Publications by authors named "Toshiya Kamiyama"

159 Publications

High HbA1c is a risk factor for complications after hepatectomy and influences for hepatocellular carcinoma without HBV and HCV infection.

Hepatobiliary Surg Nutr 2021 Aug;10(4):454-463

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Background: Currently, the population with type 2 diabetes mellitus (DM) is increasing worldwide. However, the influence of DM or hyperglycemia on the outcome of resected hepatocellular carcinoma (HCC) is unclear.

Methods: We analyzed 756 patients with HCC who underwent hepatectomy. These patients were assigned to an HbA1c ≥7.0% (H-A1c; n=100) or HbA1c <7.0% (L-A1c; n=656) group depending on their HbA1c level at admission. We investigated prognoses, clinicopathological characteristics and surgical outcomes including morbidities of HCC patients with high HbA1c, prognoses according to the treatment for DM were also investigated.

Results: Among all patients and those with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, overall survival (OS) and relapse-free survival (RFS) did not differ significantly between the H-A1c and L-A1c groups. In contrast, the 5-year OS rate of the H-A1c group was 55% and that of the L-A1c group 71% among patients without HBV and HCV (NBNC patients) (P=0.03). Among NBNC patients, the median RFS of the H-A1c group was 13 months, and that of the L-A1c group was 26 months (P=0.02). In addition, metformin use was an independent favorable factor for both OS and RFS. The H-A1c group had significantly higher rates of hyperbilirubinemia, wound infection, and pneumonia.

Conclusions: HCC patients with high HbA1c might have poor prognoses for both survival and recurrence in NBNC-HCC. High HbA1c may also be a risk factor for morbidities after hepatectomy. Metformin use may constitute a good option for NBNC patients with HCC.
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http://dx.doi.org/10.21037/hbsn.2020.01.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350996PMC
August 2021

Combined treatment of an aortosplenic bypass followed by coil embolization in the treatment of pancreaticoduodenal artery aneurysms caused by median arcuate ligament compression: a report of two cases.

Surg Case Rep 2021 Aug 4;7(1):174. Epub 2021 Aug 4.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo, 060-8638, Japan.

Background: Pancreaticoduodenal artery aneurysms (PDAAs) are rare visceral aneurysms, and prompt intervention/treatment of all PDAAs is recommended at the time of diagnosis to avoid rupture of aneurysms. Herein, we report two cases of PDAA caused by the median arcuate ligament syndrome, treated with surgical revascularization by aortosplenic bypass followed by coil embolization.

Case Presentation: Case 1 A 54-year-old woman presented with a chief complaint of severe epigastralgia and was diagnosed with two large fusiform inferior PDAAs and celiac axis occlusion. To preserve the blood flow of the pancreatic head, duodenum, liver, and spleen, we performed elective surgery to release the MAL along with aortosplenic bypass. At 6 days postoperatively, transcatheter arterial embolization was performed. At the 8-year 6-month follow-up observation, no recurrent perfusion of the embolized PDAAs or rupture had occurred, including the non-embolized small PDAA, and the bypass graft had excellent patency. Case 2 A 39-year-old man who had been in good health was found to have a PDAA with celiac stenosis during a medical checkup. Computed tomography and superior mesenteric arteriography showed severe celiac axis stenosis and a markedly dilated pancreatic arcade with a large saccular PDAA. To preserve the blood flow of the pancreatic arcade, we performed elective surgery to release the MAL along with aortosplenic bypass. At 9 days postoperatively, transcatheter arterial embolization was performed. At the 6-year 7-month follow-up observation, no recurrent perfusion or rupture of the PDAA had occurred, and the bypass graft had excellent patency.

Conclusion: Combined treatment with bypass surgery and coil embolization can be an effective option for the treatment of PDAAs associated with celiac axis occlusion or severe stenosis.
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http://dx.doi.org/10.1186/s40792-021-01260-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339153PMC
August 2021

Genomewide transcriptomic profiling identifies a gene signature for predicting recurrence in early-stage hepatocellular carcinoma.

Clin Transl Med 2021 06;11(6):e405

Center for Gastrointestinal Research, Center from Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.

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http://dx.doi.org/10.1002/ctm2.405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181200PMC
June 2021

Diagnostic timing dependent characteristics of acute kidney injury following hepatectomy: a retrospective historical cohort analysis.

HPB (Oxford) 2021 May 18. Epub 2021 May 18.

Department of Gastroenterological Surgery I, Hokkaido University Hospital, N14, W5, Kita-ku, Sapporo, 060-8648, Japan.

Background: The timing of diagnosis of post-hepatectomy acute kidney injury (AKI) has rarely been investigated. The aim of this retrospective study was to reveal the differences between AKI subtypes following hepatectomy, as classified by timing of diagnosis.

Method: Post-hepatectomy AKI was classified as very transient AKI (vtAKI; criteria satisfied by the serum creatinine value immediately after surgery) or non-transient AKI (ntAKI; all other AKI types except for vtAKI). Multivariate logistic regression analyses for both AKI types were performed separately to identify differences in known perioperative AKI risk factors. The impacts of each AKI subtype on postoperative complications, hospital stay and renal outcome at discharge were also evaluated.

Results: AKI was diagnosed in 135 of 750 patients (18.0%); 82 and 53 patients were classified as vtAKI and ntAKI, respectively. In multivariate analysis, even among the perioperative factors associated with whole AKI, there were distinct relationships depending on vtAKI or ntAKI. Furthermore, only ntAKI was associated with postoperative complications, longer hospital stays and impaired renal function at discharge.

Conclusions: Based on the results of this study, future post-hepatectomy AKI studies should only include ntAKI and exclude vtAKI, as vtAKI has minimal clinical impact despite accounting for a significant proportion of AKI patients.

Clinical Trial Registrations: None.
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http://dx.doi.org/10.1016/j.hpb.2021.05.003DOI Listing
May 2021

The impact of elastography with virtual touch quantification of future remnant liver before major hepatectomy.

Quant Imaging Med Surg 2021 Jun;11(6):2572-2585

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Background: Liver elastography with virtual touch quantification (VTQ) measures the velocity of the shear wave generated by a short-duration acoustic force impulse, with values expressed in units of velocity (m/s). VTQ can evaluate right or left hepatic lobes separately. VTQ might be appropriate for the evaluation of future remnant liver after hepatectomy.

Methods: We analyzed 95 patients underwent liver elastography with VTQ and both future remnant liver and resected side before hepatectomy of more than two sections, except for central bisectionectomy. We divided the patients into a high VTQ group (≥1.52 m/s, n=37, 39%) and a low VTQ group (<1.52 m/s, n=58, 61%) according to the VTQ of future remnant liver. Transient elastography could not be performed in 22 cases due to tumor size. We defined the group with liver stiffness measurement (LSM) ≥7.9 kPa as the high LSM group (n=29, 40%) and those with LSM <7.9 kPa as the low LSM group (n=44, 60%). We investigated the outcome after hepatectomy and the correlations between the VTQ of future remnant liver and other indicators for hepatic fibrosis.

Results: The high VTQ group showed significantly higher postoperative ascites (19% 3%; P=0.01), pathological fibrosis (19% 5%; P=0.03), and rates of patients with postoperative T-bil ≥2.0 mg/dL (70% 40%; P<0.01). The high LSM group showed no significant postoperative outcomes compared to the low LSM group. The high VTQ group showed a higher frequency of male gender (78% 57%; P=0.03), higher indocyanine green retention rate at 15 min (ICGR15) (10.5% 6.3%; P<0.01), hyaluronic acid (100 67 ng/mL; P=0.02), type IV collagen 7S (7.6 . 5.1 ng/mL; P<0.01), Mac-2 binding protein glycan isomer (M2BPGi) (1.19 1.00; P=0.01), Fibrosis-4 (FIB-4) index (2.25 1.76; P=0.01), and aspartate aminotransferase to platelet ratio index (APRI) score (0.64 0.41; P<0.01). We also observed an especially strong positive correlation between the high VTQ and hyaluronic acid or type IV collagen 7S.

Conclusions: Elastography with VTQ for future remnant liver before major hepatectomy is an accurate and useful method as a preoperative evaluation.
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http://dx.doi.org/10.21037/qims-20-1073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107315PMC
June 2021

A case of laparoscopic hepatectomy for a primary hepatic neuroendocrine tumor.

Clin J Gastroenterol 2021 Jun 15;14(3):876-880. Epub 2021 May 15.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.

Neuroendocrine tumors (NETs) account for approximately 1-2% of all gastrointestinal tumors. In particular, primary hepatic NETs (PHNETs) are extremely rare. A 42-year-old female patient was given a diagnosis of liver tumor after a medical check-up with ultrasonography. An enhanced CT scan and MRI were suggestive for a hepatic hemangioma or adenoma, but the possibility of hepatocellular carcinoma could not be denied. Moreover, this tumor grew larger, so we performed a laparoscopic partial hepatectomy for the diagnosis and treatment of the patient. Pathological examination revealed that the tumor cells were spindle-shaped, forming glandular-tubular structures, and had less visible nucleoli and increased mitotic figures on H&E staining. Immunohistochemical findings indicated that CK19, MOC-31, CD56, synaptophysin, and chromogranin A were positive; CK7, AFP, and glypican-3 were negative; and the Ki-67 index was 3.6%, so the final diagnosis was a PHNET G2. PHNETs differ from other NETs, as they do not produce biologically active polypeptides or amines. As a result, there are no manifestations of carcinoid syndrome. In addition, PHNETs grow slowly, and most patients show no symptoms in the early stages. Laparoscopic hepatectomy is a very useful procedure for diagnosis and treatment in such cases and can be performed safely.
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http://dx.doi.org/10.1007/s12328-021-01403-9DOI Listing
June 2021

Treatment outcomes of stereotactic body radiation therapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinomas.

Hepatol Res 2021 Aug 11;51(8):870-879. Epub 2021 May 11.

Department of Radiation Oncology, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

Aim: To report the outcomes of stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinoma patients.

Methods: From January 2005 to July 2018, 63 patients with 74 lesions with a maximum diameter ≤52 mm were treated by stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system. No patient with a Child-Pugh Score ≥9 was included, and 85.6% had a score of 5 or 6. Using the biological effective dose (BED) with an α/β ratio of 10 (BED ), the median dose in BED at the reference point was 76.8 Gy (range 60-122.5 Gy). Overall survival (OS) and local control rates were assessed using the Kaplan-Meier method.

Results: With a median follow-up period of 24.6 months (range 0.9-118.4 months), the 1-year and 2-year OS rates were 86.8% (95% confidence interval [95% CI] 75.8-93.3) and 71.1% (57.8-81.6), respectively. The 2-year OS was 89.6% in patients with the baseline modified albumin-bilirubin (mALBI) grade =1, and 61.7% in patients with grade ≥2a. In the multivariate analysis, the mALBI grade (=1 vs. ≥2a) was a significant factor for OS (p = 0.028, 95% CI 1.11-6.18). The 1-year and 2-year local control rates were 100% (100-100%) and 92.0% (77.5-97.5%). The local control rates were significantly higher in the BED ≥100 Gy group than in the BED <100 Gy group (2-year 100% vs. 86.5%, p = 0.049) at the reference point.

Conclusion: This retrospective study of stereotactic body radiotherapy using real-time tumor-tracking radiotherapy for hepatocellular carcinoma showed favorable outcomes with lower incidence of toxicities, especially in patients treated with BED ≥100 Gy to the reference point.
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http://dx.doi.org/10.1111/hepr.13649DOI Listing
August 2021

Serum fatty acid-binding protein 5 is a significant factor in hepatocellular carcinoma progression independent of tissue expression level.

Carcinogenesis 2021 Jun;42(6):794-803

Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Fatty acid-binding protein 5 (FABP5) is highly expressed in hepatocellular carcinoma (HCC) tissues and is related to HCC progression. In this study, we analyzed the potential of serum FABP5 (sFABP5) as a tumor marker in HCC and its clinical significance in HCC progression. We compared the sFABP5 concentration in patients with HCC (HCC group) with that of patients with hepatitis without HCC (hepatitis group). Moreover, we measured the FABP5 expression levels in resected HCC tissues (tFABP5) and analyzed their relationship with sFABP5. We also performed cell-based assays using FABP5 knockout and overexpressing HCC cell lines to analyze the effect of extrinsic FABP5 (exFABP5) on HCC cells. We showed that sFABP5 was not a useful tumor marker for HCC, as HCC and sFABP5 were not correlated. However, sFABP5 and tFABP5 significantly correlated with survival after surgery for HCC, while sFABP5 and tFABP5 were independent of each other. In cell-based assays, exFABP5 was taken up by HCC cell lines and positively affected cell survival under glucose-depleted conditions by complementing the endogenous FABP5 function. In conclusion, sFABP5 had a significant impact on HCC progression irrespective of tFABP5 by augmenting cell viability under glucose-depleted conditions. As tFABP5 and sFABP5 are important factors that are independent of each other in HCC progression, both of them should be considered independently in improving the prognosis of patients with HCC.
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http://dx.doi.org/10.1093/carcin/bgab025DOI Listing
June 2021

Central Hepatectomy Versus Major Hepatectomy for Centrally Located Hepatocellular Carcinoma: A Propensity Score Matching Study.

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

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

Background: In terms of anatomical liver sectionectomy approaches, both a central hepatectomy (CH) and major hepatectomy (MH) are feasible options for a centrally located hepatocellular carcinoma (HCC).

Methods: We retrospectively reviewed the surgical outcomes of central HCC patients who underwent CH or MH. MH includes hemihepatectomy or trisectionectomy, whereas CH involves a left medial sectionectomy, right anterior sectionectomy, or central bisectionectomy. The surgical outcomes were compared before and after propensity score matching (PSM).

Results: A total of 233 patients were enrolled, including 132 in the CH group and 101 in the MH group. The MH group cases were pathologically more advanced and had poorer overall survival rates than the CH group. After PSM, 68 patients were selected into each group, both of which showed similar overall and recurrence-free survival outcomes. The CH group showed a tendency for a longer operation time; however, other perioperative outcomes were similar between the two groups. Multivariate analyses of our matched HCC patients revealed that the type of surgery (CH or MH) was not an independent prognostic factor. More patients in the matched CH group experienced a repeat hepatectomy for recurrence and no patients in this group underwent a preoperative portal vein embolization.

Conclusions: The short- and long-term surgical outcomes of CH and MH for a centrally located HCC are similar under a matched clinicopathological background. CH has the advantage of not requiring a preoperative portal vein embolization and increased chances of conducting a repeat hepatectomy for recurrence.
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http://dx.doi.org/10.1245/s10434-021-09751-zDOI Listing
March 2021

Functional transition: Inconsistently parallel to the increase in future liver remnant volume after preoperative portal vein embolization.

World J Gastrointest Surg 2021 Feb;13(2):153-163

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.

Background: Preoperative portal vein embolization (PVE) is a widely used strategy to enable major hepatectomy in patients with insufficient liver remnant. PVE induces hypertrophy of the future liver remnant (FLR) and a shift of the functional reserve to the FLR. However, whether the increase of the FLR volume (FLRV) corresponds to the functional transition after PVE remains unclear.

Aim: To investigate the sequential relationship between the increase in FLRV and functional transition after preoperative PVE using 3-dimensional (3D) computed tomography (CT) and Tc-galactosyl-human serum albumin (Tc-GSA) single-photon emission computed tomography (SPECT) fusion images.

Methods: Thirty-three patients who underwent major hepatectomy following PVE at the Department of Gastroenterological Surgery I, Hokkaido University Hospital between October 2013 and March 2018 were enrolled. Three-phase dynamic multidetector CT and Tc-GSA SPECT scintigraphy were performed at pre-PVE, and at 1 and 2 wk after PVE; 3D Tc-GSA SPECT CT-fused images were constructed from the Digital Imaging and Communications in Medicine data using 3D image analysis system. Functional FLRV (FFLRV) was defined as the total liver volume × (FLR volume counts/total liver volume counts) on the 3D Tc-GSA SPECT CT-fused images. The calculated FFLRV was compared with FLRV.

Results: FFLRV increased by a significantly larger extent than FLRV at 1 and 2 wk after PVE ( < 0.01). The increase in FFLRV and FLRV was 55.1% ± 41.6% and 26.7% ± 17.8% ( < 0.001), respectively, at 1 wk after PVE, and 64.2% ± 33.3% and 36.8% ± 18.9% ( < 0.001), respectively, at 2 wk after PVE. In 3 of the 33 patients, FFLRV levels decreased below FLRV at 2 wk. One of the three patients showed rapidly progressive fatty changes in FLR. The biopsy at 4 wk after PVE showed macro- and micro-vesicular steatosis of more than 40%, which improved to 10%. Radical resection was performed at 13 wk after PVE. The patient recovered uneventfully without any symptoms of pos-toperative liver failure.

Conclusion: The functional transition lagged behind the increase in FLRV after PVE in some cases. Evaluating both volume and function is needed to determine the optimal timing of hepatectomy after PVE.
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http://dx.doi.org/10.4240/wjgs.v13.i2.153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898185PMC
February 2021

ASO Author Reflections: Anatomical Liver Sectionectomy for Centrally Located Hepatocellular Carcinoma.

Ann Surg Oncol 2021 Feb 25. Epub 2021 Feb 25.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

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http://dx.doi.org/10.1245/s10434-021-09791-5DOI Listing
February 2021

Laparoscopic hepatectomy for hepatic angiomyolipoma with preoperative diagnosis of other malignancy: a report of 2 cases.

Surg Case Rep 2021 Feb 8;7(1):44. Epub 2021 Feb 8.

Department of Gastroenterological Surgery I, Hokkaido University Hospital, Kita-ku, Kita 15, Nishi 7, Sapporo, Hokkaido, 060-8638, Japan.

Background: Hepatic angiomyolipoma (HAML) is a rare liver tumor, and hepatectomy is the only effective treatment. Due to the difficulty of correct diagnosis of HAML before surgery by image studies, more than 36.6% of reported HAMLs are misdiagnosed as other malignant liver tumors before surgery. As there are only few reported cases in which HAMLs were removed using laparoscopic hepatectomy, the effectiveness of laparoscopic hepatectomy for such HAMLs in which are diagnosed as other malignant liver tumor before surgery has not been reported. Case presentation Case 1: a 58-year-old female with a history of treatment for autoimmune hepatitis was preoperatively diagnosed with hepatocellular carcinoma (size: 20 mm) in segment 7 (S7) of the liver. The tumor was removed by laparoscopic partial resection and was diagnosed as a HAML through a pathological examination. The patient's postoperative course was good, and she was recurrence-free at 37 months after the hepatectomy. Case 2: a 29-year-old female with a history of surgery for a right mature cystic teratoma was referred to our department to receive treatment for a growing 20-mm liver tumor with some calcification, which arose in S3 of the liver. A metastatic liver tumor derived from the mature cystic teratoma was suspected, and laparoscopic left lateral sectionectomy was performed. The liver tumor was diagnosed as a HAML after a pathological examination. The patient's postoperative course was unremarkable, and more than 54 months have passed since the hepatectomy without any recurrence.

Conclusions: Two cases in which HAMLs were preoperatively diagnosed as other malignant liver tumor were successfully removed by laparoscopic hepatectomy with a correct postoperative diagnosis. Laparoscopic hepatectomy for the present 2 cases of HAML seemed to be effective for providing a correct diagnosis after the curative removement of liver tumor with a smaller invasion compared to open hepatectomy, and for denying risk of dissemination of the malignant tumor by needle biopsy that had to be considered before ruling out malignant tumor.
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http://dx.doi.org/10.1186/s40792-021-01125-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870739PMC
February 2021

Impact of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging on the prognosis of hepatocellular carcinoma after surgery.

JGH Open 2021 Jan 30;5(1):41-49. Epub 2020 Oct 30.

Department of Gastroenterological Surgery I Hokkaido University Graduate School of Medicine Sapporo Japan.

Background And Aim: Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (EOB-MRI) has been recognized as a useful imaging technique to distinguish the biological behavior of hepatocellular carcinoma (HCC).

Methods: We analyzed 217 hepatectomy recipients with HCCs measuring 10 cm or less. We divided the patients into a decreased intensity (DI) group ( = 189, 87%) and an increased or neutral intensity (INI) group ( = 28, 13%) according to the ratio of tumor intensity to liver intensity during the hepatobiliary phase (HBP). According to the ratio of the maximum tumor diameter (including peritumoral hypointensity) between HBP images and precontrast T1-weighted images (RHBPP), we divided the patients as follows: The group whose RHBPP was ≥1.036 was the high RHBPP group ( = 60, 28%), and the group whose RHBPP was <1.036 was the low RHBPP group ( = 157, 72%). We investigated the prognoses and clinicopathological characteristics of these patients.

Results: DI INI was not a prognostic factor for either survival or recurrence; however, a high RHBPP was an independent predictor of unfavorable survival and recurrence in patients. In addition, the INI group showed significantly lower α-fetoprotein (AFP) levels and higher rates of well-differentiated HCC and ICGR15 ≥15% than the DI group. The high RHBPP group showed significantly higher rates of vascular invasion and poorly differentiated HCC than the low RHBPP group.

Conclusions: A high RHBPP by EOB-MRI is a preoperative predictor of vascular invasion and an unfavorable prognostic factor for survival and recurrence. These patients might be considered for highly curative operations such as anatomical liver resection.
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http://dx.doi.org/10.1002/jgh3.12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812518PMC
January 2021

Current role of intraoperative ultrasonography in hepatectomy.

Surg Today 2021 Jan 4. Epub 2021 Jan 4.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 5, West 7, Kita-ku, Sapporo, 060-8638, Japan.

Hepatectomy had a high mortality rate in the previous decade because of inadequate techniques, intraoperative blood loss, liver function reserve misdiagnoses, and accompanying postoperative complications. However, the development of several modalities, including intraoperative ultrasonography (IOUS), has made hepatectomy safer. IOUS can provide real-time information regarding the tumor position and vascular anatomy of the portal and hepatic veins. Systematic subsegmentectomy, which leads to improved patient outcomes, can be performed by IOUS in open and laparoscopic hepatectomy. Although three-dimensional (3D) computed tomography and gadoxetic acid-enhanced magnetic resonance imaging have been widely used, IOUS and contrast-enhanced IOUS are important modalities for risk analyses and making decisions regarding resectability and operative procedures because of the vital anatomical information provided and high sensitivity for liver tumors, including "disappearing" liver metastases. Intraoperative color Doppler ultrasonography can be used to delineate the vascular anatomy and evaluate the blood flow volume and velocity in hepatectomy patients and recipients of deceased- and living-donor liver transplantation after vessel reconstruction and liver positioning. For liver surgeons, IOUS is an essential technique to perform highly curative hepatectomy safely, although recent advances have also been made in virtual modalities, such as real-time virtual sonography with 3D visualization.
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http://dx.doi.org/10.1007/s00595-020-02219-9DOI Listing
January 2021

Analysis of the correlation between alterations in N‑glycans and invasiveness in liver cancer cell lines.

Oncol Rep 2020 Dec 8;44(6):2757-2769. Epub 2020 Oct 8.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060‑8638, Japan.

The N‑glycoforms of glycoproteins modify protein function and control a number of biological pathways. The aim of the present study was to investigate the correlation between alterations in N‑glycans and cancer aggressiveness in terms of cancer cell invasion ability. The expression of urokinase‑type plasminogen activator (uPA) and N‑acetylglucosaminyltransferase V (GnT‑V) in liver cancer cell lines was analyzed by western blotting. Cell invasiveness was analyzed by Matrigel invasion assays. uPA and GnT‑V expression in liver cancer cell lines was knocked down by RNA interference. Furthermore, uPA was overexpressed in liver cancer cells using lentiviral vectors, and a mutant strain of HepG2 cells overexpressing uPA deficient in N‑glycans was established. A glycoblotting‑assisted matrix‑assisted laser desorption/ionization‑time‑of‑flight/mass spectrometry‑based quantitative analysis of liver cancer cell lines was performed, in which invasiveness was altered by modifying the expression of uPA and GnT‑V. N‑glycan profiles were found to differ between the highly invasive liver cancer cell line HLE and the less invasive cell line HepG2. The expression of several N‑glycans, including a form with m/z=1892, was changed according to invasiveness controlled by knockdown and overexpression of uPA. The invasiveness of HepG2 cells with mutant uPA did not increase regardless of the level of expression of uPA. Following GnT‑V knockdown and N‑glycan alteration, uPA expression did not change, whereas cell invasiveness decreased. One N‑glycan (m/z=1892) was common among N‑glycans in the comparative analysis between HLE and HepG2, HLE and uPA knockdown HLE, HepG2 and uPA‑overexpressing HepG2, and HLE and GnT‑V knockdown HLE cells and among N‑glycan profiles in human uPA. Therefore, N‑glycosylation is an important factor controlling invasiveness of liver cancer cells, and a specific N‑glycan (m/z=1892) associated with the invasion of liver cancer cells via uPA was identified in the present study.
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http://dx.doi.org/10.3892/or.2020.7795DOI Listing
December 2020

A rare case of cavernous hemangioma accompanied with diffuse hepatic hemangiomatosis.

Surg Case Rep 2020 Oct 1;6(1):251. Epub 2020 Oct 1.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido, Japan.

Background: Hepatic cavernous hemangioma (CH) is the most common hepatic benign tumor. Most cases are solitary, asymptomatic, and found incidentally. In symptomatic cases with rapidly growing tumors and coagulopathy, surgical treatment is considered. In rare cases, diffuse hepatic hemangiomatosis (DHH) is reported as a comorbidity. The etiology of DHH is unknown.

Case Presentation: A 29-year-old female patient had a history of endometriosis treated with oral contraceptives. Hepatic CH was incidentally detected in the segment IVa of the liver according to the Couinaud classification. Follow-up computed tomography (CT) and ultrasound sonography showed the growth of the lesion and formation of multiple new lesions near the first. Enhanced CT and magnetic resonance imaging (MRI) revealed that the new lesions were different from CH. Although oral contraceptives were stopped, all lesions grew in size. Malignancy and possibility of rupture of these tumors were considered due to the clinical course, and we opted for surgical removal of the tumors. Left liver lobectomy and cholecystectomy were performed. Surgical findings were small red spot spreading and a mass in segment IV of the liver. Pathological examination revealed a circumscribed sponge-like tumor with diffuse irregular extension to the adjacent area. Both of the lesions consisted of blood-filled dilated vascular spaces lined by flat endothelium without atypia. The diagnosis was hepatic CH with DHH. The patient was discharged on postoperative day 12 uneventfully.

Conclusion: We report the successful resection of CH with DHH. The case findings suggest a relationship between oral contraceptive use and enlargement of CH and DHH. Although DHH has been poorly understood, a few previously published cases reported DHH occurrence in patients using oral contraceptives. In such cases, the decision to perform surgical resection should be made after careful examination.
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http://dx.doi.org/10.1186/s40792-020-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530161PMC
October 2020

Role of Wnt5a in suppressing invasiveness of hepatocellular carcinoma via epithelial-mesenchymal transition.

Oncol Lett 2020 Nov 21;20(5):268. Epub 2020 Sep 21.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.

Inappropriate activation of the canonical Wnt signaling pathway is associated with progression of hepatocellular carcinoma (HCC). However, the association between the non-canonical pathway activated by Wnt5a and HCC is not well known. The present study investigated the significance of Wnt5a expression in HCC. Immunohistochemical staining of Wnt5a was performed on specimens from 243 patients who underwent hepatic resection for HCC. The present study investigated whether Wnt5a expression was associated with clinical and pathological factors and prognosis. Wnt5a expression in human HCC cell lines was investigated using western blotting. The effects of overexpression or knockdown of Wnt5a were evaluated using proliferation and invasion assays. Changes in epithelial-mesenchymal transition (EMT)-related molecules were investigated using western blotting. Wnt5a negativity was significantly associated with poor tumor differentiation and positive vascular invasion. In univariate analysis, Wnt5a negativity was identified as a significant prognostic factor for overall survival (OS). Multivariate analysis of OS demonstrated that Wnt5a negativity was an independent prognostic factor. Wnt5a expression was lower in HLE and HLF cells than in HepG2 and Huh7 cells. Knockdown of Wnt5a by short hairpin RNA transfection increased the proliferation and invasiveness of Huh7 cells, and decreased the expression levels of E-cadherin. In HLF cells, overexpression of Wnt5a inhibited invasiveness and decreased the expression levels of vimentin. Wnt5a negativity was associated with poor tumor differentiation and positive vascular invasion, and was an independent poor prognostic factor in patients with HCC. Wnt5a may be a tumor suppressor involved in EMT-mediated changes in invasiveness.
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http://dx.doi.org/10.3892/ol.2020.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517569PMC
November 2020

Adenomatous polyposis coli-binding protein end-binding 1 promotes hepatocellular carcinoma growth and metastasis.

PLoS One 2020 21;15(9):e0239462. Epub 2020 Sep 21.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

This study was performed to determine the clinical significance of adenomatous polyposis coli (APC)-binding protein end-binding 1 (EB1) in hepatocellular carcinoma (HCC) and to characterize its biochemical role in comparison with previous reports. We performed immunohistochemical staining to detect EB1 expression in tissues from 235 patients with HCC and investigated its correlations with clinicopathological features and prognosis. We also investigated the roles of EB1 in cell proliferation, migration, and tumorigenesis in vitro and in vivo by siRNA- and CRISPR/Cas9-mediated modulation of EB1 expression in human HCC cell lines. The results showed that EB1 expression was significantly correlated with several important factors associated with tumor malignancy, including histological differentiation, portal vein invasion status, and intrahepatic metastasis. Patients with high EB1 expression in HCC tissue had poorer overall survival and higher recurrence rates than patients with low EB1 expression. EB1 knockdown and knockout in HCC cells reduced cell proliferation, migration, and invasion in vitro and inhibited tumor growth in vivo. Further, genes encoding Dlk1, HAMP, and SLCO1B3 that were differentially expressed in association with EB1 were identified using RNA microarray analysis. In conclusion, elevated expression of EB1 promotes tumor growth and metastasis of HCC. EB1 may serve as a new biomarker for HCC, and genes coexpressed with EB1 may represent potential targets for therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239462PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505586PMC
November 2020

Hepatectomy Combined with Diaphragmatic Resection for Hepatocellular Carcinoma with Diaphragmatic Involvement: A Propensity Score-Matched Analysis.

Ann Surg Oncol 2020 Oct 25;27(11):4153-4163. Epub 2020 Jun 25.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

Purpose: We evaluated the short- and long-term surgical outcomes of hepatectomy combined with diaphragmatic resection for hepatocellular carcinoma (HCC) with diaphragmatic involvement.

Methods: We retrospectively reviewed the surgical outcomes of HCC patients with diaphragmatic resection (DR group) and HCC patients without diaphragmatic resection (non-DR group). We applied 1:1 propensity score matching (PSM) to these subjects.

Results: The study included 46 patients in DR group and 828 patients in non-DR group. The DR group cases were pathologically more advanced, and both overall and relapse-free survival among the patients in this group with pathological diaphragmatic invasion were similar to cases with pathological diaphragmatic fibrous adhesion. There were 40 patients from each group subjected to PSM. In these matched cohorts, there was no statistically significant difference between the two groups regarding perioperative outcomes, overall survival, and relapse-free survival. Multivariate analyses of our matched HCC patients revealed that alpha-fetoprotein expression and tumor size were independent prognostic factors for overall survival and poor differentiation for relapse-free survival, whereas neither diaphragmatic invasion nor diaphragmatic resection were prognostic indicators. The most frequent site of recurrence in non-DR group was the liver, whereas the most frequent site of recurrence in DR group was the lung before and after PSM.

Conclusions: The short- and long-term surgical outcomes of DR HCC cases are equivalent to their non-DR counterparts under a matched clinicopathological background. Hepatectomy combined with DR is an acceptable treatment for HCC with either diaphragmatic fibrous adhesion or diaphragmatic invasion.
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http://dx.doi.org/10.1245/s10434-020-08754-6DOI Listing
October 2020

ASO Author Reflections: Is Hepatectomy Plus Diaphragmatic Resection for Hepatocellular Carcinoma with Diaphragmatic Involvement Justified?

Ann Surg Oncol 2020 Oct 23;27(11):4164-4165. Epub 2020 Jun 23.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

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http://dx.doi.org/10.1245/s10434-020-08755-5DOI Listing
October 2020

Lenvatinib in patients with unresectable hepatocellular carcinoma who do not meet the REFLECT trial eligibility criteria.

Hepatol Res 2020 Aug 9;50(8):966-977. Epub 2020 Jul 9.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Aim: This study aimed to determine the efficacy and safety of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC) who did not meet REFLECT eligibility criteria (phase 3 clinical trial).

Methods: In this multicenter retrospective study, patients with unresectable HCC treated with lenvatinib between 2018 and 2019 and had adequate clinical data were included. Objective response rate, progression-free-survival (PFS) and safety were evaluated according to meeting or not meeting the REFLECT eligibility criteria and according to the criteria of the REFLECT trial.

Results: Of the 105 patients included, 61% (64 of 105) did not meet the REFLECT eligibility criteria. Safety and median PFS of lenvatinib were similar between the patients who did and those who did not meet the criteria. Among the patients who did not meet the criteria, 28, 27, 14, six, seven and five had a history of tyrosine kinase inhibitor (TKI) treatment, Child-Pugh score B, HCC in ≥50% of the liver, reduced platelet count, bile duct invasion and main portal vein invasion, respectively. The efficacy and safety of lenvatinib for patients with or without Child-Pugh-score B or HCC in ≥50% of the liver were similar. Although treatment outcome was not significantly different, patients with TKI treatment history tended to have longer median PFS, whereas those with main portal vein invasion tended to have shorter median PFS.

Conclusion: Lenvatinib was effective for patients who did not meet the REFLECT inclusion criteria. However, the treatment outcome may vary according to several factors, such as a history of TKI treatment and tumor invasion.
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http://dx.doi.org/10.1111/hepr.13511DOI Listing
August 2020

Prognoses, outcomes, and clinicopathological characteristics of very elderly patients with hepatocellular carcinoma who underwent hepatectomy.

World J Surg Oncol 2020 Jun 10;18(1):122. Epub 2020 Jun 10.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15-West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.

Objectives: The aim was to evaluate the prognostic factors, clinicopathological characteristics, and surgical outcomes after hepatectomy in very elderly patients with hepatocellular carcinoma (HCC).

Methods: We analyzed 796 patients with HCC from 2000 to 2017. Patients aged 80 years or older were classified into the very elderly group (group VE; n = 49); patients younger than 80 years old and aged 65 years or older were classified into the elderly group (group E; n = 363), and patients younger than 65 years old were classified into the young group (group Y; n = 384). We investigated the prognoses, clinicopathological characteristics, and surgical outcomes after hepatectomy.

Results: The number of surgical procedures and outcomes, including morbidities, was not significantly different. Groups VE, E, and Y showed similar prognoses in terms of both survival and recurrence. In group VE, prothrombin activity (PA) < 80% and PIVKA-II ≥ 400 mAU/ml were unfavorable factors for survival, and PIVKA-II ≥ 400 mAU/ml and the presence of portal venous invasion (PVI), hepatic venous invasion, and fibrosis were unfavorable factors for recurrence. In group E, ChE < 180 IU/l, AFP ≥ 20 ng/ml, tumor size ≥ 10 cm, and the presence of multiple tumors, PVI, and hepatic venous invasion (HVI) were unfavorable factors for survival, and ChE < 180 IU/l, tumor size ≥ 10 cm, and the presence of multiple tumors, PVI, and HVI were unfavorable factors for recurrence. In group Y, AFP ≥ 20 ng/ml, the presence of multiple tumors, poor differentiation, PVI, HVI, and blood loss ≥ 400 ml were unfavorable factors for survival, and PA < 80%, albumin < 3.5 g/dl, AFP ≥ 20 ng/ml, tumor size ≥ 10 cm, and the presence of multiple tumors, poor differentiation, and PVI were unfavorable factors for recurrence.

Conclusions: Tumor factors might have limited influence on the prognosis of very elderly patients, and liver function reserve might be important for the long-term survival of very elderly patients. Hepatectomy can be performed safely, even in very elderly patients. Hepatectomy should not be avoided in very elderly patients with HCC if patients have a good general status because these patients have the same prognoses as nonelderly individuals.
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http://dx.doi.org/10.1186/s12957-020-01899-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288547PMC
June 2020

Predictive value of gadoxetic acid enhanced magnetic resonance imaging for posthepatectomy liver failure after a major hepatectomy.

J Hepatobiliary Pancreat Sci 2020 Aug 21;27(8):531-540. Epub 2020 Jun 21.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Background: We assessed the usefulness of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging for the prediction of posthepatectomy liver failure (PHLF) after a major hepatectomy.

Methods: We reviewed 140 cases involving a hepatectomy of two or more sections between 2010 and 2016 (study cohort). We used the standardized remnant hepatocellular uptake index (SrHUI) which was calculated by: SrHUI = future remnant liver volume × [(signal intensity of remnant liver on hepatobiliary phase images/signal intensity of spleen on hepatobiliary phase images) - 1]/body surface area. Validation of the SrHUI was performed in another cohort of 52 major hepatectomy cases between 2017 and 2018 (validation cohort).

Results: The SrHUI of patients with PHLF was significantly lower than that of non-PHLF cases. Receiver operating characteristic analysis and the Youden index revealed that the SrHUI cutoff value for the prediction of PHLF and PHLF grade ≥ B were 0.313 L/m and 0.257 L/m , respectively. In the validation cohort, the cutoff value of SrHUI for the prediction of PHLF or PHLF grade ≥ B had a sensitivity of 75.0% or 88.8%, and specificity of 78.1% or 91.6%, respectively.

Conclusions: The SrHUI value is a predictor for PHLF after a major hepatectomy.
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http://dx.doi.org/10.1002/jhbp.769DOI Listing
August 2020

Development of an artificial intelligence system using deep learning to indicate anatomical landmarks during laparoscopic cholecystectomy.

Surg Endosc 2021 04 18;35(4):1651-1658. Epub 2020 Apr 18.

Faculty of Medicine, Department of Gastroenterological and Pediatric Surgery, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita, 879-5593, Japan.

Background: The occurrence of bile duct injury (BDI) during laparoscopic cholecystectomy (LC) is an important medical issue. Expert surgeons prevent intraoperative BDI by identifying four landmarks. The present study aimed to develop a system that outlines these landmarks on endoscopic images in real time.

Methods: An intraoperative landmark indication system was constructed using YOLOv3, which is an algorithm for object detection based on deep learning. The training datasets comprised approximately 2000 endoscopic images of the region of Calot's triangle in the gallbladder neck obtained from 76 videos of LC. The YOLOv3 learning model with the training datasets was applied to 23 videos of LC that were not used in training, to evaluate the estimation accuracy of the system to identify four landmarks: the cystic duct, common bile duct, lower edge of the left medial liver segment, and Rouviere's sulcus. Additionally, we constructed a prototype and used it in a verification experiment in an operation for a patient with cholelithiasis.

Results: The YOLOv3 learning model was quantitatively and subjectively evaluated in this study. The average precision values for each landmark were as follows: common bile duct: 0.320, cystic duct: 0.074, lower edge of the left medial liver segment: 0.314, and Rouviere's sulcus: 0.101. The two expert surgeons involved in the annotation confirmed consensus regarding valid indications for each landmark in 22 of the 23 LC videos. In the verification experiment, the use of the intraoperative landmark indication system made the surgical team more aware of the landmarks.

Conclusions: Intraoperative landmark indication successfully identified four landmarks during LC, which may help to reduce the incidence of BDI, and thus, increase the safety of LC. The novel system proposed in the present study may prevent BDI during LC in clinical practice.
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http://dx.doi.org/10.1007/s00464-020-07548-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940266PMC
April 2021

Long-term prognostic factors of patients with hepatocellular carcinoma who survive over 10 years after hepatectomy.

J Surg Oncol 2020 Jun 20;121(8):1209-1217. Epub 2020 Mar 20.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

Background And Objectives: The aim was to evaluate long-term prognostic factors in hepatocellular carcinoma (HCC) patients who survived over 10 years after hepatectomy and compare prognostic factors between patients with recurrence who died and survived 10 years after initial hepatectomy.

Methods: We analyzed the HCC patients without recurrence over 10 years after hepatectomy (n = 35), those with recurrence who survived over 10 years (n = 48), and those who died within 10 years (n = 132).

Results: The rate of recurrence was 16.3%, 10-year overall survival rate was 38.6%, and the 10-year recurrence-free survival (RFS) rate was 16.7%. Nonviral, solitary tumor, well differentiation, and without severe fibrosis were independent favorable factors for long-term RFS. High cholinesterase levels, small tumors and without portal vein invasion were independent favorable factors for long-term survival among patients with recurrence. Long-term survivors with recurrence showed significantly low early recurrence, extrahepatic recurrence, multiple intrahepatic recurrences.

Conclusion: Important factors for long-term prognoses in HCC patients were a solitary tumor, small tumors, and no advanced fibrosis. A treatment for nonviral hepatitis is needed to achieve long-term RFS. Even patients who relapse might survive long term if they have a late or solitary intrahepatic recurrence, nonsevere cirrhosis, and curative treatment at recurrence.
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http://dx.doi.org/10.1002/jso.25910DOI Listing
June 2020

Preoperative chemotherapy in colorectal cancer patients with synchronous liver metastasis.

Mol Clin Oncol 2020 Apr 30;12(4):374-383. Epub 2020 Jan 30.

Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan.

The response to preoperative chemotherapy is useful for predicting prognosis in unresectable and resectable disease. However, the prognostic benefit of chemotherapy prior to hepatectomy in patients with colorectal carcinoma and resectable or marginally resectable liver metastases remains unclear. The present study investigated the effect of preoperative chemotherapy on the prognosis of patients with colorectal cancer and resectable or marginally resectable synchronous liver metastasis. A total of 106 patients were retrospectively reviewed, who underwent hepatectomy for colorectal metastasis. The prognosis of 64 patients who received neoadjuvant chemotherapy (NAC) were compared with the 42 patients who did not (non-NAC). Furthermore, a total of 43 patients who responded to chemotherapy were compared with the 21 who did not. Preoperative chemotherapy was administered for 5.7 months, wherein 50 patients (78%) received a single regimen, and 54 (84%) received oxaliplatin. There were more patients with <3 metastases and maximum diameters <5 cm in the non-NAC group. The median survival time was 86.0 and 71.6 months in the NAC and non-NAC groups, respectively (P=0.33). Subgroup analysis on the basis of tumor size and number showed no prognostic differences between the two groups. The median survival time was longer in responders than in non-responders (85 vs. 56 months; P=0.01). However, the median relapse-free survival was equivalent in both groups (16.4 and 10.7 months). Preoperative chemotherapy did not prolong survival. Furthermore, it did not prevent recurrence, even in clinical responders. Therefore, it should not be routinely offered to patients with resectable liver metastasis before their hepatectomy.
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http://dx.doi.org/10.3892/mco.2020.1992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057917PMC
April 2020

Impaired O-Glycosylation at Consecutive Threonine TTX Motifs in Mucins Generates Conformationally Restricted Cancer Neoepitopes.

Biochemistry 2020 03 20;59(12):1221-1241. Epub 2020 Mar 20.

Graduate School of Life Science and Faculty of Advanced Life Science, Hokkaido University, N22, W11, Kita-ku, Sapporo 001-0021, Japan.

Autoantibody signatures of circulating mucin fragments stem from cancer tissues, and microenvironments are promising biomarkers for cancer diagnosis and therapy. This study highlights dynamic epitopes generated by aberrantly truncated immature O-glycosylation at consecutive threonine motifs (TTX) found in mucins and intrinsically disordered proteins (IDPs). NMR analysis of synthetic mucin models having glycosylated TTX motifs and colonic MUC2 tandem repeats (TRs) containing TTP and TTL moieties unveils a general principle that O-glycosylation at TTX motifs generates a highly extended and rigid conformation in IDPs. We demonstrate that the specific conformation of glycosylated TTX motifs in MUC2 TRs is rationally rearranged by concerted motions of multiple dihedral angles and noncovalent interactions between the carbohydrate and peptide region. Importantly, this canonical conformation of glycosylated TTX motifs minimizes steric crowding of glycans attached to threonine residues, in which -glycans possess restricted orientations permitting further sugar extension. An antiadhesive microarray displaying synthetic MUC2 derivatives elicited the presence of natural autoantibodies to MUC2 with impaired O-glycosylation at TTX motifs in sera of healthy volunteers and patients diagnosed with early stage colorectal cancer (CRC). Interestingly, autoantibody levels in sera of the late stage CRC patients were distinctly lower than those of early stage CRC and normal individuals, indicating that the anti-MUC2 humoral response to MUC2 neoepitopes correlates inversely with the CRC stage of patients. Our results uncovered the structural basis of the creation of dynamic epitopes by immature O-glycosylation at TTX motifs in mucins that facilitates the identification of high-potential targets for cancer diagnosis and therapy.
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http://dx.doi.org/10.1021/acs.biochem.0c00007DOI Listing
March 2020

Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting.

JGH Open 2020 Feb 10;4(1):54-60. Epub 2019 Jun 10.

Department of Gastroenterology and Hepatology, Graduate School of Medicine Hokkaido University Sapporo Japan.

Background And Aim: Lenvatinib has been recently approved as a first-line systematic therapy for patients with advanced hepatocellular carcinoma (HCC) based on the results of the phase 3 clinical trial REFLECT. This trial excluded patients with a history of systemic chemotherapy, bile duct invasion, and Child-Pugh grade B. We aimed to investigate the efficacy and safety of lenvatinib for these patients and in the real-world setting.

Methods: Among patients who were administered lenvatinib for advanced HCC between April and October 2018 in Hokkaido University Hospital and related hospitals, we evaluated those who were followed for more than 2 months and whose treatment response was evaluated via dynamic computed tomography at baseline and 2 months after treatment initiation. Meanwhile, patients were excluded if they had decompensated liver cirrhosis, were followed up less than 2 months, or were not evaluated at 2 months. Patients were also stratified according to compliance with the REFLECT inclusion criteria for further analysis.

Results: A total of 41 patients were included; more than 50% did not meet the REFLECT inclusion criteria. In total, 5 (12.2%), 20 (48.8%), 12 (29.3%), and 4 (9.3%) showed complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 61.2%. The objective response rate and disease control rate were similar between patients who did and did not meet the REFLECT inclusion criteria. Moreover, the safety profile was also similar between the two patient groups.

Conclusion: Lenvatinib showed high early response rate and tolerability in patients with advanced HCC. Favorable outcomes were similarly observed in patients who did not meet the REFLECT inclusion criteria.
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http://dx.doi.org/10.1002/jgh3.12209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008153PMC
February 2020

Prognostic impact of CD8+ T cell distribution and its association with the HLA class I expression in intrahepatic cholangiocarcinoma.

Surg Today 2020 Aug 10;50(8):931-940. Epub 2020 Feb 10.

Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-ku, Kita 15, Nishi 7, Sapporo, Hokkaido, 060-8638, Japan.

Purpose: A lack of effective systemic therapy is one reason for the poor prognosis of intrahepatic cholangiocarcinoma. Newly developed immune checkpoint inhibitors function by minimizing CD8+ T cell suppression to improve tumor-specific responses. This study aimed to examine the characteristics of CD8+ T cells in intrahepatic cholangiocarcinoma.

Methods: Clinicopathological data, including the overall survival, of 69 cases of postoperative intrahepatic cholangiocarcinoma were prospectively investigated. We then immunohistochemically stained for CD8, Foxp3, CD163, PD-L1, and human leukocyte antigen (HLA) class I and counted the number of CD8+ T cells, Foxp3+ T cells, and CD163+ macrophages in different areas (outer border, interborder, and intratumor).

Results: A significant difference was found in the 5-year overall survival between the CD8+ T cell high group (45.5%) and low group (24.7%) in the outer border area (p = 0.0103). Furthermore, the number of CD8+ T cells and the high expression of HLA class I were positively correlated (p = 0.0341).

Conclusion: The number of CD8+ T cells in the outer border area of the tumor correlated with the HLA class I expression of intrahepatic cholangiocarcinoma and may therefore be a prognostic factor for patients with postoperative intrahepatic cholangiocarcinoma.
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http://dx.doi.org/10.1007/s00595-020-01967-yDOI Listing
August 2020
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