Surgical management of right hepatectomy after coronary artery bypass grafting using the right gastroepiploic artery: a case report and literature review.

BACKGROUND: Coronary artery bypass grafting (CABG) using the right gastroepiploic artery (RGEA) is a well-established, safe procedure. However, problems with RGEA grafts in subsequent abdominal surgeries can lead to fatal complications. This report presents the first case of right hepatectomy for hepatocellular carcinoma after CABG using the RGEA. CASE PRESENTATION: We describe a case in which a right hepatectomy for an 81-year-old male patient with hepatocellular carcinoma was safely performed after CABG using a RGEA graft. Preoperatively, three-dimensional computed tomography (3D- CT) images were constructed to confirm the run of the RGEA graft. The operation was conducted with the standby of a cardiovascular surgeon if there was a problem with the RGEA graft. The RGEA graft had formed adhesions with the hepatic falciform ligament, necessitating meticulous dissection. After the right hepatectomy, the left hepatic lobe descended into the vacated space, exerting traction on the RGEA. However, this traction was mitigated by suturing the hepatic falciform ligament to the abdominal wall, ensuring stability of the RGEA. There were no intraoperative or postoperative complications. CONCLUSION: It is crucial to confirm the functionality and anatomy of the RGEA graft preoperatively, handle it gently intraoperatively, and collaborate with cardiovascular surgeons.

Simultaneous colonic metastasis of advanced gastric cancer: a case report.

BACKGROUND: Although distant metastasis in gastric cancer can be present at the time of the initial diagnosis, colonic metastasis is extremely rare. This report describes a case of simultaneous colonic metastasis of advanced gastric cancer. CASE PRESENTATION: The patient was a 78-year-old woman with nausea and epigastric pain. Upper gastrointestinal endoscopy revealed an advanced invasive ulcerative tumor in the lesser curvature of the stomach extending from the anterior to the middle portion. Colonoscopy revealed a 4-mm polyp-like lesion in the mid-transverse colon; therefore, a polypectomy was performed. Both gastric and colonic tumors showed poorly differentiated adenocarcinoma with signet ring cell carcinoma. After providing informed consent, the patient underwent a total gastrectomy. Histologic examination showed similar morphologic features of both gastric and colonic tumors. Immunohistochemistry staining showed that these tumor cells were positive for cytokeratin (CK) 7 and negative for CK20. CONCLUSIONS: This was an extremely rare case of simultaneous colonic metastasis of advanced gastric cancer. Because missed metastasis can result in a poorer prognosis, we propose a systemic search including colonoscopy for patients with advanced gastric cancer, especially cases involving poorly differentiated adenocarcinoma or signet ring cell carcinoma.

The usefulness of laparoscopic surgery for inguinal endometriosis.

BACKGROUND: Inguinal endometriosis is a rare clinical disease with an unclear etiology and pathogenesis, and its diagnosis requires accurate medical history-taking and histological examination. However, surgical treatment for the condition has not yet been standardized. This report presents two cases of inguinal endometriosis. CASE PRESENTATION: The first patient was a 36-year-old woman who complained of pain and swelling in her right inguinal region. Physical examination revealed a soft, tender right inguinal mass. The size of the mass repeatedly increased and decreased during menstruation and did not show swelling with abdominal pressure. Magnetic resonance imaging showed a 3.5 × 2.5 cm mass with high intensity on T2-weighted imaging in the right inguinal canal, and no communication was found between the lesion site and the abdominal cavity. We diagnosed this case as inguinal endometriosis and managed it using an anterior approach and laparoscopic observation. The second patient was a 51-year-old woman who presented with an intermittently painful mass in her right inguinal region. The mass tended to increase in size, with worsening pain before menstruation. Abdominal computed tomography revealed a 2 × 2 cm cystic mass in the right inguinal region. We made a diagnosis of inguinal ectopic endometriosis and decided to operate via the totally extraperitoneal (TEP) method for excision plus transabdominal observation. The postoperative course in both cases was uneventful with no recurrence. CONCLUSIONS: Inguinal endometriosis is a rare entity that should be suspected in patients with cyclical symptoms of inguinal pain and swelling that correlate with their menstrual cycle, which might otherwise be attributed to inguinal hernia. It is crucial to make a preoperative diagnosis based on a careful medical review, physical examination, and imaging studies, and to make an appropriate surgical plan. Particularly, in the case of ectopic inguinal endometriosis involving the canal of Nuck, laparoscopic observation is useful for the intraoperative diagnosis of inguinal endometriosis to help rule out the involvement of other abdominal sites. However, it is important to select and modify the surgical technique to avoid rupturing the endometrisis mass and prevent postoperative recurrence.

Combined resection of the gastroduodenal artery without revascularization in distal pancreatectomy with en bloc celiac axis resection (extended DP-CAR) for pancreatic cancer: A case report.

INTRODUCTION: Distal pancreatectomy with en bloc celiac axis resection (DP-CAR) is performed to remove locally advanced pancreatic cancer (LAPC) that involves the celiac axis (CA), the common hepatic artery (CHA), or the root of the splenic artery (SpA). It is not usually applied to LAPC involving both the CA and the gastroduodenal artery (GDA) because transection of the GDA cannot assure hepatic perfusion. Preserving the replaced hepatic artery might allow combined resection of the GDA without revascularization. PRESENTATION OF CASE: A 78-year-old woman who was diagnosed with LAPC of the pancreatic head and body that invaded the GDA and proper hepatic artery, as well as the CA. The left hepatic artery (LHA) was solitarily branched from the left gastric artery (LGA), which was branched from proximal to the confluence of the CHA and the SpA. The root of the LGA was intact. We successfully performed DP-CAR with combined resection of the GDA, without revascularization, by preserving the LGA. DISCUSSION: This is the first English literature case of extended DP-CAR with preservation of the replaced LHA (r-LHA). Aberrant right and left hepatic arteries are common variations. Checking the arterial variations is very important when deciding the treatment strategy for LAPC, especially in cases that appear unresectable. CONCLUSION: Our case indicated that the r-LHA alone can supply the entire liver in extended DP-CAR. The resectability must be decided with close evaluations of the vessel variations and the tumor status.

Long-term disease-free survival of an undifferentiated pleomorphic sarcoma of the spleen: A case report and literature review.

INTRODUCTION: Undifferentiated pleomorphic sarcoma (UPS) primarily occurs in the soft tissues of the extremities, trunk, and retroperitoneum. As the primary UPS of the spleen (splenic UPS) is extremely rare, to the best of our knowledge, only 19 cases have been reported in English literature. No cases of long-term survival without a local or distant recurrence have been reported. PATIENT CONCERNS: We report the case of a 37-year-old man who was referred to our hospital for a splenic tumor. He had no past medical or relevant familial history. On abdominal computed tomography (CT), a low attenuation solid mass and cystic component with mural calcifications were present at the lower pole of his spleen. The fluorodeoxyglucose-positron emission tomography (CT) indicated it as malignant tumor of the spleen. DIAGNOSES: The patient's provisional diagnosis was deduced to be angiosarcoma, which was the most common malignant tumor of the spleen. INTERVENTIONS: An elective laparoscopic splenectomy was performed, and the histology of the tumor was consistent with UPS (pT1, pN0, cM0, and AJCC8th). No adjuvant therapy was administered. OUTCOMES: Ten years have passed since the patient's splenectomy, and he continues to do well, without evidence of local or distant recurrence. LESSONS: To the best of our knowledge, this is the first case of long-term recurrence-free survival after surgical management of a splenic UPS. It is probable that radical splenectomy during the disease played the most important role in the patient's long-term survival. Understanding the characteristic findings of a splenic UPS in an abdominal CT may help to diagnose properly.

Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis.

Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.

Covid-19 and Liver Injury: Role of Inflammatory Endotheliopathy, Platelet Dysfunction, and Thrombosis.

Liver injury, characterized predominantly by elevated aspartate aminotransferase and alanine aminotransferase, is a common feature of coronavirus disease 2019 (COVID-19) symptoms caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Additionally, SARS-CoV-2 infection is associated with acute-on-chronic liver failure in patients with cirrhosis and has a notably elevated mortality in patients with alcohol-related liver disease compared to other etiologies. Direct viral infection of the liver with SARS-CoV-2 remains controversial, and alternative pathophysiologic explanations for its hepatic effects are an area of active investigation. In this review, we discuss the effects of SARS-CoV-2 and the inflammatory environment it creates on endothelial cells and platelets more generally and then with a hepatic focus. In doing this, we present vascular inflammation and thrombosis as a potential mechanism of liver injury and liver-related complications in COVID-19.

Intrapulmonary Pharmacokinetic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients With Pneumonia and Healthy Subjects.

Cefiderocol is a siderophore cephalosporin for the treatment of infections caused by gram-negative bacteria including carbapenem-resistant strains. The aim of this study was to develop an intrapulmonary pharmacokinetic (PK) model of cefiderocol and assess the PK profile in lungs. An intrapulmonary PK model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 patients with pneumonia requiring mechanical ventilation and 20 healthy subjects. Subsequently, the model was applied to assess the ELF exposure of 125 patients with nosocomial pneumonia. Monte Carlo simulations were performed to calculate the probability of target attainment for the percentage of time for which free ELF concentrations exceed the minimum inhibitory concentration (MIC) over the dosing interval (%fT>MIC,ELF ). The developed model adequately described ELF concentrations and suggested the delayed distribution in ELF for patients with pneumonia compared to healthy subjects. Lung penetration ratio of cefiderocol in patients with pneumonia was calculated to be 34%, which was 1.4-fold that in healthy subjects. The estimated %fT>MIC,ELF was 100% in most of patients with nosocomial pneumonia, and no PK/pharmacodynamic relationship with %fT>MIC,ELF was found for microbiological or clinical outcome. The probability of target attainment for 100% fT>MIC,ELF was ≥ 99.5% against MICs ≤2 µg/mL and ≥87.0% against MICs ≤4 µg/mL regardless of renal function. The median of simulated ELF trough concentrations at steady state was >4 µg/mL regardless of renal function. These results reveal the adequacy of cefiderocol exposure in plasma and ELF at the recommended dosing regimens adjusted on the basis of renal function in critically ill patients with pneumonia.

Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: A series of 43 cases.

AIM: Coronavirus disease (COVID-19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID-19 patients. The aim of this study is to identify pathological microthrombi in COVID-19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation. METHODS: Forty-three post-mortem liver biopsy samples from COVID-19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated. RESULTS: We found liver sinusoidal microthrombosis in 23 COVID-19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10-fold, p = 0.04; AST: 11-fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p < 0.01), whereas SEA was not (p = 0.73). In COVID-19 livers, strong vWF staining in liver sinusoidal endothelial cells was associated with significantly increased platelet adhesion (1.7-fold, p = 0.0016), compared to those with weak sinusoidal vWF (2-fold, p < 0.0001). Sinusoidal erythrocyte aggregation in 19 (83%) liver samples was mainly seen in zone 2. Livers with SEA had significantly higher fibrinogen (1.6-fold, p = 0.031) compared to those without SEA in COVID-19 patients. CONCLUSIONS: Liver PMT is a pathologically important thrombosis associated with liver injury in COVID-19, while SEA is a unique morphological feature of COVID-19 patient livers. Sinusoidal vWF and hyperfibrinogenemia could contribute to PMT and SEA formation.

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

BACKGROUND AND AIMS: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. METHODS: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. RESULTS: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. CONCLUSION: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. LAY SUMMARY: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection.

Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gram-negative bacteria, including carbapenem-resistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 ml/min, and it is adjusted for patients with <60 ml/min or ≥120 ml/min CrCL. A population pharmacokinetic (PK) model was constructed using 3,427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors, including infection sites and mechanical ventilation, were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was >90% against MICs of ≤4 µg/ml for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients, including the patients with augmented renal function, ventilation, and/or severe illness.

γ-H2AX as a potential indicator of radiosensitivity in colorectal cancer cells.

Preoperative radiotherapy improves local disease control and disease-free survival in patients with advanced rectal cancer; however, a reliable predictive biomarker for the effectiveness of irradiation has yet to be elucidated. Phosphorylation of H2A histone family member X (H2AX) to γ-H2AX is induced by DNA double-strand breaks and is associated with the development of colorectal cancer (CRC). The current study aimed to clarify the relationship between γ-H2AX expression and CRC radiosensitivity in vitro and in vivo. H2AX levels were analyzed in datasets obtained from cohort studies and γ-H2AX expression was investigated by performing immunohistochemistry and western blotting using clinical CRC samples from patients without any preoperative therapy. In addition, the CRC cell lines WiDr and DLD-1 were subjected to irradiation and/or small interfering RNA-H2AX, after which the protein levels of γ-H2AX were examined in samples obtained from patients undergoing preoperative chemoradiotherapy. To quantify the observable effect of treatment on cancer cells, outcomes were graded as follows: 1, mild; 2, moderate; and 3, marked, with defined signatures of cellular response. Datasets obtained from cohort studies demonstrated that H2AX mRNA levels were significantly upregulated and associated with distal metastasis and microsatellite instability in CRC tissues, in contrast to that of normal tissues. In addition, γ-H2AX was overexpressed in clinical samples. In vitro, following irradiation, γ-H2AX expression levels increased and cell viability decreased in a time-dependent manner. Combined irradiation and γ-H2AX knockdown reduced the viability of each cell line when compared with irradiation or γ-H2AX knockdown alone. Furthermore, among clinical CRC samples from patients undergoing preoperative chemoradiotherapy, levels of γ-H2AX in the grade 1 group were significantly higher than those in grade 2 or grade 3. In conclusion, γ-H2AX may serve as a novel predictive marker and target for preoperative radiotherapy effectiveness in patients with CRC.

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects.

BACKGROUND: Naldemedine is a peripherally acting µ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. OBJECTIVES: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. METHODS: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. RESULTS: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC0-inf 1.78-fold and Cmax 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC0-inf 2.91-fold and 1.90-fold, and Cmax 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC0-inf by 83% and Cmax by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. CONCLUSIONS: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided.

Surgical Outcome and Hepatic Regeneration after Hepatic Resection for Hepatocellular Carcinoma in Elderly Patients.

INTRODUCTION: The rising proportion of elderly patients (aged 80 yearsor above) in our population means that more elderly patients are undergoing hepatectomy. METHODS: Five-hundred and thirty patients who underwent hepatectomy for hepatocellular carcinoma (HCC) were retrospectively analyzed with respect to their preoperative status and perioperative results, including remnant liver regeneration. The remnant liver volume was postoperatively measured with multidetector CT on postoperative day 7 and 1, 2, 5, and 12 months after surgery. An elderly group (aged 80 or older) was compared with a non-elderly group (aged less than 80 years). RESULTS: Underlying diseases of the cardiovascular system were significantly more common in the elderly group (57.8%, p = 0.0008). The postoperative incidence of Clavien-Dindo Grade IIIa or higher complications was 20.0% in the elderly group and 24.3% in the non-elderly group, and this difference was not significant. As for regeneration of the remnant liver after resection, this was not morphologically delayed compared to the non-elderly group. CONCLUSIONS: In this study, we have demonstrated that safe, radical hepatectomy, similar to procedures performed on non-elderly patients, can be performed on patients with HCC aged 80 and older with sufficient perioperative care.

Safety, Tolerability, and Pharmacokinetics of the Novel Anti-influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings.

BACKGROUND AND OBJECTIVE: Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. This first-in-human phase I study evaluated the safety, tolerability, and pharmacokinetics of baloxavir marboxil/baloxavir acid in healthy Japanese volunteers (Study 1), while food effects were evaluated in a separate phase I, crossover study in healthy Japanese volunteers (Study 2). METHODS: Study 1 participants were randomized to single-dose oral baloxavir marboxil (6, 20, 40, 60, or 80 mg; n = 6 per dose) or placebo (n = 10), while Study 2 participants (n = 15) received single-dose oral baloxavir marboxil 20 mg in fasted, fed, and before-meal states. RESULTS: Baloxavir marboxil was well tolerated; there were few treatment-emergent adverse events and no serious adverse events/deaths. The mean plasma baloxavir acid concentration 24 h after single-dose (C24) oral baloxavir marboxil 6 mg was 6.92 ng/mL, exceeding the target C24 (6.85 ng/mL) estimated in nonclinical studies. In Study 1, baloxavir acid exposure demonstrated dose-proportional increases in the fasted state, with maximum plasma concentration generally attained within 3.5 h. Terminal elimination half-life ranged from 49 to 91 h. In Study 2, exposure was decreased and apparent clearance increased in the fed and before-meal states versus the fasted state; however, exposure exceeded the target C24 in all states. CONCLUSION: Single-dose oral baloxavir marboxil was well tolerated, had a favorable safety profile, and had favorable pharmacokinetic characteristics, including a long half-life, supporting single oral dosing. The baloxavir acid area under the plasma concentration-time curve decreased with food intake by approximately 40%.

Evaluation of Drug-Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Baloxavir marboxil is a prodrug that is metabolized to baloxavir acid, which suppresses viral replication by inhibiting cap-dependent endonuclease with a single oral administration. As the mode of action of baloxavir marboxil is different from that of neuraminidase inhibitors, such as oseltamivir, combination treatment with these drugs can be a treatment option, particularly for severe influenza infection. The aim of this study was to assess the drug-drug interaction between baloxavir marboxil and oseltamivir. METHODS: Eighteen healthy adult subjects received three treatments in a crossover fashion: single administration of baloxavir marboxil 40 mg alone, repeated twice-daily administration of oseltamivir at 75 mg for 5 days, or single administration of baloxavir marboxil at 40 mg in combination with repeated twice-daily administration of oseltamivir at 75 mg for 5 days. RESULTS: The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of baloxavir acid after co-administration compared to baloxavir marboxil alone were 1.03 (0.92-1.15) and 1.01 (0.96-1.06), respectively. The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of oseltamivir carboxylate, the active form of oseltamivir, after co-administration compared to oseltamivir alone were 0.96 (0.93-1.00) and 0.99 (0.96-1.01), respectively, at steady state on day 5. Treatment-emergent adverse events reported were mild and not considered to be related to the study drug. CONCLUSION: The lack of a clinically meaningful drug-drug interaction between baloxavir marboxil and oseltamivir has been established.

Nogo-B (Reticulon-4B) functions as a negative regulator of the apoptotic pathway through the interaction with c-FLIP in colorectal cancer cells.

Nogo-B is a member of the Nogo/Reticulon-4 family and has been reported to be an inducer of apoptosis in certain types of cancer cells. However, the role of Nogo-B in human cancer remains less understood. Here, we demonstrated the functions of Nogo-B in colorectal cancer cells. In clinical colorectal cancer specimens, Nogo-B was obviously overexpressed, as determined by immunohistochemistry; and Western blot analysis showed its expression level to be significantly up-regulated. Furthermore, knockdown of Nogo-B in two colorectal cancer cell lines, SW480 and DLD-1, by transfection with si-RNA (siR) resulted in significantly reduced cell viability and a dramatic increase in apoptosis with insistent overexpression of cleaved caspase-8 and cleaved PARP. The transfection with Nogo-B plasmid cancelled that apoptosis induced by siRNogoB in SW480 cells. Besides, combinatory treatment with siR-Nogo-B/staurosporine (STS) or siR-Nogo-B/Fas ligand (FasL) synergistically reduced cell viability and increased the expression of apoptotic signaling proteins in colorectal cancer cells. These results strongly support our contention that Nogo-B most likely played an oncogenic role in colorectal cancer cells, mainly by negatively regulating the extrinsic apoptotic pathway in them. Finally, we revealed that suppression of Nogo-B caused down-regulation of c-FLIP, known as a major anti-apoptotic protein, and activation of caspase-8 in the death receptor pathway. Interaction between Nogo-B and c-FLIP was shown by immunoprecipitation and immunofluorescence studies. In conclusion, Nogo-B was shown to play an important negative role in apoptotic signaling through its interaction with c-FLIP in colorectal cancer cells, and may thus become a novel therapeutic target for colorectal cancer.

Short- and Long-Term Results of Laparoscopic Parenchyma-Sparing Hepatectomy for Small-Sized Hepatocellular Carcinoma: A Comparative Study Using Propensity Score Matching Analysis.

The aim of this study was to evaluate the degree of invasiveness and the clinical outcomes of laparoscopic parenchyma-sparing hepatectomy (LPSH) for a maximum hepatocellular carcinoma (HCC) size ≤5 cm. Sixty-one LPSHs and 175 open parenchyma-sparing hepatectomies (OPSHs) for small-sized HCC were analyzed using a propensity score matching analysis. The median operative time was significantly shorter in the LPSH group (194 min) than in the OPSH group (275 minutes) (P < 0.0001). The estimated blood loss was significantly lower in the LPSH group (100 mL) than in the OPSH group (380 mL) (P < 0.0001). The incidences of superficial incisional surgical site infections and respiratory complications were significantly lower in the LPSH group than in the OPSH group (P = 0.0161 and 0.0285, respectively). During the postoperative course, the white blood cell counts and C-reactive protein levels were significantly lower in the LPSH group. There were no differences in overall survival and disease-free survival (P = 0.1293 and 0.4039, respectively), and no significant differences in terms of type of recurrence and site of intrahepatic recurrence (P = 0.1410). The data from the present series suggest the lesser invasiveness and safety of LPSH even for small-sized HCC patients.

Comparison of Regeneration of Remnant Liver After Hemihepatectomy with or Without the Middle Hepatic Vein.

BACKGROUND: There is no consensus about remnant liver regeneration associated with middle hepatic vein (MHV) resecting. METHODS: Seventy-five patients who underwent hemihepatectomy were retrospectively analysed with respect to remnant liver regeneration. The liver remnant volume (LRV) and each sectional volume were postoperatively measured with multidetector computed tomography at day 7 and months 1, 2, 5, and 12 after the operation. RESULTS: In right hemihepatectomy cases, the regeneration rate of LRV in the MHV preservation group was significantly higher than that of the MHV resection group at months 5 and 12. In particular, the regeneration rate of remnant segment IV peaked at day 7 and was shrunk after 1 month, and was significant higher in the MHV preservation group. In left hemihepatectomy cases, the regeneration rate of LRV at month 12 was significantly higher in the MHV preservation group. The regeneration rate of the remnant anterior section peaked at 1 month and was shrunk. CONCLUSION: In this study, the MHV should be preserved or reconstructed whenever possible during hepatic hemihepatectomy. Hepatic regeneration in the MHV perfusion region becomes poor within 7 days to 1 month after surgery (UMIN000023714).

Laparoscopic Hepatic Resection Using Extracorporeal Pringle Maneuver.

BACKGROUND: Laparoscopic hepatic resection (LHR) has been developed as a novel minimally invasive surgery. However, despite improvements in equipment and procedures, intraoperative hemorrhage remains an issue that requires great precaution. To reduce the amount of intraoperative blood loss, we perform the Pringle maneuver, aimed at occluding the inflow of blood into the liver during LHR. This article describes our experience performing LHR using the Pringle maneuver, including postoperative results, and discusses the safety and effectiveness of the Pringle maneuver. METHODS: Data from 83 patients who underwent laparoscopic partial right hepatic resection with or without the Pringle maneuver were retrospectively analyzed with respect to surgical outcomes, safety, and utility. RESULTS: In LHR, the amount of bleeding was significantly lower in cases that included the Pringle maneuver (P = .0314). However, there were no differences in the duration of surgery, surgical margin, rate of curative resections, and incidence of postoperative complications. Laboratory data collected after surgery showed no significant difference between the two groups regardless of whether blood flow was occluded or not. CONCLUSIONS: The Pringle maneuver may be effective in reducing the amount of intraoperative blood loss during laparoscopic partial right hepatic resection, although the difference is not clinically significant. Rather, the reduction in bleeding can reduce the stress experienced by the operator while keeping the transection stump of the liver dry. Particularly, the extracorporeal Pringle maneuver using cotton tape is simple and convenient and can be carried out within a short amount of time.