肝癌に対する経動脈的治療におけるマイクロカテーテル挿入可能ポー トの開発

PURPOSE: To develop an implantable port in which a microcatheter can be inserted for a combination therapy of repeated transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) for advanced liver cancer. MATERIALS AND METHODS: The design of a currently used implantable port was modified. A funnel part was constructed in the port. The septum was punctured by a 20-gauge indwelling needle, and 2.0-Fr non-tapered microcatheter was inserted into the port. In the in vitro studies, the advance of a microcatheter out of the funnel part was evaluated via seven different septum puncture sites. A 5-Fr indwelling catheter connected to the port was placed in a vascular model, and a microcatheter catheterization was evaluated. In an in vivo study, the port-catheter system was implanted in the hepatic artery in a pig. A microcatheter was percutaneously inserted through the port into the hepatic arterial branches, and embolization was performed. RESULTS: In the in vitro studies, the microcatheter was smoothly advanced out of the port and catheterizations into the hepatic arteries were successful via all septum puncture sites. In the in vivo study, repeated selective embolization through the port was successfully conducted on 7, 14 and 21 days after the implantation. CONCLUSION: The developed implantable port can be used for repeated catheter insertion into the hepatic artery. The combination of repeated TACE and HAIC could be possible using this device.博士（医学）・甲第710号・令和元年6月26日© Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2018This is a post-peer-review, pre-copyedit version of an article published in Cardiovascular and interventional radiology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s00270-018-2111-0

無症候性腎機能障害が膵頭十二指腸切除術後臨床経過に及ぼす影響

BACKGROUND: Although recent large-scale clinical studies have shown that preoperative renal insufficiency is associated with increased risk of postoperative complications after pancreatoduodenectomy (PD), it is unknown whether asymptomatic renal dysfunction has an impact on postoperative course after PD. METHODS: Two hundred and fifty-four patients who underwent PD between 2007 and 2013 were enrolled. Renal function was evaluated by the preoperative estimated glomerular filtration rate (eGFR). Patients were divided into two groups according to the cutoff value of 55 of eGFR. RESULTS: Thirty-five patients were classified as the low eGFR group, while 219 were classified as the normal group. There were differences between groups in age, comorbidity and pancreatic texture. The incidence of overall postoperative complication, grade B/C pancreatic fistula and severe complication in the low eGFR group was significantly higher than that in the normal group. Multivariate analysis identified low eGFR as an independent risk factor for severe postoperative complications and grade B/C pancreatic fistula after PD. However, there were no differences in mortality and survival between the low and normal eGFR groups. CONCLUSIONS: We have demonstrated for the first time that preoperative asymptomatic renal dysfunction may be a significant risk factor for severe morbidity and clinically relevant pancreatic fistula after PD.博士（医学）・乙第1394号・平成29年3月15日© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.This is the peer reviewed version of the following article: http://dx.doi.org/10.1002/jhbp.286, which has been published in final form at http://dx.doi.org/10.1002/jhbp.286. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving

膜乳化デバイスによるエマルションを用いたウサギVX2肝腫瘍モデノレへの肝動脈化学塞栓術における抗腫瘍効果、薬物動態の検討

Purpose: To evaluate the phamacokinetics of epirubicin in conventional transarterial chemoembolization using a developed pumping emulsification device with a microporous glass membrane in VX2 rabbits. Materials and methods: Epirubicin solution (10 mg/mL) was mixed with ethiodized oil (1:2 ratio) using the device or 3-way stopcock. Forty-eight rabbits with VX2 liver tumor implanted 2 weeks prior to transarterial chemoembolization were divided into 2 groups: a device group (n = 24) and a 3-way-stopcock group (n = 24). Next, 0.5 mL of emulsion was injected into the hepatic artery, followed by embolization using 100-300-μm microspheres. The serum epirubicin concentrations (immediately after, 5 minutes after, and 10 minutes after) and the tumor epirubicin concentrations (20 minutes after and 48 hours after) were measured after transarterial chemoembolization. Histopathologic evaluation was performed with a fluorescence microscope. Results: The area under the curve and maximum concentrations of epirubicin in plasma were 0.45 ± 0.18 μg min/mL and 0.13 ± 0.06 μg/mL, respectively, in the device group and 0.71 ± 0.45 μg min/mL and 0.22 ± 0.17 μg/mL, respectively, in the 3-way-stopcock group (P = .013 and P = .021, respectively). The mean epirubicin concentrations in VX2 tumors at 48 hours in the device group and the 3-way-stopcock group were 13.7 ± 6.71 and 7.72 ± 3.26 μg/g tissue, respectively (P = .013). The tumor necrosis ratios at 48 hours were 62 ± 11% in the device group and 51 ± 13% in the 3-way-stopcock group (P = .039). Conclusions: Conventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.博士（医学）・乙第1443号・令和元年12月5日Copyright © 2019 SIR. Published by Elsevier Inc. All rights reserved

ラット肝腫瘍モデルにおける化学療法の早期効果判定に有用なダイナミック造影超音波のパラメータについて

Objectives: The objective of the study is to determine a parameter on the time-intensity curve (TIC) of dynamic contrast-enhanced ultrasonography (DCE-US) that best correlates with tumor growth and to evaluate whether the parameter could correlate with the early response to irinotecan in a rat liver tumor model. Material and Methods: Twenty rats with tumors were evaluated (control: Saline, n = 6; treatment: Irinotecan, n = 14) regarding four parameters from TIC: Peak intensity (PI), k value, slope (PI × k), and time to peak (TTP). Relative changes in maximum tumor diameter between day 0 and 10, and parameters in the first 3 days were evaluated. The Mann-Whitney U-test was used to compare differences in tumor size and other parameters. Pearson’s correlation coefficients (r) between tumor size and parameters in the control group were calculated. In the treatment group, relative changes of parameters in the first 3 days were compared between responder and non-responder (<20% and ≥20% increase in size on day 10, respectively). Results: PI, k value, PI × k, and TTP significantly correlated with tumor growth (r = 0.513, 0.911, 0.665, and 0.741, respectively). The mean RC in k value among responders (n = 6) was significantly lower than non-responders (n = 8) (mean k value, 4.96 vs. 72.5; P = 0.003). Conclusion: Parameters of DCE-US could be a useful parameter for identifying early response to irinotecan.博士（医学）・甲第879号・令和5年3月15

化学療法を施行した膵癌患者に対する喫煙の影響

OBJECTIVE: Smoking may affect pharmacokinetics of chemotherapeutic agents and hemodynamics of the smokers, thereby influencing adverse events and efficacy of chemotherapy in patients with pancreatic cancer (PC). The aim of this study was to clarify how smoking totally affected patients with PC receiving current chemotherapy. METHODS: We evaluated the impact of smoking status on the performance of chemotherapy and survival in 262 patients with PC including 158 resectable and 104 unresectable PC. RESULTS: There were more male and younger patients in current smokers than in nonsmokers. In unresectable PC, current smokers had more metastatic tumors than locally advanced tumors compared with nonsmokers. In current smokers receiving chemotherapy, the baseline white blood cell count, neutrophil count, and hemoglobin concentration were significantly higher in current smokers than in nonsmokers. Furthermore, grades 3 to 4 neutropenia was observed more often in nonsmokers than smokers. On the other hand, the performance and efficacy of the planned adjuvant chemotherapy were similar between smokers and nonsmokers. More importantly, there was no significant difference in overall prognosis between smokers and nonsmokers receiving chemotherapy. CONCLUSIONS: Smoking status has no significant impact on the efficacy of current chemotherapy for both resectable and unresectable PC.博士（医学）・乙第1393号・平成29年3月15日Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.This is a non-final version of an article published in final form in "http://dx.doi.org/10.1097/MPA.0000000000000395

ラット凍結肩モデルを用いた経カテーテル的動脈塞栓術の効果に関する検討

Purpose: To assess the angiographic findings and the effects of transcatheter arterial embolization on physical activity and histopathology using a frozen shoulder rat model. Materials and methods: First, the angiographic and histopathologic findings of rats in which the shoulder was immobilized with molding plaster for 6 weeks (n = 4) were compared to control rats with normal non-immobilized shoulders (n = 4). Next, a total of 16 frozen shoulder rats were divided into 2 groups. In the transcatheter arterial embolization group (n = 8), imipenem/cilastatin was injected into the left thoracoacromial artery. The changes of physical activity before and after procedures were evaluated and compared with a saline-injected control group (n = 8). Histopathologic findings were also compared between the 2 groups. Results: Angiography revealed abnormal shoulder staining in all of the rats with a frozen shoulder. On histopathology, the numbers of microvessels and mononuclear inflammatory cells in the synovial membrane of the joint capsule were significantly higher compared with the control rats (both P = .03). In the transcatheter arterial embolization group, the running distance and speed were improved (P = .03 and P = .01, respectively), whereas there were no significant differences in the control group. The number of microvessels and mononuclear inflammatory cells in the transcatheter arterial embolization group were significantly lower than the control group (P = .002 and P = .001, respectively). Conclusions: The rat frozen shoulder model revealed the development of neovascularization. Transcatheter arterial embolization decreased the number of blood vessels and inflammatory changes in the frozen shoulder and increased the moving distance and speed of the rats.博士（医学）・甲第789号・令和3年3月15日Copyright © 2020 SIR(Society of Interventional Radiology). Published by Elsevier Inc. All rights reserved

超吸水性ポリマー球状塞栓物質の高張食塩水を用いた膨潤抑制法の開発

PURPOSE: To analyze size changes of superabsorbent polymer (SAP) microspheres with the reduced expansion technique, and to evaluate pharmacological advantages of transarterial chemoembolization using cisplatin-loaded SAP microspheres with the reduced expansion technique. MATERIALS AND METHODS: In an in vitro study, diluted contrast materials containing different concentrations of sodium ions were examined to expand SAP microspheres and determined the reduced expansion technique. Size distributions of cisplatin-loaded SAP microspheres were analyzed. In an in vivo study, TACE was performed using cisplatin-loaded SAP microspheres with the reduced expansion and control techniques in 18 VX2 rabbits. RESULTS: The degree of expansion was reduced to the greatest extent by using a mixture of non-ionic contrast material and 10% NaCl at a 4:1 ratio. The mean diameter of the reduced expansion of cisplatin-loaded SAP microspheres was 188.4 μm, while that of the control expansion was 404.9 μm. The plasma platinum concentrations of the reduced expansion group at 5 min after TACE were significantly higher than those of the control expansion group (2.19 ± 0.77 vs. 0.75 ± 0.08 μg/mL, P = .01). The tumor platinum concentrations of the reduced expansion group at 1 h were significantly higher than those of the control expansion group (10.76 ± 2.57 vs. 1.57 ± 0.14 μg/g, P = .044). CONCLUSION: The expanding level of SAP microspheres can be reduced by using hypertonic saline. Cisplatin-loaded SAP microspheres with the reduced expansion technique have the advantages of achieving higher cisplatin tissue concentration in TACE for liver tumors.博士（医学）・甲第709号・令和元年6月26日© Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2018This is a post-peer-review, pre-copyedit version of an article published in Cardiovascular and interventional radiology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s00270-018-1990-4

膵癌術後予防肝動注におけるリザーバー留置術の検討 : 従来法とcoaxialシステムの比較

PURPOSE: Previous reports have shown the effectiveness of adjuvant hepatic arterial infusion chemotherapy (HAIC) in pancreatic cancer. However, percutaneous catheter placement is technically difficult after pancreatic surgery. The purpose of this study was to evaluate the feasibility and outcome of HAIC using a coaxial technique compared with conventional technique for postoperative pancreatic cancer. MATERIALS AND METHODS: 93 consecutive patients who received percutaneous catheter-port system placement after pancreatectomy were enrolled. In 58 patients from March 2006 to August 2010 (Group A), a conventional technique with a 5-Fr indwelling catheter was used and in 35 patients from September 2010 to September 2012 (Group B), a coaxial technique with a 2.7-Fr coaxial catheter was used. RESULTS: The overall technical success rates were 97.1 % in Group B and 86.2 % in Group A. In cases with arterial tortuousness and stenosis, the success rate was significantly higher in Group B (91.7 vs. 53.8 %; P = 0.046). Fluoroscopic and total procedure times were significantly shorter in Group B: 14.7 versus 26.7 min (P = 0.001) and 64.8 versus 80.7 min (P = 0.0051), respectively. No differences were seen in the complication rate. The 1 year liver metastasis rates were 9.9 % using the conventional system and 9.1 % using the coaxial system (P = 0.678). The overall median survival time was 44 months. There was no difference in the survival period between two systems (P = 0.312). CONCLUSIONS: The coaxial technique is useful for catheter placement after pancreatectomy, achieving a high success rate and reducing fluoroscopic and procedure times, while maintaining the safety and efficacy for adjuvant HAIC in pancreatic cancer.博士（医学）・乙第1380号・平成28年7月8日© Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2016The final publication is available at Springer via http://dx.doi.org/10.1007/s00270-016-1292-