Publications by authors named "Koji Ando"

235 Publications

Infusion-related reaction to ramucirumab plus FOLFIRI in patients with advanced colorectal cancer.

Int J Clin Oncol 2021 Sep 2. Epub 2021 Sep 2.

Department of Clinical Oncology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.

Background: An infusion-related reaction (IRR) is a well-known adverse event related to monoclonal antibodies, and antihistamine premedication is recommended to prevent IRRs. Ramucirumab plus FOLFIRI therapy is the standard second-line treatment for metastatic colorectal cancer (CRC). Ramucirumab is a fully human antibody, suggesting that the incidence of IRRs is lower, however, the current recommendation for the proper use of ramucirumab is antihistamine premedication, but the incidence and severity of ramucirumab-induced IRR without antihistamine premedication have not been elucidated.

Methods: A retrospective study to evaluate the incidence of ramucirumab-induced IRRs in unresectable CRC patients treated by ramucirumab plus FOLFIRI therapy. If the incidence of IRR without antihistamine premedication was not higher than that of cetuximab in a previous report (5.7%), planning a prospective study was considered.

Results: A total of 147 patients with unresectable CRC who had been treated by ramucirumab plus FOLFIRI therapy were identified. Of them, 106 (72%) patients received intravenous antihistamine premedication. An IRR occurred in 2 patients (1.4%), 1 grade 2 and 1 grade 3. They received antihistamine and steroid premedication. On the other hand, IRRs were not observed in 41 patients without antihistamine premedication, and the incidence of IRRs was significantly lower compared with the previous report of cetuximab (p < 0.001).

Conclusion: The incidence of ramucirumab-induced IRRs without antihistamine premedication is low. Not using antihistamine premedication can decrease medical costs. These findings warrant further investigation in large-scale cohorts to clarify the incidence and severity of ramucirumab-induced IRRs and further clarify the proper use of ramucirumab.
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http://dx.doi.org/10.1007/s10147-021-02004-9DOI Listing
September 2021

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

Conserved and context-dependent roles for pdgfrb signaling during zebrafish vascular mural cell development.

Dev Biol 2021 Nov 24;479:11-22. Epub 2021 Jul 24.

Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01650, United States. Electronic address:

Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle cells. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these zebrafish mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects.
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http://dx.doi.org/10.1016/j.ydbio.2021.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410673PMC
November 2021

Correction to: Expression of CD44 variant 9 induces chemoresistance of gastric cancer by controlling intracellular reactive oxygen spices accumulation.

Gastric Cancer 2021 Sep;24(5):1100-1101

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

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http://dx.doi.org/10.1007/s10120-021-01205-5DOI Listing
September 2021

Clinical Impact of Primary Tumor Location in Metastatic Colorectal Cancer Patients Under Later-Line Regorafenib or Trifluridine/Tipiracil Treatment.

Front Oncol 2021 15;11:688709. Epub 2021 Jun 15.

Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Background: Primary tumor location (PTL) is an important prognostic and predictive factor in the first-line treatment of metastatic colorectal cancer (mCRC). Although regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been introduced recently, the clinical impact of PTL in these treatments is not well understood.

Materials And Methods: We retrospectively evaluated patients with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, angiogenesis inhibitors, anti-epidermal growth factor receptor therapy (if RAS wild-type), and no prior use of REG and FTD/TPI. The impact of PTL on overall survival (OS) was evaluated using Cox proportional hazard models based on baseline characteristics.

Results: A total of 550 patients (223 patients in the REG group and 327 patients in the FTD/TPI group) were included in this study, with 122 patients with right-sided tumors and 428 patients with left-sided tumors. Although the right-sided patients had significantly shorter OS compared with the left-sided patients by univariate analysis ( = 0.041), a multivariate analysis revealed that PTL was not an independent prognostic factor (hazard ratio, 0.95; = 0.64). In a subgroup analysis, the OS was comparable between the REG and FTD/TPI groups regardless of PTL ( for interactions = 0.60).

Conclusions: In the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.
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http://dx.doi.org/10.3389/fonc.2021.688709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239287PMC
June 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

Expression of CD44 variant 9 induces chemoresistance of gastric cancer by controlling intracellular reactive oxygen spices accumulation.

Gastric Cancer 2021 Sep 8;24(5):1089-1099. Epub 2021 May 8.

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

Background: CD44 variant 9 (CD44v9) has been reported to suppress reactive oxygen spices (ROS) in association with antioxidant factors such as glutathione (GSH) and glutathione peroxidase 2 (GPx2), resulting in promoted tumor growth.

Methods: CD44v9 and GPx2 expression were investigated by immunohistochemistry in resected specimens from 193 gastric cancer (GC) patients without preoperative chemotherapy and in pretreatment biopsy specimens from 29 GC patients with preoperative chemotherapy. We analyzed the relationship between CD44v9 expression and clinicopathological factors, prognosis, and pathological response to chemotherapy. In GC cell lines, we examined the relationship between CD44v9 expression and chemotherapeutic sensitivity.

Results: In patients without preoperative chemotherapy, CD44v9 expression was significantly associated with depth of invasion, lymphatic permeation, vascular invasion, distant metastasis and GPx2 expression. In multivariate analysis, CD44v9 expression was an independent poor prognosis factor for overall survival and recurrence-free survival. In patients with preoperative chemotherapy, CD44v9 expression was significantly associated with worse pathological response and GPx2 expression. In GC cell lines, downregulation of CD44v9 expression enhanced chemotherapeutic sensitivity to 5-fluorouracil with changing GSH and ROS levels.

Conclusions: CD44v9-positive expression was associated with chemotherapeutic resistance by controlling intracellular accumulated ROS, suggesting that CD44v9 may be a predictive biomarker for chemotherapy in GC.
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http://dx.doi.org/10.1007/s10120-021-01194-5DOI Listing
September 2021

Protocol for analysis of integrin-mediated cell adhesion of lateral plate mesoderm cells isolated from zebrafish embryos.

STAR Protoc 2021 Jun 31;2(2):100428. Epub 2021 Mar 31.

Department of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Lateral plate mesoderm (LPM) cells differentiate into various cell types including endothelial and hematopoietic cells. In zebrafish embryos, LPM cells migrate toward the midline along the ventral surfaces of somites during which their cell fate specification depends upon efficient integrin-mediated cell adhesion and migration. Herein, we present a protocol for analysis of integrin-mediated cell adhesion of LPM cells isolated from zebrafish embryos. This allows the study of the molecular mechanisms underlying integrin activation required for LPM cell fate specification. For complete details on the use and execution of this protocol, please refer to Rho et al. (2019).
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http://dx.doi.org/10.1016/j.xpro.2021.100428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044719PMC
June 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

Monitoring FTD in the peripheral blood mononuclear cells of elderly patients with metastatic colorectal cancer administered FTD plus bevacizumab as first-line treatment.

Cancer Sci 2021 Jun 3;112(6):2436-2441. Epub 2021 May 3.

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

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD-positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD-positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD-positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single-arm phase 2 trial of FTD/TPI plus bevacizumab as a first-line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD-positive PBMC on days 8, 15, and 29 were 39.3% (30.7%-52.2%), 66.9% (40.0%-75.3%), and 13.5% (5.7%-26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD-positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554-0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events.
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http://dx.doi.org/10.1111/cas.14904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177777PMC
June 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

Survival Benefit of Crossover Administration of Regorafenib and Trifluridine/Tipiracil Hydrochloride for Patients With Metastatic Colorectal Cancer: Exploratory Analysis of a Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study (REGOTAS).

Front Oncol 2021 8;11:576036. Epub 2021 Mar 8.

Clinical Oncology Division, Kochi Health Sciences Center, Kochi, Japan.

The survival benefits of regorafenib (REG) and trifluridine/tipiracil hydrochloride (TFTD) have been demonstrated in chemorefractory patients with metastatic colorectal cancer (mCRC). However, the effects of crossover administration of REG and TFTD on patient survival remain unclear. The present study evaluated the association between exposure to REG and TFTD and overall survival (OS) in patients with mCRC using data from the REGOTAS study. We analyzed patients registered in the REGOTAS study, which retrospectively compared the efficacy and safety of use of REG or TFTD as later-line chemotherapy for chemorefractory mCRC patients. We compared the survival outcomes of cohort A (treated using both REG and TFTD) and cohort B (treated using either REG or TFTD). A total of 550 patients (cohort A, = 252; cohort B, = 298) met the inclusion criteria. The median OS was significantly increased in cohort A compared with cohort B [9.6 months (95% confidence interval (CI), 8.9-10.9 months) vs. 5.2 months (95% CI, 4.4-6.0 months), < 0.001]. Multivariate analysis revealed that cohort A was independently associated with a significant increase in OS [A vs. B: Hazard ratios (HR), 0.58; 95% CI, 0.47-0.72; < 0.001]. Subgroup analysis adjusted using multivariate Cox model revealed a consistently better trend in most subgroups for cohort A compared with cohort B. Our study revealed prolonged survival in patients treated with REG and TFTD. Therefore, all active agents, including REG and TFTD, should be made available to mCRC patients.
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http://dx.doi.org/10.3389/fonc.2021.576036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982575PMC
March 2021

Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors.

Clin Colorectal Cancer 2021 06 10;20(2):e129-e138. Epub 2020 Dec 10.

Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA. Electronic address:

Purpose: The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response.

Patients And Methods: The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with anti-phospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically.

Results: We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93).

Conclusion: The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors.
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http://dx.doi.org/10.1016/j.clcc.2020.11.005DOI Listing
June 2021

Efficacy and Cardiovascular Adverse Events of Long-term Treatment with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Report from the Nagasaki CML Study Group.

Intern Med 2021 Jul 22;60(14):2207-2216. Epub 2021 Feb 22.

Department of Hematology, Sasebo City General Hospital, Japan.

Objective The standard treatment for chronic myeloid leukemia (CML) is the continuous use of tyrosine kinase inhibitors (TKIs), which results in a favorable prognosis for the majority of patients. Recent studies have identified cardiovascular diseases (CVDs) as late adverse events (AEs) related to TKIs. In this study, we evaluated the long-term efficacy and AEs of TKIs, focusing on CVDs. Methods We performed a retrospective survey of CML patients (diagnosed from 2001 to 2016) treated with TKIs in Nagasaki Prefecture. Clinical data were obtained from their medical records. We analyzed the survival, estimated cumulative incidence of CVDs, and risk factors for CVD among CML patients treated with TKIs. Results The overall survival rate of 264 CML patients treated with TKIs (median age 58 years old) was 89.6% [95% confidence interval (CI), 84.9-92.9%], and 80.5% (95% CI, 73.4-85.9%) at 5 and 10 years after the CML diagnosis, respectively. CVD events occurred in 26 patients (9.8%, median age 67.5 years old) with a median 65.5 months of TKI treatment. The cumulative incidences at 2 and 5 years was 2.4% (95% CI, 1.0-4.8%) and 5.2% (95% CI, 2.8-8.6%), respectively. Hypertension and a high SCORE chart risk at the diagnosis of CML were associated with CVD events during TKI treatment. Conclusion TKI treatment contributed to the long-term survival of CML patients in Nagasaki Prefecture in a "real-world" setting, but the incidence of CVDs seemed to be increased in these patients. A proper approach to managing risk factors for CVD is warranted to reduce CVD events during TKI treatment.
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http://dx.doi.org/10.2169/internalmedicine.6620-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355380PMC
July 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

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

Randomized phase II study comparing the efficacy and safety of SOX versus mFOLFOX6 as neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer (KSCC1301).

BMC Cancer 2021 Jan 5;21(1):23. Epub 2021 Jan 5.

Department of Surgery, Kurume University School of Medicine, Kurume, Japan.

Background: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT.

Methods: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety.

Results: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable.

Conclusion: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases.

Trial Registration: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.
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http://dx.doi.org/10.1186/s12885-020-07766-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786922PMC
January 2021

Trifluridine/tipiracil plus bevacizumab as a first-line treatment for elderly patients with metastatic colorectal cancer (KSCC1602): A multicenter phase II trial.

Cancer Med 2021 01 29;10(2):454-461. Epub 2020 Nov 29.

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

Background: A previous Phase I/II study demonstrated that TAS-102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer.

Methods: This is a multicenter, single-arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression-free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs).

Results: Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70-88); the ECOG-PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3-4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%).

Conclusions: FTD/TPI plus Bev is an effective and well-tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross-resistance with 5-fluorouracil.

Clinical Trial Registration: UMIN clinical trials registry (UMIN000025241).
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http://dx.doi.org/10.1002/cam4.3618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877360PMC
January 2021

Protocol of the EFFORT study: a prospective study of FOLFIRI plus aflibercept as second-line treatment after progression on FOLFOXIRI plus bevacizumab or during maintenance treatment in patients with unresectable/metastatic colorectal cancer.

BMC Cancer 2020 Nov 17;20(1):1116. Epub 2020 Nov 17.

Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, 812-8582, Japan.

Background: FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC.

Methods: EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m IV over 90 min, with levofolinate 200 mg/m IV over 2 h, followed by fluorouracil 400 mg/m bolus and fluorouracil 2400 mg/m continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer.

Discussion: This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered.

Trial Registration: Japan Registry of Clinical Trials jRCTs071190003 . Registered April 18, 2019.
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http://dx.doi.org/10.1186/s12885-020-07576-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672899PMC
November 2020

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

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

No clear survival benefit of azacitidine for lower-risk myelodysplastic syndromes: A retrospective study of Nagasaki.

Cancer Sci 2020 Dec 23;111(12):4490-4499. Epub 2020 Oct 23.

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The efficacy of azacitidine (AZA) on survival of lower risk (LR) - myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long-term survival benefit of AZA for patients with LR-MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR-MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis-stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection-related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR-MDS patients.
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http://dx.doi.org/10.1111/cas.14653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734160PMC
December 2020

Tunneling matrix element and tunneling pathways of protein electron transfer calculated with a fragment molecular orbital method.

J Chem Phys 2020 Sep;153(10):104104

Department of Information and Sciences, Tokyo Woman's Christian University, 2-6-1 Zenpukuji, Suginami-ku, Tokyo 167-8585, Japan.

Practical ways to calculate the tunneling matrix elements and analyze the tunneling pathways for protein electron-transfer (ET) reactions with a fragment molecular orbital (FMO) method are presented. The straightforward use of minimal basis sets only for the atoms involved in the covalent bond detachment in FMO can properly describe the ETs through the protein main-chains with the cost-effective two-body corrections (FMO2) without losing the quality of double-zeta basis sets. The current FMO codes have been interfaced with density functional theory, polarizable continuum model, and model core potentials, with which the FMO-based protein ET calculations can consider the effects of electron correlation, solvation, and transition-metal redox centers. The reasonable performance of the FMO-based ET calculations is demonstrated for three different sets of protein-ET model molecules: (1) hole transfer between two tryptophans covalently bridged by a polyalanine linker in the ideal α-helix and β-strand conformations, (2) ET between two plastoquinones covalently bridged by a polyalanine linker in the ideal α-helix and β-strand conformations, and (3) hole transfer between ruthenium (Ru) and copper (Cu) complexes covalently bridged by a stretch of a polyglycine linker as a model for Ru-modified derivatives of azurin.
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http://dx.doi.org/10.1063/5.0018423DOI Listing
September 2020

Efficacy of endoscopic ultrasound with artificial intelligence for the diagnosis of gastrointestinal stromal tumors.

J Gastroenterol 2020 Dec 11;55(12):1119-1126. Epub 2020 Sep 11.

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

Background: Although endoscopic ultrasound (EUS) is reported to be suitable for determining the layer from which subepithelial lesions (SELs) originate, it is difficult to distinguish gastrointestinal stromal tumor (GIST) from non-GIST using only EUS images. If artificial intelligence (AI) can be used for the diagnosis of SELs, it should provide several benefits, including objectivity, simplicity, and quickness. In this pilot study, we propose an AI diagnostic system for SELs and evaluate its efficacy.

Methods: Thirty sets each of EUS images with SELs ≥ 20 mm or < 20 mm were prepared for diagnosis by an EUS diagnostic system with AI (EUS-AI) and three EUS experts. The EUS-AI and EUS experts diagnosed the SELs using solely the EUS images. The concordance rates of the EUS-AI and EUS experts' diagnoses were compared with the pathological findings of the SELs.

Results: The accuracy, sensitivity, and specificity for SELs < 20 mm were 86.3, 86.3, and 62.5%, respectively for the EUS-AI, and 73.3, 68.2, and 87.5%, respectively, for the EUS experts. In contrast, accuracy, sensitivity, and specificity for SELs ≥ 20 mm were 90.0, 91.7, and 83.3%, respectively, for the EUS-AI, and 53.3, 50.0, and 83.3%, respectively, for the EUS experts. The area under the curve for the diagnostic yield of the EUS-AI for SELs ≥ 20 mm (0.965) was significantly higher than that (0.684) of the EUS experts (P = 0.007).

Conclusion: EUS-AI had a good diagnostic yield for SELs ≥ 20 mm. EUS-AI has potential as a good option for the diagnosis of SELs.
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http://dx.doi.org/10.1007/s00535-020-01725-4DOI Listing
December 2020

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

Constrained Density Functional Theory Molecular Dynamics Simulation of Deprotonation in Aqueous Silicic Acid.

J Phys Chem B 2020 09 11;124(38):8323-8330. Epub 2020 Sep 11.

Department of Information and Sciences, Tokyo Womans Christian University, 2-6-1 Zenpukuji, Suginami-ku, Tokyo 167-8585, Japan.

The solubility of silicic acid in water is so low that the molecular mechanism behind the physical properties such as p remains poorly understood, despite the importance in fields such as chemistry and geology. Theoretical calculations provide the molecular-level information on such a rare chemical species yet face difficulties in the selection of reaction coordinates and the rare-event sampling of proton transfers (PTs) in condensed phases. We propose a straightforward calculation scheme of p with molecular dynamics (MD) simulation and the constrained density functional theory (CDFT), which provides structural and dynamical properties such as radial distribution functions, vibrational spectra, and reaction paths. The calculated reaction free energies of deprotonations agreed with experiments within a few kcal/mol. Analysis of the solvation structure shows that, after deprotonation, the hydronium ion DO repels away from the deprotonated silicic acid SiO(OD) without forming a stable contact-ion pair. The calculated vibrational spectra are consistent with the spectroscopic measurements, and the dynamical analysis of the reaction path quantifies the couplings of the OD stretch vibrations of silicic acid and water to the PT reaction in terms of the vertical energy-gap coordinate that includes both the solute and the solvent components.
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http://dx.doi.org/10.1021/acs.jpcb.0c05096DOI Listing
September 2020
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