Publications by authors named "Kazuyuki Nagai"

42 Publications

Pancreatoduodenectomy with portal vein resection for pancreatic body cancer in a patient with situs inversus totalis.

Surg Oncol 2022 Jul 8;43:101815. Epub 2022 Jul 8.

Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan.

Background: Situs inversus totalis (SIT) is a rare congenital condition characterized by complete transposition (right-to-left reversal) of the thoracic and abdominal organs. The estimated prevalence of SIT is 1 per 8000-25,000 live births [1]. Surgery for abdominal diseases in patients with SIT is technically demanding because of anatomical variations [2-4]; the importance of preoperative radiological assessment has been reported [4]. We report a case of SIT with complex vascular anomalies and pancreatic body cancer who underwent pancreatoduodenectomy with combined resection of the portal vein.

Methods: A 79-year-old man with asymptomatic SIT was referred to our hospital for the treatment of pancreatic cancer that was incidentally found during a medical check-up. Abdominal computed tomography (CT) revealed a hypovascular tumor in the pancreatic body with a diameter of 32 mm involving the portal vein. He did not have SIT-associated diseases such as Kartagener syndrome or other malformations but had complex anomalies of vascular anatomy, especially in the hepatic arterial system, in addition to mirror-image transposition.

Results: The operation was performed successfully with a full understanding of the vascular anatomy based on precise preoperative evaluation of CT images, including three-dimensional reconstruction images. The operative time was 710 min, and blood loss was 1237 mL. The Union for International Cancer Control (UICC) pathological stage was Stage III (T2, N2, M0).

Conclusion: Pancreatoduodenectomy with portal vein resection for pancreatic cancer in patients with SIT is a complex procedure. Precise preoperative assessment of CT images with three-dimensional reconstruction is crucial to understanding vascular anatomy and safely performing surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.suronc.2022.101815DOI Listing
July 2022

Acute coronary syndrome after liver transplantation in a young primary biliary cholangitis recipient with dyslipidemia: a case report.

Surg Case Rep 2022 Jun 17;8(1):113. Epub 2022 Jun 17.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Primary biliary cholangitis (PBC) is a chronic, progressive liver disease associated with dyslipidemia. There is a consensus that PBC does not accelerate coronary artery disease despite high cholesterol levels, so the screening test for the coronary artery is not routinely performed before liver transplantation (LT). To date, no report has described the potential risk of PBC-related dyslipidemia for developing acute coronary syndrome (ACS) after LT.

Case Presentation: A 40-year-old Asian female with a known history of PBC underwent ABO-incompatible living-donor LT, with her husband as the donor. Although she had high cholesterol and triglyceride levels that were refractory to medications, she passed all routine preoperative examinations, including cardiopulmonary function tests and infection screenings. One week after LT, she developed ACS with 90% stenosis of both the left anterior descending artery and left circumflex artery. Emergent stent implantation was successfully performed followed by dual antiplatelet therapy. The long history of PBC and associated severe dyslipidemia for 10 years would have accelerated the atherosclerosis, causing latent stenosis in the coronary artery. Inapparent stenosis might have become apparent due to unstable hemodynamics during the acute phase after LT.

Conclusions: PBC-related dyslipidemia potentially brings a risk for developing ACS after LT. This experience suggests that the preoperative evaluation of the coronary artery should be considered for high-risk patients, especially those who have drug-resistant dyslipidemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40792-022-01470-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206063PMC
June 2022

The Benefits of Fibrinolysis Combined with Venous Systemic Oxygen Persufflation (VSOP) in a Rat Model of Donation after Circulatory Death and Orthotopic Liver Transplantation.

Int J Mol Sci 2022 May 9;23(9). Epub 2022 May 9.

Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany.

Organ shortage has led to the increasing utilization of livers retrieved from donors after circulatory death (DCD). These pre-damaged organs are susceptible to further warm ischemia and exhibit minimal tolerance for cold storage. The aim was thus to examine the effects of fibrinolysis combined with Venous Systemic Oxygen Persufflation (VSOP) on the preservation of DCD livers in vivo. Livers of male Lewis rats were explanted after 45 min of warm ischemia, cold-stored for 18 h, and transplanted into a recipient animal. Livers were left untreated or underwent either VSOP or fibrinolysis via Streptokinase (SK) or received combined SK and VSOP. Combined treatment exhibited improved microvascular flow at 168 h ( = 0.0009) and elevated microperfusion velocity at 24 h post-transplantation ( = 0.0007). Combination treatment demonstrated increased portal venous flow (PVF) at 3 and 24 h post-transplantation ( = 0.0004, < 0.0001), although SK and VSOP analogously achieved increases at 24 h ( = 0.0036, = 0.0051). Enzyme release was decreased for combination treatment ( = 0.0002, = 0.0223) and lactate dehydrogenase (LDH) measurements were lower at 24 h post-transplantation ( = 0.0287). Further supporting findings have been obtained in terms of serum cytokine levels and in the alterations of endothelial injury markers. The combination treatment of SK + VSOP might provide improved organ integrity and viability and may therefore warrant further investigation as a potential therapeutic approach in the clinical setting of DCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms23095272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099893PMC
May 2022

Laparoscopic pancreatoduodenectomy for a metastatic tumor in a portal annular pancreas.

Surg Oncol 2022 Jun 14;42:101772. Epub 2022 Apr 14.

Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan.

Background: Portal annular pancreas (PAP), also called circumportal pancreas, is a congenital pancreatic anomaly in which the portal and/or mesenteric veins are surrounded by pancreatic parenchyma [1,2]. Joseph et al. classified PAP into three types (according to the fusion pattern of the pancreatic parenchyma and ductal system [1]), each of which they subdivided (based on the relation to the portal confluence) into the suprasplenic, infrasplenic, and mixed type [1,3]. The most common type is IIIa [1,4], where the portal vein (suprasplenic) is encased by the uncinate process with an anteportal main pancreatic duct.

Methods: The patient was a 78-year-old woman who had undergone left nephrectomy for renal cell carcinoma five years prior. We performed laparoscopic pancreatoduodenectomy for a metastatic tumor of the head of a type IIIa PAP (Fig. 1). The anteportal pancreas was transected, and dissection was performed around the superior mesenteric artery using a right approach. The retroportal pancreas was transected using a linear stapler with bioabsorbable polyglycolic acid felt. We performed pancreatojejunostomy for the anteportal stump of the pancreas containing a main pancreatic duct; the retroportal stump was not reconstructed, because it had no major pancreatic ducts on preoperative imaging.

Results: The operative time was 505 minutes, and the blood loss was 70 ml. The postoperative course was uneventful, and the patients was discharged on postoperative day 12.

Conclusion: Laparoscopic pancreatoduodenectomy was performed successfully in a patient with a type IIIa PAP. The retroportal pancreas can be transected using a linear stapler, without reconstruction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.suronc.2022.101772DOI Listing
June 2022

Impact of neoadjuvant intensity-modulated radiation therapy on borderline resectable pancreatic cancer with arterial abutment; a prospective, open-label, phase II study in a single institution.

BMC Cancer 2022 Jan 29;22(1):119. Epub 2022 Jan 29.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Borderline resectable pancreatic cancer (BRPC) is a category of pancreatic cancer that is anatomically widely spread, and curative resection is uncommon with upfront surgery. Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that delivers precise radiation to a tumor while minimizing the dose to surrounding normal tissues. Here, we conducted a phase 2 study to estimate the curability and efficacy of neoadjuvant chemoradiotherapy using IMRT (NACIMRT) for patients with BRPC with arterial abutment (BRPC-A).

Methods: A total of 49 BRPC-A patients were enrolled in this study and were treated at our hospital according to the study protocol between June 2013 and March 2021. The primary endpoint was microscopically margin-negative resection (R0) rates and we subsequently analyzed safety, histological effect of the treatment as well as survivals among patients with NACIMRT.

Results: Twenty-nine patients (59.2%) received pancreatectomy after NACIMRT. The R0 rate in resection patients was 93.1% and that in the whole cohort was 55.1%. No mortality was encountered. Local therapeutic effects as assessed by Evans classification showed good therapeutic effect (Grade 1, 3.4%; Grade 2a, 31.0%; Grade 2b, 48.3%; Grade 3, 3.4%; Grade 4, 3.4%). Median disease-free survival was 15.5 months. Median overall survival in the whole cohort was 35.1 months. The only independent prognostic pre-NACIMRT factor identified was serum carbohydrate antigen 19-9 (CA19-9) > 400 U/ml before NACIMRT.

Conclusions: NACIMRT showed preferable outcome without significant operative morbidity for BRPC-A patients. NACIMRT contributes to good local tumor control, but a high initial serum CA19-9 implies poor prognosis even after neoadjuvant treatment.

Trial Registration: UMIN-CTR Clinical Trial: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000011776 Registration number: UMIN000010113. Date of first registration: 01/03/2013.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-022-09244-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800301PMC
January 2022

Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: An international dual-institutional study.

Pancreatology 2022 Jan 28;22(1):123-129. Epub 2021 Oct 28.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: /Objectives: Although the presence of lymph node metastasis (LNM) defines malignant potential, preoperative prediction of LNM has not been established for non-functional pancreatic neuroendocrine neoplasm (NF-PNEN). We sought to develop a prediction system using only preoperatively available factors that would stratify the risk of LNM for NF-PNEN.

Methods: We retrospectively reviewed patients who underwent R0/1 resection of NF-PNEN at Kyoto University (2007-2019) and the University of California, San Francisco (2010-2019). Risk stratification of LNM was developed using preoperative factors by the logistic regression analysis. Long-term outcomes were compared across the risk groups.

Results: A total of 131 patients were included in this study. Lymph nodes were pathologically examined in 116 patients, 23 (20%) of whom had LNM. Radiological tumor size [1.5-3.5 cm (odds ratio: 13.5, 95% confidence interval: 1.77-398) and >3.5 cm (72.4, 9.06-2257) against ≤1.5 cm], <50% cystic component (8.46 × 10^6, 1.68 × 10^106-), and dilatation of main pancreatic duct ≥5 mm (31.2, 3.94-702) were independently associated with LNM. When patients were classified as the low-risk (43 patients), intermediate-risk (44 patients), and high-risk groups (29 patients), proportions of LNM differed significantly across the groups (0%, 14%, and 59%, respectively). Recurrence-free survival (RFS) of the low- and intermediate-risk groups were significantly better than that of the high-risk group (5-year RFS rates of 92.2%, 85.4%, and 47.1%, respectively).

Conclusions: The prediction system using preoperative radiological factors stratifies the risk of LNM for NF-PNEN. This stratification helps to predict malignant potential and determine the surgical procedure and necessity of regional lymphadenectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pan.2021.10.005DOI Listing
January 2022

Impact of vascular abnormality on contrast-enhanced CT and high C-reactive protein levels on postoperative pancreatic hemorrhage after pancreaticoduodenectomy: A multi-institutional, retrospective analysis of 590 consecutive cases.

Pancreatology 2021 Jan 1;21(1):263-268. Epub 2020 Dec 1.

Department of Surgery, Division of Hepato-biliary-pancreatic Surgery and Transplantation, Kyoto University, Japan.

Background: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy.

Methods: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis.

Results: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT.

Conclusion: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pan.2020.11.007DOI Listing
January 2021

Postoperative pancreatic fistulas decrease the survival of pancreatic cancer patients treated with surgery after neoadjuvant chemoradiotherapy: A retrospective analysis.

Surg Oncol 2020 Dec 24;35:527-532. Epub 2020 Oct 24.

Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Hospital, Japan.

Background And Objectives: A postoperative pancreatic fistula (POPF) is a critical complication after surgery for pancreatic cancer. Whether a POPF affects the long-term prognosis of pancreatic cancer cases remains controversial. This study aimed to clarify the effect of a POPF on the long-term prognosis of pancreatic cancer patients, especially after neoadjuvant chemoradiotherapy (NACRT).

Methods: Patients who underwent curative pancreatectomy for pancreatic cancer between January 2012 and June 2019 at Kyoto University Hospital were retrospectively investigated. A fistula ≥ Grade B was considered a POPF.

Results: During the study period, 148 patients underwent upfront surgery (Upfront group), and 52 patients underwent surgery after NACRT (NACRT group). A POPF developed in 16% of patients in the Upfront group and 13% in the NACRT group (p = 0.824). In the Upfront group, development of a POPF did not have a significant effect on recurrence-free survival (p = 0.766) or overall survival (p = 0.863). However, in the NACRT group, development of a POPF significantly decreased recurrence-free survival (HR 5.856, p = 0.002) and overall survival (HR 7.097, p = 0.020) on multivariate analysis.

Conclusions: The development of a POPF decreases the survival of pancreatic cancer patients treated by surgery after NACRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.suronc.2020.10.010DOI Listing
December 2020

Left-posterior approach for artery-first en bloc resection in laparoscopic distal pancreatectomy for left-sided pancreatic cancer.

Langenbecks Arch Surg 2020 Dec 6;405(8):1251-1258. Epub 2020 Nov 6.

Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine Kyoto University, 54 Shogoin Kawarahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Purpose: We describe a "left-posterior approach" in which the important steps in laparoscopic distal pancreatectomy (LDP) for left-sided pancreatic cancer are accomplished in the direction caudal and dorsal to the pancreas.

Methods: The patients who underwent LDP with a left-posterior approach at our hospital from January 2016 to April 2020 were reviewed to evaluate the short-term postoperative outcomes. In LDP, we first dissected retroperitoneal tissues above the left renal vein and superior mesenteric artery, yielding the mobilization of the pancreatic body widely. Then, the splenic artery was divided behind the ventrally lifted pancreas as an artery-first approach. The regional lymphadenectomy was performed in an en bloc manner consecutively in the same operative field. The neck of the pancreas was transected with a linear stapler after mobilization of the spleen.

Results: In nine patients (five men and four women) aged 76 years (range: 64-82 years), the operative time was 398 min (276-482 min) with the estimated blood loss of 40 ml (0-80 ml). No patients developed grade B/C pancreatic fistula or delayed gastric emptying. Postoperative complications classified as grade III in the Clavien-Dindo classification occurred in one patient (abdominal abscess). The pathology confirmed R0 resection in all patients who had pancreatic cancer (n = 5), IPMNs (n = 3), and high-grade pancreatic intraepithelial neoplasia (PanIN) (n = 1). The number of retrieved lymph nodes was 35 (11-49).

Conclusion: The procedure with a left-posterior approach is a rational surgical technique in LDP for left-sided pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00423-020-02021-8DOI Listing
December 2020

The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation.

Transplant Direct 2020 Sep 12;6(9):e591. Epub 2020 Aug 12.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants.

Methods: Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function.

Results: Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly ( = 0.0007 and  = 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 ( < 0.05). In addition, trametinib suppressed functional differentiation of naive CD4 T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited ( < 0.001,  < 0.05, and  < 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 ( < 0.05 and  = 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function.

Conclusions: Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4 T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TXD.0000000000001045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423917PMC
September 2020

Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response.

Sci Rep 2020 07 21;10(1):12086. Epub 2020 Jul 21.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan.

The in vitro culture period prior to cell transplantation (i.e. pancreatic islet transplantation) enables cell modification and is thus advantageous. However, the islet preconditioning method has not been fully explored. Here we present a simple approach for islet preconditioning that uses the antibiotic mitomycin C (MMC), which has antitumor activity, to reduce islet immunogenicity and prevent proinflammatory events in an intraportal islet transplantation model. Freshly isolated mice islets were treated for 30 min with 10 μg/mL MMC or not, cultured for 20 h and transplanted into the livers of syngeneic or allogeneic diabetic mouse recipients. In the allogeneic model, MMC preconditioning significantly prolonged graft survival without requiring immunosuppressants. In vitro, MMC treatment suppressed the expression of proinflammatory cytokines in islet allografts, while immunohistochemical studies revealed the suppression of inflammatory cell infiltration into MMC-treated allografts relative to untreated allografts. Furthermore, MMC preconditioning significantly suppressed the mRNA expression of proinflammatory cytokines into the transplant site and induced the differentiation of regulatory T cells with the ability to suppress CD4 T cell-mediated immune responses. In conclusion, islet preconditioning with MMC prolonged graft survival in an intraportal islet transplantation model by suppressing proinflammatory events and inducing potentially regulatory lymphocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-69009-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374693PMC
July 2020

Middle Hepatic Vein Branch-Guided Approach for Laparoscopic Resection of Liver Segment 8 Is Simple, Reliable, and Reproducible.

Ann Surg Oncol 2020 Dec 27;27(13):5195. Epub 2020 May 27.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08652-xDOI Listing
December 2020

Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress.

Endocr Relat Cancer 2020 07;27(7):431-439

Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-20-0028DOI Listing
July 2020

Risk factors for short recurrence-free survival after resection of pancreatic neuroendocrine tumor (PanNET) liver metastases: which patients should undergo resection?

Scand J Gastroenterol 2020 Apr 30;55(4):479-484. Epub 2020 Mar 30.

Department of Surgery, Kyoto University, Kyoto, Japan.

In the treatment of metastatic pancreatic neuroendocrine tumors (PanNETs), surgical resection is the first choice if curative resection is expected. However, most patients develop recurrence after resection of liver metastasis. Because one of the benefits of resection is to gain a tumor-free period for the patients, it is important to identify which patients achieve longer recurrence-free survival (RFS) by resection. In this study, the clinicopathological factors associated with RFS after resection of metastatic PanNETs in the liver were evaluated to identify the patient group that is suitable for resection. Consecutively diagnosed patients with PanNET liver metastasis with resection at our hospital from January 2000 to July 2019 were evaluated. A total of 26 metastatic PanNET patients with primary liver resections were evaluated. The median follow-up time was 48.3 months. There were 18 NET recurrences of the total 26 resections, with a median RFS of 17.9 months. Independent risk factors for short RFS were a high Ki67 index ( = .009) and the number of resected tumors ( = .045). When the cut-off value for the Ki67 index was 5.0% and that for the number of resected tumors was 6, Ki67 > 5.0% tumors had shorter RFS (4.9 months vs. 38.2 months  = .006), and patients with tumors > = 7 tumors had shorter RFS (4.7 months vs. 27.5 months  = .001). These findings indicate that good candidates for resection of metastatic tumors of PanNETs could be patients with low Ki67 tumors and a small number of metastatic tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00365521.2020.1743352DOI Listing
April 2020

Usefulness of F-FDG-PET/CT in the diagnosis and prediction of recurrence of pancreatic neuroendocrine neoplasms.

J Hepatobiliary Pancreat Sci 2020 Jul 14;27(7):414-420. Epub 2020 May 14.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan.

Background: Although F-FDG-PET/CT is a widely used diagnostic tool for several malignancies, its efficacy in diagnosing pancreatic neuroendocrine tumors is reported to be controversial because of the short-term follow-up.

Methods: We retrospectively compared demographics and pathological features between F-FDG-positive and -negative diseases. Additionally, we evaluated whether the avidity of F-FDG-PET/CT affected earlier recurrence after curative treatment of non-functioning tumors. The median duration of observation was 65.6 months.

Results: Seventy-two patients were enrolled. F-FDG-positive diseases were pathologically advanced and significantly associated with metastatic behavior. In a multivariate analysis, metastatic behavior and WHO tumor grade was independently associated with F-FDG accumulation. Only 25% of functional tumors (4/16) and 8% of insulinomas (1/12) were F-FDG-positive. In a Kaplan-Meier analysis in patients with non-functioning tumors (n = 56), F-FDG-positivity was significantly correlated with poorer recurrence-free survival (RFS) but had no correlation with overall survival. In univariate analysis of factors associated with shorter RFS, male gender, prevalence of nodal metastasis, WHO tumor grade ≥G2, or F-FDG-positive disease were significantly higher in patients with shorter RFS, whereas only F-FDG-positivity was associated with shorter RFS in multivariate analyses.

Conclusions: The avidity of F-FDG-PET/CT was associated with metastatic behavior of pancreatic neuroendocrine tumors and recurrence after treatment of non-functioning tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jhbp.734DOI Listing
July 2020

Combination of postoperative C-reactive protein value and computed tomography imaging can predict severe pancreatic fistula after pancreatoduodenectomy.

HPB (Oxford) 2020 02 12;22(2):282-288. Epub 2019 Aug 12.

Department of Surgery, Division of Hepatobiliarypancreatic Surgery and Transplantation, Kyoto University, Japan.

Background: Recent management after pancreatoduodenectomy recommends either omission of prophylactic drainage or early removal. This potentially makes the diagnosis of postoperative pancreatic fistula (POPF) difficult because the diagnosis is based on the amylase value of drain effluent. The aim of this study was to determine if severe POPF could be predicted independent of drainage information.

Methods: Records of consecutive patients who underwent pancreatoduodenectomy between 2012 and 2018 were included for further analysis. The presence of a peripancreatic collection (PC) on routine postoperative (day7) computed tomography (early CT) and perioperative characteristics were analyzed.

Results: PC appeared in 82/211 patients (39%) and was associated with clinically relevant POPF (p < 0.001). The C-reactive protein (CRP) on postoperative day5 was a good predictor of severe POPF (needing interventional therapy or Grade C) (area under the receiver operating characteristics curve, 0.802; 95% confidence interval, 0.702-0.875). Presence of a PC and a high CRP value were independent risk factors for severe POPF following multivariate analysis. The combination of CRP<5.0 mg/dL on postoperative day 5 and the absence of a PC had 98% negative predictive value.

Conclusion: The combination of CRP measurement and PC evaluation by early CT was useful in predicting severe POPF after pancreatoduodenectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hpb.2019.06.020DOI Listing
February 2020

Impact of Graft Quality and Fluid Overload on Postoperative Massive Ascites After Living Donor Liver Transplantation.

Transplant Proc 2019 Jul - Aug;51(6):1779-1784. Epub 2019 Jul 10.

Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, Kyoto, Japan.

After living donor liver transplantation, we encounter cases with massive ascites, which is difficult to manage. We analyzed the risk factors for massive ascites after living donor liver transplantation. The subjects were 100 adult recipients who underwent living donor liver transplantation at Kyoto University Hospital from 2013 to 2017. We retrospectively assessed patient, graft, operative factors, and percent fluid overload, which were defined as [(weight on the day - preoperative weight)/preoperative weight] × 100%. We defined the massive ascites group as having a14-day average ascites ≥ 2500 mL and the mild ascites group as having a 14-day average ascites < 2500 mL. Forty-seven patients were included in the massive group, and 53 patients were included in the mild group. There was no difference in short- and long-term survival. In multivariate analysis, the presence of preoperative ascites (P = .0008), 14-day average percent fluid overload ≥ 14.5% (P = .0095), graft-to-recipient weight ratio < 0.86 (P = .0253), and donors' age ≥ 47 years (P = .0466) were identified as independent risk factors for massive ascites after living donor liver transplantation. A liver graft with a small graft-to-recipient weight ratio or from an elderly donor, which may indicate poor graft quality, presence of preoperative ascites, and postoperative fluid overload were associated with massive ascites after living donor liver transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.transproceed.2019.03.038DOI Listing
November 2019

Older Donor Age Is a Risk Factor for Negative Outcomes After Adult Living Donor Liver Transplantation Using Small-for-Size Grafts.

Liver Transpl 2019 10 14;25(10):1524-1532. Epub 2019 Aug 14.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Adult-to-adult living donor liver transplantation (ALDLT) using small-for-size grafts (SFSGs), ie, a graft with a graft-to-recipient weight ratio (GRWR) <0.8%, has been a challenge that should be carefully dealt with, and risk factors in this category are unclear. Therefore, we aimed to examine the risk factors and outcomes of ALDLT using SFSGs over a 13-year period in 121 patients who had undergone their first ALDLT using SFSGs. Small-for-size syndrome (SFSS), early graft loss, and 1-year mortality were encountered in 21.6%, 14.9%, and 18.4% of patients, respectively. By multivariate analysis, older donor age (≥45 years) was an independent risk factor for SFSS (odds ratio [OR], 4.46; P = 0.004), early graft loss (OR, 4.11; P = 0.02), and 1-year mortality (OR, 3.76; P = 0.02). Child-Pugh C class recipients were associated with a higher risk of SFSS development (P = 0.013; OR, 7.44). Despite no significant difference between GRWR categories in the multivariate outcome analysis of the whole population, in the survival analysis of the 2 donor age groups, GRWR <0.6% was associated with significantly lower 1-year survival than the other GRWR categories in the younger donor group. Moreover, in the high final portal venous pressure (PVP) group (>15 mm Hg), younger ABO-compatible donors showed 100% 1-year survival with a significant difference from the group of other donors. Older donor age was an independent risk factor for SFSS, early graft loss, and 1-year mortality after ALDLT using SFSGs. GRWR should not be <0.6%, and PVP modulation is indicated when grafts from older or ABO-incompatible donors are used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.25601DOI Listing
October 2019

The Impact of a Nitric Oxide Synthase Inhibitor (L-NAME) on Ischemia⁻Reperfusion Injury of Cholestatic Livers by Pringle Maneuver and Liver Resection after Bile Duct Ligation in Rats.

Int J Mol Sci 2019 Apr 29;20(9). Epub 2019 Apr 29.

Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Medical Faculty, 52074 Aachen, Germany.

The Pringle maneuver (PM) has been widely used to control blood loss during liver resection. However, hepatic inflow occlusion can also result in hepatic ischemia-reperfusion injury (IRI), especially in patients with a cholestatic, fibrotic, or cirrhotic liver. Here we investigate a nitric oxide synthase (NOS) inhibitor N-Nitroarginine methyl ester (L-NAME) on IRI after the PM and partial hepatectomy of cholestatic livers induced by bile duct ligation (BDL) in rats. Control group (non-BDL/no treatment), BDL + T group (BDL/L-NAME treatment) and BDL group (BDL/no treatment) were analyzed. Cholestasis was induced by BDL in the L-NAME and BDL group and a 50% partial hepatectomy with PM was performed. L-NAME was injected before PM in the BDL + T group. Hepatocellular damage, portal venous flow, microcirculation, endothelial lining, and eNOS, iNOS, interleukin (IL)-6, and transforming growth factor-β (TGF-β) were evaluated. Microcirculation of the liver in the BDL + T group tended to be higher. Liver damage and apoptotic index were significantly lower and Ki-67 labeling index was higher in the BDL + T group while iNOS and TGF-β expression was decreased. This was corroborated by a better preserved endothelial lining. L-NAME attenuated IRI following PM and improved proliferation/regeneration of cholestatic livers. These positive effects were considered as the result of improved hepatic microcirculation, prevention of iNOS formation, and TGF-β mRNA upregulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20092114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539833PMC
April 2019

Predictive value of the Ki67 index for lymph node metastasis of small non-functioning pancreatic neuroendocrine neoplasms.

Surg Today 2019 Jul 5;49(7):593-600. Epub 2019 Mar 5.

Department of Surgery, Kyoto University, 54 Shogoin, Kawaracho, Sakyo, Kyoto, 606-8507, Japan.

Background: We evaluated the clinicopathological factors associated with lymph node metastasis in patients with non-functioning pancreatic neuroendocrine neoplasms (PanNENs), focusing on the risk factors and range of lymph node metastasis for tumors ≤ 2 cm in diameter.

Methods: The subjects of this study were patients with PanNENs consecutively diagnosed at our hospital between January, 2000 and June, 2018. We analyzed 69 patients who underwent R0 resection of a non-functioning sporadic PanNEN with no distant metastasis, as well as 43 patients with tumors ≤ 20 mm in radiological diameter.

Results: Nineteen patients (27.5%), including 7 (16.3%) with a small PanNEN, had lymph node metastasis. A large radiological diameter, a high Ki67 index, and cyst formation correlated significantly with positive lymph node metastasis. In patients with tumors ≤ 20 mm in diameter, a high Ki67 index correlated significantly with lymph node metastasis. When we set the cut-off Ki67 index as 3.3%, 2 of 43 patients had lymph node metastasis. Tumors in the uncinate process readily metastasized to the region around the superior mesenteric artery.

Conclusions: These findings suggest that a high Ki67 index indicates a risk of lymph node metastasis for tumors ≤ 20 mm in diameter and that lymphadenectomy should be performed in the region spatially adjacent to the primary tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-019-01779-9DOI Listing
July 2019

Computer tomographic assessment of postoperative peripancreatic collections after distal pancreatectomy.

Langenbecks Arch Surg 2018 May 27;403(3):349-357. Epub 2018 Mar 27.

Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Syogoinkawaharacho 54, Sakyo-ku, Kyoto, Japan.

Background: Peripancreatic collections occur frequently after distal pancreatectomy. However, the sequelae of peripancreatic collections vary from case to case, and their clinical impact is uncertain. In this study, the correlations between CT findings of peripancreatic collections and complications after distal pancreatectomy were investigated.

Methods: Ninety-six consecutive patients who had undergone distal pancreatectomy between 2010 and 2015 were retrospectively investigated. The extent and heterogeneity of peripancreatic collections and background clinicopathological characteristics were analyzed. The extent of peripancreatic collections was calculated based on three-dimensional computed tomography images, and the degree of heterogeneity of peripancreatic collections was assessed based on the standard deviation of their density on computed tomography.

Results: Of 85 patients who underwent postoperative computed tomography imaging, a peripancreatic collection was detected in 77 (91%). Patients with either a large extent or a high degree of heterogeneity of peripancreatic collection had a significantly higher rate of clinically relevant pancreatic fistula than those without (odds ratio 5.95, 95% confidence interval 2.12-19.72, p = 0.001; odds ratio 8.0, 95% confidence interval 2.87-24.19, p = 0.0001, respectively).

Conclusions: A large and heterogeneous peripancreatic collection was significantly associated with postoperative complications, especially clinically relevant postoperative pancreatic fistula. A small and homogenous peripancreatic collection could be safely observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00423-018-1668-zDOI Listing
May 2018

Comparison of Recurrence Between Pancreatic and Duodenal Neuroendocrine Neoplasms After Curative Resection: A Single-Institution Analysis.

Ann Surg Oncol 2018 Feb 21;25(2):528-534. Epub 2017 Nov 21.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan.

Background: The primary site of a neuroendocrine neoplasms (NEN) around the head of the pancreas is sometimes difficult to assess before resection, and the characteristics of the primary site around this region have not been elucidated for recurrence after curative resection. In this study, the clinicopathologic characteristics of pancreatic NEN (PanNEN) and duodenal NEN (DuNEN) were evaluated, and the risk factors as well as the recurrence types after resection were investigated.

Methods: Consecutively diagnosed NEN patients at the authors' hospital from January 2000 to July 2016 were evaluated in this study. For 117 PanNEN patients and 31 non-ampullary DuNEN patients, R0 resection was achieved. The median follow-up period was 8.1 years.

Results: In this study, 27 PanNEN patients (23.1%) had recurrences, with a median disease-free survival (DFS) of 133 months, whereas 11 DuNEN patients (35.5%) had recurrences, with a median DFS of 156 months. The PanNEN patients tended to have primary recurrence in the liver (85.2%), followed by lymph nodes (11.1%). The independent risk factors for short DFS were lymph node metastasis at resection (p = 0.001) and microvascular invasion (p = 0.048). In contrast, the DuNEN patients were likely to have lymph node metastasis (81.8%). The independent risk factors for short DFS were lymph node metastasis at resection (p = 0.003) and large diameter (p = 0.013).

Conclusions: Most initial recurrences of PanNEN occurred in the liver, whereas those of DuNEN appeared in lymph nodes, suggesting that proper diagnosis of the primary site and appropriate imaging methods for surveillance after resection are necessary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-017-6260-1DOI Listing
February 2018

Improving Research Practice in Rat Orthotopic and Partial Orthotopic Liver Transplantation: A Review, Recommendation, and Publication Guide.

Eur Surg Res 2015 29;55(1-2):119-38. Epub 2015 Jul 29.

Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, Aachen, Germany.

Background: Due to a worldwide shortage of donor organs for liver transplantation, alternative approaches, such as split and living donor liver transplantations, were introduced to increase the donor pool and reduce mortality on liver transplant waiting lists. Numerous details concerning the mechanisms and pathophysiology of liver regeneration, small-for-size syndrome, rejection, and tolerance in partial liver transplantation facilitated the development of various animal models. The high number of preclinical animal studies contributed enormously to our understanding of many clinical aspects of living donor and partial liver transplantations.

Summary: Microsurgical rat models of partial orthotopic liver transplantation are well established and widely used. Nevertheless, several issues regarding this procedure are controversial, not clarified, or not yet properly standardized (graft rearterialization, size reduction techniques, etc.). The major aim of this literature review is to give the reader a current overview of rat orthotopic liver transplantation models with a special focus on partial liver transplantation. The aspects of model evolution, microsurgical training, and different technical problems are analyzed and discussed in detail. Our further aim in this paper is to elaborate a detailed publication guide in order to improve the quality of reporting in the field of rat liver transplantation according to the ARRIVE guidelines and the 3R principle. Key Messages: Partial orthotopic liver transplantation in rats is an indispensable, reliable, and cost-efficient model for transplantation research. A certain consensus on different technical issues and a significant improvement in scientific reporting are essential to improve transparency and comparability in this field as well as to foster refinement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000437095DOI Listing
June 2016

Impact of oxygen free radicals in rat partial liver transplantation.

J Surg Res 2014 Oct 9;191(2):469-75. Epub 2014 May 9.

Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany. Electronic address:

Background: Due to the shortage of suitable organs, the demand for partial liver transplantation from living donors has increased worldwide. N-acetylcysteine (NAC) has shown protective effects as a free radical scavenger during hypothermic preservation and warm ischemia-reperfusion liver injury; however, no study has reported the effects in partial liver transplantation. The aim of this study was to analyze the impact of NAC on liver graft microcirculation and graft function after partial liver transplantation in rats.

Methods: Orthotopic partial liver transplantations were performed in 40 rats following cold storage in histidine-tryptophan-ketoglutarate solution for 3 h with 20 mM NAC (NAC group, n = 20) or without (control group, n = 20). We assessed portal circulation, graft microcirculation, and biochemical analyses of plasma at 1, 3, 24, and 168 h after portal reperfusion.

Results: (Control versus NAC, median and range): Portal venous pressure was significantly lower with NAC (P = 0.03). Microcirculation measured by laser Doppler was significantly improved with NAC throughout the time course (P = 0.003). Alanine aminotransferase levels were significantly lower in the NAC group (P < 0.05). Total antioxidative capacity was significantly higher in the NAC group at 1 h after reperfusion (Trolox equivalents: median, 3 μM; range, 2.9-6.7 versus median, 16.45 μM; range, 10.4-18.8). Lipid peroxidation was significantly abrogated in the NAC group (median, 177.6 nmol/mL; range, 75.9-398.1 versus median, 71.5 nmol/mL; range, 58.5-79 at 3 h).

Conclusions: This study showed that NAC treatment during cold storage resulted in improved microcirculation and preservation quality of partial liver graft likely because of enhanced antioxidant capacity and reduced lipid peroxidation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jss.2014.05.002DOI Listing
October 2014

Graft reconditioning with nitric oxide gas in rat liver transplantation from cardiac death donors.

Transplantation 2014 Mar;97(6):618-25

1 Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, Kyoto, Japan. 2 Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany. 3 Address correspondence to: Shintaro Yagi, M.D., Ph.D., Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Liver transplant outcomes using grafts donated after cardiac death (DCD) remain poor.

Methods: We investigated the effects of ex vivo reconditioning of DCD grafts with venous systemic oxygen persufflation using nitric oxide gas (VSOP-NO) in rat liver transplants. Orthotopic liver transplants were performed in Lewis rats, using DCD grafts prepared using static cold storage alone (group-control) or reconditioning using VSOP-NO during cold storage (group-VSOP-NO). Experiment I: In a 30-min warm ischemia model, graft damage and hepatic expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and endothelin-1 (ET-1) were examined, and histologic analysis was performed 2, 6, 24, and 72 hr after transplantation. Experiment II: In a 60-min warm ischemia model, grafts were evaluated 2 hr after transplantation (6 rats/group), and survival was assessed (7 rats/group).

Results: Experiment I: Group-VSOP-NO had lower alanine aminotransferase (ALT) (P<0.001), hyaluronic acid (P<0.05), and malondialdehyde (MDA) (P<0.001), hepatic interleukin-6 expression (IL-6) (P<0.05), and hepatic tumor necrosis factor-alpha (TNF-α) expression (P<0.001). Hepatic eNOS expression (P<0.001) was upregulated, whereas hepatic iNOS (P<0.01) and ET-1 (P<0.001) expressions were downregulated. The damage of hepatocyte and sinusoidal endothelial cells (SECs) were lower in group-VSOP-NO.Experiment II: VSOP-NO decreased ET-1 and 8-hydroxy-2'deoxyguanosine (8-OHdG) expression and improved survival after transplantation by 71.4% (P<0.01).

Conclusion: These results suggest that VSOP-NO effectively reconditions warm ischemia-damaged grafts, presumably by decreasing ET-1 upregulation and oxidative damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000000025DOI Listing
March 2014

How to successfully resect 70 % of the liver in pigs to model an extended hepatectomy with an insufficient remnant or liver transplantation with a small-for-size graft.

Surg Today 2014 Nov 12;44(11):2201-7. Epub 2014 Feb 12.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan,

An insufficient remnant in extended hepatectomy and small-for-size graft in liver transplantation are critical matters in the field of liver surgery, and reliable and reproducible animal models that can provide clinically relevant and reliable data are needed. We herein describe our detailed surgical procedures for performing 70 % hepatectomy in pigs, and discuss the critical anatomical features, key techniques and pitfalls based on our experience. The porcine liver is divided into four lobes. The right lateral lobe (RLL) accounts for 30 % of the liver volume. Important points, such as selective temporal clamping of the arterial branch, confirmation of a related demarcation line, a two-step process to skeletonize Glisson's capsules during liver resection and selective ligation of the portal venous branch to the right medial lobe without inducing any subtle injuries to Glisson's capsules from the RLL to common bile duct, are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-014-0862-zDOI Listing
November 2014

Surgical procedures for a rat model of partial orthotopic liver transplantation with hepatic arterial reconstruction.

J Vis Exp 2013 Mar 7(73):e4376. Epub 2013 Mar 7.

Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University.

Orthotopic liver transplantation (OLT) in rats using a whole or partial graft is an indispensable experimental model for transplantation research, such as studies on graft preservation and ischemia-reperfusion injury, immunological responses, hemodynamics, and small-for-size syndrome. The rat OLT is among the most difficult animal models in experimental surgery and demands advanced microsurgical skills that take a long time to learn. Consequently, the use of this model has been limited. Since the reliability and reproducibility of results are key components of the experiments in which such complex animal models are used, it is essential for surgeons who are involved in rat OLT to be trained in well-standardized and sophisticated procedures for this model. While various techniques and modifications of OLT in rats have been reported since the first model was described by Lee et al. in 1973, the elimination of the hepatic arterial reconstruction and the introduction of the cuff anastomosis technique by Kamada et al. were a major advancement in this model, because they simplified the reconstruction procedures to a great degree. In the model by Kamada et al., the hepatic rearterialization was also eliminated. Since rats could survive without hepatic arterial flow after liver transplantation, there was considerable controversy over the value of hepatic arterialization. However, the physiological superiority of the arterialized model has been increasingly acknowledged, especially in terms of preserving the bile duct system and the liver integrity. In this article, we present detailed surgical procedures for a rat model of OLT with hepatic arterial reconstruction using a 50% partial graft after ex vivo liver resection. The reconstruction procedures for each vessel and the bile duct are performed by the following methods: a 7-0 polypropylene continuous suture for the supra- and infrahepatic vena cava; a cuff technique for the portal vein; and a stent technique for the hepatic artery and the bile duct.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/4376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622100PMC
March 2013

Impact of venous-systemic oxygen persufflation with nitric oxide gas on steatotic grafts after partial orthotopic liver transplantation in rats.

Transplantation 2013 Jan;95(1):78-84

Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany.

Background: Steatotic livers are associated with poor graft function after transplantation. We investigated the effects of venous-systemic oxygen persufflation with nitric oxide gas (VSOP-NO) on steatotic partial livers after transplantation.

Methods: Steatotic livers induced by fasting for 2 days and subsequent refeeding for 3 days with a fat-free, carbohydrate-rich diet were reduced in size by 50% and transplanted into Lewis rats after 3 hr of cold storage in histidine-tryptophan-ketoglutarate solution. Gaseous oxygen with nitric oxide (40 ppm) was insufflated into the grafts through the suprahepatic vena cava during cold storage (VSOP-NO group; n=20). Transplantation of cold-static stored steatotic and normal grafts served as controls (Steatotic-Control and Normal-Control, respectively; n=20 for each group).

Results: The graft microcirculation and portal venous flow were increased by VSOP-NO compared with Steatotic-Control (P<0.001 for both). Serum alanine aminotransferase and interleukin-6 levels were lower in VSOP-NO versus Steatotic-Control group (P=0.03 for both). Messenger RNA expression for inducible nitric oxide synthase, which was increased in Steatotic-Control livers 3 hr after transplantation (P=0.02 vs. that at 1 hr), was suppressed by VSOP-NO. Although serum nitrite levels were decreased 1 hr after transplantation in Steatotic-Control (P=0.06 vs. Normal-Control), the VSOP-NO group showed increased levels comparable to Normal-Control. In livers 24 hr after transplantation, moderate vacuolization of hepatocytes by histology with the immunohistochemical expression of nitrotyrosine, indicative of nitrative stress, was found in Steatotic-Control, whereas these findings were less apparent in VSOP-NO-treated livers.

Conclusions: Application of VSOP-NO for steatotic partial livers reduces hepatocellular damage and improves graft viability and microcirculation after transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0b013e318277e2d1DOI Listing
January 2013

Splenectomy does not offer immunological benefits in ABO-incompatible liver transplantation with a preoperative rituximab.

Transplantation 2012 Jan;93(1):99-105

Department of Hepatobiliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan.

Background: Preformed anti-ABO antibodies are primarily responsible for antibody-mediated rejection (AMR) after ABO-incompatible (ABO-I) liver transplantation (LT) resulting in lethal hepatic necrosis and biliary complications. Splenectomy, an integral part of protocol for ABO-I LT, decreases anti-ABO antibodies. With the preoperative rituximab prophylaxis, role of the splenectomy for ABO-I LT is now under debate. We investigated the necessity of splenectomy by retrospective analyses of the short-term anti-ABO antibody response and long-term outcomes of ABO-I LT.

Methods: Thirty-seven ABO-I LTs performed from May 2006 through July 2009, at Kyoto University Hospital, Kyoto, Japan, were retrospectively analyzed. Twenty-seven patients who underwent splenectomy (splenectomy group) received 329.6 ± 35.8 mg rituximab 17.7 ± 11.9 days before living donor LT. Ten patients without splenectomy (nonsplenectomy group) received 320.0 ± 10.3 mg rituximab 26.6 ± 21.3 days before transplantation. All patients received a posttransplant hepatic artery infusion with prostaglandin E1 and methylprednisolone. Perioperative anti-ABO immunoglobulin M and immunoglobulin G antibody titers, rejections, biliary complications, infections, and survival results were compared.

Results: Preoperative rituximab with plasma exchange effectively reduced anti-ABO antibodies in both patient groups at the time of LT. There was no statistically significant difference observed in anti-ABO immunoglobulin M and immunoglobulin G antibody titers between the "splenectomy" and "nonsplenectomy" groups during the initial 8 weeks. The clinical outcomes, including AMR, biliary complications, infections, and survival, were similar in both the groups.

Conclusions: Preoperative rituximab effectively decreased the anti-ABO antibodies sufficiently to prevent the AMR irrespective of splenectomy. Splenectomy does not offer any immunological benefit in ABO-I LT with preoperative rituximab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0b013e318239e8e4DOI Listing
January 2012

Impact of venous systemic oxygen persufflation supplemented with nitric oxide gas on cold-stored, warm ischemia-damaged experimental liver grafts.

Liver Transpl 2012 Feb;18(2):219-25

Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, Aachen, Germany.

The increasing shortage of donor organs has led to the increasing use of organs from non-heart-beating donors. We aimed to assess the impact of venous systemic oxygen persufflation (VSOP) supplemented with nitric oxide (NO) gas during the cold storage (CS) of warm ischemia (WI)-damaged experimental liver grafts. Rat livers (n = 5 per group) were retrieved after 30 minutes of WI induced by cardiac arrest (the WI group) and were thereafter preserved for 24 hours by CS in histidine tryptophan ketoglutarate solution. During CS, gaseous oxygen was insufflated via the caval vein with 40 ppm NO (the VSOP-NO group) or without NO (the VSOP group). Cold-stored livers without WI served as controls. Liver viability was assessed after the preservation period by normothermic isolated reperfusion for 45 minutes with oxygenated Krebs-Henseleit buffer. After 45 minutes of reperfusion, the VSOP-NO-treated livers showed significantly lower alanine aminotransferase values than the WI-damaged livers (10.2 ± 0.2 versus 78.2 ± 14.6 IU/L), whereas the control livers showed no differences from the VSOP-NO-treated livers. The mitochondrial enzyme release was lower in the VSOP-NO group (4.0 ± 0.7 IU/L) versus the WI group (18.2 ± 4.9 IU/L). An increased portal vein pressure was observed throughout reperfusion (45 minutes) in the WI group (21.7 ± 0.2 mm Hg) versus the VSOP-NO group (12.2 ± 0.8 mm Hg) and the control group (19.9 ± 0.4 mm Hg). Furthermore, the NO concentration in the perfusate after 5 minutes of reperfusion was highest in the VSOP-NO group. The release of malondialdehyde into the perfusate was significantly reduced in the VSOP-NO group (0.9 ± 0.1 nmol/mL) versus the WI group (31.3 ± 5.3 nmol/mL). In conclusion, the resuscitation of livers after 30 minutes of WI to a level comparable to that of nonischemically damaged livers is possible with VSOP supplemented with NO gas. Moreover, the application of VSOP with NO minimizes the extent of injuries caused by oxygen free radicals during preservation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.22442DOI Listing
February 2012
-->