-
Journal of Nuclear Medicine : Official... Jun 2022Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI)-based radiotracers has been developed...
Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI)-based radiotracers has been developed and had excellent performance for diagnosis outcomes in clinical applications. Yet, their fast clearance and insufficient tumor retention have hampered their further clinical application in cancer treatment. In this study, we developed 2 albumin binder-conjugated FAPI radiotracers, TEFAPI-06 and TEFAPI-07. They were derived from FAPI-04 and were optimized by conjugating 2 types of well-studied albumin binders, 4-(-iodophenyl) butyric acid moiety (TEFAPI-06) and truncated Evans blue moiety (TEFAPI-07), to try to overcome the above limitations at the expense of prolonging the blood circulation. TEFAPI-06 and TEFAPI-07 were synthesized and labeled with Ga, Y, and Lu successfully. A series of cell assays was performed to identify the binding affinity and FAP specificity in vitro. PET imaging, SPECT imaging, and biodistribution studies were performed to evaluate the pharmacokinetics in pancreatic cancer patient-derived xenograft (PDX) animal models. The cancer treatment efficacy of Lu-TEFAPI-06 and Lu-TEFAPI-07 were evaluated in pancreatic cancer PDX-bearing mice. The binding affinities (dissociation constants) to FAP of Ga-TEFAPI-06 and Ga-TEFAPI-07 were 10.16 ± 2.56 nM and 7.81 ± 2.28 nM, respectively, which were comparable with that of Ga-FAPI-04. Comparative PET imaging of HT-1080-FAP and HT-1080 tumor-bearing mice and a blocking study showed the FAP-targeting ability in vivo of these 2 tracers. Compared with Lu-FAPI-04, PET imaging, SPECT imaging, and biodistribution studies of TEFAPI-06 and TEFAPI-07 demonstrated their remarkably enhanced tumor accumulation and retention, respectively. Notable tumor growth inhibition by Lu-TEFAPI-06 and Lu-TEFAPI-07 were observed, whereas the control group and the group treated by Lu-FAPI-04 showed a slight therapeutic effect. Two albumin binder-conjugated FAPI radiopharmaceuticals have been developed and evaluated in vitro and in vivo. Significantly improved tumor uptake and retention were observed, compared with the original FAPI tracer. Both Lu-TEFAPI-06 and Lu-TEFAPI-07 showed remarkable growth inhibition of PDX tumors, whereas the side effects were almost negligible, demonstrating that these radiopharmaceuticals are promising for further clinical translational studies.
Topics: Albumins; Animals; Cell Line, Tumor; Endopeptidases; Fibroblasts; Gallium Radioisotopes; Humans; Membrane Proteins; Mice; Pancreatic Neoplasms; Radiopharmaceuticals; Tissue Distribution
PubMed: 34593598
DOI: 10.2967/jnumed.121.262533 -
The New England Journal of Medicine Mar 2021Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown.
METHODS
We conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment.
RESULTS
A total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group.
CONCLUSIONS
In patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom. (Funded by the Health Innovation Challenge Fund; ATTIRE EudraCT number, 2014-002300-24; ISRCT number, N14174793.).
Topics: Adult; Albumins; Ascites; Female; Hospitalization; Humans; Infusions, Intravenous; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Pulmonary Edema; Serum Albumin; Treatment Failure
PubMed: 33657293
DOI: 10.1056/NEJMoa2022166 -
Current Medical Research and Opinion Dec 2020Positive fluid balance is common among critically ill patients and leads to worse outcomes, particularly in sepsis, acute respiratory distress syndrome, and acute kidney... (Review)
Review
OBJECTIVE
Positive fluid balance is common among critically ill patients and leads to worse outcomes, particularly in sepsis, acute respiratory distress syndrome, and acute kidney injury. Restrictive fluid infusion and active removal of accumulated fluid are being studied as approaches to prevent and treat fluid overload. Use of human albumin solutions has been investigated in different phases of restrictive fluid resuscitation, and this narrative literature review was undertaken to evaluate hypoalbuminemia and the roles of human serum albumin with respect to hypovolemia and its management.
METHODS
PubMed/EMBASE search terms were: "resuscitation," "fluids," "fluid therapy," "fluid balance," "plasma volume," "colloids," "crystalloids," "albumin," "hypoalbuminemia," "starch," "saline," "balanced salt solution," "gelatin," "goal-directed therapy" (English-language, pre-January 2020). Additional papers were identified by manual searching of reference lists.
RESULTS
Restrictive fluid administration, plus early vasopressor use, may reduce fluid balance, but in some cases fluid overload cannot be entirely avoided. Deresuscitation, with fluid actively removed through diuretics or ultrafiltration, reduces duration of mechanical ventilation and intensive care unit stay. Combining hyperoncotic human albumin solution with diuretics increases hemodynamic stability and diuresis. Hyperoncotic albumin corrects hypoalbuminemia and raises colloid osmotic pressure, limiting edema formation and potentially improving endothelial function. Serum levels of albumin relative to C-reactive protein and lactate may predict which patients will benefit most from albumin therapy.
CONCLUSIONS
Hyperoncotic human albumin solution facilitates restrictive fluid therapy and the effectiveness of deresuscitative measures. Current evidence is mostly from observational studies, and more randomized trials are needed to better establish a personalized approach to fluid management.
Topics: Albumins; Colloids; Critical Illness; Crystalloid Solutions; Fluid Therapy; Humans; Hypoalbuminemia; Hypovolemia; Intensive Care Units; Perioperative Care; Respiration, Artificial; Resuscitation; Sepsis; Serum Albumin, Human; Water-Electrolyte Balance
PubMed: 33090028
DOI: 10.1080/03007995.2020.1840970 -
Journal of Intensive Care Medicine Aug 2023The best type of resuscitation fluids for sepsis and septic shock patients remains unclear. The aim of this study was to evaluate the efficacy of different... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The best type of resuscitation fluids for sepsis and septic shock patients remains unclear. The aim of this study was to evaluate the efficacy of different concentrations of albumin on reducing the mortality rate of theses patients by meta-analysis.
MATERIALS AND METHODS
PubMed, EMBASE, and Web of Science databases were used for screening the relevant studies. Randomized controlled trials (RCTs) were eligible if they compared the effects of albumin with crystalloid on mortality in patients with sepsis and septic shock. Data were examined and extracted by two reviewers independently. Any disagreements were resolved by consensus with or without the help from a third reviewer. Data including mortality, sample size of the patients, and resuscitation endpoints were extracted. Meta-analysis was carried based on the corresponding odds ratios with 95% confidence intervals.
RESULTS
Eight studies with a total of 5124 septic patients and 3482 septic shock patients were included in this study. Compared with crystalloid, the use of albumin may represent a trend toward reduced the 90-day mortality of septic patients (OR 0.91 [0.80, 1.02]; = .11) and significantly improved the outcome of septic shock patients (OR 0.85 [0.74, 0.99]; = .04). Further analysis showed a potentially beneficial role of both 4% to 5% and 20% albumin on reducing the mortality of septic patients. The use of 20% albumin significantly decreased the 90-day mortality of septic shock patients (OR 0.81 [0.67, 0.98]; = .03), which was better than 4% to 5% albumin and crystalloid.
CONCLUSIONS
Albumin treatment, particularly 20% albumin, significantly reduced the 90-day mortality in septic shock patients. Both 4% to 5% and 20% of albumin may work better than crystalloid in improving the survival rate of patients with sepsis, but more relative RCTs are required for validation.
Topics: Humans; Shock, Septic; Crystalloid Solutions; Randomized Controlled Trials as Topic; Sepsis; Albumins
PubMed: 37078161
DOI: 10.1177/08850666231170778 -
JAMA Jul 2022In cardiac surgery, albumin solution may maintain hemodynamics better than crystalloids and reduce the decrease in platelet count and excessive fluid balance, but... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
In cardiac surgery, albumin solution may maintain hemodynamics better than crystalloids and reduce the decrease in platelet count and excessive fluid balance, but randomized trials are needed to compare the effectiveness of these approaches in reducing surgical complications.
OBJECTIVE
To assess whether 4% albumin solution compared with Ringer acetate as cardiopulmonary bypass prime and perioperative intravenous volume replacement solution reduces the incidence of major perioperative and postoperative complications in patients undergoing cardiac surgery.
DESIGN, SETTING, AND PARTICIPANTS
A randomized, double-blind, single-center clinical trial in a tertiary university hospital during 2017-2020 with 90-day follow-up postoperatively involving patients undergoing on-pump coronary artery bypass grafting; aortic, mitral, or tricuspid valve surgery; ascending aorta surgery without hypothermic circulatory arrest; and/or the maze procedure were randomly assigned to 2 study groups (last follow-up was April 13, 2020).
INTERVENTIONS
The patients received in a 1:1 ratio either 4% albumin solution (n = 693) or Ringer acetate solution (n = 693) as cardiopulmonary bypass priming and intravenous volume replacement intraoperatively and up to 24 hours postoperatively.
MAIN OUTCOMES AND MEASURES
The primary outcome was the number of patients with at least 1 major adverse event: death, myocardial injury, acute heart failure, resternotomy, stroke, arrhythmia, bleeding, infection, or acute kidney injury.
RESULTS
Among 1407 patients randomized, 1386 (99%; mean age, 65.4 [SD, 9.9] years; 1091 men [79%]; 295 women [21%]) completed the trial. Patients received a median of 2150 mL (IQR, 1598-2700 mL) of study fluid in the albumin group and 3298 mL (IQR, 2669-3500 mL) in the Ringer group. The number of patients with at least 1 major adverse event was 257 of 693 patients (37.1%) in the albumin group and 234 of 693 patients (33.8%) in the Ringer group (relative risk albumin/Ringer, 1.10; 95% CI, 0.95-1.27; P = .20), an absolute difference of 3.3 percentage points (95% CI, -1.7 to 8.4). The most common serious adverse events were pulmonary embolus (11 [1.6%] in the albumin group vs 8 [1.2%] in the Ringer group), postpericardiotomy syndrome (9 [1.3%] in both groups), and pleural effusion with intensive care unit or hospital readmission (7 [1.0%] in the albumin group vs 9 [1.3%] in the Ringer group).
CONCLUSIONS AND RELEVANCE
Among patients undergoing cardiac surgery with cardiopulmonary bypass, treatment with 4% albumin solution for priming and perioperative intravenous volume replacement solution compared with Ringer acetate did not significantly reduce the risk of major adverse events over the following 90 days. These findings do not support the use of 4% albumin solution in this setting.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02560519.
Topics: Aged; Albumins; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Coronary Artery Bypass; Double-Blind Method; Female; Fluid Therapy; Heart Diseases; Humans; Isotonic Solutions; Male; Middle Aged; Solutions
PubMed: 35852528
DOI: 10.1001/jama.2022.10461 -
Journal of Hepatology Sep 2022The choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension is unclear. 5% albumin was superior to normal saline in the FRISC study. We... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
The choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension is unclear. 5% albumin was superior to normal saline in the FRISC study. We compared the efficacy and safety of 20% albumin, which has greater oncotic properties, to plasmalyte in reversing sepsis-induced hypotension.
METHODS
Critically ill patients with cirrhosis underwent open-label randomization to receive either 20% albumin (0.5-1.0 g/kg over 3 hours; n = 50) or plasmalyte (30 ml/kg over 3 hours, n = 50). The primary endpoint of the study was the attainment of mean arterial pressure (MAP) above 65 mmHg at 3 hours.
RESULTS
Baseline characteristics were comparable in albumin and plasmalyte groups; arterial lactate (6.16±3.18 mmol/L vs. 6.38±4.77 mmol/L; p = 0.78), MAP (51.4±6.52 mmHg vs. 49.9±4.45 mmHg; p = 0.17) and SOFA score (10.8±2.96 vs. 11.1±4.2; p = 0.68), respectively. Most patients were alcoholics (39%) and had pneumonia (40%). In the intention-to-treat analysis, albumin was superior to plasmalyte in achieving the primary endpoint (62% vs. 22%; p <0.001). A faster decline in arterial lactate (p = 0.03), a reduced need for dialysis (48% vs. 62%; p = 0.16), and a longer time to initiation of dialysis (in hours) (68.13±47.79 vs. 99.7± 63.4; p = 0.06) were seen with albumin. However, the 28-day mortality rate was not different (58% vs. 62%, p = 0.57) and treatment had to be discontinued in 11 (22%) patients in the albumin group due to adverse effects compared to no discontinuations in the plasmalyte group.
CONCLUSION
In patients with cirrhosis and sepsis-induced hypotension, 20% albumin leads to a faster improvement in hemodynamics and lactate clearance than plasmalyte, while 28-day survival was similar. However, patients on 20% albumin need to be closely monitored as it was more often associated with pulmonary complications.
CLINICAL TRIAL REGISTRATION
NCT02721238.
LAY SUMMARY
The current randomized-controlled trial performed in critically ill patients with cirrhosis and sepsis-induced hypotension highlights that 20% albumin restores arterial pressure more quickly but causes more pulmonary complications than plasmalyte. The impact on renal functions was also modest. These effects did not result in improvement in survival at 28 days. Plasmalyte is safer and well-tolerated and can be considered for volume resuscitation in patients with cirrhosis and sepsis-induced hypotension.
Topics: Albumins; Critical Illness; Electrolytes; Fluid Therapy; Humans; Hypotension, Controlled; Lactic Acid; Liver Cirrhosis; Sepsis; Shock, Septic
PubMed: 35460725
DOI: 10.1016/j.jhep.2022.03.043 -
Organogenesis Dec 2022Mesenchymal stem cells (MSC) and induced pluripotent stem cells (iPSC) have been reported to be able to differentiate to hepatocyte in vitro with varying degree of...
Mesenchymal stem cells (MSC) and induced pluripotent stem cells (iPSC) have been reported to be able to differentiate to hepatocyte in vitro with varying degree of hepatocyte maturation. A simple method to decellularize liver scaffold has been established by the Department of Histology, Faculty of Medicine, Universitas Indonesia, in SCTE IMERI lab. This study aims to evaluate hepatocyte differentiation from iPSCs compared to MSCs derived in our decellularized liver scaffold. The research stages started with iPSC culture, decellularization, seeding cell culture into the scaffold, and differentiation into hepatocytes for 21 days. Hepatocyte differentiation from iPSCs and MSCs in the scaffolds was characterized using hematoxylin-eosin, Masson Trichrome, and immunohistochemistry staining to determine the fraction of the differentiation area. RNA samples were isolated on days 7 and 21. Expression of albumin, CYP450, and CK-19 genes were analyzed using the qRT-PCR method. Electron microscopy images were obtained by SEM. Immunofluorescence examination was done using HNF4-α and CEBPA markers. The results of this study in hepatocyte-differentiated iPSCs compared with hepatocyte-differentiated MSCs in decellularized liver scaffold showed lower adhesion capacity, single-cell-formation and adhered less abundant, decreased trends of albumin, and lower CYP450 expression. Several factors contribute to this result: lower initial seeding number, which causes only a few iPSCs to attach to certain parts of decellularized liver scaffold, and manual syringe injection for recellularization, which abruptly and unevenly creates pattern of single-cell-formation by hepatocyte-differentiated iPSC in the scaffold. Hepatocyte-differentiated MSCs have the advantage of higher adhesion capacity to collagen fiber decellularized liver scaffold. This leads to positive result: increase trends of albumin and higher CYP450 expression. Hepatocyte maturation is shown by diminishing CK-19, which is more prominent in hepatocyte-differentiated iPSCs in decellularized liver scaffold. Confirmation of mature hepatocyte-differentiated iPSCs in decellularized liver scaffold maturation is positive for HNF4-a and CEBPA. The conclusion of this study is hepatocyte-differentiated iPSCs in decellularized liver scaffold is mature with lower cell-ECM adhesion, spatial cell distribution, albumin, and CYP450 expression than hepatocyte-differentiated MSCs in decellularized liver scaffold.
Topics: Albumins; Cell Differentiation; Hepatocytes; Induced Pluripotent Stem Cells; Liver; Tissue Scaffolds
PubMed: 35435152
DOI: 10.1080/15476278.2022.2061263 -
Transfusion Medicine Reviews Jan 2023Therapeutic plasma exchange (TPE) has traditionally been used to selectively remove pathologic contents including autoantibodies, abnormal proteins, immune complexes, or... (Review)
Review
Therapeutic plasma exchange (TPE) has traditionally been used to selectively remove pathologic contents including autoantibodies, abnormal proteins, immune complexes, or toxins from a patient's plasma. In addition to the removal of molecular contributors to disease, fluid replacement and infusion of beneficial plasma constituents including albumin can be tapered based on the pathophysiologic mechanisms of the offending disease. This treatment modality has shown efficacy in symptomatic relief and slowing of disease progression for various neurologic, immunologic, and hematologic diseases. This review outlines the rationale for TPE in the treatment of Alzheimer's Disease (AD) through a potential mechanism leveraging the concentration gradient of amyloid β peptides and the infusion of albumin, and critically reviews the clinical evidence for treatment of AD using TPE and albumin replacement. This review also highlights potential sources of bias that must be considered in conjunction with the evidence of efficacy for the use of TPE in AD.
Topics: Humans; Albumins; Alzheimer Disease; Amyloid beta-Peptides; Plasma Exchange; Plasmapheresis
PubMed: 36357257
DOI: 10.1016/j.tmrv.2022.09.005 -
Journal of Clinical Pharmacy and... Aug 2021The purpose of this paper was to discuss the limitations of the studies serving as the evidence for recommendations in clinical practice guidelines concerning albumin... (Review)
Review
WHAT IS KNOWN AND OBJECTIVE
The purpose of this paper was to discuss the limitations of the studies serving as the evidence for recommendations in clinical practice guidelines concerning albumin use for cirrhosis-related complications, review relevant studies published since the guidelines and suggest directions for future investigations.
COMMENT
There are no recent comprehensive clinical practice guidelines concerning albumin. Instead, more recent albumin guidelines reflect areas of specialty practice such as those by American and European associations for the study of the liver and liver disease. Studies published since the guidelines are useful for helping to define the most appropriate indications for albumin with respect to cirrhosis-related complications, as well as directions for future research.
WHAT IS NEW AND CONCLUSION
Albumin has a long history of attempts to define appropriate uses by meta-analysis, but given the high cost and episodic shortages of albumin, there is a need for adequately powered randomized controlled trials using current state-of-the-art care evaluating the use of albumin to prevent or treat cirrhosis-related complications.
Topics: Albumins; Biomarkers; Comorbidity; Humans; Liver Cirrhosis; Liver Diseases; Paracentesis; Practice Guidelines as Topic; Randomized Controlled Trials as Topic
PubMed: 34101215
DOI: 10.1111/jcpt.13461 -
European Journal of Nuclear Medicine... Aug 2023Fibroblast activation protein-α (FAP)-targeting radioligands have recently demonstrated high diagnostic potential. However, their therapeutic value is impaired by the...
Head-to-head comparison of different classes of FAP radioligands designed to increase tumor residence time: monomer, dimer, albumin binders, and small molecules vs peptides.
PURPOSE
Fibroblast activation protein-α (FAP)-targeting radioligands have recently demonstrated high diagnostic potential. However, their therapeutic value is impaired by the short tumor residence time. Several strategies have been tested to overcome this limitation, but a head-to-head comparison has never been done. With the aim to identify strengths and limitations of the suggested strategies, we compared the monomer FAPI-46 versus (a) its dimer (FAPI-46-F1D), (b) two albumin binders conjugates (FAPI-46-Ibu (ibuprofen) and FAPI-46-EB (Evans Blue)), and (c) cyclic peptide FAP-2286.
METHODS
Lu-labeled ligands were evaluated in vitro in cell lines with low (HT-1080.hFAP) and high (HEK-293.hFAP) humanFAP expression. SPECT/CT imaging and biodistribution studies were conducted in HT-1080.hFAP and HEK-293.hFAP xenografts. The areas under the curve (AUC) of the tumor uptake and tumor-to-critical-organs ratios and the absorbed doses were estimated.
RESULTS
Radioligands showed IC in the picomolar range. Striking differences were observed in vivo regarding tumor uptake, residence, specificity, and total body distribution. All [Lu]Lu-FAPI-46-based radioligands showed similar uptake between the two tumor models. [Lu]Lu-FAP-2286 showed higher uptake in HEK-293.hFAP and the least background. The AUC of the tumor uptake and absorbed dose was higher for [Lu]Lu-FAPI-46-F1D and the two albumin binder conjugates, [Lu]Lu-FAPI-46-Ibu and [Lu]Lu-FAPI-46-EB, in HT1080.hFAP xenografts and for [Lu]Lu-FAPI-46-EB and [Lu]Lu-FAP-2286 in HEK293.hFAP xenografts. The tumor-to-critical-organs AUC values and the absorbed doses were in favor of [Lu]Lu-FAP-2286, but tumor-to-kidneys.
CONCLUSION
The study indicated dimerization and cyclic peptide structures as promising strategies for prolonging tumor residence time, sparing healthy tissues. Albumin binding strategy outcome depended on the albumin binding moiety. The peptide showed advantages in terms of tumor-to-background ratios, besides tumor-to-kidneys, but its tumor uptake was FAP expression-dependent.
Topics: Humans; HEK293 Cells; Tissue Distribution; Cell Line, Tumor; Albumins; Peptides; Peptides, Cyclic; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes
PubMed: 37261473
DOI: 10.1007/s00259-023-06272-7