Feasibility and Outcomes of Direct Dual Portal Vein Anastomosis in Living Donor Liver Transplantation Using the Right Liver Graft With Anatomic Portal Vein Variations.

BACKGROUND: Portal vein (PV) reconstruction is a crucial factor in successful living donor liver transplantation (LDLT). In LDLT using the right liver grafts with anatomic PV variations, we sometimes encounter dual PV anastomosis. In this study we describe PV variations of donor liver in detail as well as our experiences with PV reconstruction in right liver grafts with PV variations. METHODS: We performed LDLT in 149 recipients between 2002 and 2016. PV variations of donor liver were classified into 3 major anatomic patterns, and we retrospectively analyzed the procedure and postoperative complications of PV anastomosis. RESULTS: PV variations in donor livers were classified as type A (normal type) in 125 patients, type B (trifurcation type) in 7 (4.7%), and type C (caudal origin of the right posterior branch) in 17 (11.4%). Among 75 right liver grafts, 10 (13.3%) had anatomic PV variations. In 9 of 10 recipients, dual PV of the graft were anastomosed to dual PV branches of the recipient in direct end-to-end fashion. In the remaining recipient, the posterior portal branch of the graft was anastomosed to the recipient portal trunk through the interposed venous graft in end-to-end fashion and the anterior portal branch of the graft was anastomosed to the side wall of the interposed venous graft. These 10 recipients did not develop any postoperative complications associated with PV anastomosis, although 3 of the 149 recipients (2.0%) developed complications associated with PV anastomosis, such as thrombosis and necrosis. CONCLUSION: Dual PV anastomosis of the right liver graft is safe and feasible in LDLT, even in anatomic PV variations.

De Novo Malignancy Following Adult-to-Adult Living Donor Liver Transplantation Focusing on Posttransplantation Lymphoproliferative Disorder.

OBJECTIVE: In patients with living donor liver transplantation (LDLT), late-onset complications sometimes develop because of long-term use of immunosuppressive drugs. One of the immunosuppressive drug-related complications is de novo malignancies resulting in reduced survival. PATIENTS AND METHODS: Among 153 patients undergoing LDLT, we retrospectively reviewed the medical records of 97 adult recipients (February 2002 to May 2017), who had been followed-up at our hospital for more than one year after LDLT. The median age was 52 years old (20-70) and the median observational period was 6.9 years (2.4-15.3). RESULTS: De novo malignancy after adult LDLT developed in 11.3% (11/97) of patients, including posttransplantation lymphoproliferative disorder (PTLD) (n = 4) (2 in the brain and 2 in abdominal lymph nodes), lung cancer (n = 1), pancreatic cancer (n = 1), gastric cancer (n = 1), laryngeal cancer (n = 1), lower gingival cancer (n = 1), bladder cancer (n = 1), and melanoma (n = 1). Age at cancer diagnosis ranged from 36 to 70 years old with an average age of 61 years. The interval from LDLT to cancer diagnosis was 8.3 years (3.9-12.2). Four patients (36.6%) including PTLD (n = 2), lung cancer (n = 1), and pancreatic cancer (n = 1) died of cancer and all of them were diagnosed with cancer within 10 years after LDLT. Six patients were diagnosed with cancer more than 10 years after LDLT and all of them survived after treatment of cancer. CONCLUSION: De novo malignancy was found in 11.3% of LDLT patients, and more than half of this population subset developed tumors 10 years after LDLT. Long-term close follow-up should be performed by taking any kinds of de novo malignancy into consideration.

High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis.

Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis.

Discontinuation of Hepatitis B Immunoglobulin by Long-term Hepatitis B Vaccine Inoculation in Preventing Hepatitis B Recurrence After Liver Transplantation.

INTRODUCTION: For the patients undergoing liver transplantation for hepatitis B virus (HBV)-related diseases, hepatitis B immunoglobulin (HBIG) should be administered to prevent reinfection. Because HBIG is highly expensive and a blood product, an alternative strategy using HBV vaccination has been made in an attempt to discontinue use of HBIG. The aim of this study was to evaluate the impact of long-term HBV vaccination for discontinuation of HBIG, paying attention to the status of active immunization using T-cell proliferation assay. PATIENTS AND METHODS: Among the 144 recipients who underwent liver transplantation in our hospital, 16 had HBV-related liver diseases; the 14 patients who had received vaccination were subjects in our study. To evaluate the status of active immunization, T-cell proliferation was examined by counting the number of T cells after adding HBV vaccine to the culture supernatant of T cells, and tumor necrosis factor α and interferon γ were measured in the culture supernatant. RESULTS: The ratio of male/female was 13/1 (median age: 55 years; range: 37 years to 67 years). The median follow-up time was 102 months (range: approximately 14 months to 148 months). All 14 patients were free of HBV recurrence. HBIG-free status could be achieved in 9 patients (64.3%) during the treatment period for more than 50 months after beginning of HBV vaccination, of whom 5 (35.7%) became HBV vaccine-free. T-cell proliferation was confirmed by fact that the stimulation index ranged from 2.34 to 5.2 in the patients who were HBIG-free. CONCLUSION: Long-term HBV vaccination after LT is a useful and effective treatment in preventing HBV recurrence, allowing the discontinuation of HBIG treatment.

Influence of Angiotensin-converting Enzyme Genetic Polymorphism on Late Renal Dysfunction After Adult-to-adult Living-donor Liver Transplantation.

BACKGROUND: Late renal dysfunction (LRD) is known to be one of the most important complications to affect long-term outcome after living-donor liver transplantation (LDLT). The relationship between angiotensin-converting enzyme insertion (I)/deletion (D) gene polymorphism and renal function after LDLT are still unknown. The aim of this study was to elucidate the risk factors for LRD after LDLT, focusing on ACE gene polymorphism. MATERIALS AND METHODS: Among the 94 recipients who underwent adult-to-adult LDLT between March 2002 and September 2009, the total number of subjects who survived more than 1 year after LDLT and in whom angiotensin-converting enzyme genotype could be measured was 64. LRD was defined as estimated glomerular filtration rate level less than 60 mL/min/1.73 m(2) at any point after 1 year from undergoing LDLT. RESULTS: LRD was found in 24 patients (37.5%). The incidence of LRD was significantly higher in D/D type than in I/I or I/D type: 85.7% (6/7) vs. 42.1% (8/19), 35.7% (10/38) (P = .010). Preoperative estimated glomerular filtration rate was significantly lower in D/D type than in I/I, I/D types, and postoperatively they were significantly lower in D/D type at 2, 3, and 4 years after LDLT. By multivariate analysis, age and hypertension were the independent risk factors for LRD. The 10-year survival rate was much lower in the recipients with LRD than in those without LRD at 66.7% versus 87.5%, respectively (P = .053). CONCLUSION: In conclusion, age and hypertension were determined as significant independent risk factors for LRD after adult-to-adult LDLT, and the recipients with D/D genotype should be strictly cared for the development of LRD.

Cord blood processing by a novel filtration system.

OBJECTIVES: Availability of cord blood (CB) processing has been limited by the need for electrically aided centrifugal techniques, which often produce only low final cell product yield. Here, we describe development and characterization of a novel filter device aimed at allowing CB processing, using gentle gravity-led flow. MATERIALS AND METHODS: CB was processed with a novel filter device (CellEffic CB, consisting of non-woven fabric), without any centrifugation. Cells were harvested by flushing the filter with either HES or physiological saline solution (SALINE). Differential cell counts and viability analysis, combined with Fluorescence-Activated Cell Sorting (FACS) (total nucleated cells [TNC], mononuclear cells [MNC], CD45+ CD34+ cells, hematopoietic precursor cells [HPCs]) and clonogenic assay, were employed for analysis of CB pre- and post-processing, and after freeze/thawing. RESULTS: Processing using the novel filter yielded high quality RBC depletion while maintaining good recovery of TNC, MNC, CD34+, HPCs and colony forming unit (CFU) output. The filter performed equally well using HES or SALINE. Gravity-led flow provided gentle cell movement and protection of the stem cell compartment. Post-thaw CFU output was maintained particularly, an important indicator for CB banking. CONCLUSIONS: Geographical limitations of CB transplantation and banking have required a non-electrical, non-centrifugal solution. This novel filter CellEffic CB device revealed rapid yet gentle cell processing while maintaining the stem/progenitor cell compartment required for both haematological and regenerative medicine therapies.

Fatal carotid blowout syndrome after BNCT for head and neck cancers.

Boron neutron capture therapy (BNCT) is high linear energy transfer (LET) radiation and tumor-selective radiation that does not cause serious damage to the surrounding normal tissues. BNCT might be effective and safe in patients with inoperable, locally advanced head and neck cancers, even those that recur at previously irradiated sites. However, carotid blowout syndrome (CBS) is a lethal complication resulting from malignant invasion of the carotid artery (CA); thus, the risk of CBS should be carefully assessed in patients with risk factors for CBS after BNCT. Thirty-three patients in our institution who underwent BNCT were analyzed. Two patients developed CBS and experienced widespread skin invasion and recurrence close to the carotid artery after irradiation. Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion from recurrent lesions after irradiation is an ominous sign of CBS onset and lethal consequences.

Total skin electron beam therapy using an inclinable couch on motorized table and a compensating filter.

Total skin electron beam is a specialized technique that involves irradiating the entire skin from the skin surface to only a few millimetres in depth. In the Stanford technique, the patient is in a standing position and six different directional positions are used during treatment. Our technique uses large electron beams in six directions with an inclinable couch on motorized table and a compensating filter was also used to spread the electron beam and move its intensity peak. Dose uniformity measurements were performed using Gafchromic films which indicated that the surface dose was 2.04 ± 0.05 Gy. This technique can ensure the dose reproducibility because the patient is fixed in place using an inclinable couch on a motorized table.

Hypertension and hepatitis C virus infection are strong risk factors for developing late renal dysfunction after living donor liver transplantation: significance of renal biopsy.

BACKGROUND: Late renal dysfunction (LRD) after liver transplantation develops due to several factors such as viral hepatitis, calcineurin inhibitor, diabetes mellitus, and hypertension. The aim of our study was to clarify the risk factors for LRD after living donor liver plantation (LDLT) by using simple criteria for LRD and paying special attention to the significance of renal biopsy. PATIENTS AND METHODS: Among the 98 recipients undergoing LDLT between March 2002 and June 2008, there were 77 patients who survived more than 1 year and had been followed at our clinic. LRD was simply defined as a postoperative serum creatinine level of 1.5/L or more at any point in time after 1 year from undergoing LDLT. The perioperative risk factors for developing LRD after LDLT were analyzed by uni- and multivariate analyses, and regardless of serum creatinine level, a renal biopsy was indicated when the patient developed clinical symptoms. RESULTS: Comparing the risk factors between 22 patients with LRD and 55 without LRD, univariate analysis revealed recipient's age, generation, hypertension, hepatitis C virus (HCV) antibody-positive, pretransplantation serum creatinine level, and graft-to-recipient weight ratio to be significant risk factors. By multivariate analysis, HCV and hypertension were selected as independent risk factors. Renal biopsy was indicated in the 4 patients with proteinuria, all of whom were positive for HCV. However, by histologic and/or electron micrographic analyses, only 1 patient was diagnosed with HCV-related membranous proliferative nephritis, 1 with diabetic nephropathy, and 2 with drug (tacrolimus) -induced renal dysfunction. CONCLUSION: Although HCV and hypertension were determined to be independent risk factors for LRD after LDLT, a renal biopsy should be performed when clinical symptoms develop regardless of creatinine levels to provide appropriate treatment.

Biliary complications in 108 consecutive recipients with duct-to-duct biliary reconstruction in living-donor liver transplantation.

BACKGROUND: Biliary complications remain the leading cause of postoperative complications after living-donor liver transplantation (LDLT) in patients undergoing duct-to-duct choledochocholedochostomy. The aim of this study was to analyze the causes of these complications. METHODS: One hundred eight patients who underwent LDLT with duct-to-duct biliary reconstruction at Mie University Hospital were enrolled in this study. The mean follow-up time was 58.4 months (range, 3-132). The most recent 18 donors underwent indocyanine green (ICG) fluorescence cholangiography for donor hepatectomy. The development of biliary complications was retrospectively analyzed. Biliary complications were defined as needing endoscopic or radiologic treatment. RESULTS: Biliary leakages and strictures occurred in 6 (5.6%) and 15 (13.9%) of the recipients, respectively, and 3 donors (2.7%) experienced biliary leakage. However, since the introduction of ICG fluorescence cholangiography, we have not encountered any biliary complications in either donors or recipients. Biliary leakage was an independent risk factor for the development of biliary stricture (P = .013). Twelve (80%) of the 15 recipients with biliary stricture had successful nonoperative endoscopic or radiologic management, and 3 patients underwent surgical repair with hepaticojejunosotomy. CONCLUSIONS: Biliary leakage was an independent factor for biliary stricture. ICG fluorescence cholangiography might be helpful to reduce biliary complications after LDLT in both donors and recipients.

Project for the development of the linac based NCT facility in University of Tsukuba.

A project team headed by University of Tsukuba launched the development of a new accelerator based BNCT facility. In the project, we have adopted Radio-Frequency Quadrupole (RFQ)+Drift Tube Linac (DTL) type linac as proton accelerators. Proton energy generated from the linac was set to 8MeV and average current was 10mA. The linac tube has been constructed by Mitsubishi Heavy Industry Co. For neutron generator device, beryllium is selected as neutron target material; high intensity neutrons are generated by the reaction with beryllium and the 80kW proton beam. Our team chose beryllium as the neutron target material. At present beryllium target system is being designed with Monte-Carlo estimations and heat analysis with ANSYS. The neutron generator consists of moderator, collimator and shielding. It is being designed together with the beryllium target system. We also acquired a building in Tokai village; the building has been renovated for use as BNCT treatment facility. It is noteworthy that the linac tube had been installed in the facility in September 2012. In BNCT procedure, several medical devices are required for BNCT treatment such as treatment planning system, patient positioning device and radiation monitors. Thus these are being developed together with the linac based neutron source. For treatment planning system, we are now developing a new multi-modal Monte-Carlo treatment planning system based on JCDS. The system allows us to perform dose estimation for BNCT as well as particle radiotherapy and X-ray therapy. And the patient positioning device can navigate a patient to irradiation position quickly and properly. Furthermore the device is able to monitor movement of the patient׳s position during irradiation.

Reirradiation for recurrent malignant brain tumor with radiotherapy or proton beam therapy. Technical considerations based on experience at a single institution.

BACKGROUND AND PURPOSE: Radiotherapy for recurrent malignant brain tumors is usually limited because of the dose tolerance of the normal brain tissue. The goal of the study was to evaluate the efficacy and feasibility of reirradiation for patients with recurrent malignant brain tumors. PATIENTS AND METHODS: The subjects comprised 26 patients with recurrent malignant brain tumors treated with conventional radiotherapy (RT, n = 8), stereotactic radiotherapy (SRT, n = 10), and proton beam therapy (PBT, n = 8) at our institute. Fifteen patients had glioblastoma, 6 had WHO grade 3 glioma, and 5 had other tumors. The dose of initial radiotherapy was 34.5-94.4 Gy. Different radiation schedules were compared using the equivalent dose in 2-Gy fractions. RESULTS: Reirradiation was completed in all patients without a severe acute reaction. The reirradiation doses were 30-60 Gy (median, 42.3 Gy) and the total doses for the initial and second treatments were 64.5-150.4 Gy (median, 100.0 Gy). Currently, 11 patients are alive (median follow-up period, 19.4 months) and 15 are dead. The median survival and local control periods after reirradiation of the 26 patients were 18.3 and 9.3 months, respectively. For the 15 patients with glioblastoma, these periods were 13.1 and 11.0 months, respectively. Two patients showed radiation necrosis that was treated by surgery or conservative therapy. CONCLUSION: Reirradiation for recurrent malignant brain tumor using conventional RT, SRT, or PBT was feasible and effective in selected cases. Further investigation is needed for treatment optimization for a given patient and tumor condition.

Proton beam therapy for malignancy in Bloom syndrome.

BACKGROUND AND PURPOSE: Bloom syndrome is a DNA repair disorder that is hypersensitive to radiotherapy. We describe the first case in which proton beam therapy (PBT) was used in a patient with Bloom syndrome to treat oropharyngeal cancer. PATIENTS AND METHODS: The patient was a 32-year-old woman with Bloom syndrome who was diagnosed with oropharyngeal cancer staged as T2N2bM0 poorly differentiated squamous cell carcinoma. The primary tumor was located on the right tongue base and extended to the right lateral pharyngeal wall. Several right upper region lymph nodes were positive for metastases. RESULTS: We selected PBT in anticipation of dose reduction to normal tissue. The clinical target volume was defined as the area of the primary tumor and lymph node metastases plus an 8-mm margin. After treatment with 36 GyE (Gray equivalent) in 20 fractions (4-5 fractions per week), dietary intake was decreased by mucositis and intravenous hyperalimentation was started. Termination of treatment for 2.5 weeks was required to relieve mucositis. Administration of 59.4 GyE in 33 fractions markedly reduced the size of the primary tumor, but also caused moderate mucositis that required termination of PBT. One month later, lung metastases and breast cancer developed and the patient died 9 months after PBT. At this time the reduction in size of the primary tumor was maintained without severe late toxicity. CONCLUSION: We obtained almost complete response for a radiosensitive patient with a deficiency of DNA repair, indicating the excellent dose concentration of proton beam therapy.

Living donor liver transplantation for the patients with portal vein thrombosis: use of an interpositional venous graft passed posteriorly to the pancreatic parenchyma without using jump graft.

BACKGROUND: It is difficult to reconstruct the portal vein (PV) using a long interpositional venous graft in living donor liver transplant (LDLT) patients with portal vein thrombosis (PVT), which involves the confluence of the superior mesenteric vein (SMV) and splenic vein (SV). We successfully performed LDLT for three patients with PVT using an interpositional vascular conduit passing posterior to the pancreas without a jump graft. METHODS: Three of 130 patients who underwent LDLT in our hospital between March 2002 and June 2011 required this technique. After indentifying the location of the SMV, SV and gastrocolic trunk, we ligated and cut the posterior superior pancreaticoduodenal vein and other short branches from the PV. The PV was drawn inferiorly to the pancreas and transected at the confluence of SMV and SV. The external iliac vein or internal jugular vein was sacrificed as a graft for anastomosis to the cut end of the SMV using 6-0 polypropylene running sutures. Then the venous graft was drawn superiorly to the pancreas by passing it posterior to the pancreas parenchyma for anastomosis to the liver graft PV. The interpositional vein was placed posterior to the pancreas where the PV used to be. RESULTS: All three patients displayed favorable postoperative courses with the Doppler ultrasound demonstrating good portal flow perioperatively. The postoperative portogram demonstrated patency of the vascular graft. CONCLUSION: This method is easy and helpful to treat portal vein thrombosis, by providing the shortest route between the PV of the donor and the SMV of the recipient.

Two-week cast immobilization induced chronic widespread hyperalgesia in rats.

It has been postulated that physical immobilization is an essential factor in developing chronic pain after trauma or surgery in an extremity. However, the mechanisms of sustained immobilization-induced chronic pain remain poorly understood. The present study, therefore, aimed to develop a rat model for chronic post-cast pain (CPCP) and to clarify the mechanism(s) underlying CPCP. To investigate the effects of cast immobilization on pain behaviours in rats, one hindlimb was immobilized for 2 weeks with a cast and remobilization was conducted for 10 weeks. Cast immobilization induced muscle atrophy and inflammatory changes in the immobilized hindlimb that began 2 h after cast removal and continued for 1 week. Spontaneous pain-related behaviours (licking and reduction in weight bearing) in the immobilized hindlimb were observed for 2 weeks, and widespread mechanical hyperalgesia in bilateral calves, hindpaws and tail all continued for 5-10 weeks after cast removal. A sciatic nerve block with lidocaine 24 h after cast removal transitorily abolished bilateral mechanical hyperalgesia in CPCP rats, suggesting that sensory inputs originating in the immobilized hindlimb contribute to the mechanism of both ipsilateral and contralateral hyperalgesia. Intraperitoneal injection of the free radical scavengers 4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxy1 or N-acetylcysteine 24 h after cast removal clearly inhibited mechanical hyperalgesia in bilateral calves and hindpaws in CPCP rats. These results suggest that cast immobilization induces ischaemia/reperfusion injury in the hindlimb and consequent production of oxygen free radicals, which may be involved in the mechanism of widespread hyperalgesia in CPCP rats.

Prospective randomised comparative study of visual foam sclerotherapy alone or in combination with ultrasound-guided foam sclerotherapy for treatment of superficial venous insufficiency: preliminary report.

OBJECTIVE: The aim of the study is to compare ultrasound-guided foam sclerotherapy (UGFS: injection of foam sclerosant under ultrasound guidance) of the great saphenous vein (GSV) combined with visual foam sclerotherapy (VFS: injection of foam sclerosant under visual control) for varicose tributary veins and VFS alone in the treatment of GSV reflux. DESIGN AND METHODS: A total of 133 limbs in 97 patients with GSV reflux were randomised to receive either VFS alone or VFS combined with UGFS. In both groups, 1% polidocanol foam was used. Assessments included duplex ultrasonography, evaluation of Venous Clinical Severity Scores (VCSS) and CEAP (clinical, etiologic, anatomic, and pathophysiologic) scores. Ultrasonographic inspection of the foam in the GSV was carried out during 5 min before compression was applied. The primary 'end' point of the study was obliteration of the GSV at 6 months. RESULTS: A total of 51 limbs in 48 patients were treated with UGFS + VFS and the remaining 52 limbs in 49 patients were treated with VFS alone. There were no significant inter-group differences in patient age, male: female ratio, height, weight, body mass index, CEAP clinical scores or VCSS. The GSV diameter was 6.0 ± 1.7 mm (median ± interquartile range) in the UGFS + VFS group and 5.7 ± 1.6 mm in the VFS group (p = 0.419). The mean injected volume of foam for varicose tributary veins was 4 ± 2 ml in the UGFS + VFS group and 6 ± 2 ml in the VFS group, a significantly higher amount of foam being used in the latter (p < 0.001). However, the mean total amount of foam was greater in limbs treated with UFGS + VFS than in those treated with VFS alone (p = 0.017). Ultrasonographic inspection revealed complete vasospasm of the GSV in 37 (72.5%) limbs in the UGFS + VFS group and 29 (55.8%) in the VFS group during sclerotherapy (p = 0.097). At 6-month follow-up, complete occlusion was found in 23 limbs (45.1%) treated with UGFS + VFS and in 22 limbs (42.3%) treated with VFS. The difference between the two groups was not significant (p = 0.775). Reflux was absent in 30 limbs (58.8%) treated with UGFS + VFS and in 37 (71.2%) treated with VFS (p = 0.190). There was no inter-group difference in post-treatment VCSS (p = 0.223). CONCLUSIONS: These results show that UGFS + VFS and VFS are equally effective for the treatment of GSV reflux, despite the lower volume of foam used for VFS alone.