Publications by authors named "Takahiro Yoshikawa"

97 Publications

Acute tubulointerstitial nephritis in a patient with early bronchial tuberculosis.

J Formos Med Assoc 2021 Jul 20. Epub 2021 Jul 20.

Department of Hypertension and Nephrology, NTT Medical Centre Tokyo, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.

Patients with chronic kidney disease (CKD) are commonly at high risk of tuberculosis (TB). Conversely, TB rarely causes tubulointerstitial nephritis. A 75-year-old Japanese man who was undergoing periodic follow-ups for CKD stage G3aA3 with membranous nephropathy was diagnosed with acute kidney injury (AKI) (estimated glomerular filtration rate [eGFR]: 15 mL/min/1.73 m) without prerenal AKI. He reported developing recent-onset cough 3 weeks prior to presenting to us. Renal biopsy revealed acute tubulointerstitial nephritis along with known membranous nephropathy. CD4 helper T cells comprised most lymphocytes in the tubulointerstitium. Results of the interferon-gamma release assay, sputum smear test, polymerase chain reaction (PCR), and culture test were positive for TB. Chest computed tomography revealed thickening of the left bronchial wall; therefore, a diagnosis of early bronchial TB was made; his urine culture and PCR were negative for TB. At four months after TB treatment with no immunosuppressive therapy, his eGFR improved to 50 mL/min/1.73 m, and based on this progress, the AKI was diagnosed as tuberculosis-associated tubulointerstitial nephritis (TATIN). Although TATIN typically occurs with chronic or miliary tuberculosis, it is very rare in early bronchial TB. Identification of TATIN is important in kidney diseases of unknown etiology, and treatment with anti-TB drugs is necessary.
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http://dx.doi.org/10.1016/j.jfma.2021.07.010DOI Listing
July 2021

Neural correlates of the improvement of cognitive performance resulting from enhanced sense of competence: A magnetoencephalography study.

PLoS One 2021 23;16(7):e0255272. Epub 2021 Jul 23.

Department of Sports Medicine, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan.

The alterations in neural activity related to the improvement of cognitive performance, which would be leading to better academic performance, remain poorly understood. In the present study, we assessed neural activity related to the improvement of task performance resulting from academic rewards. Twenty healthy male volunteers participated in this study. All participants performed four sessions of a 1-back-Stroop task under both target and control conditions. An image indicating that the task performance of each participant was above average and categorized as being at almost the highest level was presented immediately after each session under the target condition, whereas a control image did not indicate task performance. Neural activity during the 1-back-Stroop task was recorded by magnetoencephalography. The correction rate of the 1-back-Stroop task in the final session relative to that in the first under the target condition was increased compared with the control condition. Correlation analysis revealed that the decreases in alpha band power in right Brodmann's area (BA) 47 and left BA 7 were positively associated with the increased correction rate caused by the target condition. These findings are expected to contribute to a better understanding of the neural mechanisms underlying the improvement of cognitive performance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255272PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301610PMC
July 2021

Anti-neutrophil cytoplasmic antibody-associated vasculitis accompanied by type II heparin-induced thrombocytopenia resulting in asymptomatic cerebral infarction: a case report.

BMC Nephrol 2021 Jun 14;22(1):220. Epub 2021 Jun 14.

Department of Hypertension and Nephrology, NTT Medical Centre, 5-9-22, Higasi- Gotanda, Shinagawa-ku, 141-8625, Tokyo, Japan.

Background: Heparin-induced thrombocytopenia (HIT) involves platelet activation and aggregation caused by heparin or HIT antibodies associated with poor survival outcomes. We report a case of HIT that occurred after hemodialysis was started for rapidly progressive glomerulonephritis (RPGN), which was caused by anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), and ultimately resulted in asymptomatic cerebral infarction.

Case Presentation: A 76-year-old Japanese man was urgently admitted to our hospital for weight loss and acute kidney injury (serum creatinine: 12 mg/dL). Hemodialysis therapy was started using heparin for anticoagulation. Blood testing revealed elevated titers of myeloperoxidase anti-neutrophil cytoplasmic antibodies, and renal biopsy revealed crescentic glomerulonephritis with broad hyalinization of most of the glomeruli and a pauci-immune staining pattern. These findings fulfilled the diagnostic criteria for microscopic polyangiitis, and the patient was diagnosed with RPGN caused by AAV. Steroid pulse therapy, intermittent pulse intravenous cyclophosphamide, and oral steroid therapy failed to improve the patient's renal function, and maintenance dialysis was started. However, on day 15, his platelet count had decreased to 47,000/µL, with clotting observed in the hemodialysis catheter. Magnetic resonance imaging of the head identified acute asymptomatic brain infarction in the left occipital lobe, and a positive HIT antibody test result supported a diagnosis of type II HIT. During hemodialysis, the anticoagulant treatment was changed from heparin to argatroban. Platelet counts subsequently normalized, and the patient was discharged. A negative HIT antibody test result was observed on day 622.

Conclusions: There have been several similar reports of AAV and HIT co-existence. However, this is a rare case report on cerebral infarction with AAV and HIT co-existence. Autoimmune diseases are considered risk factors for HIT, and AAV may overlap with other systemic autoimmune diseases. To confirm the relationship between these two diseases, it is necessary to accumulate more information from future cases with AAV and HIT co-existence. If acute thrombocytopenia and clotting events are observed when heparin is used as an anticoagulant, type II HIT should always be considered in any patient due to its potentially fatal thrombotic complications.
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http://dx.doi.org/10.1186/s12882-021-02433-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204417PMC
June 2021

Relationship Between Infection and Arteriosclerosis.

Int J Gen Med 2021 23;14:1533-1540. Epub 2021 Apr 23.

Department of Hypertension and Nephrology, NTT Medical Centre, Tokyo, Japan.

It is reported that () infection may be linked to non-digestive tract diseases, such as arteriosclerosis including dyslipidemia, diabetes, obesity, hypertension, and cardiovascular disease. Therefore, we reviewed recent studies available in PubMed dealing with the mechanisms of arteriosclerosis due to infection and the effects of eradication. Conventional studies suggested that infection may increase the risk of arteriosclerosis. A large interventional study is required to clarify the causal relationships and the effects of bacterial eradication.
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http://dx.doi.org/10.2147/IJGM.S303071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079247PMC
April 2021

Selective formation of a phenathridine derivative by photodegradation of azilsartan.

Bioorg Med Chem Lett 2021 06 1;41:128011. Epub 2021 Apr 1.

Research & Development, KONGO CHEMICAL CO., LTD, Himata, Toyama 9300912, Japan.

Photodegradation of azilsartan produces a phenanthridine derivative, with its molecular structure determined by H and C NMR spectroscopy. This structure is confirmed by single-crystal X-ray diffraction and alternative synthesis. The phenanthridine ring formation is explained through the ring closure of an imidoylnitrene intermediate produced by decarboxylation of the 5-oxo-1,2,4-oxadiazole ring (oxadiazolone).
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http://dx.doi.org/10.1016/j.bmcl.2021.128011DOI Listing
June 2021

Unresectable hilar cholangiocarcinoma treated with chemoradiotherapy: a 9-year survival case.

Int Cancer Conf J 2021 Jan 19;10(1):41-45. Epub 2020 Sep 19.

Department of Surgery, Nara Medical University, 840 Shijo-cho Kashihara-shi, Nara, 634-8522 Japan.

Patients with advanced unresectable hilar cholangiocarcinoma have poor prognosis, and the survival is usually short. Herein, we report a 9-year survival case of unresectable hilar cholangiocarcinoma treated with chemoradiotherapy. A 64-year-old male patient presented with hilar cholangiocarcinoma. The tumor was located in the right hepatic duct, and it extended from the bifurcation of the anterior and posterior branches to the periphery. In the left side, the tumor extended from the umbilical portion to B2 and B3. However, there was no distant metastasis. The patient was then diagnosed with locally advanced, unresectable hilar cholangiocarcinoma and was treated with chemoradiotherapy. He received a total dose of 60 Gy in 30 daily fractions via intensity-modulated radiation therapy. In addition, he received gemcitabine chemotherapy for 5 years. There has been neither re-elevation of carbohydrate antigen 19-9 levels nor tumor relapse for 5 years during chemotherapy. Therefore, gemcitabine treatment was discontinued. However, the patient experienced tumor relapse 3 years after the last chemotherapy. Hence, chemotherapy with gemcitabine and cisplatin was initiated. At present, 1 year has passed after treatment for recurrence, and the patient has survived for 9 years since the initial treatment. Herein, we report a rare case of long-term survival with chemoradiotherapy in locally advanced unresectable hilar cholangiocarcinoma.
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http://dx.doi.org/10.1007/s13691-020-00445-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797402PMC
January 2021

Clinical Importance of CD200 Expression in Colorectal Liver Metastasis.

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

Department of Surgery, Nara Medical University, Kashihara, Nara, Japan.

Background: Approximately 30% of patients diagnosed with colorectal cancer (CRC) develop liver metastases. We evaluated the role of CD200, a potent immunosuppressive molecule, in colorectal liver metastases (CRLM).

Methods: We examined 110 patients who underwent curative liver resection for CRLM at our institution between 2000 and 2016. Based on the results of immunohistochemical analysis, the patients were divided into high-CD200 (n = 47) and low-CD200 (n = 63) expression groups. The relationships between CD200 expression and various clinicopathological outcomes were investigated.

Results: The overall survival (OS) of patients in the high-CD200 group was significantly worse than that in the low-CD200 group (p = 0.009). Multivariate analysis showed that the independent prognostic factors in CRLM were maximum tumor size > 30 mm (p = 0.002), preoperative carcinoembryonic antigen level > 20 ng/mL (p < 0.001), primary CRC N2-3 (p = 0.049), and high-CD200 expression (p = 0.004). Furthermore, CD4+, CD8+, and CD45RO+ tumor-infiltrating lymphocytes in CRLM were significantly higher in the low-CD200 group than in the high-CD200 group (p = 0.005, p = 0.001, and p < 0.001, respectively). In addition, patients who had received preoperative chemotherapy had higher CD200 expression than those who had not received preoperative chemotherapy, and OS was significantly worse in patients in the high-CD200 group who had received preoperative chemotherapy.

Conclusions: CD200 expression was an independent prognostic factor in CRLM. CD200 may play a critical role in tumor immunity in CRLM, and can therefore be used as a potential therapeutic target in CRLM.
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http://dx.doi.org/10.1245/s10434-020-09471-wDOI Listing
January 2021

Preventative effects of ramelteon against postoperative delirium after elective liver resection.

PLoS One 2020 2;15(11):e0241673. Epub 2020 Nov 2.

Department of Surgery, Nara Medical University, Kashihara-shi, Nara, Japan.

Background: Postoperative delirium was reported to be associated with increased postoperative mortality after liver resection. Therefore, it is crucial to prevent postoperative delirium in such cases. Ramelteon, an agonist of melatonin receptor has been suggested to be useful for preventing delirium. The aim of this study was to examine whether ramelteon is effective at preventing delirium after elective liver resection.

Methods: The cases of patients who underwent liver resection at Nara Medical University (Nara, Japan) between January 2014 and August 2018 were analyzed. During the period from January 2017 to August 2018, ramelteon was prospectively administered to patients who underwent liver resection [8 mg/day on the day before surgery and on postoperative days 1 to 3] (ramelteon group), whereas ramelteon was not administered during the period from January 2014 to December 2016 (control group). The perioperative outcomes of the two groups were compared.

Results: There were 120 patients in the ramelteon group and 186 patients in the control group. No significant intergroup differences in background factors, including age, gender, and preoperative serological laboratory data, were detected. The incidence of postoperative delirium was significantly lower in the ramelteon group (5.8% vs. 15.1%, P = 0.035). Multivariate analysis revealed that being aged ≥75 (P = 0.002), being male (P = 0.020), cardiovascular disease (P = 0.023), blood loss ≥1000ml (P = 0.001) and the absence of ramelteon treatment (P = 0.046) were independent risk factors for postoperative delirium.

Conclusion: The administration of ramelteon might reduce the risk of postoperative delirium after elective liver resection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241673PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605698PMC
December 2020

Outcomes in Patients with Chronic Kidney Disease After Liver Resection for Hepatocellular Carcinoma.

World J Surg 2021 Feb 21;45(2):598-606. Epub 2020 Oct 21.

Department of Surgery, Nara Medical University, 840 Shijo-cho Kashihara-shi, Nara, 634-8522, Japan.

Background: The aim of this study was to clarify the feasibility of liver resection in hepatocellular carcinoma (HCC) patients with chronic kidney disease (CKD).

Methods: In all, 204 patients who underwent primary liver resection for HCC between 2011 and 2019 were analyzed. Short-term and long-term outcomes were compared between the CKD and control groups. The CKD group was defined by a preoperative estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m and chronic kidney disease Stage 3B or higher.

Results: Twenty-eight patients (13.7%) had CKD. No significant differences were observed in the overall complication rates between the groups (46.4% vs. 34.7% p = 0.229). The incidence of bile leakage was significantly higher in the CKD group than in the control group (14.3% vs. 4.0% p = 0.048), and the median postoperative hospital stay was significantly longer in the CKD group (11 vs. 9 days p = 0.031). No significant differences were found in the disease-free survival between the two groups (p = 0.763), but overall survival (OS) was significantly worse in the CKD group than in the control group (p = 0.022). In the multivariable analysis, a CKD diagnosis (hazard ratio, 2.261; 95% confidence interval (CI), 1.139-4.486 p = 0.020) was identified as an independent poor prognostic factor for OS. The percentage of patients who died from cardiovascular disease was significantly higher in the CKD group (27.3% vs. 2.3% p = 0.023).

Conclusions: Liver resection for HCC in CKD patients is associated with acceptable perioperative outcomes. However, cardiovascular disease may negatively affect the OS of CKD patients after liver resection.
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http://dx.doi.org/10.1007/s00268-020-05829-zDOI Listing
February 2021

The prognosis and recurrence pattern of right- and left- sided colon cancer in Stage II, Stage III, and liver metastasis after curative resection.

Ann Coloproctol 2020 Sep 18. Epub 2020 Sep 18.

Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, 634-8522 Nara, Japan.

Purpose: Primary tumor location of colon cancer has been reported to affect the prognosis after curative resection. However, some reports suggested the impact was varied by tumor stage. This study analyzed the prognostic impact of the sidedness of colon cancer in Stages II, III, and liver metastasis after curative resection using propensity matched analysis.

Methods: Right-sided colon cancer was defined as a tumor located from cecum to splenic flexure, while any more distal colon cancer was defined as a left-sided colon cancer. Patients who underwent curative resection at Nara Medical University hospital between 2000 and 2016 were analyzed.

Results: There were 110 patients with Stage II, 100 patients with Stage III, and 106 patients with liver metastasis. After propensity matching, 28 pairs with Stage II and 32 pairs with Stage III were identified. In the patients with Stage II, overall survival and recurrence-free survival were not significantly different for right- and left-sided colon cancers. In the patients with Stage III, overall survival and recurrence-free survival were significantly worse in right-sided colon cancer. In those with liver metastasis, overall survival of right-sided colon cancer was significantly worse than left-sided disease, while recurrence-free survival was similar. Regarding metachronous liver metastasis, the difference was observed only in the patients whose primary colon cancer was stage III. In each stage, significantly higher rate of peritoneal recurrence was found in those with right-sided colon cancer.

Conclusion: Sidedness of colon cancer had a significant and varied prognostic impact in patients with Stage II, III, and liver metastasis after curative resection.
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http://dx.doi.org/10.3393/ac.2020.09.14DOI Listing
September 2020

Primary undifferentiated carcinoma with osteoclast-like giant cells in liver and rapidly developing multiple metastases after curative hepatectomy: a case report.

Int Cancer Conf J 2020 Oct 18;9(4):244-248. Epub 2020 Aug 18.

Department of Surgery, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara 634-8522 Japan.

A 64-year-old man was diagnosed with cholangiocellular carcinoma based on preoperative computed tomography and magnetic resonance imaging and underwent laparoscopic segmentectomy (Segment 8) of the liver for radical operation. Pathological examination revealed the presence of an undifferentiated carcinoma with osteoclast-like giant cells, which were categorized as T3N0M0 and Stage III based on the third English edition of the Japanese classification of liver cancer. The patient was treated with three courses of combination chemotherapy, which included gemcitabine (1000 mg/m) and cisplatin (25 mg/m), as well as S-1 (120 mg/day) for adjuvant chemotherapy. At two months after the operation, CT revealed multiple liver- and lung metastases. Thereafter, the patient was prescribed the molecularly targeted drug, lenvatinib (12 mg/day). However, lenvatinib was not effective, as evident by the extension of several metastases. Testing for microsatellite instability was negative. The patient died 5 months after the operation. We experienced a case of primary undifferentiated carcinoma with osteoclast-like giant cells in the liver showed rapidly developing multiple metastases after curative liver resection.
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http://dx.doi.org/10.1007/s13691-020-00436-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450028PMC
October 2020

Clamp-Crush Technique for Laparoscopic Liver Resection.

Ann Surg Oncol 2021 Feb 13;28(2):866. Epub 2020 Jul 13.

Department of Surgery, Nara Medical University, Nara, Japan.

Liver parenchymal transection is the most important process in laparoscopic liver resection (LLR). Various surgical methods and devices for LLR have been applied including the cavitron ultrasonic surgical aspirator, ultrasonic scalpel, and staplers. Very few reports have investigated the clamp--crush technique for LLR.12 Current study shows a clamp-crush technique for LLR and evaluates its perioperative outcomes. The clamp-crush technique was performed using simple forceps and the Pringle maneuver under a low central venous pressure. The vessels that remained after crushing were clipped if they were thick; or removed with an ultrasonic cutting-coagulation system if they were thin. Sixty-one LLRs were performed using the clamp-crush technique. Pathological cirrhosis was observed in 22 patients (36.0%). The types of resection were as follows: 31 wedge resections (50.8%), 11 segmentectomies (19.0%), 9 sectionectomies (14.8%), and 10 hemihepatectomies (16.4%). The intraoperative blood loss was 62 ml; the surgical duration was 272 min. The postoperative major complication (Clavien-Dindo ≥ IIIa) rate was 4.9%. The median hospital stay was 8 days (range = 4-53 days). A 76-year-old female underwent right LLR for a 9-cm HCC. The right hepatic artery and portal vein were dissected separately. After mobilizing the liver, parenchymal transection was performed using the clamp-crush technique. The middle hepatic vein was totally exposed. Intraoperative blood loss was 32 ml and the surgical duration was 5 h 32 min with no postoperative complications. The clamp-crush technique is safe and feasible for LLR and could contribute to quick parenchymal transection and flattening of the transection plane.
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http://dx.doi.org/10.1245/s10434-020-08822-xDOI Listing
February 2021

Evaluation of changes in oral health-related quality of life over time in patients with Sjögren's syndrome.

Mod Rheumatol 2021 May 30;31(3):669-677. Epub 2020 Jul 30.

Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.

Objectives: To assess oral health-related quality of life (OHRQoL) and changes in OHRQoL in 3 years of patients with Sjögren's symdrome (SS).

Methods: Thirty-five SS patients and 23 non-SS individuals were enrolled. OHRQoL were quantitatively evaluated using the shortened Oral Health Impact Profile (OHIP-14). After 3 years, 22 patients and 14 controls tool the OHIP-14 survey again.

Results: The SS group had a significantly higher OHIP-14 score, which indicated a lower OHRQoL, than the non-SS group. Among individual questions in the OHIP-14, scores for 'trouble pronouncing words', 'uncomfortable to eat foods', 'self-conscious', and 'diet unsatisfactory' were markedly higher in the SS group than in the non-SS group. The OHIP-14 score significantly increased in 3 years in the SS group. Furthermore, there was an inverse correlation between the change rate of salivary flow rate and change of OHIP-14 scores in 3 years in patients with SS whose OHIP-14 score increased. Scores for 'irritable with other people', 'difficulty doing usual jobs', 'felt life less satisfying', and 'unable to function' significantly increased in 3 years.

Conclusion: In SS, OHRQoL decreased in 3 years, which was associated with a decrease in saliva secretion. Moreover, troubles related to psychosocial aspects in SS patients were found to intensify over time.
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http://dx.doi.org/10.1080/14397595.2020.1795391DOI Listing
May 2021

Influence of the Glissonean Pedicle Transection Approach in Spiegel Lobe-Preserving Left Hepatectomy on Spiegel Lobe Volume and Remnant Liver Functions.

World J Surg 2020 09;44(9):3079-3085

Department of Surgery, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, 634-8522, Japan.

Background: The extrahepatic surgical technique in liver resection can be divided into glissonean pedicle transection and glissonean separated transection approaches. In this study, we compared remnant liver function and liver regeneration involving the Spiegel lobe between these two approaches regarding Spiegel lobe-preserving left hepatectomy.

Methods: We enrolled 31 patients who underwent Spiegel lobe-preserving left hepatectomy for malignant hepatobiliary diseases between April 2008 and January 2020. The postoperative Spiegel lobe volume was measured using a volume analyzer at 3 and 6 months postoperatively.

Results: Of the 31 patients, 22 and 9 were included in the glissonean separated transection and glissonean pedicle transection groups, respectively. There was no significant between-group difference in the preoperative Spiegel lobe volume. However, the volumes at 3 and 6 months postoperatively were significantly larger in the glissonean pedicle transection group than in the glissonean transection group (29.92 mL vs. 13.00 mL; P < 0.001 and 28.43 mL vs. 15.01 mL; P < 0.001, respectively). There was no significant between-group difference in postoperative remnant liver function.

Conclusions: The postoperative Spiegel lobe volume was larger, and liver regeneration was better with the glissonean pedicle transection approach because of transection for Spiegel branch of the portal vein. It is desirable to preserve Spiegel branch in possible cases when surgeons select the glissonean separated transection approach based on the location and size of the tumors.
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http://dx.doi.org/10.1007/s00268-020-05548-5DOI Listing
September 2020

Pulmonary complications after laparoscopic liver resection.

Surg Endosc 2021 04 13;35(4):1659-1666. Epub 2020 Apr 13.

Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-shi, Nara, 634-8522, Japan.

Background: Although postoperative pulmonary complications (PPCs) are one of the common complications after liver surgery and might be avoided with the use of a laparoscopic approach, few reports have focused on the comparison of PPCs between laparoscopic liver resection (LLR) and open liver resection (OLR). The aim of this study was to clarify the effect of LLR on PPCs.

Methods: The study included 307 patients who underwent liver resection, excluding biliary reconstruction, at our institution between 2014 and 2018. Patients were divided into the OLR and LLR groups. The perioperative outcomes and PPCs were compared between the two groups using propensity score matching. On day 3 after liver surgery, all patients had chest radiography to confirm the presence of pleural effusion, including cases that required thoracentesis, and pneumonia.

Results: Of the 307 patients, 172 and 135 patients were included in OLR and LLR groups, respectively. After propensity score matching, 65 patients were included in each group. Compared with the matched OLR group, the matched LLR group had significantly lower intraoperative blood loss (P < 0.001); rate of intraoperative blood transfusion (P = 0.011); overall PPCs (P = 0.032); and number of cases with chest radiography-confirmed pleural effusion (P = 0.048), pleural effusion requiring thoracentesis (P = 0.029), and pneumonia (P = 0.012). Moreover, postoperative hospital stay was significantly shorter in the matched LLR group than in the matched OLR group.

Conclusions: Compared with OLR, LLR might be a better surgical approach to avoid PPCs.
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http://dx.doi.org/10.1007/s00464-020-07549-wDOI Listing
April 2021

Characteristics of Five-year Survivors After Liver Resection for Colorectal Liver Metastases in Modern Chemotherapy.

Anticancer Res 2020 Feb;40(2):1107-1116

Department of Surgery, Nara Medical University, Nara, Japan.

Background/aim: The aim of this study was to evaluate whether modern chemotherapy has changed characteristics of actual five-year survivors after liver resection for colorectal liver metastasis (CRLM).

Patients And Methods: The records of 210 patients, who underwent curative liver resection for CRLM at our institution between January 1990 and May 2014, were reviewed. The patients treated before 2004 when modern chemotherapy was not introduced were compared with the patients treated after 2005.

Results: Actual five-year survivor rates were significantly higher after 2005 (33.3% vs. 49.0%, p=0.022). Preoperative characteristics of actual five-year survivors were not different. The median survival time after non-resectable recurrence was significantly longer after 2005 (20.3 vs. 8.7 months, p=0.002). The proportion of 5-year survivors with recurrent site was significantly higher after 2005 (34.0% vs. 10.5%, p=0.019).

Conclusion: Actual five-year survivors have increased by modern chemotherapy. However, approximately one-third of them were not cured.
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http://dx.doi.org/10.21873/anticanres.14050DOI Listing
February 2020

Neural effects of acute stress on appetite: A magnetoencephalography study.

PLoS One 2020 22;15(1):e0228039. Epub 2020 Jan 22.

Department of Sports Medicine, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.

Stress is prevalent in modern society and can affect human health through its effects on appetite. Therefore, in the present study, we aimed to clarify the neural mechanisms by which acute stress affects appetite in healthy, non-obese males during fasting. In total, 22 volunteers participated in two experiments (stress and control conditions) on different days. The participants performed a stress-inducing speech-and-mental-arithmetic task under both conditions, and then viewed images of food, during which, their neural activity was recorded using magnetoencephalography (MEG). In the stress condition, the participants were told to perform the speech-and-mental-arithmetic task again subsequently to viewing the food images; however, another speech-and-mental-arithmetic task was not performed actually. Subjective levels of stress and appetite were then assessed using a visual analog scale. Electrocardiography was performed to assess the index of heart rate variability reflecting sympathetic nerve activity. The findings showed that subjective levels of stress and sympathetic nerve activity were increased in the MEG session in the stress condition, whereas appetite gradually increased in the MEG session only in the control condition. The decrease in alpha band power in the frontal pole caused by viewing the food images was greater in the stress condition than in the control condition. These findings suggest that acute stress can suppress the increase of appetite, and this suppression is associated with the frontal pole. The results of the present study may provide valuable clues to gain a further understanding of the neural mechanisms by which acute stress affects appetite. However, since the stress examined in the present study was related to the expectation of forthcoming stressful event, our present findings may not be generalized to the stress unrelated to the expectation of forthcoming stressful event.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975544PMC
May 2020

Ischaemia-reperfusion injury with Pringle's maneuver induces unusually large von Willebrand factor multimers after hepatectomy.

Thromb Res 2019 Nov 5;183:20-27. Epub 2019 Sep 5.

Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan. Electronic address:

Introduction: von Willebrand factor (VWF) is synthesised in vascular endothelial cells and released into the plasma as unusually large VWF multimers (UL-VWFMs). Sinusoidal endothelial cells are a major target of ischaemia-reperfusion injury due to liver surgery. This study aimed to clarify the effect of hepatectomy on UL-VWFMs.

Materials And Methods: Thirty-five patients who underwent hepatectomy were eligible for the study. Plasma ADAMTS13 activity and VWF antigen levels were measured by enzyme-linked immunosorbent assay and multimer analysis of plasma VWF was performed according to Ruggeri and Zimmerman's method. For analyses, patients were categorised according to UL-VWFM positivity after hepatectomy.

Results: Plasma ADAMTS13 activity significantly decreased from 61.0% (27.7%-126.2%) before operation to 37.4% (20.2%-71.4%) on postoperative day 7 (p < 0.001). Plasma VWF antigen levels significantly increased from 172.1% (80.5%-412.8%) before operation to 361.0% (154.7%-745.8%) on postoperative day 2, which remained high until postoperative day 7 (p < 0.001). Seven patients remained UL-VWFMs-negative and 22 patients became UL-VWFMs-positive after operation. Pringle's maneuver duration was significantly longer and blood loss volume was significantly higher in the UL-VWFMs-positive group (p = 0.001 and p = 0.003, respectively). By multivariable analysis, Pringle's maneuver duration [odds ratio 1.049, 95% confidence interval (CI) 1.001-1.098; p = 0.043] was significantly associated with increased UL-VWFMs level after hepatectomy. UL-VWFMs index was significantly correlated with Pringle's maneuver duration (r = 0.444, p = 0.017).

Conclusions: Plasma UL-VWFMs levels increased after hepatectomy due to ischaemia-reperfusion injury with Pringle's maneuver.
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http://dx.doi.org/10.1016/j.thromres.2019.09.005DOI Listing
November 2019

Neural effects of hand-grip-activity induced fatigue sensation on appetite: a magnetoencephalography study.

Sci Rep 2019 07 30;9(1):11044. Epub 2019 Jul 30.

Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.

It has been reported that physical activity not only increases energy expenditure, but also affects appetite. However, little remains known about the effects of physical activity-induced fatigue sensation on appetite. In the present study, classical conditioning related to fatigue sensation was used to dissociate fatigue sensation from physical activity. The participants were 20 healthy male volunteers. After overnight fasting, on day 1, the participants performed hand-grip task trials for 10 min with listening to a sound. The next day, they viewed food images with (target task) and without (control task) listening to the sound identical to that used on day 1, and their neural activity during the tasks were recorded using magnetoencephalography. The subjective levels of appetite and fatigue sensation were assessed using a visual analog scale. The subjective level of fatigue increased and that of appetite for fatty foods showed a tendency toward increase in the target task while the subjective level of fatigue and that of appetite for fatty foods were not altered in the control task. In the target task, the decrease of theta (4-8 Hz) band power in the supplementary motor area (SMA), which was observed in the control task, was suppressed, and the suppression was positively correlated with appetite for fatty foods, suggesting hand grip activity-induced fatigue sensation may increase the appetite for fatty food; this increase could be related to neural activity in the SMA. These findings are expected to contribute to the understanding of the neural mechanisms of appetite in relation to fatigue.
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http://dx.doi.org/10.1038/s41598-019-47580-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667433PMC
July 2019

Significance of Herpesvirus Entry Mediator Expression in Human Colorectal Liver Metastasis.

Ann Surg Oncol 2019 Nov 16;26(12):3982-3989. Epub 2019 Jul 16.

Department of Surgery, Nara Medical University, Kashihara-Shi, Nara, Japan.

Background: Herpesvirus entry mediator (HVEM) has been suggested to play various roles in cancer biology. The authors report that HVEM expression in tumor cells is associated with a reduction in the number of tumor-infiltrating lymphocytes and a poor prognosis after surgical resection in various human gastrointestinal cancers. This study aimed to clarify the clinical significance of HVEM expression in human colorectal liver metastasis (CRLM).

Methods: This study examined the cases of 104 patients with CRLM who underwent curative liver resection at Nara Medical University between 2000 and 2014. The median follow-up period was 50.2 months. Immunohistochemical staining was performed using antibodies against HVEM, CD4, CD8, and CD45RO.

Results: High HVEM expression was observed in 49 patients (47.1%) with CRLM. Expression of HVEM was not associated with age, gender, administration of preoperative chemotherapy, tumor size, number of tumors, or histologic differentiation. The high-HVEM group exhibited significantly worse overall survival (OS) than the low-HVEM group (P = 0.002). Multivariate analysis showed that high HVEM expression in CRLM, age of 70 years or older, and having five or more tumors are independent poor prognostic factors for OS (hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.41-7.93; P = 0.006). The number of tumor-infiltrating CD8+ and CD45RO+ T cells was significantly lower in the high-HVEM group than in the low-HVEM group. High HVEM expression in primary colorectal cancer was significantly associated with synchronous CRLM, but not with metachronous CRLM.

Conclusions: Tumor HVEM expression might play a critical role in CRLM.
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http://dx.doi.org/10.1245/s10434-019-07625-zDOI Listing
November 2019

Decreased alpha-band oscillatory brain activity prior to movement initiated by perception of fatigue sensation.

Sci Rep 2019 03 8;9(1):4000. Epub 2019 Mar 8.

RIKEN, Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.

Fatigue is a health problem prevalent in modern societies. Fatigue sensation plays an important role as a biological alarm urging rest to maintain homeostasis, and clarifying the neural mechanisms related to fatigue sensations by which we decide to engage in rest is therefore essential. This study enrolled healthy male volunteers and showed that the decrease in alpha-band power as assessed by magnetoencephalography of the left Brodmann's area (BA) 6 before perception of fatigue when a button-press based on the level of fatigue was required was smaller than that before perception of the intention to move when a voluntary button-press was required. In addition, the decrease of alpha-band power in the left BA 6 before the perception of fatigue was not altered compared with that in the right BA 6 when a button-press based on the level of fatigue was required. These results suggest that the button-press based on the perception of fatigue is not prepared before the perception of fatigue. These findings will advance the understanding of the neural mechanisms related to subjective feelings such as fatigue sensation.
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http://dx.doi.org/10.1038/s41598-019-40605-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408540PMC
March 2019

Exposure to paraben and triclosan and allergic diseases in Tokyo: A pilot cross-sectional study.

Asia Pac Allergy 2019 Jan 21;9(1):e5. Epub 2019 Jan 21.

Allergy Center, National Center for Child Health and Development, Tokyo, Japan.

Background: Previous studies have reported that exposure to paraben (Pb) and triclosan (TCS) is associated with allergies. However, Pb and TCS exposure in the Japanese population is not fully understood.

Objectives: The present study was aimed to examine such exposure among Japanese individuals with allergic diseases.

Methods: This cross-sectional study included the International Study of Asthma and Allergies in Childhood questionnaire survey to evaluate allergic outcomes and the collection of urine samples to examine Pb and TCS exposure.

Results: Pb containing daily commodities was used in 84.8% children. Pb use was positively associated with current atopic dermatitis (adjusted odds ratio, 4.61; 95% confidence interval, 1.23-17.3). Urinary Pb concentrations were increased significantly in those with current atopic dermatitis (AD) (median, 4.58 vs. 0; < 0.0001), and showed an increased tendency in those with current wheeze (median, 3.45 vs. 1.81; = 0.0535) in participants ≤15 years old. Urinary TCS concentration was under the limit of detection in all children.

Conclusion: Urinary levels of Pb were associated with current AD in children. We should pay more attention about Pb and TCS.
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http://dx.doi.org/10.5415/apallergy.2019.9.e5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365653PMC
January 2019

Serum neopterin as well as ferritin, soluble interleukin-2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis.

Mod Rheumatol 2019 Sep 7;29(5):814-820. Epub 2019 Feb 7.

Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine , Hyogo , Japan.

: This study identified biomarkers that can be used to assess disease activity and response to therapy in patients with interstitial lung disease complicating anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive clinically amyopathic dermatomyositis (CADM). : In 15 patients with interstitial lung disease complicating anti-MDA5 Ab-positive CADM, anti-MDA5 Ab, neopterin, interleukin (IL)-18, ferritin, and soluble interleukin 2 receptor (sIL-2R) levels were measured in cryopreserved serum specimens before and at multiple times after remission induction therapy, and their correlations were assessed. : Anti-MDA5 Ab, neopterin, IL-18, ferritin, and sIL-2R levels did not differ significantly between patients who survived and those who succumbed to the disease. In many cases, serum anti-MDA5 Ab titers were over the upper limit (over 150 index value) before treatment in the usual measuring method, and gradually decreased to the normal range at stable phase. Meanwhile, serum neopterin levels (21.6 [15.3-48.3] nmol/L) were significantly elevated in newly diagnosed patients and fell to 6.8 (5-11.4) nmol/L at 6 months after treatment introduction. : Elevated serum neopterin as well as ferritin, sIL-2R, KL-6, and anti-MDA5 Ab titer might help identify patients with interstitial lung disease complicated with DM and might be useful in monitoring response to therapy.
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http://dx.doi.org/10.1080/14397595.2018.1548918DOI Listing
September 2019

Liver Regeneration After Major Liver Resection for Hepatocellular Carcinoma in the Elderly.

J Invest Surg 2020 Apr 2;33(4):332-338. Epub 2018 Nov 2.

Department of Surgery, Nara Medical University, 840 Shijo-cho Kashihara-shi, Nara 634-8522, Japan.

: With an aging population, more elderly patients are being considered for hepatic resection for hepatocellular carcinoma (HCC). This study aimed to evaluate postoperative outcomes including liver regeneration after major hepatectomy for HCC in the elderly.: We assessed 41 patients who underwent major hepatectomy (≥3 segments) at our institute between 2000 and 2013. Patients were divided into two age groups, elderly group (age ≥70 years,  = 23) and younger group (age <70 years,  = 18). Clinicopathological data and outcomes were retrospectively compared. To evaluate the effect of aging on liver regeneration, we measured liver volumes preoperatively and at 1 and 6 months after liver resection using a 3D simulation imaging system.: Overall and major complications after hepatectomy were not different between elderly and younger groups, and no case of mortality was recorded. Moreover, recurrence-free and overall survivals were similar in both groups. With regard to liver regeneration, no differences were observed between elderly and younger groups at 1 and 6 months after liver resection. Baseline liver functions were comparable between the groups. Furthermore, the only factor associated with liver regeneration was resected liver volume ( = 0.631,  < 0.001). Age was not correlated with liver regeneration rate ( = 0.00537,  = 0.695).: Liver regeneration after major hepatectomy for HCC was not affected by age and that resected liver volume is an important factor for liver regeneration. Short- and long-term outcomes after major hepatectomy were similar in elderly and younger patients.
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http://dx.doi.org/10.1080/08941939.2018.1517839DOI Listing
April 2020

A Novel Navigation for Laparoscopic Anatomic Liver Resection Using Indocyanine Green Fluorescence.

Ann Surg Oncol 2018 Dec 14;25(13):3982. Epub 2018 Sep 14.

Department of Surgery, Nara Medical University, Kashihara-shi, Nara, Japan.

Background: Among all laparoscopic liver resection techniques, anatomic liver resection is one of the most challenging procedures, with disorientation readily occurring during the laparoscopic approach compared with the open approach.1 Thus, navigation is warranted for laparoscopic anatomic liver resection. Recent research has remarkably established intraoperative fluorescence imaging techniques using indocyanine green fluorescence (ICG) in the field of liver surgery.24 This report describes real-time navigation for anatomic liver resection using the novel ICG system, PINPOINT (Stryker, Kalamazoo, MI).

Methods: The target Glissonian pedicle was identified and temporally clamped after confirmation of blood supply to the preserved adjacent segment using ultrasonography. Next, 1.5 mg of ICG was intravenously administered using the negative counterstaining method. After 3 min of administration, the ICG-stained area could be readily recognized. Parenchymal transection was subsequently initiated along the interface between the ICG-positive and ICG-negative areas using the Pringle maneuver.

Results: Using PINPOINT, laparoscopic anatomic liver resection was performed for 16 patients. The extent of liver resection comprised two left hepatectomies, three right-anterior sectionectomies, three right-anterior sectionectomies, and eight segmentectomies. The identification rate of clear demarcations in the ICG images was 100%. The intraoperative blood loss was 226 mL, and the operative time was 305 min. Only one patient encountered the major postoperative complication of ascites, and all the patients attained R0 resection.

Conclusions: Because the images provided by the ICG system are clearer than conventional ICG images, it could facilitate real-time navigation for laparoscopic anatomic liver resection.
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http://dx.doi.org/10.1245/s10434-018-6768-zDOI Listing
December 2018

Neural activity induced by visual food stimuli presented out of awareness: a preliminary magnetoencephalography study.

Sci Rep 2018 02 15;8(1):3119. Epub 2018 Feb 15.

Department of Sports Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.

Obesity is a major public health problem in modern society. Appetitive behavior has been proposed to be partially driven by unconscious decision-making processes and thus, targeting the unconscious cognitive processes related to eating behavior is essential to develop strategies for overweight individuals and obese patients. Here, we presented food pictures below the threshold of awareness to healthy male volunteers and examined neural activity related to appetitive behavior using magnetoencephalography. We found that, among participants who did not recognize food pictures during the experiment, an index of heart rate variability assessed by electrocardiography (low-frequency component power/high-frequency component power ratio, LF/HF) just after picture presentation was increased compared with that just before presentation, and the increase in LF/HF was negatively associated with the score for cognitive restraint of food intake. In addition, increased LF/HF was negatively associated with increased alpha band power in Brodmann area (BA) 47 caused by food pictures presented below the threshold of awareness, and level of cognitive restraint was positively associated with increased alpha band power in BA13. Our findings may provide valuable clues to the development of methods assessing unconscious regulation of appetite and offer avenues for further study of the neural mechanisms related to eating behavior.
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http://dx.doi.org/10.1038/s41598-018-21383-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814400PMC
February 2018

Significance of bacterial culturing of prophylactic drainage fluid in the early postoperative period after liver resection for predicting the development of surgical site infections.

Surg Today 2018 Jun 29;48(6):625-631. Epub 2018 Jan 29.

Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Purposes: The relationship between the results of bacterial drainage fluid cultures in the early postoperative period after liver resection and the development of surgical site infections (SSIs) is unclear. We evaluated the diagnostic value of bacterial cultures of drainage fluid obtained on postoperative day (POD) 1 after liver resection.

Methods: The cases of all consecutive patients who underwent elective liver resection from January 2014 to December 2016 were analyzed. The association between a positive culture result and the development of SSIs was analyzed.

Results: A total of 195 consecutive patients were studied. Positive drainage fluid cultures were obtained in 6 patients (3.1%). A multivariate analysis revealed that a positive drainage fluid culture was an independent risk factor for SSIs (odds ratio: 8.04, P = 0.035), and combined resection of the gastrointestinal tract was a risk factor for a positive drainage fluid culture (P = 0.006). Among the patients who did not undergo procedures involving the gastrointestinal tract, there was no association between drainage fluid culture positivity and SSIs.

Conclusions: The detection of positive culture results for drainage fluid collected on POD 1 after liver resection was associated with SSIs. However, among patients who did not undergo procedures involving the gastrointestinal tract, it was not a predictor of SSIs.
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http://dx.doi.org/10.1007/s00595-018-1629-8DOI Listing
June 2018

[A case of anti-PL-7 antibody positive polymyositis with thrombotic microangiopathy].

Nihon Rinsho Meneki Gakkai Kaishi 2017 ;40(6):450-455

Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine.

  A 65-year-old woman with a 17-year history of polymyositis and 8-year history of rheumatoid arthritis who was treated with a low dose of prednisolone and tacrolimus (Tac) was admitted to our hospital because of general malaise and hypertension. Blood tests showed thrombocytopenia, hemolytic anemia with fragmented erythrocytes, and hypercreatinemia. Based on these clinical features, she was diagnosed with thrombotic micro-angiopathy (TMA). Thrombocytopenia and hemolytic anemia with fragmented erythrocytes improved with the discontinuation of Tac and plasma exchange; however, hypertension and renal dysfunction persisted. TMA due to calcineurin inhibitor (CNI) nephropathy was suspected based on the histopathological findings of renal biopsy. However, the condition was atypical of a CNI nephropathy because the trough level of Tac was lower than that reported previously and renal dysfunction persisted after drug discontinuation. She had mild sclerodactylia and Raynaud's symptoms, although the diagnostic criteria for systemic sclerosis (SSc) were not satisfied. Moreover, the patient tested positive for anti PL-7 antibody. The relationship between anti PL-7 antibody and pathogenesis of SSc has been reported. In this case, it was suspected that CNI nephropathy worsened because of the potential basic factors of SSc. These findings indicate that TMA may occur in patients testing positive for anti PL-7 antibody who are treated with Tac.
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http://dx.doi.org/10.2177/jsci.40.450DOI Listing
February 2018

Does anatomic resection improve the postoperative outcomes of solitary hepatocellular carcinomas located on the liver surface?

Surgery 2018 02 28;163(2):285-290. Epub 2017 Nov 28.

Department of Surgery, Nara Medical University, Japan.

Background: It is unclear whether anatomic resection achieves better outcomes than nonanatomic resection in patients with hepatocellular carcinoma. This study aimed to compare the outcomes of anatomic resection and nonanatomic resection for hepatocellular carcinoma located on the liver surface via one-to-one propensity score-matching analysis.

Methods: Data from all consecutive patients who underwent liver resection for primary solitary hepatocellular carcinoma at Nara Medical University Hospital, Japan, January 2007- December 2015 were retrieved. Superficial hepatocellular carcinomas were defined as hepatocellular carcinoma that extended to a depth of < 3 cm from the liver surface and measured < 5 cm in diameter. The prognoses of the patients with superficial hepatocellular carcinoma who underwent anatomic resection and nonanatomic resection were compared.

Results: In this study 23 patients with superficial hepatocellular carcinoma underwent anatomic resection and 70 patients who underwent nonanatomic resection. The recurrence-free survival rate of the patients who underwent anatomic resection was better than that of the patients who underwent nonanatomic resection (P = .006), while no such difference was observed for nonsuperficial hepatocellular carcinoma. After the propensity score-matching procedure, the resected liver volume and operation time were the only background or clinical characteristics to exhibit significant differences between the anatomic resection (n = 20) and nonanatomic resection groups (n = 20). The recurrence-free survivial rate of the patients who underwent anatomic resection was significantly than that of the patients that underwent nonanatomic resections (P = .030), but overall survival did not differ significantly between the groups (P = .182).

Conclusion: Anatomic resection decreases the risk of tumor recurrence and improves recurrence-free survival compared with nonanatomic resection in patients with superficial hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.surg.2017.08.024DOI Listing
February 2018

Evidence for unconscious regulation of performance in fatigue.

Sci Rep 2017 11 23;7(1):16103. Epub 2017 Nov 23.

RIKEN, Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.

Since fatigue is prevalent in modern societies, it is necessary to clarify the neural mechanisms of fatigue. The regulation of performance through fatigue sensation is one of the mechanisms that decreases performance in fatigue. However, it is unknown whether subjective feeling of fatigue is necessary for the regulation of performance. Here, we examined whether decreased performance occurs without increased fatigue sensation through the experiment which was designed to test if fatigue can be learned unconsciously. Healthy male volunteers performed a fatigue-inducing hand-grip task for 10 min while viewing a target image presented without awareness. On the next day, they viewed a control and the target images presented with awareness and the neural activity caused by viewing the images was measured using magnetoencephalography. Results showed the level of fatigue sensation was not altered but grip-strength was decreased by viewing the target image on the second day. The level of beta band power in Brodmann's area 31 was increased by viewing the target image and this increase was negatively associated with the decrease of grip-strength caused in the hand-grip task. These findings demonstrated that fatigue can be learned unconsciously and that there is a mechanism to decrease performance without fatigue sensation.
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http://dx.doi.org/10.1038/s41598-017-16439-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700951PMC
November 2017
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