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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 model of cefiderocol and assess pharmacokinetic profile in lungs. An intrapulmonary pharmacokinetic model of cefiderocol was developed using the concentration data in plasma and epithelial lining fluid (ELF) from 7 pneumonia patients requiring mechanical ventilation and 20 healthy subjects. Subsequently, the model was applied to assess the ELF exposure of 125 nosocomial pneumonia patients. Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for percentage of time for which free ELF concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC,ELF ). The developed model adequately described ELF concentrations and suggested the delayed distribution in ELF for pneumonia patients compared to healthy subjects. Lung penetration ratio of cefiderocol in pneumonia patients was calculated to be 34%, which was 1.4 fold of that in healthy subjects. The estimated %fT>MIC,ELF was 100% in most of nosocomial pneumonia patients, and no pharmacokinetic/pharmacodynamic relationship with %fT>MIC,ELF was found for microbiological or clinical outcome. The PTA 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 higher than 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 based on renal function in critically ill pneumonia patients. This article is protected by copyright. All rights reserved.

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, Graphical abstract

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.

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.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.The patient's provisional diagnosis was deduced to be angiosarcoma, which was the most common malignant tumor of the spleen.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.Ten years have passed since the patient's splenectomy, and he continues to do well, without evidence of local or distant recurrence.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.

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, 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 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.

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.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.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.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.

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. 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. 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. The lack of a clinically meaningful drug–drug interaction between baloxavir marboxil and oseltamivir has been established.

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.

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC ( fT MIC ). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fT MIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.

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.

There is no consensus about remnant liver regeneration associated with middle hepatic vein (MHV) resecting. 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. 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. 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 liver resection (LLR) has been developed as a minimally invasive surgery. However, challenges such as difficulty securing visibility and limited control of forceps make it difficult to complete LLR in hepatic segments VI, VII, and VIII. To overcome these challenges, we devised a surgical technique using intercostal ports. We termed this approach the lateral approach. This work describes our experience performing LLR using this approach and discusses the safety and effectiveness of this approach. Between April 2011 and December 2016, data from 91 patients who underwent LLR with or without the intercostal port at a single institution were retrospectively analyzed regarding surgical outcomes, safety, and utility. LLR was performed for 32 patients with the intercostal port and for 59 patients without the intercostal port. The conversion rates to open surgery with and without intercostal ports were 3.1 and 25.4% (P = 0.008). In hepatic segments VII and VIII, the rates of conversion to open surgery were significantly lower for cases involving intercostal ports (6.7 vs. 42.9 and 0 vs. 38.9%; P = 0.035 and 0026, respectively); however, there were no differences in hepatic segment VI (0 vs. 7.4%; P = 0.563). There were no differences in operative time, blood loss volume, surgical margin, curative resection rate, or postoperative complication rate for LLR in all segments (VI, VII, and VIII). No adverse events due to placement of the intercostal port were observed in this set of patients. LLR using the lateral approach and intercostal ports for hepatic segments VII and VIII resulted in a significant decrease in conversion rates to open surgery.

Background: Routine drainage after partial hepatic resection has long been controversial. Methods: Three hundred and twenty-eight patients who underwent hepatic resections for liver tumors without biliary-enteric and gastrointestinal anastomoses were analyzed using propensity score matching analysis with respect to if and when a prophylactic drain was used and for how long. The criteria for drain placement were established and validated. Results: Our criteria for drain placement were chosen according to postoperative percutaneous abdominal drainage risk factors, organ/space surgical site infections (SSIs), hepatic resection method, intraoperative bile leakage and operative time (≥300 min). The organ/space SSI rate was significantly lower in the group in which abdominal drain removal occurred 2 days after surgery. We decided to remove the abdominal drains on postoperative day 2 when the drain-fluid bilirubin concentration was less than 3 times the serum bilirubin concentration. After our criteria for drain management were developed in 2011, the number of inserted drains, postoperative percutaneous abdominal drainages, postoperative complications, SSI rates and postoperative hospital stays were significantly lower. Conclusions: Our criteria for abdominal drain management facilitate favorable postoperative outcomes.

We present a case of afferent loop syndrome (ALS) occurring after pancreaticoduodenectomy (PD) in a patient who had previously undergone total gastrectomy (TG), and review the English-language literature concerning reconstruction procedures following PD in patients who had undergone TG. The patient was a 69-year-old man who had undergone TG reconstruction by a Roux-en-Y method at age 58 years. The patient underwent PD for pancreas head adenocarcinoma. A jejunal limb previously made at the prior TG was used for pancreaticojejunostomy and hepaticojejunostomy. Despite normal patency of the hepaticojejunostomy, he suffered from repeated postoperative cholangitis which was brought on by ALS due to shortness of the jejunal limb (15 cm in length). We therefore performed receliotomy in which the hepaticojejunostomy was disconnected and reconstructed using a new Y limb 40-cm in length constructed in a double Roux-en-Y fashion. The refractory cholangitis resolved immediately after the receliotomy and did not recur. Review of the literature revealed the lack of any current consensus for a standard procedure for reconstruction following PD in patients who had previously undergone TG. This issue warrants further attention, particularly given the expected future increase in the number of PDs in patients with a history of gastric cancer.