Median Arcuate Ligament Syndrome (MALS) in Hepato-Pancreato-Biliary Surgery: A Narrative Review and Proposed Management Algorithm.

Median arcuate ligament syndrome (MALS) is an uncommon condition characterized by the compression of the celiac trunk by the median arcuate ligament. Due to the anatomical proximity to the foregut, MALS has significant implications in hepato-pancreato-biliary (HPB) surgery. It can pose complications in pancreatoduodenectomy and orthotopic liver transplantation, where the collateral arterial supply from the superior mesenteric artery is often disrupted. The estimated prevalence of MALS in HPB surgery is approximately 10%. Overall, there is consensus for a cautious approach to MALS when embarking on complex foregut surgery, with a low threshold for intraoperative median arcuate ligament release or hepatic artery reconstruction. The role of endovascular intervention in the management of MALS prior to HPB surgery continues to evolve, but more evidence is required to establish its efficacy. Recognizing the existing literature gap concerning optimal management in this population, we describe our tertiary center experience as a clinical algorithm to facilitate decision-making. Research question: What is the significance and management of median arcuate ligament syndrome in patients undergoing hepato-pancreato-biliary surgery?

Prevalence, Risk Factors, Clinical Features, and Outcome of Influenza-Associated Pulmonary Aspergillosis in Critically Ill Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) increasingly is being reported in critically ill patients. We conducted this systematic review and meta-analysis to examine the prevalence, risk factors, clinical features, and outcomes of IAPA. STUDY QUESTION: What are the prevalence, risk factors, clinical features, and outcomes of IAPA in critically ill patients? STUDY DESIGN AND METHODS: Studies reporting IAPA were searched in the following databases: PubMed MEDLINE, CINAHL, Cochrane Library, Embase, Scopus, Cochrane Trials, and ClinicalTrials.gov. We performed one-group meta-analysis on risk factors, clinical features, morbidity, and mortality using random effects models. RESULTS: We included 10 observational studies with 1,720 critically ill patients with influenza, resulting in an IAPA prevalence of 19.2% (331 of 1,720). Patients who had undergone organ transplantation (OR, 4.8; 95% CI, 1.7-13.8; I2 = 45%), harbored a hematogenous malignancy (OR, 2.5; 95% CI, 1.5-4.1; I2 = 0%), were immunocompromised (OR, 2.2; 95% CI, 1.6-3.1; I2 = 0%), and underwent prolonged corticosteroid use before admission (OR, 2.4; 95% CI, 1.4-4.3; I2 = 51%) were found to be at a higher risk of IAPA developing. Commonly reported clinical and imaging features were not particularly associated with IAPA. However, IAPA was associated with more severe disease progression, a higher complication rate, and longer ICU stays and required more organ supports. Overall, IAPA was associated with a significantly elevated ICU mortality rate (OR, 2.6; 95% CI, 1.8-3.8; I2 = 0%). INTERPRETATION: IAPA is a common complication of severe influenza and is associated with increased mortality. Early diagnosis of IAPA and initiation of antifungal treatment are essential, and future research should focus on developing a clinical algorithm. TRIAL REGISTRY: International Prospective Register of Systematic Reviews; No.: CRD42022284536; URL: https://www.crd.york.ac.uk/prospero/.

Effects of transfusing older red blood cells and platelets on obstetric patient outcomes: A retrospective cohort study.

OBJECTIVE: To investigate associations between transfusion of blood products close to the end of shelf-life and clinical outcomes in obstetric inpatients. METHODS: Mortality and morbidity were compared in patients transfused exclusively with red blood cells (RBC) stored for less than 21 days (fresh) versus RBC stored for 35 days or longer (old), and platelets (PLT) stored for 3 days or fewer (fresh) versus 4 days or longer (old) in Queensland, Australia from 2007 to 2013. Multivariable models were used to examine associations between these groups of blood products and clinical end points. RESULTS: There were 3371 patients who received RBC and 280 patients who received PLT of the eligible storage durations. Patients transfused with old RBC received fewer transfusions (2.7 ± 1.8 vs. 2.3 ± 1.0 units; P < 0.001). However, a higher rate of single-unit transfusions was also seen in those patients who exclusively received old RBC (252 [9.3%] vs. 92 [13.7%]; P = 0.003). Comparison of fresh vs. old blood products revealed no differences in the quantities of transfused RBC (9.5 ± 5.9 vs. 9.1 ± 5.2 units; P = 0.680) or PLT (1.5 ± 0.8 vs. 1.4 ± 1.1 units; P = 0.301) as well as the length of hospital stay for RBC (3 [2-5] vs. 3 [2-5] days; P = 0.124) or PLT (5 [4-8] vs. 6 [4-9] days; P = 0.120). CONCLUSION: Transfusing exclusively older RBC or PLT was not associated with increased morbidity or mortality.

Hemostatic Profiles of Patients Who Underwent Transcatheter Versus Surgical Aortic Valve Replacement Versus Percutaneous Coronary Intervention.

Guidelines for transcatheter aortic valve replacement (TAVR) antithrombotic prophylaxis are extrapolated predominantly from percutaneous coronary intervention (PCI) data. Here, we examined temporal coagulation changes occurring in the early perioperative period to determine the pathobiologic validity of this supposition. This was a prospective observational study of consecutive patients who underwent transfemoral TAVR (n = 27), PCI (n = 12), or surgical aortic valve replacement (SAVR) requiring cardiopulmonary bypass and cross-clamping (n = 12). Blood samples were taken at 4 time points: T1 (baseline), after general anesthesia or sedation; T2, after heparin administration; T3, at the end of the procedure; and T4, 6 hours after the procedure. The samples were assessed concurrently using standard laboratory coagulation tests and viscoelastic tests of whole blood clotting, including the latest generation thromboelastometry (ROTEM sigma) and thromboelastometry (TEG 6s). Patients in the TAVR cohort were older and a had lower baseline hemoglobin level than patients in the PCI and SAVR cohorts. The baseline platelet function was similar between the TAVR and PCI cohorts and impaired in the SAVR cohort Figure S1. The baseline hemostatic measures were comparable among cohorts. Regarding the per-patient change from baseline, the TAVR cohort showed an overall more prothrombotic state than the other cohorts, with the most marked differences from the SAVR cohort after intraoperative heparin administration and from the PCI cohorts 6 hours after the procedure. In addition, the ROTEM and TEG parameters were well correlated but not interchangeable. In conclusion, patients who underwent TAVR have a more prothrombotic hemostatic profile than PCI and SAVR patients. These findings question the current guidelines that extrapolate antithrombotic regimens from PCI to TAVR settings.

Depletion of macrophages and dendritic cells in ischemic acute kidney injury.

BACKGROUND: Inflammation is thought to play a role in ischemic acute kidney injury (AKI). We have demonstrated that macrophage and dendritic cell depletion, using liposome-encapsulated clodronate (LEC), is protective against ischemic AKI. METHODS: To determine whether macrophages or dendritic cells or both play a role in ischemic AKI, we performed ischemic AKI in CD11b-DTR mice that have a diphtheria toxin (DT)-induced depletion of CD11b cells (macrophages) and CD11c-DTR mice that have a DT-induced depletion of CD11c cells (dendritic cells). RESULTS: While LEC-treated animals had a significant functional protection from AKI, CD11b-DTR and CD11c-DTR mice were not protected against AKI despite a similar degree of renal macrophage and dendritic cell depletion. Proinflammatory cytokines are known to play a role in ischemic AKI. To determine the possible reasons for the lack of protection in CD11b-DTR and CD11c-DTR mice compared to LEC-treated mice, 32 cytokines/chemokines were measured in these mice. Of the cytokines/chemokines measured, IL-6, MCP-1, GMCSF, IL-1ß and CXCL1 (also known as IL-8 in humans or KC in mice) showed significant differences in the LEC-treated, CD11b-DTR and CD11c-DTR mice. MCP-1 and CXCL1 (known mediators of AKI), and also GMCSF and IL-1ß were increased in AKI and decreased in LEC-treated AKI but not AKI in CD11b-DTR or CD11c-DTR mice. CONCLUSIONS: These findings suggest that LEC-mediated protection from AKI is not simply mediated by depletion of renal macrophage or dendritic cell subpopulations. Protection against AKI in LEC-treated compared to CD11b-DTR or CD11c-DTR mice may be partially explained by differences in proinflammatory cytokine profiles.

CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study.

BACKGROUND: Probody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing 'off-tumor' toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab. METHODS: Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1). RESULTS: Twenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3-4 adverse events (AEs) and grade 3-4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients. CONCLUSIONS: The MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

Increased macrophage infiltration and fractalkine expression in cisplatin-induced acute renal failure in mice.

Inflammatory mechanisms contribute to cisplatin-induced acute renal failure (CisARF). Our first aim was to determine renal macrophage infiltration in CisARF. A more than 2-fold increase in CD11b-positive macrophages in the kidney on day 2 preceded the increase in blood urea nitrogen (BUN) and serum creatinine (SCr). Our next aim was to determine the chemoattractant for macrophage infiltration in CisARF. Fractalkine (CX(3)CL1) is expressed on activated endothelial cells and is a potent chemoattractant for macrophages that express its receptor (CX(3)CR1). Immunoblotting showed that whole-kidney CX(3)CL1 expression on days 1, 2, and 3 after cisplatin administration was increased. On immunofluorescence, the intensity of renal endothelial staining of CX(3)CL1 in blood vessels was significantly increased on day 2. Circulating von Willebrand factor (vWF), a measure of systemic endothelial injury, was increased on day 2. Next we determined whether macrophages played an injurious role in CisARF. Macrophages were depleted with injections of liposome-encapsulated clodronate (LEC). LEC resulted in a decrease in renal CD11b-positive macrophages on day 3. However, LEC-treated mice were not protected from CisARF on day 3. To determine the role of CX(3)CR1, both a specific anti-CX(3) CR1 antibody and CX(3) CR1(-/-) mice were used. Administration of the CX(3)CR1 antibody and CX(3) CR1(-/-) mice was not protected against CisARF. In summary, in CisARF, macrophage infiltration in the kidney, CX(3)CL1 expression in whole kidney and blood vessels, and the increase in circulating vWF precede BUN and SCr increase. However, inhibition of macrophage infiltration in the kidney or CX(3)CR1 blockade is not sufficient to prevent CisARF.

Macrophages are not the source of injurious interleukin-18 in ischemic acute kidney injury in mice.

We previously reported in ischemic acute kidney injury (AKI) in mice that caspase-1-mediated production of interleukin-18 (IL-18) is pathogenic and that macrophage depletion by liposome-encapsulated clodronate (LEC) is protective. Therefore, our aim was to determine whether macrophages are a source of IL-18 in ischemic AKI in mice. On immunofluorescence staining of the outer stripe of outer medulla, the number of macrophages double stained for CD11b and IL-18 was significantly increased in AKI and significantly decreased by LEC. Adoptive transfer of RAW 264.7 cells, a mouse macrophage line that constitutively expresses IL-18 mRNA, reversed the functional protection against AKI in both LEC-treated wild-type and caspase-1 -/- mice. To test whether IL-18 in macrophages is necessary to cause AKI, we adoptively transferred macrophages in which IL-18 was inhibited. Peritoneal macrophages isolated from wild-type mice, IL-18 binding protein transgenic (IL-18 BP Tg) mice, and IL-18 -/- mice were used. IL-18 BP Tg mice overexpress human IL-18 BP and exhibit decreased biological activity of IL-18. Adoptive transfer of peritoneal macrophages from wild-type as well as IL-18 BP Tg and IL-18 -/- mice reversed the functional protection against AKI in LEC-treated mice. In summary, adoptive transfer of RAW cells, that constitutively express IL-18, reverses the functional protection in macrophage-depleted wild-type and caspase-1 -/- mice with AKI. However, adoptive transfer of peritoneal macrophages in which IL-18 function was inhibited also reverses the functional protection in macrophage-depleted mice. In conclusion, IL-18 from adoptive transfer of macrophages is not sufficient to cause ischemic AKI.

Interleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury.

IL-18 function is neutralized in IL-18 binding protein transgenic (IL-18BP Tg) mice. First, we determined whether IL-18BP Tg mice are protected against ischemic acute kidney injury (AKI). Ischemic AKI was induced by bilateral renal pedicle clamping. IL-18BP Tg mice were functionally and histologically protected against ischemic AKI as determined by blood urea nitrogen, serum creatinine, and acute tubular necrosis score. We have demonstrated that the injurious effect of IL-18 in the kidney is independent of neutrophils and lymphocytes. Thus the effect of IL-18 inhibition on renal macrophage infiltration was determined. The number of macrophages was significantly reduced in IL-18BP Tg compared with wild-type kidneys. To determine the cytokines and chemokines that are dependent on IL-18, we performed flow cytometry based assays. Multiple chemokines/cytokines, IL-3, IL-6, IL-15, IL-18, leukemia inhibitory factor, macrophage colony-stimulating factor, macrophage inflammatory protein-2, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 were significantly increased in AKI vs. sham kidneys. Only CXCL1 (also known as KC or IL-8) was significantly increased in AKI vs. sham kidneys and significantly reduced in IL-18BP Tg AKI vs. wild-type AKI kidneys. To determine whether macrophages are the source of CXCL1 in the kidney, we depleted macrophages with liposomal encapsulated clodronate. CXCL1 was significantly decreased in macrophage-depleted vs. control AKI mice. In summary, in ischemic AKI in mice, 1) IL-18BP Tg mice are functionally and histologically protected, 2) macrophage infiltration in the kidney and CXCL1 are significantly reduced in IL-18BP Tg mice, and 3) macrophage depletion significantly reduces CXCL1 in the kidney. In conclusion, protection against ischemic AKI in IL-18BP Tg mice is associated with less macrophage infiltration and less production of CXCL1 in the kidney.

Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice.

Fractalkine (CX3CL1) is expressed on injured endothelial cells and is a potent chemoattractant and adhesion molecule for macrophages carrying the fractalkine receptor (CX3CR1). The aim of this study was to investigate the role of CX3CL1, and its ligand CX3CR1, in ischemic acute renal failure (ARF) in mice. On immunoblotting, CX3CL1 protein expression in the kidney increased markedly in ischemic ARF. On immunofluorescence staining, the intensity of CX3CL1 staining in blood vessels was significantly more prominent in ischemic ARF compared with controls. A specific anti-CX3CR1 antibody (25 microg i.p. 1 h before induction of ischemia) was functionally and histologically protective against ischemic ARF. CX3CR1 is predominantly expressed on macrophages. Macrophage infiltration in the kidney in ischemic ARF was significantly decreased after anti-CX3CR1 antibody treatment. To determine the role of macrophages in ischemic ARF, macrophages in the kidney were depleted using liposomal-encapsulated clodronate (LEC). LEC resulted in significant functional and histological protection against ischemic ARF. In summary, in ischemic ARF, 1) there is upregulation of CX3CL1 protein in the kidney, specifically in blood vessels; 2) CX3CR1 inhibition using a specific antibody is partially protective and is associated with reduced macrophage infiltration in the kidney; and 3) macrophage depletion in the kidney is protective.

Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.

We have demonstrated that caspase-1-deficient (caspase-1(-/-)) mice are functionally and histologically protected against cisplatin-induced acute renal failure (ARF). Caspase-1 exerts proinflammatory effects via the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil recruitment. We sought to determine the role of the cytokines IL-1beta, IL-18, and IL-6 and neutrophil recruitment in cisplatin-induced ARF. We first examined IL-1beta; renal IL-1beta increased nearly 2-fold in cisplatin-induced ARF and was reduced in the caspase-1(-/-) mice. However, inhibition with IL-1 receptor antagonist (IL-1Ra) did not attenuate cisplatin-induced ARF. Renal IL-18 increased 2.5-fold; however, methods to inhibit IL-18 using IL-18 antiserum and transgenic mice that overproduce IL-18-binding protein (a natural inhibitor of IL-18) did not protect. Renal IL-6 increased 3-fold; however, IL-6-deficient (IL-6(-/-)) mice still developed cisplatin-induced ARF. We next examined neutrophils; blood neutrophils increased dramatically after cisplatin injection; however, prevention of peripheral neutrophilia and renal neutrophil infiltration with the neutrophil-depleting antibody RB6-8C5 did not protect against cisplatin-induced ARF. In summary, our data demonstrated that cisplatin-induced ARF is associated with increases in the cytokines IL-1beta, IL-18, and IL-6 and neutrophil infiltration in the kidney. However, inhibition of IL-1beta, IL-18, and IL-6 or neutrophil infiltration in the kidney is not sufficient to prevent cisplatin-induced ARF.