Long-Term Outcomes of a Japanese Prospective Multicenter Registry Using a Heparin-Bonded Expanded Polytetrafluoroethylene Graft for Above-the-Knee Femoropopliteal Bypasses.

BACKGROUND: Despite the widespread use of PROPATEN®, a bioactive heparin-bonded expanded polytetrafluoroethylene graft, in bypass surgery, there are only a few reports of long-term results. We evaluated the long-term results of PROPATEN®use for above-knee femoropopliteal bypass (AKFPB).Methods and Results: After PROPATEN®-based AKFPB, patients were prospectively registered at 20 Japanese institutions between July 2014 and October 2017 to evaluate long-term results. During the median follow-up of 76 months (interquartile range 36-88 months) for 120 limbs (in 113 patients; mean [±SD] age 72.7±8.1 years; 66.7% male; ankle-brachial index [ABI] 0.45±0.27; lesion length 26.2±5.7 cm; chronic limb-threatening ischemia in 45 limbs), there were 8 major amputations; however, clinical improvement was sustained (mean [±SD] ABI 0.87±0.23) and the Rutherford classification grade improved in 105 (87.5%) limbs at the latest follow-up. At 8 years, the primary patency, freedom from target-lesion revascularization, secondary patency, survival, and amputation-free survival, as estimated by the Kaplan-Meier method, were 66.3±4.8%, 71.5±4.4%, 86.5±3.4%, 53.1±5.0%, and 47.4±5.3%, respectively. CONCLUSIONS: This multicenter prospective registry-based analysis showed sustained excellent clinical improvement and secondary patency for up to 8 years following PROPATEN®-based AKFPB. PROPATEN®constitutes a durable and good revascularization option for complex superficial femoral artery lesions, especially when endovascular treatment is inappropriate or an adequate venous conduit is unavailable.

Protective Effects of Hydrogen Gas Inhalation for Hindlimb Ischaemia-Reperfusion Injury in a Mouse Model.

OBJECTIVE: Ischaemia-reperfusion (I/R) injury is a severe post-operative complication that triggers an inflammatory response and causes severe damage. Hydrogen gas has anti-oxidant and anti-apoptotic properties and has been shown to be safe in humans. The study aimed to investigate whether hydrogen gas protects against skeletal muscle I/R injury. METHODS: Experimental basic research using mice. A total of 160 eight to 10 week old albino laboratory bred strain of house mice (25.8 ± 0.68 g) were used in this study. The mice were cable tied to the hindlimb under anaesthesia and then placed in an anaesthesia box filled with air and 2% isoflurane (control group); 80 mice were additionally subjected to 1.3% hydrogen gas in this mix (hydrogen group). After two hours, the cable ties were removed to initiate reperfusion, and hydrogen inhalation lasted for six hours in the hydrogen group. After six hours, the mice were taken out of the box and kept in cages under standard conditions until time for observation at 16 different time points after reperfusion: zero, two, four, six, eight, and 10 hours and one, two, three, four, five, six, seven, 14, 21, and 28 days. Five mice were sacrificed using excess anaesthesia at each time point, and the bilateral hindlimb tissues were harvested. The inflammatory effects of the I/R injury were assessed by evaluating serum interleukin-6 concentrations using enzyme linked immunosorbent assay, as well as histological and immunohistochemical analyses. Untreated mice with I/R injury were used as controls. RESULTS: Hydrogen gas showed protective effects associated with a reduction in inflammatory cell infiltration (neutrophils, macrophages, and lymphocytes), a reduced area of damaged muscle, maintenance of normal muscle cells, and replacement of damaged muscle cells with neoplastic myocytes. CONCLUSION: Inhalation of hydrogen gas had a protective effect against hindlimb I/R injury in mice, in part by reducing inflammatory cell infiltration and in part by preserving normal muscle cells.

Noninvasive graft monitoring using donor-derived cell-free DNA in Japanese liver transplantation.

AIM: To evaluate the use of donor-derived cell-free DNA (dd-cfDNA) in diagnosing graft injuries in Japanese liver transplantation (LTx), including family-related living donors. METHODS: A total of 321 samples from 10 newly operated LTx recipients were collected to monitor the early dynamics of dd-cfDNA levels after LTx. Fifty-five samples from 55 recipients were collected during protocol biopsies (PB), whereas 36 samples from 27 recipients were collected during event biopsies, consisting of 11 biopsy-proven acute rejection (AR), 20 acute dysfunctions without rejection (ADWR), and 5 chronic rejections. The levels of dd-cfDNA were quantified using a next-generation sequencer based on single nucleotide polymorphisms. RESULTS: The dd-cfDNA levels were elevated significantly after LTx, followed by a rapid decline to the baseline in patients without graft injury within 30 days post-LTx. The dd-cfDNA levels were significantly higher in the 11 samples obtained during AR than those obtained during PB (p < 0.0001), which decreased promptly after treatment. The receiver operator characteristic curve analysis of diagnostic ability yielded areas under the curve of 0.975 and 0.897 for AR (rejection activity index [RAI] ≥3) versus PB and versus non-AR (ADWR + PB). The dd-cfDNA levels during AR were elevated earlier and correlated more strongly with the RAI (r = 0.740) than aspartate aminotransferase/alanine aminotransferase. The dd-cfDNA levels were neither associated with graft fibrosis based on histology nor the status of donor-specific antibodies in PB samples. CONCLUSIONS: Donor-derived cell-free DNA serves as a sensitive biomarker for detecting graft injuries in LTx. Further large-scale cohort studies are warranted to optimize its use in differentiating various post-LTx etiologies.

Impact of wound management strategies after revascularization for chronic limb-threatening ischemia.

OBJECTIVE: There is no established consensus or guidelines for wound management after revascularization for patients with chronic limb-threatening ischemia (CLTI) without severe infection. This study is designed to evaluate the clinical effect of the wound management strategy on toe wounds after revascularization for CLTI. METHODS: This retrospective cohort study was performed at eight institutions affiliated with Keio University School of Medicine in Japan and included 261 patients who underwent revascularization for CLTI between April 2019 and July 2021. We identified 132 patients with toe wounds from the database who had restored in-line blood flow to the foot. Patients were divided into two groups by the timing of toe resection after revascularization, which dictated the wound management policy. Group A (62 patients) underwent early toe amputation for suspected osteomyelitis, whereas group B (70 patients) underwent watchful waiting. The primary outcome was wound healing after revascularization; the secondary outcome was major amputation. We compared outcomes between groups A and B after propensity score matching. RESULTS: Using propensity score matching, each patient in group A (33 patients) was matched with a patient in group B (33 patients). Wound healing in matched group A was significantly better than that in matched group B (respectively: 1-year wound healing rate: 90.0% vs 68.2%, P < .001; median wound healing time: 65 days vs 258 days, P < .01). Although five major amputations were necessary in matched group B, none were required in matched group A (P = .05). The high rate of major amputations in group B was attributed to the sudden exacerbation of infection. Limb salvage rate in matched group A exceeded matched group B (100.0% vs 90.5%: 1-year limb salvage rate, P = .02). CONCLUSIONS: Early toe amputation for highly suspected osteomyelitis in patients with CLTI with toe wounds may expedite wound healing compared with watchful waiting, potentially avoiding unnecessary major amputation. Considering the wound management strategy is crucial when evaluating wound healing outcomes in patients with CLTI with revascularization.

Five-Year Outcomes of the Bioresorbable Peripheral Remedy Stent in the Treatment of Iliac Artery Disease.

PURPOSE: To evaluate the 5-year performance of a bioresorbable vascular scaffold, the Remedy stent, for the treatment of iliac artery atherosclerotic disease. MATERIALS AND METHODS: This prospective, multicenter, single-arm clinical study evaluated 97 patients (97 lesions) with symptomatic TransAtlantic Inter-Society Consensus II A/B iliac artery lesions for 5 years after stent placement. The primary efficacy end point was 12-month primary patency compared with the prespecified standard derived from historical data with metallic stents, and the primary safety end point was the occurrence of major adverse clinical events within 5 years. All angiographic and computed tomography angiographic findings were evaluated by an independent core laboratory for quantitative vessel analysis. RESULTS: The 12-month primary patency rate was 88.6% (95% CI, 80.1%-94.4%), which was lower than the prespecified standard. No significant difference was noted between the diameter stenosis at 9 and 12 months. There were no device- or procedure-related deaths, major amputation, or distal embolization during the follow-up period. The ankle-brachial index maintained significant improvement through the 5-year period compared with that at baseline. The Kaplan-Meier estimates of freedom from target lesion revascularization (TLR), major adverse cardiovascular events, and major adverse cardiovascular and limb events were 95.8%, 91.7%, and 87.5% at 12 months and 85.4%, 72.1%, and 62.5% at 5 years, respectively. CONCLUSIONS: The 5-year follow-up outcomes, including freedom from TLR, of the Remedy stent in iliac artery lesions were satisfactory, with a good safety profile. Nevertheless, the 12-month primary patency did not meet the expected standard compared with that of contemporary metallic stents.

Prediction of need for bowel resection in acute superior mesenteric artery occlusion: A retrospective study of 48 Japanese patients.

Aim: This study aimed to predict cases of acute superior mesenteric artery (SMA) occlusion requiring bowel resection using occlusion site and time from symptom onset to diagnosis at five Japanese institutions. Advances in imaging, endovascular treatment, and perioperative management have improved the clinical outcomes of patients with acute SMA occlusion; however, in clinical practice it remains difficult to effectively determine patients requiring bowel resection. Methods: We retrospectively analyzed the data of 48 patients (mean age: 82.5 y; male: 37.5%) diagnosed with acute SMA occlusion between June 2009 and August 2018. Background data of patients who required and did not require bowel resection were compared. A multivariable predictive model was developed using the time from symptom onset to diagnosis and whether SMA occlusion was proximal, including the origin of the middle colic artery. Results: Fifteen patients (31.3%) died during the hospital stay. Atrial fibrillation (83.3%) was the most common comorbidity. The median time from symptom onset to diagnosis was 13.0 (interquartile range, 4.75-24.0) h. Laparotomy, bowel resection, and thrombus embolectomy were performed in 41 (85.4%), 26 (54.2%), and 21 (43.8%) patients, respectively. A logistic regression model achieved 78.6% sensitivity in predicting cases not requiring bowel resection. Proximal occlusion was significantly associated with the requirement for bowel resection (P = .039). Conclusion: The time from symptom onset to diagnosis and occlusion site contributed to high sensitivity in determining the need for bowel resection in patients with acute SMA occlusion. Further prospective studies are warranted to investigate the clinical impact of this model.

Long-term Outcomes of the Endurant and Excluder Stent Grafts for Endovascular Aneurysm Repair in a Japanese Cohort.

PURPOSE: To compare the long-term outcomes of the most widely used third-generation stent grafts, the Endurant and Excluder stent grafts, in Japanese patients using a multicenter registry. MATERIALS AND METHODS: A retrospective analysis of endovascular aneurysm repairs for abdominal aortic and iliac artery aneurysms using either the Endurant or the Excluder stent grafts from January 2012 to July 2019 at 10 Japanese hospitals was performed. RESULTS: A total of 332 and 378 repairs using the Endurant and Excluder stent grafts, respectively, were analyzed. Although the patients' characteristics were generally similar in the two groups, the Endurant group exhibited significantly shorter (Endurant: 31.5±18.6 mm, Excluder: 37.4±21.0 mm; p<0.001), larger (Endurant: 22.4±4.2 mm, Excluder: 21.7±3.8 mm; p=0.029), and more reversed tapered (Endurant: 12.1%, Excluder: 5.8%; p=0.003) proximal necks. The incidence of instructions for use (IFU) violations was similar between the two groups (Endurant: 59.0%, Excluder: 54.5%; p=0.223). However, the Endurant group had significantly more proximal neck-related IFU violations (54.1% and 46.3%, respectively; p=0.039), more access-related IFU violations (8.1% and 4.0%, respectively; p=0.019), and fewer bilateral hypogastric artery embolizations (5.1% and 9.3%, respectively; p=0.035) compared with the Excluder group. The incidence of intraoperative (Endurant: 3.6%, Excluder: 3.7%; p=0.950) and perioperative complications (Endurant: 3.6%, Excluder: 3.4%, p=0.899) was equivalent in the two groups. However, there was a significantly higher incidence of postoperative type II endoleaks in the Excluder group (Endurant: 28%, Excluder: 46.0%, p<0.001). Aneurysm sac regression was more frequent in the Endurant group (Endurant: 40.7%, Excluder: 31.7%, p=0.013). The Endurant group also had significantly higher rates of sac increase (Endurant: 13.0%, Excluder: 7.7%, p=0.020). Kaplan-Meier curve and log-rank analyses revealed no statistical differences in late complications (p=0.868) and overall survival (p=0.926). CONCLUSIONS: There were no statistically significant differences between the Endurant and the Excluder stent grafts in terms of intraoperative, perioperative, and late complication rates; however, the anatomical characteristics of the patients were significantly different.

Standardized upfront Glissonean approach and liver hanging maneuver reduces bile leakage from the hepatic hilum in living donors.

Biliary complications after hepatectomy in living donors have yet to be eradicated. We hypothesized that a standardized upfront Glissonean approach and liver hanging maneuver (GH) would prevent mechanical and thermal injuries to the hilar plate of the remnant liver by determining the point of bile duct division and the final destination of hepatectomy preceding liver parenchymal transection (safety) and facilitate liver transection deep within the parenchyma and allow maximum length of hilar structures (rationality). GH was implemented in 2016 and its incidence of bile leakage was retrospectively compared against the conventional technique. GH comprises six steps: (1) development of the retrohepatic avascular plane between the right hepatic vein (RHV) and the middle hepatic vein (MHV) and isolation of the hepatic vein(s); (2) isolation of the right or left Glissonean pedicle with the corresponding Glissonean pedicles of the caudate lobe; (3) for right liver grafts and left liver grafts with the caudate lobe, passage of the tape for the liver hanging maneuver along the retrohepatic avascular plane and above the hilar plate, and for left liver grafts without the caudate lobe and for left lateral section grafts, passage of the tape from between the RHV and the MHV, along the Arantius ligament, and to the right of the umbilical portion; (4) liver transection; (5) isolation of hilar structures; and (6) graft procurement. Until 2020, 62 consecutive living donors underwent GH (success rate, 100%). The incidence of bile leakage from the hepatic hilum (0%) was significantly lower than that among 59 donors who underwent the conventional technique in 2011-2015 (9%; p = 0.01). In conclusion, GH is highly effective in reducing bile leakage from the hepatic hilum in living donors.

Characteristics, Antithrombotic Patterns, and Prognostic Outcomes in Claudication and Critical Limb-Threatening Ischemia Undergoing Endovascular Therapy.

PURPOSE: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT). MATERIALS AND METHODS: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention. RESULTS: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05). CONCLUSIONS: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes. CLINICAL IMPACT: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease.

Adipose-Derived Mesenchymal Stromal/Stem Cell Line Prevents Hepatic Ischemia/Reperfusion Injury in Rats by Inhibiting Inflammasome Activation.

Mesenchymal stromal/stem cells (MSCs) have shown potential in the treatment of degenerative diseases, including ischemia/reperfusion injury (IRI), which occurs during organ transplantation and represents the main cause of post-transplant graft dysfunction. However, MSCs have heterogeneous characteristics, and studies of MSCs therapy have shown a variety of outcomes. To establish a new effective MSCs therapy, we developed an adipose-derived mesenchymal stromal/stem cell line (ASCL) and compared its therapeutic effects on primary adipose-derived MSCs (ASCs) using a hepatocyte co-culture model of hypoxia/reoxygenation in vitro and a rat model of hepatic IRI in vivo. The results showed that both ASCL and ASCs protect against hypoxia by improving hepatocyte viability, inhibiting reactive oxygen species release, and upregulating transforming growth factor-ß in vitro. In vivo, ASCL or ASCs were infused into the spleen 24 h before the induction of rat hepatic IRI. The results showed that ASCL significantly improved the survival outcomes compared with the control (normal saline infusion) with the significantly decreased serum levels of liver enzymes and less damage to liver tissues compared with ASCs. Both ASCL and ASCs suppressed NOD-like receptor family pyrin domain-containing 3 inflammasome activation and subsequently reduced the release of activated IL-1ß and IL-18, which is considered an important mechanism underlying ASCL and ASCs infusion in hepatic IRI. In addition, ASCL can promote the release of interleukin-1 receptor antagonist, which was previously reported as a key factor in hampering the inflammatory cascade during hepatic IRI. Our results suggest ASCL as a new candidate for hepatic IRI treatment due to its relatively homogeneous characteristics.

Carotid body tumor with neck metastasis due to germline SDHB variant: a case report and literature review.

Carotid body tumor involving the succinate dehydrogenase subunit B (SDHB) variant reportedly had a higher frequency of metastasis than other variants of succinate dehydrogenase. However, the correlation between genotype and phenotype among patients with carotid body tumor with SDHB gene variant remains unclear. Thus, we present a case of carotid body tumor with neck lymph metastasis caused by a novel SDHB variant, which resulted in long-term disease-free survival achieved after surgery. A 43-year-old man presented to our hospital with a 2-year history of a painless neck mass. Based on the radiographic findings, the patient was diagnosed with carotid body tumor with a possible Shamblin type III tumor. Another mass was detected and suspected to be a lymph node metastasis. The patient underwent resection of the tumor and lymph nodes. The common carotid artery, internal carotid artery, external carotid artery, internal jugular vein, vagal nerve, and hypoglossal nerve were resected with the tumor. Histopathological examination revealed a paraganglioma. The histological findings of the lymph nodes were similar to those of the carotid body tumor and were confirmed to be metastases of paraganglioma. To analyze the germline SDHx variant, a nonsense variant was detected in the SDHB gene at exon 2, c. 136C > T, p. Arg46*. During the follow-up 80 months after surgery, the patient exhibited no signs of recurrence, metastasis, or development of paragangliomas in other organs. This was the first case of carotid body tumor accompanied by neck metastasis caused by a germline nonsense SDHB variant at exon 2, c. 136C > T, p. Arg46*. Carotid body tumor with neck lymph metastasis caused by this nonsense variant could achieve long-term disease-free survival after surgery. Gene analysis, including SDHB variant, should be performed to predict the prognosis and future risk of metastasis. Genetic testing of SDHB may give a crucial information for the treatment and follow-up strategies of carotid body tumor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13691-021-00522-x.

Reappraisal of liver transplantation for erythropoietic protoporphyria: A deadly combination of disease recurrence and biliary complication.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disorder that causes the accumulation of protoporphyrin in the erythrocytes, skin, and liver. Severe protoporphyric hepatopathy results in liver failure, requiring both liver and bone marrow transplantation as a life-saving procedure and to correct the underlying enzymatic defect, respectively. CASE PRESENTATION: We report a 20-year-old man who underwent split liver transplantation using a right trisegment and caudate lobe graft for EPP-induced liver failure, but succumbed to a deadly combination of early relapse of EPP and subsequent, intractable, late-onset bile leakage from the cut surface of segment 4. EPP recurrence most likely created a high-risk situation for bile leakage from the non-communicating bile ducts of segment 4; therefore, this case shed light on the potential relationship between EPP recurrence and biliary complications. CONCLUSION: Physicians should recognize the potentially rapid and life-threatening progression of protoporphyric hepatopathy that leads to liver failure. For young patients with EPP, LT and sequential BMT should thoroughly be considered by a multidisciplinary team as soon as hepatic reserve deterioration becomes evident. Split liver transplantation should preferably be avoided and appropriate post-transplant management is critical before protoporphyrin depositions to the bile duct and hepatocyte causes irreversible damage to the liver graft.

Patients with liver cirrhosis due to nonalcoholic steatohepatitis have lesser chances for liver transplantation.

BACKGROUND: The main causes of liver cirrhosis have changed over the past decade. In Japan, the number of deceased donors is increasing but is still insufficient relative to the number of patients awaiting a liver transplant. In the present study we aimed to assess the outcomes of candidates for liver transplantation. METHODS: This was a retrospective study of adult patients who visited our department for consultation regarding liver transplantation from January 2009 to December 2020. Of a total of 601 patients, 336 were followed-up. The following data were collected and analyzed: patient's characteristics, liver etiology, Child-Pugh and MELD scores, and the eventual outcome, that is, whether liver transplantation was performed. RESULTS: Only 153 of 336 (45.5%) patients underwent liver transplantation, of which 42 (27.5%) received deceased donor liver transplantation, and 129 (38.4%) died without transplantation. The proportion of patients who underwent liver transplantation was low among patients with nonalcoholic steatohepatitis (NASH) (10.7%) (P < .001). The rate of qualified living donors was the lowest for patients with NASH (28.6%) and that for the other etiologies ranged from 55.6% to 67.4% (P = .050). CONCLUSION: Patients with liver cirrhosis due to NASH may have a lesser chance of undergoing liver transplantation from both living and deceased donors.

The hypotaurine-taurine pathway as an antioxidative mechanism in patients with acute liver failure.

The liver has been thought to protect against oxidative stress through mechanisms involving reduced glutathione (GSH) that consumes high-energy phosphor-nucleotides on its synthesis. However, hepatoprotective mechanisms in acute liver failure (ALF) where the phosphor-nucleotides are decreased in remain to be solved. Liver tissues were collected from patients with ALF and liver cirrhosis (LC) and living donors (HD) who had undergone liver transplantation. Tissues were used for metabolomic analyses to determine metabolites belonging to the central carbon metabolism, and to determine sulfur-containing metabolites. ALF and LC exhibited a significant decline in metabolites of glycolysis and pentose phosphate pathways and high-energy phosphor-nucleotides such as adenosine triphosphate as compared with HD. Conversely, methionine, S-adenosyl-l-methionine, and the ratio of serine to 3-phosphoglycerate were elevated significantly in ALF as compared with LC and HD, suggesting a metabolic boost from glycolysis towards trans-sulfuration. Notably in ALF, the increases in hypotaurine (HTU) + taurine (TU) coincided with decreases in the total amounts of reduced and oxidized glutathione (GSH + 2GSSG). Plasma NH3 levels correlated with the ratio of HTU + TU to GSH + 2GSSG. Increased tissue levels of HTU + TU vs total glutathione appear to serve as a biomarker correlating with hyperammonemia, suggesting putative roles of the HTU-TU pathway in anti-oxidative protective mechanisms.

Keio Uterus Transplantation Research: From Basic Research toward Future Clinical Application.

Uterus transplantation (UTx) is now a potential option to allow women with uterine factor infertility to give birth. However, UTx is still at an experimental stage, and basic animal studies, including in non-human primates, are needed for the accumulation of data prior to clinical application. Considering that UTx may provide new hope to Japanese women, we launched UTx research in 2009 and have since accumulated a large archive of results in the UTx research field. Furthermore, we have carried out various activities aimed at the implementation of clinical applications of UTx in Japan while clarifying the ethical and social issues involved. Currently, the clinical application of UTx in Japan is just around the corner, and it is expected that UTx research will develop further in the future. Herein, we summarize our basic experiences using non-human primates and our activities with the goal of future clinical applications.

Transplantation of bioengineered liver capable of extended function in a preclinical liver failure model.

Unlimited organ availability would represent a paradigm shift in transplantation. Long-term in vivo engraftment and function of scaled-up bioengineered liver grafts have not been previously reported. In this study, we describe a human-scale transplantable liver graft engineered on a porcine liver-derived scaffold. We repopulated the scaffold parenchyma with primary hepatocytes and the vascular system with endothelial cells. For in vivo functional testing, we performed auxiliary transplantation of the repopulated scaffold in pigs with induced liver failure. It was observed that the auxiliary bioengineered liver graft improved liver function for 28 days and exhibited upregulation of liver-specific genes. This study is the first of its kind to present 28 days of posttransplant evaluation of a bioengineered liver graft using a preclinical large animal model. Furthermore, it provides definitive evidence for the feasibility of engineering human-scale transplantable liver grafts for clinical applications.

Diagnostic Utility of Presepsin in Infections After Liver Transplantation: A Preliminary Study.

BACKGROUND Infectious complications after solid organ transplantation can be fatal, and early diagnosis and intervention are important. To the best of our knowledge, no study has examined the diagnostic utility of presepsin, a known accurate biomarker, for infectious complications after liver transplantation. This study aimed to evaluate the utility of presepsin for detecting infection and perioperative kinetics of presepsin after liver transplantation. MATERIAL AND METHODS This single-institutional prospective, observational study included 13 patients who underwent living-donor or deceased-donor liver transplantation. Perioperative serum presepsin level was measured 6 times within a week to evaluate its association with infectious complications and compare it with procalcitonin and C-reactive protein levels and leukocyte count. Postoperatively, patients were followed up for 15 days for infectious complications. RESULTS Five of the 13 patients developed infectious complications after liver transplantation. The median time for infection diagnosis was 9 postoperative days (25th-75th percentile, 7-10). Presepsin levels on 5 and 7 postoperative days were significantly higher in patients with infection than in those without (P=0.019 and P=0.011, respectively). In receiver operating characteristic analysis, area under the curve values of presepsin on 5 and 7 postoperative days (0.881 and 0.905, respectively) were higher than those of other biomarkers. The optimal cut-off value of presepsin was 1361 pg/mL on postoperative day 5 and 1375 pg/mL on postoperative day 7. CONCLUSIONS Although this study included a small number of patients, presepsin levels on postoperative days 5 and 7 may be useful indicators for infectious complications after liver transplantation.

Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC.

Maintenance treatment with infliximab for ulcerative ileitis after intestinal transplantation: A case report.

BACKGROUND: Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab, such as induction therapy, salvage treatment for acute cellular rejection, and treatment for chronic ulcerative inflammation, in intestinal transplant recipients. However, the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data. We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation (ITx). CASE SUMMARY: The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related intestinal transplant. His immunosuppression regimen consisted of daclizumab, tacrolimus, and steroids. Although he did not show rejection while on tacrolimus monotherapy, routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant. Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft. Since the endoscopic findings suggested ulcerative lesions in Crohn's disease, infliximab treatment was considered. Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab. CONCLUSION: Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient.

Long-term outcomes of living donor liver transplantation after locoregional treatment for hepatocellular carcinoma: an experience from a single institute.

PURPOSE: The precise role of downstaging or bridge therapy for cirrhotic patients with hepatocellular carcinoma (HCC) beyond or within the Milan criteria (MC) before living donor liver transplantation (LDLT) remains undefined. METHODS: We conducted a single-center, retrospective cohort study of 40 cirrhotic patients with HCC who underwent LDLT from 2000 to 2018. Dynamic computed tomography images at the initial presentation and immediately before LDLT as well as the final histopathological findings were reviewed to determine whether they met or exceeded MC. RESULTS: Overall, 29 patients underwent various pre-transplant HCC treatments, including ablation and embolization (bridge therapy, n = 20; downstaging, n = 9). Of the 9 patients who were initially beyond the MC, 4 (44.4%) were successfully downstaged to within the MC. Five patients beyond the MC immediately before LDLT demonstrated a significantly worse 5-year overall survival rate than patients within the MC (16.7% vs. 82.2%, P = 0.004), regardless of the radiological HCC stage at presentation or the final pathological tumor status. All 3 recurrent patients had HCC beyond the MC immediately before transplant and died of their disease at 13, 24, and 50 months after transplantation. CONCLUSIONS: Successful downstaging for HCC cases beyond the MC provides similar outcomes to those within the MC at presentation, regardless of the histopathological findings.