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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

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

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.

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.

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.

Currently, complete surgical resection is the most effective and the only potentially curative treatment for gallbladder carcinoma (GBC). However, GBC frequently presents various manifestations as it progresses, including liver invasion, bile duct invasion, hepatoduodenal invasion, venous invasion, and lymphatic invasion. Although there is a clear need for effective chemotherapeutic methods in the management of GBC, no standard chemotherapeutic regimen for advanced GBC has been established to date, and the prognosis remains poor. Herein, we report a case of successful treatment in a patient with advanced GBC who showed a great response to combination chemotherapy and who was subsequently able to undergo curative resection. A 38-year-old Japanese woman was first diagnosed with unknown primary cancer with bilateral ovarian, hepatic, and peritoneal metastases. Combination paclitaxel plus carboplatin chemotherapy was started at a dose of 653 mg of carboplatin and 248 mg of paclitaxel once a week for 3 weeks. After 6 cycles, the tumor had shrunk in size and was detected as only a slightly contrasted lesion in Couinaud's hepatic segments 4 and 5. One month after the final cycle of chemotherapy, we performed cholecystectomy and right lobectomy of the liver with D2 lymph node dissection. The patient exhibited an uneventful postoperative course. Five months have passed since the operation, with no signs of recurrent disease. Our findings suggest that combination chemotherapy with paclitaxel and carboplatin may be effective against advanced GBC.

Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. The aim of this study was to perform population pharmacokinetic (PopPK) analysis and evaluate probability of target attainment (PTA) in plasma and epithelial lining fluid (ELF) based on a modeling and simulation approach. Methods PopPK analysis in plasma was conducted using 3427 concentration data from 425 patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), complicated urinary tract infection (cUTI), or acute uncomplicated pyelonephritis in 3 Phase 2 or 3 studies (NCT03032380, NCT02714595, and NCT02321800), and 91 subjects without any infection in Phase 1 studies. In addition, intrapulmonary modeling was conducted using ELF concentration data from 7 pneumonia patients (NCT03862040) and 20 healthy subjects. Monte-Carlo simulations were performed by generating 1000 virtual patients for each infection site (pneumonia, BSI/sepsis, or cUTI) to predict PTA for 75% of time for which free drug concentration in plasma or ELF (only pneumonia patients) exceeds the minimum inhibitory concentration (MIC; 0.25–16 µg/mL) over dosing interval following CFDC 2 g q8h infused over 3 hours with dose adjustment based on renal function, including augmented renal clearance. Results The developed PopPK model described the plasma and ELF CFDC concentrations. Creatinine clearance, body weight, infection site, and albumin concentration were statistically significant covariates on CFDC PK in plasma. There were no clinically significant differences in CFDC plasma exposure based on infection site or with/without ventilation. The penetration ratio of ELF to free plasma in pneumonia patients (0.340) was 1.3-fold higher than that in healthy subjects (0.263). As shown in the table below, plasma PTA was >90% against MICs ≤4 μg/mL, regardless of infection site and renal function. ELF PTA in pneumonia patients was >90% against MICs ≤2 μg/mL and >85% against MICs ≤4 μg/mL, regardless of renal function. Table. Probability of Target Attainment for 75% fT>MIC or 75% fT>MIC,ELF Conclusion The recommended dosing regimen (2 g, q8h, 3-hr infusion) adjusted by renal function provided adequate exposure to CFDC in patients with infections caused by Gram-negative pathogens, irrespective of infection site and renal function. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

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.

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.

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.