Publications by authors named "Hidekazu Takahashi"

302 Publications

Surgical plume from tissue infected with human hepatitis B virus can contain viral substances.

Minim Invasive Ther Allied Technol 2021 Apr 14:1-9. Epub 2021 Apr 14.

Department of Next Generation Endoscopic Intervention, Osaka University Graduate School of Medicine, Osaka, Japan.

Introduction: Evidence on the biological danger associated with surgical plume is lacking. We examined whether surgical plume, generated by the energy devices ultrasonically activated scalpel (US) or electrocautery (EC) contains virus-related substances.

Material And Methods: Tumor mass of a hepatocellular carcinoma line was prepared in a mouse. Surgical plume generated on the mass by US or EC was collected and detection of HBs gene fragment and antigens (HBsAg or AFP) was conducted. : Detection of HBV-DNA and HBsAg was conducted following the collection of surgical plume generated from clinically obtained liver specimens from six HBV-associated hepatocellular carcinoma patients.

Results: HBs gene fragment was detected in the solutions regardless of the device used. HBsAg was detected in US and EC solutions and AFP was also detected in a US solution. HBV-DNA was detected in both devices, in all three cases whose preoperative serum HBV-DNA was positive. In the other serum-negative cases, HBV-DNA was not detected. While serum HBsAg was positive in five of six cases, it was not detected in any solution.

Conclusions: DNA fragments or antigens of virus can exist in the surgical plume generated by EC or US.
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http://dx.doi.org/10.1080/13645706.2021.1910848DOI Listing
April 2021

Use of the fiberglass reinforcement method in thermoplastic mouthguard materials to improve flexural properties for enhancement of functionality.

Dent Mater J 2021 Apr 7. Epub 2021 Apr 7.

Department of Sports Medicine/Dentistry, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University.

The purpose of this study was to evaluate the application of fiberglass reinforcement method in thermoplastic mouthguard materials to improve flexural properties and adhesive strength. Commonly used two types of commercial mouth guard materials (ethylene-vinyl acetate copolymer-based and polyolefin-based) were reinforced with glass fiber clothes by two-step hot press. Flexural strength and adhesive strength with each base material were examine via three-point bending test and delamination test, respectively. Ethylene-vinyl acetate copolymer-based fiberglass-reinforced material has significantly greater adhesive strength with base material and improvement of flexural properties compared with polyolefin-based material. These results suggest that flexural properties of both conventional commercial mouthguard materials were improved when the glass-fiber-reinforced method was applied to reinforce mouthguard materials, and more, ethylene-vinyl acetate copolymer was more desirable for the base material.
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http://dx.doi.org/10.4012/dmj.2020-402DOI Listing
April 2021

[Capecitabine and Oxaliplatin(CAPOX)plus Bevacizumab as Second-Line Chemotherapy for Metastatic Colorectal Cancer].

Gan To Kagaku Ryoho 2021 Mar;48(3):357-361

Clinical Study Group of Osaka University, Colorectal Group.

Objective: To evaluate the efficacy and safety of CAPOX plus bevacizumab as second-line chemotherapy for metastatic colorectal cancer.

Methods: In this multicenter phase Ⅱ study, the planned number of patients was 48, but owing to poor case accumulation, registration was discontinued for 20 patients. The primary endpoint was the response rate(RR). Secondary endpoints were progression-free survival(PFS), overall survival(OS), disease control rate(DCR), and safety.

Results: First-line treatment was combined with irinotecan in 14 cases and bevacizumab in 12 cases. The median number of second- line treatment courses was 7, and the median treatment period was 203 days. The reason for discontinuation of treatment was disease progression in 13 cases, adverse events in 4 cases, and other reasons in 3 cases. The best response was PR in 5 cases, SD in 8 cases, and NE in 4 cases. The RR was 25%, and the DCR was 65%. The median PFS was 7.2 months, and the median OS was 18.6 months. Grade≥3 adverse events were neutropenia in 3 cases and diarrhea and peripheral neuropathy in 2 cases each. There were no treatment-related deaths.

Conclusion: CAPOX plus bevacizumab was a safe and effective second-line treatment option for metastatic colorectal cancer.
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March 2021

ASO Visual Abstract: Application of Local Hyaluronic Acid Injection in Transanal Minimally Invasive Surgery for Anterior Rectal GIST.

Ann Surg Oncol 2021 Mar 19. Epub 2021 Mar 19.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.

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http://dx.doi.org/10.1245/s10434-021-09793-3DOI Listing
March 2021

Effects of build orientation on adaptation of casting patterns for three-unit partial fixed dental prostheses fabricated by using digital light projection.

J Prosthet Dent 2021 Feb 26. Epub 2021 Feb 26.

Professor, Department of Oral Biomaterials Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Statement Of Problem: The lost-wax technique is commonly used for fabricating partial fixed dental prostheses. The casting patterns can be fabricated by using vat photopolymerization (a type of additive manufacturing), but the adaptation of these casting patterns has not been elucidated.

Purpose: The purpose of this in vitro study was to evaluate the effect of build orientation on the adaptation of casting patterns fabricated by digital light projection (DLP).

Material And Methods: A 3-unit partial fixed dental prosthesis with mandibular left second premolar and second molar abutment teeth was scanned and virtually designed with a computer-aided design software program. The cement space was designed to be 30 μm. Specimens were fabricated with 3 build orientations: 0 degrees (with the occlusal surface parallel to the platform), 30 degrees, and 45 degrees (by rotating the file along the long axis). The casting patterns were fabricated by using DLP (Cara Print 4.0) with a photopolymerizable monomer (dima Print Cast Q). Photopolymerization, cleaning, and postpolymerization processes were performed according to the manufacturer's instructions. The adaptation of the specimens was examined by using a silicone replica method. The vertical marginal discrepancy and axial wall, occlusal, and marginal gaps were measured by using a digital measuring microscope. The effect of build orientation at each cross-sectional area was statistically analyzed by using the Kruskal-Wallis test followed by the pairwise Wilcoxon rank sum test with Bonferroni correction (α=.05).

Results: Excess polymerized resin was observed along the intaglio buccal wall at build orientations of 30 degrees and 45 degrees. Vertical marginal discrepancies in the buccolingual section ranged from -50 to 248 μm, while those in the mesiodistal section ranged from -25 to 182 μm. The gaps in the buccolingual section ranged from 0 to 236 μm, while those in the mesiodistal section ranged from 0 to 177 μm. According to the observation of vertical marginal discrepancies and gaps, the 30-degree specimens inclined during insertion, and the 45-degree specimens were not completely seated. However, the marginal gaps of the 0- and 30-degree specimens were within the clinically acceptable limit of 120 μm.

Conclusions: The limited data indicated that the build orientation influenced the adaptation of casting patterns for 3-unit partial fixed dental prostheses fabricated by using DLP. A build orientation of 0 degrees is recommended for fabricating casting patterns for 3-unit partial fixed dental prostheses because no excess polymerization of the intaglio buccal wall was observed.
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http://dx.doi.org/10.1016/j.prosdent.2021.01.006DOI Listing
February 2021

ASO Author Reflections: Opening up the Future with Transanal Minimally Invasive Surgery of Fine Techniques.

Ann Surg Oncol 2021 Mar 1. Epub 2021 Mar 1.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, 565-0871, Osaka, Japan.

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http://dx.doi.org/10.1245/s10434-021-09613-8DOI Listing
March 2021

Crenolanib Regulates ERK and AKT/mTOR Signaling Pathways in RAS/BRAF-Mutated Colorectal Cancer Cells and Organoids.

Mol Cancer Res 2021 Feb 12. Epub 2021 Feb 12.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.

Recently developed molecularly targeted therapies such as EGFR inhibitors have notably improved the prognosis of patients with cancer. However, patients with KRAS and BRAF mutations do not currently benefit from these therapies. Here, we aimed to examine potential effects of crenolanib as a new molecularly targeted therapy in colorectal cancer. We used multiple colorectal cancer cell lines to investigate the growth-inhibitory effect of crenolanib and its effect in combination with other cytotoxic agents. Primary cultures of patient-derived organoids (PDO), a model that reflects the heterogeneity of clinical colorectal cancer, were used to further validate the effects of crenolanib. Unlike cetuximab, crenolanib remarkably suppressed ERK and AKT/mTOR pathways in HT29 cells with BRAF mutation and in HCT116 cells with KRAS mutation with corresponding growth-suppressing effects. Additive or synergistic effects were observed in treatments with combination of crenolanib and other cytotoxic drugs. Moreover, crenolanib suppressed the expression of stem cell markers, such as OCT4, NANOG, and SOX2. These observations were substantiated in seven PDOs with KRAS mutation and two PDOs without KRAS/BRAF mutations, with crenolanib suppressing the growth of all PDOs regardless of their KRAS mutation status. Furthermore, crenolanib abrogated PDGF- and TGFβ-induced increase of OCT4-positive cells in PDOs. Together, these findings suggest that crenolanib may have clinical utility for patients with colorectal cancer, especially patients with KRAS/BRAF mutations. IMPLICATIONS: These findings indicate that crenolanib can be a useful target agent for patients with colorectal cancer, especially patients with KRAS/BRAF mutations.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0600DOI Listing
February 2021

An oncologic emergency case of massive dedifferentiated liposarcoma of the small bowel mesentery.

Clin J Gastroenterol 2021 Feb 10. Epub 2021 Feb 10.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2 2-2 Yamadaoka, Suita, Osaka, Japan.

We report the case of a 71-year-old man who complained of abdominal distension, pedal edema, respiratory discomfort, and weight gain. Computed tomography revealed a giant, poorly enhancing tumor occupying the entire abdomen, with abdominal ascites. The tumor was causing hydronephrosis, compression of the inferior vena cava, and elevation of the diaphragm. The patient exhibited deterioration of performance status (PS3 on the ECOG scale) and required oxygen; therefore, emergency surgery was performed. Operative findings included bloody abdominal ascites and peritoneal dissemination. The large tumor arose from the small bowel mesentery, and infiltrated into the cecum and sigmoid colon. Tumor excision with ileocecal resection and sigmoidectomy was performed. Histopathological examination revealed dedifferentiated liposarcoma. The patient was discharged on postoperative day 22, but pre-discharge CT revealed a recurrent liposarcoma in the retroperitoneum. Therefore, chemotherapy was initiated and the treatment has been continued for over 6 months after surgery. Due to the rarity of this disease, there is no consensus regarding treatment strategies for DDLPS with peritoneal dissemination or in patients with a poor general condition, especially in the setting of oncologic emergency. In this case, multimodal treatment was used to successfully manage this life-threatening state and obtain satisfactory therapeutic results.
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http://dx.doi.org/10.1007/s12328-021-01350-5DOI Listing
February 2021

Surgical resection for pelvic retroperitoneal Castleman's disease: A case report and review literature.

Biomed Rep 2021 Mar 21;14(3):29. Epub 2021 Jan 21.

Department of Gastroenterological Surgery, Osaka University, Osaka 5650871, Japan.

Castleman's disease (CD) is a rare atypical lymphoproliferation disorder first reported in 1954. Clinically, CD is classified as unicentric or multicentric CD based on anatomical distribution. Unicentric CD primarily affects the mediastinum, and rarely affects the retroperitoneal location. The standard treatment for unicentric CD is complete surgical resection; however, this can be complicated by a high degree of attachment with other organs or hypervascularity. Preoperative angiography and embolization of the arteries that feed the problematic mass can reduce intraoperative bleeding in cases of CD with hypervascularity. In the present case report, a 44-year-old man who was found to have a pelvic retroperitoneal mass with calcification based on abdominal imaging results is discussed. Due to the hypervascularity of the mass, preoperative embolization was performed. The mass was completely resected without any complications. Additionally, a review of the literature on pelvic CD and preoperative embolization of CD was performed to provide an up-to-date reference on the management and outcomes of patients with CD.
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http://dx.doi.org/10.3892/br.2021.1405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841734PMC
March 2021

Laparoscopic para-aortic lymphadenectomy after multiple previous abdominal surgeries - a video vignette.

Colorectal Dis 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita City, Japan.

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http://dx.doi.org/10.1111/codi.15545DOI Listing
January 2021

Application of Local Hyaluronic Acid Injection in Transanal Minimally Invasive Surgery for Anterior Rectal GIST.

Ann Surg Oncol 2021 Jan 16. Epub 2021 Jan 16.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

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http://dx.doi.org/10.1245/s10434-020-09569-1DOI Listing
January 2021

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, β-Catenin, and TRK pathways.

Invest New Drugs 2021 Jan 6. Epub 2021 Jan 6.

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan.

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.
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http://dx.doi.org/10.1007/s10637-020-01019-9DOI Listing
January 2021

A case of single-incision laparoscopic surgery for acute appendicitis with left ventricular assist device.

Asian J Endosc Surg 2021 Jan 3. Epub 2021 Jan 3.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.

A left ventricular assist device (LVAD) is used for patients with severe heart failure. We present a case of a 35-year-old man who had undergone LVAD implantation 2 years ago for dilated phase of hypertrophic cardiomyopathy. He had right lower abdominal pain and was diagnosed with acute appendicitis. Single-incision laparoscopic surgery for appendicitis was performed. We incised approximately 3 cm of the umbilicus carefully because the driveline of LVAD was passing just caudal to the umbilicus. LVAD is only available for patients waiting for cardiac transplantation in Japan, and the number of patients with LVAD has been increasing. Adequate anticoagulant therapy is necessary because device thrombosis often causes fatal complications, but during emergency cases, the surgeons have to be cautious of bleeding and injury to the driveline of LVAD.
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http://dx.doi.org/10.1111/ases.12914DOI Listing
January 2021

SIRT3-Mediated SOD2 and PGC-1α Contribute to Chemoresistance in Colorectal Cancer Cells.

Ann Surg Oncol 2021 Jan 3. Epub 2021 Jan 3.

Department of Gastroenterological Surgery, Osaka University, Suita, Osaka, Japan.

Background: Anticancer drugs generate excessive reactive oxygen species (ROS), which can cause cell death. Cancer cells can resist this oxidative stress, but the mechanism of resistance and associations with chemoresistance are unclear. Here, we focused on Sirtuin 3 (SIRT3), a deacetylating mitochondrial enzyme, in oxidative stress resistance in colorectal cancer (CRC).

Methods: To evaluate SIRT3-related changes in mitochondrial function, ROS (mtROS) induction, and apoptosis, we used the human CRC cell lines HT29 and HCT116 transfected with short-hairpin RNA targeting SIRT3 and small interfering RNAs targeting superoxide dismutase 2 mitochondrial (SOD2) and peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α). In 142 clinical specimens from patients with CRC, we also assessed the association of SIRT3 protein levels (high/low) and prognosis.

Results: SIRT3 expression correlated with mtROS generation and apoptosis induction in cells treated with anticancer agents. Suppressing SIRT3 increased mtROS levels and cell sensitivity to anticancer agents. SIRT3 knockdown decreased SOD2 expression and activity, and suppressing SOD2 also improved sensitivity to anticancer drugs. In addition, SIRT3 was recruited with PGC-1α under oxidative stress, and suppressing SIRT3 decreased PGC-1α expression and mitochondrial function. PGC-1α knockdown decreased mitochondrial activity and increased apoptosis in cells treated with anticancer drugs. In resected CRC specimens, high vs low SIRT3 protein levels were associated with significantly reduced cancer-specific survival.

Conclusions: SIRT3 expression affected CRC cell chemoresistance through SOD2 and PGC-1α regulation and was an independent prognostic factor in CRC. SIRT3 may be a novel target for CRC therapies and a predictive marker of sensitivity to chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-09373-xDOI Listing
January 2021

Application of Glass Fiber and Carbon Fiber-Reinforced Thermoplastics in Face Guards.

Polymers (Basel) 2020 Dec 23;13(1). Epub 2020 Dec 23.

Department of Advanced Biomaterials, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.

Face guards (FGs) are protectors that allow for the rapid and safe return of athletes who are to play after sustaining traumatic facial injuries and orbital fractures. Current FGs require significant thickness to achieve sufficient shock absorption abilities. However, their weight and thickness render the FGs uncomfortable and reduce the field of vision of the athlete, thus hindering their performance. Therefore, thin and lightweight FGs are required. We fabricated FGs using commercial glass fiber-reinforced thermoplastic (GFRTP) and carbon fiber-reinforced thermoplastic (CFRTP) resins to achieve these requirements and investigated their shock absorption abilities through impact testing. The results showed that an FG composed of CFRTP is thinner and lighter than a conventional FG and has sufficient shock absorption ability. The fabrication method of an FG comprising CFRTP is similar to the conventional method. FGs composed of commercial FRTPs exhibit adequate shock absorption abilities and are thinner and lower in weight as compared to conventional FGs.
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http://dx.doi.org/10.3390/polym13010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793102PMC
December 2020

Plasma Branched-Chain and Aromatic Amino Acids in Relation to Hypertension.

Nutrients 2020 Dec 10;12(12). Epub 2020 Dec 10.

Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.

Findings of the available studies regarding the roles of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in hypertension are inconsistent, conflicting and inconclusive. The purpose of this study was to explore and clarify the existence of any relationships of individual BCAAs and AAAs with hypertension with adjustments for potential relevant confounders. A total of 2805 healthy controls and 2736 hypertensive patients were included in the current analysis. The associations between individual amino acids and hypertension were explored by logistic regression analyses adjusted for potential confounding variables. Among the investigated amino acids, only the BCAAs showed consistently significant positive associations with hypertension in the adjusted models (-trend < 0.05 to 0.001). However, compared with the corresponding lowest quartile of individual BCAAs, the positive association with hypertension remained significant only in the highest quartile ( < 0.01 to 0.001). We confirmed in a relatively large cohort of subjects that BCAAs, not AAAs, demonstrated consistent positive associations with hypertension. The results display the promising potential for the use of BCAAs as relevant and accessible biomarkers, and provide perspectives on interventions directed towards the reduction in plasma BCAA levels in the prevention and management of hypertension.
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http://dx.doi.org/10.3390/nu12123791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764357PMC
December 2020

Effect of zinc oxide nanoparticles incorporated into tissue conditioner on antifungal, physical, and mechanical properties.

Dent Mater J 2021 Mar 2;40(2):481-486. Epub 2020 Dec 2.

Department of Oral Biomaterials Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU).

This study evaluated the antifungal, physical, and mechanical properties of tissue conditioner incorporated with different amounts of zinc oxide nanoparticles (ZnOnps) at different storage times (0, 7, and 14 days). Specimens of 0, 5, 10, 15 wt% ZnOnps, or 15 wt% nystatin incorporated into tissue conditioner were fabricated (control, 5Zn, 10Zn, 15Zn, and Nys). The direct contact test (n=6) was performed to evaluate the antifungal effect against C. albicans suspension. The penetration depth (n=6) and tensile bond strength (n=8) were evaluated following ISO 13139. The 15Zn significantly reduced C. albicans cell number compared with control at all storage times (p<0.001). The penetration depths and tensile bond strengths of the 5Zn, 10Zn, 15Zn, and Nys were not significantly different compared with control at all storage times (p>0.05). In conclusion, the 15Zn provides antifungal effect up to 14 days without adverse effects on penetration depth and tensile bond strength.
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http://dx.doi.org/10.4012/dmj.2020-095DOI Listing
March 2021

A new fat-dissociation method to detect lymph nodes in colorectal cancer: a prospective randomized study.

Sci Rep 2020 11 19;10(1):20205. Epub 2020 Nov 19.

Department of Surgery, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka, 541-8567, Japan.

Histological examination of the lymph nodes (LNs) is crucial to determine the colorectal cancer (CRC) stage. We previously reported a new fat-dissociation method (FM) to detect LNs from surgically resected mesentery. This study aimed to examine the effectiveness of FM compared with that of conventional palpation method (PM) in CRC. This single-center, open-label, randomized controlled study was performed at Osaka International Cancer Institute in Japan in 2014. Randomization was performed using a computer-generated permuted-block sequence. Patients were stratified by surgical procedures and the LN dissection area. The primary endpoint was the time required for LN identification. The secondary endpoint was the number of LNs and 5-year cancer-specific survival. The 130 enrolled patients were randomly assigned in a 1:1 ratio to the FM and the PM groups. LN identification times were 45 (range 15-80) and 15 (range 7-30) minutes in the PM and the FM groups, respectively (P < 0.001). In the PM group, body mass index and identification time were correlated (P = 0.047). The number of LN which could be examined pathologically was 16 (range 2-48) and 18 (range 4-95) in the PM and FM groups, respectively (P = 0.546). In right-sided CRC, the number of LNs was higher in the FM group than in the PM group (P = 0.031). Relapse-free survival rates and cancer-specific survival rates did not differ between the groups. In conclusion, FM reduced the time required for LN detection without reducing the number of detected LNs, making it is a useful method to detect LNs in surgical specimens.
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http://dx.doi.org/10.1038/s41598-020-77195-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678840PMC
November 2020

The meiosis-specific cohesin component stromal antigen 3 promotes cell migration and chemotherapeutic resistance in colorectal cancer.

Cancer Lett 2021 Jan 8;497:112-122. Epub 2020 Oct 8.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Chromosome instability is one of the hallmarks of cancer. Stromal antigen (STAG) 3 is a core component of the meiosis-specific cohesin complex, which regulates sister chromatid cohesion. Although aberrantly activated genes encoding the cohesin complex have been identified in cancers, little is known about the role of STAG3 in colorectal cancer (CRC). Here, we evaluated the prognostic impact and role of STAG3 in CRC. Analysis of 172 CRC surgical specimens revealed that high STAG3 expression was associated with poor prognosis. STAG3 knockdown inhibited cell migration and increased drug sensitivity to oxaliplatin, 5-fluorouracil, irinotecan hydrochloride hydrate, and BRAF inhibitor in CRC cell lines. The enhanced drug sensitivity was also confirmed in a human organoid established from a CRC specimen. Moreover, suppression of STAG3 increased γH2AX foci. Particularly, in BRAF-mutant CRC cells, STAG3 silencing suppressed the expression of snail family transcriptional repressor 1 and phosphorylation of extracellular signal-regulated kinase via upregulation of dual-specificity phosphatase 6. Our findings suggest that STAG3 is related to poor clinical outcomes and promotes metastasis and chemotherapeutic resistance in CRC. STAG3 may be a novel prognostic marker and potential therapeutic target for CRC.
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http://dx.doi.org/10.1016/j.canlet.2020.10.006DOI Listing
January 2021

A case report of anal canal cancer with pagetoid spread requiring differential diagnosis.

Int J Surg Case Rep 2020 10;75:198-202. Epub 2020 Sep 10.

Osaka University, Graduate School of Medicine, Department of Gastroenterological Surgery, Osaka, Japan.

Introduction: Paget's disease is an intraepithelial invasion by a malignant tumour and is characterised by erythema and inflammation. It can manifest as mammary or extramammary Paget's disease (EMPD), with the latter often developing in the perianal area. Anorectal cancer can cause transepithelial invasion into the epidermis, resulting in an appearance similar to that of EMPD. This is called pagetoid spread (PS), which is completely different from EMPD. These two conditions are difficult to differentiate because of the nature of intricacy and requirements of histopathology.

Presentation Of Case: We present a case in which differential diagnosis between these two conditions was not possible during the preoperative examination, resulting in difficulties in treatment. The patient was a 70-year-old woman who experienced pain in the anus since the previous month and presented with red, flat and elevated lesions.

Discussion: Treatment for dermatitis was ineffective, and endoscopic examination did not indicate rectal or anal cancer. However, immunohistochemical examination of the biopsy specimen suggested PS. Thus, two-stage operation was planned. Transanal surgery was performed to confirm the diagnosis of PS and intersphincteric resection was allowed as a radical surgery.

Conclusion: Thus, when differentiation between EMPD and PS is intricacy, two-stage operation is useful in selecting an appropriate radical surgery method, leading to preservation of anal function.
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http://dx.doi.org/10.1016/j.ijscr.2020.09.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505754PMC
September 2020

Phase I Study of the Administration of Low-dose Perioperative Human Atrial Natriuretic Peptide in Patients With Resectable Colorectal Cancer.

Anticancer Res 2020 Sep;40(9):5301-5307

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Background/aim: The aim of this single center, non-randomized, open-label, uncontrolled, interventional trial was to determine the feasibility of continuous administration of low-dose human atrial natriuretic peptide (hANP) perioperatively during curative operation for colorectal cancer patients without history of acute heart failure.

Patients And Methods: The study included three males and two females ranging from 27 to 70 years old. Continuous intravenous injection of hANP solution was started before surgery. The primary endpoint was safety of hANP administration, and the secondary endpoints were perioperative changes in ANP, b-type natriuretic peptide, electrocardiogram (ECG), and lung function.

Results: The American Society of Anaesthesiologists physical status was 1, 2, and 3 in three, one, and one patient, respectively. Grade 2 hypotension was observed in one case. No marked changes were observed between pre- and post-operation in all cases.

Conclusion: Perioperative low-dose hANP administration is feasible and safe in patients with curative colorectal cancer.
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http://dx.doi.org/10.21873/anticanres.14536DOI Listing
September 2020

Long-term outcome of patients with Crohn's disease on home parenteral nutrition.

Nutrition 2020 10 19;78:110903. Epub 2020 Jun 19.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.

Objectives: In patients with Crohn's disease (CD) and intestinal failure, home parenteral nutrition (HPN) is a necessary lifesaving treatment. The aim of this study was to investigate the long-term outcomes of patients with CD after initiation of HPN.

Methods: This study included patients with CD receiving HPN for intestinal failure. The patients were treated at Osaka University Hospital between January 2000 and December 2019. Patients' demographic characteristics, HPN dependence and complications, and mortality were analyzed. HPN dependence was estimated using the Kaplan-Meier method. Cox regression analysis was used for between-group comparisons.

Results: Twenty-one patients with CD received HPN. HPN dependence rates were 85%, 75%, 75%, and 64%, respectively, at 2, 5, 10, and 15 y after HPN initiation. Patients who weaned off HPN exhibited lower rates of immunomodulator therapy and additional intensive CD treatment (P < 0.05). Multivariate analysis revealed that not requiring additional intensive CD treatment was a significant factor in weaning off HPN. Two patients (9%) died, at a median of 14.9 y after HPN initiation, due to HPN-related liver disease and CD-associated carcinoma. Among all patients, 61% experienced catheter-related bloodstream infections (CRBSIs), with an incidence of 0.32/1000 catheter-days. Methicillin-resistant bacteria and Candida spp. each accounted for 27% of all pathogens detected in CRBSI.

Conclusions: Patients with CD receiving HPN had a good prognosis, despite frequent CRBSIs in which methicillin-resistant bacteria and fungi were common pathogens. Some patients with CD can wean off HPN, even after a long period of HPN treatment. A stable disease condition during HPN might be an important factor for weaning off HPN.
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http://dx.doi.org/10.1016/j.nut.2020.110903DOI Listing
October 2020

Dipeptidyl Peptidase 9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer.

Ann Surg Oncol 2020 Oct 30;27(11):4337-4347. Epub 2020 Jul 30.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: In recent years, systemic chemotherapy has significantly improved the prognosis of metastatic colorectal cancer (CRC); however, different patients have different responses to chemotherapeutics.

Methods: Dipeptidyl peptidase 9 (DPP9) is an enzyme in the dipeptidyl peptidase IV family that has been reported to increase drug sensitivity in acute myeloid leukemia. In this study, we examined the relationship between DPP9 expression and the prognosis of patients with CRC, as well as the role of DPP9 in anticancer drug resistance. Moreover, the effects of the DPP9 inhibitors talabostat and vildagliptin in CRC cell lines and primary cultured cells were assessed.

Results: High expression of DPP9 was associated with worse prognosis in 196 patients with CRC. Cell viability was markedly inhibited in CRC cell lines transfected with DPP9 small interfering RNA or small hairpin RNA. Talabostat suppressed proliferation in CRC cell lines and primary cultured cells, and increased their sensitivity to chemotherapy. Vildagliptin, a DPP family inhibitor currently administered for diabetes, also increased the sensitivity of CRC cells to anticancer drugs.

Conclusion: DPP9 was a poor prognostic factor for CRC and could be a new therapeutic target, while vildagliptin could be used as a repositioned drug for CRC treatment.
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http://dx.doi.org/10.1245/s10434-020-08729-7DOI Listing
October 2020

PAX 8-positive sarcomatoid carcinoma arising from the liver with aggressive phenotype: An autopsy case.

Pathol Int 2020 Oct 7;70(10):825-827. Epub 2020 Jul 7.

Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan.

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http://dx.doi.org/10.1111/pin.12985DOI Listing
October 2020

The Geriatric Nutritional Risk Index predicts postoperative complications and prognosis in elderly patients with colorectal cancer after curative surgery.

Sci Rep 2020 07 1;10(1):10744. Epub 2020 Jul 1.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Malnutrition has been considered to be associated with the prognosis of cancer. The Geriatric Nutritional Risk Index (GNRI), based on serum albumin levels, present body weight, and ideal body weight, is a simple screening tool to predict the risk of nutrition-related morbidity and mortality in elderly patients. We aimed to evaluate whether preoperative GNRI was associated with postoperative complications and prognosis in elderly patients with colorectal cancer (CRC). We retrospectively enrolled 313 CRC patients aged ≥65 years after curative surgery and classified them into an all-risk GNRI (≤98) group and a no-risk GNRI (>98) group. Kaplan-Meier analysis showed overall survival was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.009). Multivariable analyses showed low GNRI (≤98) was an independent risk factor for postoperative complications (P = 0.048) and overall survival (P = 0.001) in the patients. Among the complications, the incidence of surgical site infection, in particular, was significantly higher in the all-risk GNRI group (P = 0.008). In conclusion, low preoperative GNRI (≤98) was associated with increased postoperative complications and poor prognosis. Preoperative GNRI can be used as an identifier for potential high-risk group of morbidity and mortality in elderly CRC patients.
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http://dx.doi.org/10.1038/s41598-020-67285-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329855PMC
July 2020

Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor.

Br J Cancer 2020 09 29;123(6):955-964. Epub 2020 Jun 29.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: The protein syntenin-1 is expressed by a variety of cell types, and is upregulated in various malignancies, including melanoma, breast cancer and glioma. Although the mechanism by which elevated syntenin-1 expression contributes to cancer has been described, the exact pathway has not been elucidated.

Methods: To investigate the involvement of syntenin-1 in colorectal cancer (CRC), we performed immunohistochemical analysis of 139 CRC surgical specimens. We also examined syntenin-1 knockdown in CRC cell lines.

Results: High syntenin-1 expression was associated with less differentiated histologic grade and poor prognosis, and was an independent prognostic indicator in CRC. Syntenin-1 knockdown in CRC cells reduced the presence of cancer stem cells (CSCs), oxaliplatin chemoresistance and migration. DNA microarray analysis and quantitative real-time polymerase chain reaction showed decreased prostaglandin E2 receptor 2 (PTGER2) expression in syntenin-1-knockdown cells. PTGER2 knockdown in CRC cells yielded the same phenotype as syntenin-1 knockdown. Celecoxib, which has anti-inflammatory effects by targeting cyclooxygenase-2, reduced CSCs and decreased chemoresistance, while prostaglandin E2 (PGE2) had the opposite effect.

Conclusions: Our findings suggested that syntenin-1 enhanced CSC expansion, oxaliplatin chemoresistance and migration capability through regulation of PTGER2 expression. Syntenin-1 may be a promising new prognostic factor and target for anti-cancer therapies.
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http://dx.doi.org/10.1038/s41416-020-0965-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492211PMC
September 2020

[Two cases of rectal neuroendocrine carcinoma associated with long-standing ulcerative colitis].

Nihon Shokakibyo Gakkai Zasshi 2020 ;117(6):521-531

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University.

Two cases of neuroendocrine carcinoma, complicated with ulcerative colitis, were examined. Case 1:The patient developed ulcerative colitis at the age of 38, surgery was performed after a diagnosis of rectal cancer at the age of 53, and the patient was diagnosed with neuroendocrine carcinoma by pathological examination after resection. Post-surgery, metastatic nodules were detected in the liver and lungs. The patient is undergoing chemotherapy at this time. Case 2:The patient developed ulcerative colitis at the age of 59;at 72, a sigmoid colon tumor, in addition to multiple liver tumors, was detected. The patient was diagnosed with neuroendocrine carcinoma following biopsy. Chemotherapy was initiated;however, the patient died of cancer 12 months later.
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http://dx.doi.org/10.11405/nisshoshi.117.521DOI Listing
July 2020

Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages.

Sci Rep 2020 06 19;10(1):9972. Epub 2020 Jun 19.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7 and LysM-cre; Atg7 mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7 mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix) did not suppressed colitis in LysM-cre; Atg7 mice. In large intestinal macrophages (Mφ) of Atg7 mice, SO and Mix upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7 mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.
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http://dx.doi.org/10.1038/s41598-020-65306-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305163PMC
June 2020

Electrical contraction of the anal sphincter for intraoperative visualization of anal function.

Minim Invasive Ther Allied Technol 2020 Jun 10:1-10. Epub 2020 Jun 10.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Repairing sphincter defects to restore the anal aperture is a cornerstone of surgical treatment in cases of anal preserving surgery. Such procedures are selected and performed according to the surgeons' experience. In the present study, we aimed to investigate a method for clear and intuitive intraoperative assessment of anal function under general anesthesia. This study was conducted in three-month-old female (35 kg) domestic swine ( = 8) under standard general anesthesia. Electrical stimulation of the anal sphincter was performed using prototype electric devices, and then the anal pressure was measured by manometry. We generated an anal dysfunctional model by excising the left puborectalis muscle. Anal function was semi-quantified and visualized using anorectal manometry. Electrical stimulation with 12.5 mA output current and 15% duty ratio produced maximum anal pressure using the smallest amount of electricity. Histological examination confirmed the safety of the electrical muscular stimulation. Three-dimensional reconstruction of the results from the pressure curves of each sensor-enabled visualization of the functional anal canal. Monitoring using manometry under general anesthesia revealed the recovery of anal function upon suturing the excised puborectalis. Electrical muscular stimulation feasibly enabled visualization of anal function under general anesthesia in a porcine model.
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http://dx.doi.org/10.1080/13645706.2020.1773855DOI Listing
June 2020

Preoperative imatinib and laparoscopic intersphincteric resection for large rectal gastrointestinal stromal tumor: A case report.

Int J Surg Case Rep 2020 23;71:235-239. Epub 2020 May 23.

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita City, Osaka 565-0871, Japan.

Introduction: Anus-preserving surgery for a large rectal gastrointestinal stromal tumor (GIST) may be difficult because of the location of the tumor in the pelvis. Therefore, rectal GIST might require extensive surgery, such as abdominoperineal resection. In recent years, preoperative imatinib therapy has been used to reduce tumor size and preserve the anus in some cases. However, there have been few reports of laparoscopic anal-preserving surgery for giant rectal GIST.

Presentation Of A Case: We present the case of a 55-year-old man who was referred to our hospital for examination of a 10-cm pelvic mass in the lower rectum. Endoscopic ultrasound with fine needle aspiration was performed, and the pathological findings resulted in a diagnosis of GIST. The mass had spread to the prostate and left levator ani muscles, and as a result, surgery was deemed difficult to perform without damaging the pseudo-capsule. Therefore, preoperative chemotherapy with imatinib mesylate (IM) was performed for 8 months. The mass was reduced to 7.8 cm, and laparoscopic intersphincteric resection (ISR) was performed.

Discussion: We also review prior cases of rectal GIST where patients had undergone anal-preserving surgery following preoperative chemotherapy with IM. Our case represented the largest tumor size in a review of cases of patients who had successful anal-preserving laparoscopic surgery following preoperative chemotherapy with IM.

Conclusion: Preoperative chemotherapy with imatinib mesylate was effective for reducing the rectal GIST, and laparoscopic ISR was useful for anal preservation, even when a tumor is large.
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http://dx.doi.org/10.1016/j.ijscr.2020.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262371PMC
May 2020