Malignancy After Living Donor Liver Transplantation.

OBJECTIVES: De novo malignancy (DNM) is a major cause of death in long-term recipients of liver transplantation (LT). We herein report our experience with DNM after living-donor LT (LDLT). PATIENTS AND METHODS: A total of 111 LDLT procedures were performed in our institute from 1999 to 2022. Among them, 70 adult (>13 years old) LDLT recipients who survived for more than 1 year were included in this study. RESULTS: During a median follow-up of 146 (range, 12-285) months, 7 out of 70 recipients developed 8 DNMs, including lung cancer in 4, post-transplant lymphoproliferative disease in 3, and skin cancer in 1. One patient developed metachronal skin cancer and post-transplant lymphoproliferative disease. The pre-LT smoking history rate in patients with DNM was higher than in patients without DNM (P = .004). The survival time after DNM was 6 (1-166) months. Only 2 patients underwent R0 resection. DNM did not recur during follow-up. Other patients who underwent R1 resection and/or chemotherapy and/or radiotherapy all died due to DNMs during the follow-up. The cumulative DNM incidence was 3.5% at 10 years and 18.4% at 20 years after LDLT. The cumulative survival rate in patients with DNM was significantly worse than that in patients without DNM after LDLT (P = .049). CONCLUSION: The survival rate of patients with DNM was lower than that of those without DNM. A pre-LT smoking history is a risk factor for DNM. R0 resection is effective for improving the prognosis of patients with DNM. Regular cancer screening is important for detecting DNM early after LDLT.

[Long-Term Survival after Liver and Pulmonary Metastasectomy Following Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma-A Case Report].

The patient was a 61-year-old man with a diagnosis of carcinoma of the pancreatic head. Abdominal computed tomography( CT)showed no distant metastasis, and he underwent subtotal stomach-preserving pancreatoduodenectomy. Immediately after surgery, he received liver perfusion chemotherapy with 5-fluorouracil followed by systemic gemcitabine. Eighteen months after surgery, CT revealed liver metastasis in the S6 segment, and partial hepatectomy was performed. The pathological diagnosis was liver metastasis of pancreatic cancer. Postoperatively, the patient was treated with gemcitabine and S-1 therapy for 1 year and then switched to S-1 monotherapy for about 6 months. Four years after the initial surgery, CT showed 2 metastases in the right lung. After 2 months of S-1 monotherapy, wedge resection of the upper and lower lobes of the right lung was performed. Gemcitabine and nab-paclitaxel therapy were administered, after the metastasectomy, but pleural dissemination appeared on CT 5 years after the initial surgery. Modified FOLFIRINOX therapy was started and continued for 8 months, but CT revealed further disseminated lesions in the diaphragm. Palliative irradiation was provided, but the disease gradually progressed. After multidisciplinary treatment, the patient survived for 6 years and 3 months after the initial surgery.

Chronic hyperadiponectinemia induced by transgenic overexpression increases plasma exosomes without significantly improving glucose and lipid metabolism.

The fat-derived factor, adiponectin, is considered a salutary circulating factor. We recently demonstrated that native adiponectin binds T-cadherin and promotes intracellular biogenesis and secretion of the exosome. Exosomes play important roles in various aspects of homeostasis, including glucose and energy metabolism. However, it remains unclear whether and how the promotion of exosome production by adiponectin in vivo is beneficial for glucose and lipid metabolism. In the present study, overexpression of human adiponectin in mice resulted in an increased number of circulating exosomes, but it did not significantly improve glucose metabolism, change body weights, or change triglyceride clearance under a high-fat diet. Multiple small doses of streptozotocin increased blood glucose and decreased triglyceride clearance similarly in both wild-type and transgenic mice. Thus, these results indicated that human adiponectin overexpression in mice increases plasma exosomes but does not significantly influence glucose and lipid metabolism.

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study.

BACKGROUND: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. METHODS: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. RESULTS: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. CONCLUSIONS: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR.

[Surgery for Cholangiocarcinoma with Superficial Spread and Lymph Node Metastasis-Report of a Long-Term Survivor Who Had Positive Proximal Ductal Resection Margins with Carcinoma In Situ].

A 66-year-old man was referred to our hospital with fever and abdominal pain. CT showed a mass in the intrapancreatic bile duct but no wall thickness in the perihilar bile ducts. Neither regional lymphadenopathy nor distant metastasis was observed. Biliary cytology showed adenocarcinoma. The diagnosis was distal cholangiocarcinoma, and pancreatoduodenectomy was performed. Intraoperative frozen section examination of the ductal resection margins at the right and left hepatic ducts was positive for carcinoma in situ, and the operation ultimately completed with R1 resection. Histological examination confirmed a diagnosis of cholangiocarcinoma with superficial spread and a single positive lymph node. Adjuvant chemotherapy with S-1 was administered for 1 year. Anastomotic recurrence at the hepaticojejunostomy was found 5 years after resection; biopsy specimens revealed adenocarcinoma. Thereafter, S-1 chemotherapy was resumed, and the patient remains alive and well 9 years and 1 month after resection.

[A Case of Intraductal Papillary Mucinous Adenocarcinoma with Hepatic Dysfunction Due to Tumor Perforation into the Bile Duct].

A 58-year-old woman presented with a complaint of weight loss. Abdominal computed tomography showed dilatation of the biliary and pancreatic ducts and a mural nodule in the pancreatic duct. The diagnosis was intraductal papillary mucinous neoplasm(IPMN). Endoscopic retrograde cholangiopancreatography(ERCP)and cholangioscopy revealed a fistula between the common bile duct and the IPMN. A sudden increase in hepatobiliary enzymes was noted preoperatively. ERCP showed that the common bile duct was obstructed by mucus. A nasobiliary drainage tube was inserted into the bile duct endoscopically and kept open by daily tube washing, and the liver dysfunction improved. Total pancreatectomy, splenectomy, and regional lymph node dissection were performed. Histological examination confirmed that the primary tumor was mixed invasive intraductal papillary mucinous adenocarcinoma. The patient remains alive and well with no evidence of recurrence 18 months after resection.

[Two Operations for Intrahepatic Recurrence of Biliary Cystadenocarcinoma-A Long-Term Survivor].

We report a case of biliary cystadenocarcinoma in which long-term survival was achieved after 2 operations for intrahepatic recurrence. A 72-year-old man with biliary cystadenocarcinoma located mainly in segment 3 of the liver underwent left hepatectomy, extrahepatic bile duct resection, and lymph node dissection. Seven years and 9 months after the initial resection, he underwent partial liver resection(segment 5)for intrahepatic recurrence detected by computed tomography. Fifteen years and 7 months after the initial resection, he underwent repeat partial resection of the liver(segment 5)for intrahepatic recurrence. Histologically, these tumors were confirmed to be recurrence of biliary cystadenocarcinoma. He remains alive and well with no further recurrence 21 years and 6 months after the initial resection. This case and a literature review suggest that hepatic resection is a useful treatment option for intrahepatic recurrence of biliary cystadenocarcinoma.

Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade.

AIMS/HYPOTHESIS: Immunomodulators blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have improved the treatment of a broad spectrum of cancers. These immune checkpoint inhibitors (ICIs) reactivate the immune system against tumour cells but can also trigger autoimmune side effects, including type 1 diabetes. Mesenchymal stem cell (MSC) therapy is the most prevalent cell therapy, with tissue-regenerating, anti-fibrosis and immunomodulatory functions provided by the secretome of the cells. Here, we examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a NOD mouse model. METHODS: The purified PD-L1 monoclonal antibody was administered to induce diabetes in male NOD mice which normally do not develop diabetes. Human adipose-derived MSCs were administered by tail vein injections. T cells, macrophages and monocyte-derived macrophages expressing C-X-C motif chemokine ligand 9 (CXCL9) in pancreatic sections of NOD mice and a cancer patient who developed diabetes following the ICI treatments were analysed by immunofluorescence. Tissue localisation of the injected MSCs, plasma exosome levels and plasma cytokine profiles were also investigated. RESULTS: PD-1/PD-L1 blockade induced diabetes in 16 of 25 (64%) NOD mice which received anti-PD-L1 mAb without hMSCs [MSC(-)], whereas MSC administration decreased the incidence to four of 21 (19%) NOD mice which received anti-PD-L1 mAb and hMSCs [MSC(+)]. The PD-1/PD-L1 blockade significantly increased the area of CD3-positive T cells (6.2-fold) and macrophage-2 (Mac-2) antigen (2.5-fold)- and CXCL9 (40.3-fold)-positive macrophages in the islets. MSCs significantly reduced T cell (45%) and CXCL9-positive macrophage (67%) accumulation in the islets and the occurrence of diabetes. The insulin content (1.9-fold) and islet beta cell area (2.7-fold) were also improved by MSCs. T cells and CXCL9-positive macrophages infiltrated into the intricate gaps between the beta cells in the islets by PD-1/PD-L1 blockade. Such immune cell infiltration was largely prevented by MSCs. The most striking difference was observed in the CXCL9-positive macrophages, which normally did not reside in the beta cell region in the islets but abundantly accumulated in this area after PD-1/PD-L1 blockade and were prevented by MSCs. The CXCL9-positive macrophages were also observed in the islets of a cancer patient who developed diabetes following the administration of ICIs but few CXCL9-positive macrophages were observed in a control patient. Mechanistically, the injected MSCs accumulated in the lung but not in the pancreas and strongly increased plasma exosome levels and changed plasma cytokine profiles. CONCLUSIONS/INTERPRETATION: Our results suggest that MSCs can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and may be worth further consideration for new adjuvant cell therapy.

Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation.

Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9-derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.

Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin.

Adiponectin (APN) is a circulating protein specifically produced by adipocytes. Native APN specifically binds to T-cadherin, a glycosylphosphatidylinositol-anchored protein, mediating the exosome-stimulating effects of APN in endothelial, muscle, and mesenchymal stem cells. It was previously reported that APN has beneficial effects on kidney diseases, but the role of T-cadherin has not been clarified yet. Here, our immunofluorescence study indicated the existence of both T-cadherin and APN protein in pericytes, subsets of tissue-resident mesenchymal stem/progenitor cells positive for platelet-derived growth factor receptor ß (PDGFRß), surrounding peritubular capillaries. In an acute renal ischemia-reperfusion (I/R) model, T-cadherin-knockout (Tcad-KO) mice, similar to APN-KO mice, exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability than wild-type mice. In addition, in response to I/R-injury, the renal PDGFRß-positive cell area increased in wild-type mice, but opposingly decreased in both Tcad-KO and APN-KO mice, suggesting severe pericyte loss. Mouse primary pericytes also expressed T-cadherin. APN promoted exosome secretion in a T-cadherin-dependent manner. Such exosome production from pericytes may play an important role in maintaining the capillary network and APN-mediated inhibition of renal tubular injury. In summary, our study suggested that APN protected the kidney in an acute renal injury model by binding to T-cadherin.NEW & NOTEWORTHY In the kidney, T-cadherin-associated adiponectin protein existed on peritubular capillary pericytes. In an acute renal ischemia-reperfusion model, deficiency of adiponectin or T-cadherin exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability, accompanied by severe pericyte loss. In vitro, adiponectin promoted exosome secretion from mouse primary pericytes in a T-cadherin-dependent manner. Adiponectin plays an important role in maintaining the capillary network and amelioration of renal tubular injury by binding to T-cadherin.

Plasma xanthine oxidoreductase activity in Japanese patients with type 2 diabetes across hospitalized treatment.

AIMS/INTRODUCTION: Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine and xanthine to xanthine and uric acid, respectively. Plasma XOR activity has recently been measured in humans. However, limited information is known about plasma XOR activity in patients with type 2 diabetes mellitus, and its changes after short-term glycemic control treatment. MATERIALS AND METHODS: We enrolled 28 Japanese patients (10 men/18 women) with type 2 diabetes mellitus who were hospitalized to undergo medical treatment for diabetes. Plasma XOR activity, quantified using triple quadrupole mass spectrometry and liquid chromatography, and other clinical parameters were examined at admission and 2 weeks after treatment during hospitalization. Changes in plasma XOR activity after treatment during hospitalization and associated clinical parameters were assessed. RESULTS: At the time of admission, the median plasma XOR activity was 83.1 pmol/h/mL, with a wide range of 14.4-1150 pmol/h/mL. Multiple regression analysis identified serum aspartate transaminase and alanine transaminase levels as significant and independent factors correlating with the baseline plasma XOR. Two weeks of treatment during hospitalization was associated with a significant decrease in plasma XOR activity. Changes in serum aspartate transaminase were also the only significant and independent factor correlating with changes in plasma XOR activity. CONCLUSIONS: A close relationship was observed between plasma XOR activity and liver transaminases in patients with type 2 diabetes mellitus, cross-sectionally, and also across treatment during hospitalization.

Adiponectin Stimulates Exosome Release to Enhance Mesenchymal Stem-Cell-Driven Therapy of Heart Failure in Mice.

Mesenchymal stem/stromal cells (MSCs) are cultured adult stem cells that originally reside in virtually all tissues, and the gain of MSCs by transplantation has become the leading form of cell therapy in various diseases. However, there is limited knowledge on the alteration of its efficacy by factors in recipients. Here, we report that the cardioprotective properties of intravenously injected MSCs in a mouse model of pressure-overload heart failure largely depend on circulating adiponectin, an adipocyte-secreted factor. The injected MSCs exert their function through exosomes, extracellular vesicles of endosome origin. Adiponectin stimulated exosome biogenesis and secretion through binding to T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin, on MSCs. A pharmacological or adenovirus-mediated genetic increase in plasma adiponectin enhanced the therapeutic efficacy of MSCs. Our findings provide novel insights into the importance of adiponectin in mesenchymal-progenitor-mediated organ protections.

A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis.

A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinß1 subunit and transforming growth factor (TGF)-ß receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-ß signaling by regulating the abundance of the integrinß1 and TGF-ß receptors.NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.

Effective waist circumference reduction rate necessary to avoid the development of type 2 diabetes in Japanese men with abdominal obesity.

The aim of this study was to determine the effective waist circumference (WC) reduction rate in avoiding the development of type 2 diabetes mellitus (T2DM) in <55 years and ≥55 years Japanese men with abdominal obesity. The study subjects were 795 men with WC ≥85 cm, fasting plasma glucose <126 mg/dL, 2-hr plasma glucose on 75 g of oral glucose tolerance test <200 mg/dL, and HbA1c 5.6-6.4 % (38-40 mmol/mol) at baseline who underwent general health checkups more than twice between April 2007 and May 2015. They were divided into 5 groups based on the change in WC during the observation period (WC gain group, and four groups stratified according the rate of WC loss). The subjects were also divided into the <55 years and ≥55 years (at baseline) subgroups. The cumulative incidence rate of T2DM was analyzed and compared among the groups. The cumulative incidence rates of the largest WC loss quartile (≥5.45 %) in all age, of the largest WC loss quartile (≥5.60 %) and second largest WC loss quartile (3.44-5.59 %) in the <55 years subgroup, and of the largest WC loss quartile (≥5.37 %) in the ≥55 years subgroup were significantly lower than that of the gain group (p<0.001, p=0.009, 0.012, and 0.012, respectively). WC reduction rate of at least about 3 % in the younger (<55 years) and at least about 5 % in the older (≥55 years) non-diabetic Japanese men with abdominal obesity can effectively reduce the chance of development of T2DM.

A Novel Mutation in the type Iα Regulatory Subunit of Protein Kinase A (PRKAR1A) in a Cushing's Syndrome Patient with Primary Pigmented Nodular Adrenocortical Disease.

A 40-year-old man presented with Cushing's syndrome due to bilateral adrenal hyperplasia with multiple nodules. Computed tomography scan results were atypical demonstrating an enlargement of the bilateral adrenal glands harboring multiple small nodules, but the lesion was clinically diagnosed to be primary pigmented nodular adrenocortical disease (PPNAD) based on both endocrinological test results and his family history. We performed bilateral adrenalectomy and confirmed the diagnosis histologically. An analysis of the patient and his mother's genomic DNA identified a novel mutation in the type Iα regulatory subunit of protein kinase A (PRKAR1A) gene; p.E17X (c.49G>T). This confirmed the diagnosis of PPNAD which is associated with Carney Complex.