Is preoperative weight reduction of living-donor liver transplant recipients and donors harmful to postoperative outcomes?

PURPOSE: Although the incidence of recipients and donors with overweight and obesity is increasing worldwide, few reports have focused on outcomes of preoperative weight reduction (WR) in living-donor liver transplantation (LDLT). Therefore, we examined the outcomes and the impact of WR on the postoperative course. METHODS: We analyzed 217 consecutive LDLT procedures performed from 2017 to 2022. We divided the recipients and donors into a WR group and non-WR group. RESULTS: Twenty-two recipients (10.1%) achieved WR (preoperative recipient WR [RWR] group), reducing their weight by 6.8% ± 6.0% within 2.2 ± 1.4 months with a significant decrease in body mass index (BMI) (P < .0001). The RWR group showed no significant differences in short-term postoperative outcomes (operative factors, postoperative liver function tests, amount of ascites, and morbidity) or in the graft survival rate as a long-term outcome (P = .24) compared with the non-RWR group. Forty-one donors (18.9%) achieved WR (preoperative donor WR [DWR] group), reducing their weight by 9.7% ± 6.3% within 3.2 ± 5.8 months with a significant decrease in BMI (P < .0001). Compared with the non-DWR group, the DWR group showed no significant differences in short-term postoperative outcomes between themselves and recipients or in the graft survival rate (P = .49). Furthermore, WR resulted in an increase to 32 donor-eligible and 6 recipient-eligible patients. CONCLUSION: WR in LDLT recipients and donors had no harmful effect on postoperative outcomes and should lead to increase recipients' chance of undergoing LDLT and to expand the donor pool.

Impact of electrical muscle stimulation on serum myostatin level and maintenance of skeletal muscle mass in patients undergoing living-donor liver transplantation: Single-center controlled trial.

AIM: Sarcopenia is reportedly associated with a poor prognosis in patients who undergo living-donor liver transplantation (LDLT), most of whom are not able to tolerate muscle strengthening exercise training. Myostatin is one of the myokines and a negative regulator of skeletal muscle growth. The clinical feasibility of an electrical muscle stimulation (EMS) system, which exercises muscle automatically by direct electrical stimulation, has been reported. In this study, we aimed to determine the effect of perioperative application of SIXPAD, which is a type of EMS system, with reference to the serum myostatin and sarcopenia in LDLT patients. METHOD: Thirty patients scheduled for LDLT were divided into a SIXPAD group (n = 16) and a control group (n = 14). In the SIXPAD group, EMS was applied to the thighs twice daily. The serum myostatin was measured in samples obtained before use of SIXPAD and immediately before LDLT. The psoas muscle index (PMI) at the level of the third lumbar vertebra and the quadriceps muscle area were compared on computed tomography images before use of SIXPAD and 1 month after LDLT. RESULTS: The preoperative serum myostatin was found to be higher in LDLT patients than in healthy volunteers and EMS significantly reduced the serum myostatin. Electrical muscle stimulation prevented a postoperative reduction not only in the area of the quadriceps muscles but also in the PMI despite direct stimulation of the thigh muscles. CONCLUSION: Stimulation of muscles by EMS decreases the serum myostatin and helps to maintain skeletal muscle in patients who have undergone LDLT.

A successful case of deceased-donor liver transplantation from a donor with Marfan syndrome: a case report.

BACKGROUND: Liver transplantation is the definitive therapy for patients with decompensated cirrhosis. Marfan syndrome is a systemic inheritable connective tissue disease associated with fibrillin-1 gene mutations, which cause abnormalities in connective tissue. Vascular changes due to Marfan syndrome occur mostly in the main vessels due to the high amount of connective tissue within the vessel wall and the high pressure and blood flow to which they are exposed. The incidence of changes in visceral arteries is about 0.42% and usually presents with cystic medial necrosis. This report is the first deceased-donor liver transplantation with a donor with Marfan syndrome with a history of abdominal surgery. CASE PRESENTATION: A patient in his 50s underwent liver transplantation for decompensated alcoholic cirrhosis. The donor, a 50s male with Marfan syndrome, was diagnosed with brain-death due to a cerebral hemorrhage caused by a cerebral aneurysm. The donor's clinical presentation as Marfan syndrome was aortic dissection, with multiple surgical procedures performed from the aortic root to the abdominal aorta. An intraoperative biopsy of the hepatic artery showed no abnormality, so this organ was considered appropriate. The surgery was completed without any problems of the arterial anastomosis. The patient's postoperative course was uneventful, and he was transferred to a hospital for recuperation on the 18th postoperative day. One year after the surgery, the patient is still alive without any complications from the transplantation or arterial problems. CONCLUSIONS: Even if the patient had a history of surgery for vascular anomalies extending to the abdominal aorta due to Marfan syndrome, the patient can be a donor for liver transplantation under appropriate judgment, including intraoperative biopsy.

Pretreatment eosinophil count predicts response to atezolizumab plus bevacizumab therapy in patients with hepatocellular carcinoma.

AIM: Pretreatment peripheral blood markers have value in predicting the treatment outcome of various cancers. In particular, the eosinophil count has recently gained attention. However, no study has reported the influence of the pretreatment eosinophil count on the outcomes of atezolizumab plus bevacizumab (ATZ/BEV), which is the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (u-HCC). METHODS: We enrolled 114 patients with u-HCC treated with ATZ/BEV (n = 48) or lenvatinib (n = 66). The patients receiving ATZ/BEV or lenvatinib were divided into two groups by calculating the cutoff value of the pretreatment eosinophil count. The groups were compared regarding the clinicopathological characteristics, outcomes, and incidence of adverse events (AEs). RESULTS: Twenty-three of 48 patients (47.9%) who received ATZ/BEV therapy were categorized as the ATZ/BEV-eosinophil-high group, which had better responses than the ATZ/BEV-eosinophil-low group (P = 0.0090). Kaplan-Meier curves revealed a trend toward significantly better progression-free survival (PFS) in the ATZ/BEV-eosinophil-high group than the ATZ/BEV-eosinophil-low group (the median PFS: 4.7 months in the ATZ/BEV-eosinophil-low group vs 12.6 months in the ATZ/BEV-eosinophil-high group; P = 0.0064). Multivariate analysis showed that a low eosinophil count was an independent risk factor for worse PFS after ATZ/BEV therapy (P = 0.0424, hazard ratio: 2.24, 95% confidence interval: 1.02-4.89). AEs (≥ grade 3) were significantly more likely to occur in the ATZ/BEV-eosinophil-high group (P = 0.0285). The outcomes did not significantly differ between the LEN-eosinophil-high group and the LEN-eosinophil-low group. CONCLUSION: A high pretreatment eosinophil count predicted a better response to ATZ/BEV therapy for u-HCC and was associated with the incidence of AEs (≥ grade 3).

Impact of albumin-lymphocyte-platelet-C-reactive protein index as a prognostic indicator of hepatocellular carcinoma after resection: Associated with nuclear factor erythroid 2-related factor 2.

AIM: To investigate the prognostic value of the preoperative albumin-lymphocyte-platelet-C-reactive protein (ALPC) index in patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. We also evaluated the relationship between the ALPC index and the phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) levels. METHODS: Data were analyzed retrospectively from 256 patients who underwent resection for HCC. For cross-validation, patients were divided into the training and testing cohort. We assessed eight combinations of inflammatory markers for predictive value for recurrence. We examined the associations of the ALPC index with recurrence-free survival and overall survival in univariate and multivariate analyses (Cox proportional hazards model). Immunohistochemical staining of p-Nrf2 was performed on tumor samples of 317 patients who underwent hepatic resection for HCC. RESULTS: A high preoperative ALPC index correlated with a high serum albumin concentration, small tumor size, low rate of poor differentiation, solitary tumor, early Barcelona Clinic Liver Cancer stage, and low rate of microscopic intrahepatic metastasis in the training dataset. A high preoperative ALPC index correlated with a high serum albumin concentration, high serum alpha-fetoprotein concentration, small tumor size, a low rate of poor differentiation and a low rate of microscopic intrahepatic metastasis in the testing dataset. A higher preoperative ALPC index was an independent predictor of longer recurrence-free survival and overall survival in the training and testing datasets. A high ALPC index was associated with negative p-Nrf2 expression in HCC tumor cells. CONCLUSIONS: We showed that a high ALPC index was an independent prognostic factor for patients with HCC undergoing curative hepatic resection.

Impact of TP53-induced glycolysis and apoptosis regulator on malignant activity and resistance to ferroptosis in intrahepatic cholangiocarcinoma.

TP53-induced glycolysis and apoptosis regulator (TIGAR) is an important gene that encodes a regulatory enzyme of glycolysis and reactive oxygen species (ROS) detoxification and is associated with worse prognosis in various cancers. Ferroptosis is a recently identified type of programmed cell death that is triggered by iron-dependent lipid peroxidation. There are no reports on the prognostic impact of TIGAR on intrahepatic cholangiocarcinoma (ICC), and its role in ferroptosis is unclear. Ninety ICC patients who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. The regulation of malignant activity by TIGAR and the association between ferroptosis and TIGAR were investigated in vitro. Twenty-two (24.4%) patients were categorized into TIGAR-high and -low groups by immunohistochemical staining. There were no noticeable differences in background factors between the two groups, but TIGAR positivity was an independent prognostic factor in disease-free survival (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.04-3.85, p = 0.0378) and overall survival (HR, 2.10; 95% CI, 1.03-4.30, p = 0.00422) in a multivariate analysis. In vitro, TIGAR knockdown (KD) decreased cell motility (cell proliferation/migration/invasion/colony-forming capabilities) and elevated ROS and lipid peroxidation. This indicated that TIGAR KD induced ferroptosis. TIGAR KD-induced ferroptosis was suppressed using liproxstatin. TIGAR KD decreased the expression of glutathione peroxidase 4, known as factor-suppressing ferroptosis. The combination of TIGAR KD with cisplatin significantly induced more ferroptosis. In conclusion, TIGAR is associated with poor outcomes in ICC patients and resistance to ferroptosis.

Hand-assisted laparoscopic splenectomy and gastropancreatic fold division: a less-invasive simplified technique of Hassab's procedure for refractory esophagogastric varices.

Some patients with refractory esophagogastric varices require surgery, such as gastric devascularization and splenectomy (Hassab's procedure). However, these patients are at risk of perioperative morbidities when undergoing devascularization to develop collateral vessels. We performed a more simplified procedure, splenectomy, and en bloc gastropancreatic fold division (GPFD) with hand-assisted laparoscopic surgery. Four patients with refractory esophagogastric varices and portal hypertension underwent splenectomy and GPFD. We reviewed patients' perioperative laboratory and morphological data, operative variables, and postoperative outcomes. Esophagogastric varices improved in 3 (75%) of the 4 patients. In one patient, esophageal varices (F1RC0) were observed 3 years after surgery, but they required no treatment and only received follow-up. Treatment with splenectomy and GPFD is not only less invasive than Hassab's procedure but also provides effective outcomes for refractory esophagogastric varices.

Supermassive black hole feeding and feedback observed on subparsec scales.

Active galaxies contain a supermassive black hole at their center that grows by accreting matter from the surrounding galaxy. The accretion process in about the central 10 parsecs has not been directly resolved in previous observations because of the small apparent angular sizes involved. We observed the active nucleus of the Circinus Galaxy using submillimeter interferometry. A dense inflow of molecular gas was evident on subparsec scales. We calculated that less than 3% of this inflow is accreted by the black hole, with the rest being ejected by multiphase outflows, providing feedback to the host galaxy. Our observations also reveal a dense gas disk surrounding the inflow that is gravitationally unstable, which drives the accretion into about the central 1 parsec.

Stent Graft of Pseudoaneurysm Rupture After Subtotal Stomach-preserving Pancreaticoduodenectomy.

BACKGROUND/AIM: Pseudoaneurysm rupture (PR) after subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) is a potentially fatal complication. PATIENTS AND METHODS: This study included 122 patients who underwent SSPPD at the Matsuyama Red Cross Hospital between January 2016 and December 2021. RESULTS: PR occurred in five patients (4.1%) after SSPPD. Preoperative diagnoses were cancers of the pancreatic head, distal bile duct, and gallbladder. All patients had postoperative Grade B or C pancreatic fistulas. PR occurred on postoperative days 8, 13, 20, 45, and 46. Bleeding sites were at the gastroduodenal artery transection, left gastric artery, and right hepatic artery. Four patients underwent peripheral stent graft placement, and one underwent haemostasis by coiling. Stent grafts for the gastroduodenal artery transected stamp were placed in the common hepatic artery, and in the superior mesenteric artery for PR in the right hepatic artery. All patients who underwent stent graft placement were treated with antiplatelet therapy; no complications or stent occlusion were observed in these patients. However, two patients died of cancer recurrence, 4 and 8 months after stent graft placement. The longest survival post stent graft placement was 50 months. CONCLUSION: Peripheral stent graft placement for the treatment of PR after SSPPD can maintain peripheral blood flow and haemostasis.

Detection of stellar light from quasar host galaxies at redshifts above 6.

The detection of starlight from the host galaxies of quasars during the reionization epoch (z > 6) has been elusive, even with deep Hubble Space Telescope observations1,2. The current highest redshift quasar host detected3, at z = 4.5, required the magnifying effect of a foreground lensing galaxy. Low-luminosity quasars4-6 from the Hyper Suprime-Cam Subaru Strategic Program (HSC-SSP)7 mitigate the challenge of detecting their underlying, previously undetected host galaxies. Here we report rest-frame optical images and spectroscopy of two HSC-SSP quasars at z > 6 with the JWST. Using near-infrared camera imaging at 3.6 and 1.5 µm and subtracting the light from the unresolved quasars, we find that the host galaxies are massive (stellar masses of 13 × and 3.4 × 1010 M☉, respectively), compact and disc-like. Near-infrared spectroscopy at medium resolution shows stellar absorption lines in the more massive quasar, confirming the detection of the host. Velocity-broadened gas in the vicinity of these quasars enables measurements of their black hole masses (1.4 × 109 and 2.0 × 108 M☉, respectively). Their location in the black hole mass-stellar mass plane is consistent with the distribution at low redshift, suggesting that the relation between black holes and their host galaxies was already in place less than a billion years after the Big Bang.

Association of gut microbiota with portal vein pressure in patients with liver cirrhosis undergoing living donor liver transplantation.

Background and Aim: Many recent studies have shown a relationship between various systemic diseases and the gut microbiota (GM), with the gut-liver axis receiving particular attention. In contrast, no report has comprehensively shown the effects of GM on the pathophysiology of patients undergoing living donor liver transplantation (LDLT). Method: We enrolled 16 recipients who underwent LDLT for liver cirrhosis, and 17 donors constituted the reference group. We examined the differences in GM between recipients and donors. We also examined the relationships between GM, short-chain fatty acids, and portal vein pressure (PVP) in recipients. Results: There was no significant difference in alpha-diversity between the recipients and donors, but there was variation in beta-diversity among the recipients. The abundance of the phylum Bacteroidetes was significantly higher in recipients than in donors (P = 0.016), and it was positively correlated with PVP (r = 0.511, P = 0.043). Propionic acid, which is a component of short-chain fatty acids, was positively correlated with PVP (r = 0.544, P = 0.0295), the phylum Bacteroidetes (r = 0.677, P = 0.004), and total bilirubin concentration (r = 0.501, P = 0.048). Propionic acid was negatively correlated with serum albumin concentration (r = -0.482, P = 0.043). Conclusion: Our findings suggest relationships between fecal Bacteroidetes levels, propionic acid concentrations, and PVP in patients with liver cirrhosis undergoing LDLT.

Ligation of left gastric vein may cause delayed gastric emptying after pancreatoduodenectomy: a retrospective study.

BACKGROUND: This study aimed to determine which running pattern of the left gastric vein (LGV) is most frequently ligated in subtotal stomach-preserving pancreatoduodenectomy (SSPPD) and how LGV ligation affects delayed gastric emptying (DGE) after SSPPD. METHODS: We retrospectively analysed 105 patients who underwent SSPPD between January 2016 and September 2021. We classified the running pattern of LGV as follows: type 1 runs dorsal to the common hepatic artery (CHA) or splenic artery (SpA) to join the portal vein (PV), type 2 runs dorsal to the CHA or SpA and joins the splenic vein, type 3 runs ventral to the CHA or SpA and joins the PV, and type 4 runs ventral to the CHA or SpA and joins the SpV. Univariate and multivariate analyses were used to identify differences between patients with and without DGE after SSPPD. RESULTS: Type 1 LGV running pattern was observed in 47 cases (44.8%), type 2 in 23 (21.9%), type 3 in 12 (11.4%), and type 4 in 23 (21.9%). The ligation rate was significantly higher in type 3 (75.0%) LGVs (p < 0.0001). Preoperative obstructive jaundice (p = 0.0306), LGV ligation (p < 0.0001), grade B or C pancreatic fistula (p = 0.0116), and sepsis (p = 0.0123) were risk factors for DGE in the univariate analysis. Multivariate analysis showed that LGV ligation was an independent risk factor for DGE (odds ratio: 13.60, 95% confidence interval: 3.80-48.68, p < 0.0001). CONCLUSION: Type 3 LGVs are often ligated because they impede lymph node dissection; however, LGV preservation may reduce the occurrence of DGE after SSPPD.

Synchronous gallbladder metastasis originating from residual gastric cancer: a case report and the review of literature.

BACKGROUND: Gastric cancer rarely metastasizes to the gallbladder. Furthermore, there has never been a case report of simultaneous gallbladder metastasis from residual gastric cancer. Here, we report a case of synchronous gallbladder metastasis originating from a residual gastric cancer. CASE PRESENTATION: A 67-year-old man underwent a follow-up upper endoscopy 18 months after a partial gastrectomy for gastric cancer; an ulcerative lesion was found in the remnant stomach at the gastrojejunal anastomosis. A biopsy revealed gastric signet-ring cell carcinoma (SRCC). A full-body examination revealed no abnormalities other than gallstones in the gallbladder. With a diagnosis of residual gastric cancer (cT2N0M0 cStage I), the patient underwent open total gastrectomy and cholecystectomy. Macroscopic findings of the resected specimen revealed thickening of the gallbladder wall; however, no obvious neoplastic lesions were found on the mucosal surface of the gallbladder. The pathological findings showed that the SRCC had invaded the submucosa of the gastrojejunostomy site with a high degree of lymphatic invasion and lymph node metastases. SRCCs were also found in the lymphatic vessels of the gallbladder wall. These findings suggested the possibility of gallbladder metastasis through lymphatic vessels. The patient and his family members refused postoperative chemotherapy. Ten months after the operation, the patient experienced respiratory failure due to lymphangitis carcinomatosa and died. CONCLUSIONS: At present, it is difficult to determine whether resection of the gallbladder contributes to an improved prognosis of gastric cancer patients. However, reports in such cases demonstrate that gallbladder metastasis could be a poor predictor of prognosis for gastric cancer.

Recurrent intraductal papillary neoplasm of the bile duct due to intraductal dissemination: a case report and literature review.

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a subtype of biliary tumor. The 5-year survival rate of patients with IPNB who underwent curative resection is 81%. However, IPNB is known to often recur in other parts of the bile duct. Nevertheless, its mechanism remains poorly understood. Herein, we report the case of a patient with recurrent IPNB, which was considered to be attributed to intraductal dissemination in the common bile duct at 12 months after curative resection. We also made a review of the existing literature. CASE PRESENTATION: A 69-year-old man was referred to our hospital for the evaluation and dilation of an intrahepatic bile duct (IHBD) mass. Computed tomography (CT) findings confirmed a mass in the left hepatic duct. Left trisectionectomy, extrahepatic bile duct resection with biliary reconstruction, and regional lymph node dissection were performed. Intraoperative examination of the resection margin at the common bile duct and posterior segmental branch of the hepatic duct was negative for the presence of malignant cells. Histologically, the tumor showed intraductal papillary growth of the mucinous epithelium and was diagnosed as non-invasive IPNB. It had a papillary structure with atypical epithelial cells lined up along the neoplastic fibrovascular stalks. Immunohistochemically, this was as a gastric-type lesion. At 12 postoperative months, CT revealed a 1.5-cm mass in the lower remnant common bile duct. We performed subtotal stomach-preserving pancreaticoduodenectomy. The tumor exhibited papillary growth and was microscopically and immunohistochemically similar to the first tumor. At approximately 16 months after the patient's second discharge, CT showed an abdominal mass at the superior mesenteric plexus, which was diagnosed as recurrent IPNB. Chemotherapy is ongoing, and the patient is still alive. In this case, as described in many previous reports, IPNB recurred below the primary lesion in the bile duct. CONCLUSION: Based on our review of previous reports on IPNB recurrence, intraductal dissemination was considered one of the mechanisms underlying recurrence after multicentric development. Considering the high frequency and oncological conversion of recurrence in IPNB, regular follow-up examination is essential to achieve better prognosis in patients with recurrent IPNB.

DsRNA Sequencing for RNA Virus Surveillance Using Human Clinical Samples.

Although viruses infect various organs and are associated with diseases, there may be many unidentified pathogenic viruses. The recent development of next-generation sequencing technologies has facilitated the establishment of an environmental viral metagenomic approach targeting the intracellular viral genome. However, an efficient method for the detection of a viral genome derived from an RNA virus in animal or human samples has not been established. Here, we established a method for the efficient detection of RNA viruses in human clinical samples. We then tested the efficiency of the method compared to other conventional methods by using tissue samples collected from 57 recipients of living donor liver transplantations performed between June 2017 and February 2019 at Kyushu University Hospital. The viral read ratio in human clinical samples was higher by the new method than by the other conventional methods. In addition, the new method correctly identified viral RNA from liver tissues infected with hepatitis C virus. This new technique will be an effective tool for intracellular RNA virus surveillance in human clinical samples and may be useful for the detection of new RNA viruses associated with diseases.

Pancreatic enzymatic mediastinitis followed by total gastrectomy with splenectomy: report of two cases.

BACKGROUND: Acute mediastinitis is a rare disease that rapidly progresses with a high mortality rate. Its most common cause is direct injury of the mediastinum, including iatrogenic causes such as cardiac surgery or upper endoscopy. Enzymatic mediastinitis is a rare complication of a pancreatic fistula caused by the inflammatory digestion of the parietal peritoneum spreading to the mediastinum. Here, we present two cases of enzymatic mediastinitis caused by total gastrectomy with splenectomy. One of them was successfully treated and cured after early diagnosis and transabdominal drainage. CASE PRESENTATION: Case 1 was that of a 60-year-old man (body mass index [BMI] 27) with a medical history of diabetes and hypertension who was diagnosed with advanced gastric cancer in the upper body of the stomach. A total gastrectomy with splenectomy was performed. The patient experienced acute respiratory failure 24 h after surgery. Pulmonary embolism was suspected, so a computed tomography (CT) scan was performed; however, no relevant causes were found. Although he was immediately intubated and treated with catecholamine, he died in the intensive care unit (ICU) 40 h after surgery. Post-mortem findings revealed retroperitonitis caused by a pancreatic fistula spreading towards the mediastinum, causing severe mediastinitis; a review of the CT scan revealed pneumomediastinum. We concluded that the cause of death was enzymatic mediastinitis due to post-gastrectomy pancreatic fistula. Case 2 involved a 61-year-old man (BMI 25) with a medical history of appendicitis who was diagnosed with advanced gastric cancer at the gastric angle between the lesser curvature and the pylorus, spreading to the upper body of the stomach. A total gastrectomy with splenectomy was also performed. The patient had a high fever 3 days after the surgery, and a CT scan revealed pneumomediastinum, indicating mediastinitis. As the inflammation was below the bronchial bifurcation, we chose a transabdominal approach for drainage. The patient was successfully treated and discharged. CONCLUSION: Acute mediastinitis caused by gastrectomy is rare. The acknowledgment of abdominal surgery as a cause of mediastinitis is important. In treating mediastinitis caused by abdominal surgery, transabdominal drainage may be a minimally invasive yet effective method if the inflammation is mainly located below the bifurcation of the trachea.

Lethal multiple colon necrosis and perforation due to fulminant amoebic colitis: a surgical case report and literature review.

BACKGROUND: Amoebiasis caused by the protozoan species Entamoeba histolytica rarely develops into fulminant amoebic colitis (FAC), but when it does, it shows an aggressive clinical course including colonic perforation, necrotizing colitis, and high mortality. Surgical treatment for FAC patients should be carried out urgently. However, even after surgery, the mortality rate can be 40-50%. Although FAC is one of the most unfavorable surgical diseases with a poor prognosis, there are a few reports on the perioperative diagnosis and management of FAC based on autopsy findings. We herein report the surgical case of a 64-year-old man who developed multiple colon necrosis and perforation due to FAC. A detailed autopsy revealed FAC as the cause of death. Additionally, we reviewed the existing literature on FAC patients who underwent surgery and followed their perioperative diagnosis and management. CASE PRESENTATION: A 64-year-old man presented with anorexia, diarrhea, and altered consciousness on arrival to our hospital. Computed tomography revealed a large mass in the upper right lobe of his lung, and the patient was admitted for close investigation. Bloody diarrhea, lower abdominal pain, and hypotension were observed soon after admission. Urgent abdominal contrast-enhanced computed tomography scan revealed extensive intestinal ischemia, intestinal pneumatosis, and free intra-abdominal gas. The preoperative diagnosis was bowel necrosis and perforation with intussusception of the small intestinal tumor. Emergency subtotal colectomy and enterectomy were performed soon after the contrast-enhanced computed tomography. He was taken to an intensive care unit after surgery. However, he could not recover from sepsis and died with disseminated intravascular coagulation and multiple organ failure on the 10th-day post-surgery. A histopathological examination of the resected colon showed transmural necrosis and massive amoebae invasion. He was diagnosed with FAC. An autopsy revealed that he had developed pulmonary large cell carcinoma with small intestinal metastasis. The death was caused by intestinal ischemia, necrosis and the perforation of the residual bowel caused by amoebae invasion. CONCLUSIONS: Since FAC is a lethal disease with a high mortality rate and antibiotic therapies except metronidazole are ineffective, preoperative serological testing and perioperative metronidazole therapy in FAC patients can dramatically improve their survival rates.

Ponesimod suppresses hepatitis B virus infection by inhibiting endosome maturation.

The discovery of novel antivirals to treat hepatitis B virus (HBV) infection is urgently needed, as the currently available drugs mainly target viral proteins at replication step, whereas host factors also play significant roles in HBV infection. Although numerous studies have reported candidate drugs for HBV treatment, there remains a need to find a new drug that may target other steps of the HBV life cycle. In this study, by drug screening of a 533 G-protein-coupled receptors (GPCRs)-associated compound library, we identified ponesimod, a selective agonist of sphingosine-1-phosphate receptor 1 (S1P1), as a drug candidate for the suppression of HBV infection. However, the anti-HBV effect of ponesimod is independent of S1P1 and other sphingosine-1-phosphate receptors (S1PRs). Treatment with ponesimod at an early step of infection but not at a post-entry step significantly reduced the HBV relaxed circular DNA (rcDNA) level in a dose-dependent manner. Ponesimod treatment did not inhibit attachment, binding, or internalization of HBV particles via endocytosis through an interaction with sodium taurocholate cotransporting polypeptide (NTCP) or epidermal growth factor receptor (EGFR). Importantly, during the transportation of HBV particles to the nucleus, co-localization of HBV with early endosomes but not with late endosomes and lysosomes was induced by the treatment with ponesimod, suggesting that ponesimod interferes with the conversion of early endosomes to late endosomes without significant damage to cellular growth. Conclusion: Ponesimod is a promising anti-HBV drug targeting the endosome maturation of HBV. This finding can be applied to the development of novel antivirals that target the trafficking pathway of HBV particles.

Various miRNAs compensate the role of miR-122 on HCV replication.

One of the determinants for tissue tropism of hepatitis C virus (HCV) is miR-122, a liver-specific microRNA. Recently, it has been reported that interaction of miR-122 to HCV RNA induces a conformational change of the 5'UTR internal ribosome entry site (IRES) structure to form stem-loop II structure (SLII) and hijack of translating 80S ribosome through the binding of SLIII to 40S subunit, which leads to efficient translation. On the other hand, low levels of HCV-RNA replication have also been detected in some non-hepatic cells; however, the details of extrahepatic replication remain unknown. These observations suggest the possibility that miRNAs other than miR-122 can support efficient replication of HCV-RNA in non-hepatic cells. Here, we identified a number of such miRNAs and show that they could be divided into two groups: those that bind HCV-RNA at two locations (miR-122 binding sites I and II), in a manner similar to miR-122 (miR-122-like), and those that target a single site that bridges sites I and II and masking both G28 and C29 in the 5'UTR (non-miR-122-like). Although the enhancing activity of these non-hepatic miRNAs were lower than those of miR-122, substantial expression was detected in various normal tissues. Furthermore, structural modeling indicated that both miR-122-like and non-miR-122-like miRNAs not only can facilitate the formation of an HCV IRES SLII but also can stabilize IRES 3D structure in order to facilitate binding of SLIII to the ribosome. Together, these results suggest that HCV facilitates miR-122-independent replication in non-hepatic cells through recruitment of miRNAs other than miR-122. And our findings can provide a more detailed mechanism of miR-122-dependent enhancement of HCV-RNA translation by focusing on IRES tertiary structure.

Rimonabant suppresses RNA transcription of hepatitis B virus by inhibiting hepatocyte nuclear factor 4α.

Chronic infection with hepatitis B virus (HBV) sometime induces lethal cirrhosis and hepatocellular carcinoma. Although nucleot(s)ide analogs are used as main treatment for HBV infection, the emergence of the drug-resistant viruses has become a problem. To discover novel antivirals with low side effects and low risk of emergence of resistant viruses, screening for anti-HBV compounds was performed with compound libraries of inhibitors targeting G-protein-coupled receptors (GPCRs). HepG2-hNTCP C4 cells infected with HBV were treated with various GPCR inhibitors and harvested at 14 day postinfection for quantification of core protein in the first screening or relaxed circular DNA in the second screening. Finally, we identified a cannabinoid receptor 1 inhibitor, rimonabant, as a candidate showing anti-HBV effect. In HepG2-hNTCP C4 cells, treatment with rimonabant suppressed HBV propagation at the viral RNA transcription step but had no effect on entry or covalently closed circular DNA level. The values of half maximal inhibitory concentration, half maximal effective concentration, and selectivity index of rimonabant in primary human hepatocyte (PHH) are 2.77 µm, 40.4 µm, and 14.6, respectively. Transcriptome analysis of rimonabant-treated primary hepatocytes by RNA sequencing revealed that the transcriptional activity of hepatocyte nuclear factor 4α (HNF4α), which is known to stimulate viral RNA synthesis, was depressed. By treatment of PHH with rimonabant, the expression level of HNF4α protein and the production of the messenger RNAs (mRNAs) of downstream factors promoted by HNF4α were reduced while the amount of HNF4α mRNA was not altered. These results suggest that treatment with rimonabant suppresses HBV propagation through the inhibition of HNF4α activity.