;46(13):2560-2561

Dept. of Surgery, Saiseikai Yahata General Hospital.

We report a case of long-term survival in a 65-year-old woman with recurrent appendix cancer. In March 2002, she was diagnosed with appendix cancer and underwent ileocecal resection. The pathological diagnosis was mucinous cystadenocarcinoma, pT2N0M0, Stage Ⅰ. In April 2006, ovariohysterectomy was performed for right ovarian metastases. In February 2011, tumor resection was performed for disseminated recurrence after 4 courses of systemic chemotherapy(bevacizumab plus mFOLFOX6). Although no recurrent lesions had been detected on imaging, stepwise elevation of serum CEA level was observed from June 2016. In November 2017, computed tomography scan revealed a slow-growing tumor on the liver. We performed partial resection of the right hemidiaphragm for the disseminated tumor, and the pathological diagnosis was mucinous adenocarcinoma. The patient has been on continuous postoperative follow-up without recurrence until June 2019. Appendix cancer is relatively rare and has a worse prognosis compared to colorectal cancer because of higher frequency of disseminated metastases. With the multimodality therapy, our patient showed long-term survival over 17 years despite a disseminated recurrence. In cases of mucinous cystadenocarcinoma of the appendix, persistent follow-up and aggressive treatment are recommended.
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December 2019

[A Case Report of Gastrointestinal Bleeding with Difficulty in Diagnosis].

Gan To Kagaku Ryoho 2019 Dec;46(13):2134-2136

Dept. of Surgery, Saiseikai Yahata General Hospital.

The authors report a case involving a 55-year-old female patient who presented with melena and anemia 8 years ago. Esophagogastroduodenoscopy, colonoscopy, and CT did not reveal any sign of lesions except multiple uterine myoma. On reevaluation after the onset of melena, we did not find any lesions. However, the patient had a recurrent episode of melena with progressive anemia(Hb level 12.8 g/dL→9.8 g/dL). CT revealed a 29mm mass in the right side of the pelvis, which was retrospectively observed in the past CT scan, although its position had changed. We suspected gastrointestinal stromal tumor (GIST). Small intestine fluoroscopy revealed the tumor with effusion of barium inside the translucent areas of the ileum. For diagnostic treatment, laparoscopic partial jejunum resection was performed. Pathological diagnostic examination revealed that the tumor consisted of spindle cell disarray with moderate density, fewer heterocysts, and rare mitosis. The tumor cells were c-kit positive and CD34 negative in immunohistochemistry. All the results were consistent with GIST. Eight years had passed before diagnosis and surgical treatment were performed. This case report emphasizes the difficulty of diagnose of GIST because of its low malignancy and slow progression.
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December 2019

KIF15 Expression in Tumor-associated Monocytes Is a Prognostic Biomarker in Hepatocellular Carcinoma.

Cancer Genomics Proteomics 2020 Mar-Apr;17(2):141-149

Department of Surgery, Kyushu University, Beppu Hospital, Oita, Japan

Background/aim: Kinesin family member 15 (KIF15) participates in the transport of macromolecules in essential cellular processes. In this study we evaluated the clinical relevance of KIF15 expression in hepatocellular carcinoma (HCC).

Materials And Methods: Association between KIF15 expression and clinical outcomes in HCC patients was analyzed using three independent cohorts. Localization of KIF15 expression was assessed by immunohistochemical analysis. Co-culture experiments were performed using healthy donor peripheral blood mononuclear cells (PBMC) and HCC cell lines.

Results: Immunohistochemical analysis showed that KIF15 was mainly expressed in inflammatory monocytes around cancer cells. Multivariate analysis indicated high KIF15 expression was an independent poor prognostic factor for survival. HCC cells with high expression of minichromosome maintenance protein 2 (MCM2) were located close to KIF15-expressing inflammatory monocytes. The proliferation ability of HCC cells was increased by co-culture with PBMC.

Conclusion: High KIF15 expression in inflammatory monocytes in tumor tissues may serve as a prognostic marker for poor outcome in HCC.
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http://dx.doi.org/10.21873/cgp.20174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078836PMC
September 2020

N-Cadherin mRNA Levels in Peripheral Blood Could Be a Potential Indicator of New Metastases in Breast Cancer: A Pilot Study.

Int J Mol Sci 2020 Jan 14;21(2). Epub 2020 Jan 14.

Ueo Breast Surgical Hospital, 188-2 haya, Oita 870-0854, Japan.

Background: There is growing evidence that patients with metastatic breast cancer whose disease progresses from a new metastasis (NM) have a worse prognosis than that of patients whose disease progresses from a pre-existing metastasis. The aim of this pilot study is to identify a blood biomarker predicting NM in breast cancer.

Methods: The expression of epithelial (cytokeratin 18/19) or mesenchymal (plastin-3, vimentin, and N-cadherin) markers in the peripheral blood (PB) of recurrent breast cancer patients undergoing chemotherapy with eribulin or S-1 was measured over the course of treatment by RT-qPCR. The clinical significance of preoperative N-cadherin expression in the PB or tumor tissues of breast cancer patients undergoing curative surgery was assessed by RT-qPCR or using public datasets. Finally, N-cadherin expression in specific PB cell types was assessed by RT-qPCR.

Results: The expression levels of the mesenchymal markers N-cadherin and vimentin were high in the NM cases, whereas that of the epithelial marker cytokeratin 18 was high in the pre-existing metastasis cases. High preoperative N-cadherin expression in PB or tumor tissues was significantly associated with poor recurrence-free survival. N-cadherin was expressed mainly in polymorphonuclear leukocytes in PB.

Conclusion: N-cadherin mRNA levels in blood may serve as a novel prognostic biomarker predicting NM, including recurrence, in breast cancer patients.
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http://dx.doi.org/10.3390/ijms21020511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013704PMC
January 2020
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