Platelets mediate the clearance of senescent red blood cells by forming prophagocytic platelet-cell complexes.

ABSTRACT: In humans, ∼0.1% to 0.3% of circulating red blood cells (RBCs) are present as platelet-RBC (P-RBC) complexes, and it is 1% to 2% in mice. Excessive P-RBC complexes are found in diseases that compromise RBC health (eg, sickle cell disease and malaria) and contribute to pathogenesis. However, the physiological role of P-RBC complexes in healthy blood is unknown. As a result of damage accumulated over their lifetime, RBCs nearing senescence exhibit physiological and molecular changes akin to those in platelet-binding RBCs in sickle cell disease and malaria. Therefore, we hypothesized that RBCs nearing senescence are targets for platelet binding and P-RBC formation. Confirming this hypothesis, pulse-chase labeling studies in mice revealed an approximately tenfold increase in P-RBC complexes in the most chronologically aged RBC population compared with younger cells. When reintroduced into mice, these complexes were selectively cleared from the bloodstream (in preference to platelet-free RBC) through the reticuloendothelial system and erythrophagocytes in the spleen. As a corollary, patients without a spleen had higher levels of complexes in their bloodstream. When the platelet supply was artificially reduced in mice, fewer RBC complexes were formed, fewer erythrophagocytes were generated, and more senescent RBCs remained in circulation. Similar imbalances in complex levels and senescent RBC burden were observed in humans with immune thrombocytopenia (ITP). These findings indicate that platelets are important for binding and clearing senescent RBCs, and disruptions in platelet count or complex formation and clearance may negatively affect RBC homeostasis and may contribute to the known risk of thrombosis in ITP and after splenectomy.

Metabolic and transcriptional activities underlie stationary-phase Pseudomonas aeruginosa sensitivity to Levofloxacin.

IMPORTANCE: The bacterial pathogen Pseudomonas aeruginosa is responsible for a variety of chronic human infections. Even in the absence of identifiable resistance mutations, this pathogen can tolerate lethal antibiotic doses through phenotypic strategies like biofilm formation and metabolic quiescence. In this study, we determined that P. aeruginosa maintains greater metabolic activity in the stationary phase compared to the model organism, Escherichia coli, which has traditionally been used to study fluoroquinolone antibiotic tolerance. We demonstrate that hallmarks of E. coli fluoroquinolone tolerance are not conserved in P. aeruginosa, including the timing of cell death and necessity of the SOS DNA damage response for survival. The heightened sensitivity of stationary-phase P. aeruginosa to fluoroquinolones is attributed to maintained transcriptional and reductase activity. Our data suggest that perturbations that suppress transcription and respiration in P. aeruginosa may actually protect the pathogen against this important class of antibiotics.

Molecular docking technology and network pharmacology based on Rhapontici Radix-Cremastrae Pseudobulbus drug pair in treating breast cancer.

OBJECTIVE: Network pharmacology is a bioinformatics-based research strategy for identifying the mechanisms of drugs and promoting drug development. This study used network pharmacology to investigate the mechanism of the Loulu-Cremastrae Pseudobulbus drug pair treating breast cancer (BC). MATERIALS AND METHODS: The ingredients and potential targets of the drug pair were searched with Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCSMP). National Center for Biotechnology Information (NCBI) and gene cards were used to search the targets of BC. Networks of "drugs-components-targets" and protein-protein interaction were constructed through Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were carried out through common targets. Using AutoDock tool, molecular docking was performed to verify the binding between key targets and compounds. RESULTS: Finally, we selected 6 active compounds from the drug pair. A total of 61 targets were associated with the drug pair, and 15,295 targets were related to BC. 55 common targets were obtained after the intersection. The key targets included Transcription factor Jun (JUN), Heat shock protein HSP 90-alpha (HSP90AA1), and Caspase-3(CASP3). 327 terms were obtained by GO analysis. 78 pathways (p < 0.05) were identified through KEGG analysis. Molecular docking indicated that important compounds combined well with key targets. CONCLUSIONS: Various active compounds, including beta-sitosterol, 2-methoxy-9,10-dihydrophenanthrene-4,5-diol, and stigmasterol, can regulate multiple signaling pathways related to BC, such as the estrogen and prolactin signaling pathways, playing therapeutic roles in BC.

Influence of Nutritional Status on a Family-Centered Care Intervention for Older Adults with Cognitive Impairment following Hip-Fracture Surgery: Secondary Data Analysis of a Randomized Controlled Trial.

OBJECTIVES: In Taiwan, older adults with cognitive impairment who undergo hip-fracture surgery are routinely cared for by family members. This study aimed to determine if nutritional status influenced the effects of a family-centered intervention for older adults with cognitive impairment recovering from hip-fracture surgery. DESIGN: Secondary data analysis of data from a randomized controlled trial was conducted to examine the influences of nutritional status 1 month after hospital discharge on the effects of a family-centered care intervention model, which was designed for older adults with hip fracture and cognitive impairment. Outcomes were compared among participants according to nutrition status (well-nourished/poorly-nourished) and treatment approach (control/intervention). SETTING: The original study was conducted at a 3000-bed medical center from July 2015 to October 2019. PARTICIPANTS: Participants were older adults with cognitive impairment who had undergone hip-fracture surgery. Participants were assessed as poorly-nourished or well-nourished with the Mini-Nutritional Assessment (MNA) 1-month post-discharge and were then randomly assigned to either the intervention group or control group. INTERVENTION: A family-centered intervention model for family caregivers of older adults with cognitive impairment recovering from hip-fracture surgery was implemented. The intervention was delivered by geriatric nurses, which included instructions for family caregivers in overseeing exercises for strengthening the hip, understanding dietary requirements, and managing behavioral problems associated with cognitive impairment. MEASUREMENTS: Outcome measures included activities of daily living (ADLs), instrumental ADLs, hip range of motion, hip muscle strength, depression, measured with the Geriatric Depressive Scale, and physical and mental health related quality of life, measured with the Short Form Survey (SF-36), Taiwanese version. Participants were assessed at 1-, 3-, 6-, and 12-months post-discharge. RESULTS: Most of the 134 participants were assessed as poorly nourished (n = 122); 57 were the control group and 65 received the intervention. For the well-nourished participants (n = 12), four were in the intervention group and eight were controls. There were no significant differences in any outcome variables for poorly nourished participants who received the intervention compared with controls. For the sample of well-nourished participants, those who received the intervention performed significantly better in outcomes of IADLs (b = 1.74, p < .05), hip muscle strength (b = 9.64, p < .01), and physical health related quality of life (b = 10.47, p < .01). CONCLUSION: The family-centered care intervention was only effective for older adults with cognitive impairment recovering from hip-fracture surgery who were well-nourished at 1 month following hospital discharge, but not for those at risk of malnutrition. Interventions should focus on enhancing nutritional status following hip surgery which could allow the family-centered in-home intervention to be beneficial for more older adults with cognitive impairment recovering from hip-fracture surgery.

A novel flow cytometry procoagulant assay for diagnosis of vaccine-induced immune thrombotic thrombocytopenia.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe prothrombotic complication of adenoviral vaccines, including the ChAdOx1 nCoV-19 (Vaxzevria) vaccine. The putative mechanism involves formation of pathological anti-platelet factor 4 (PF4) antibodies that activate platelets via the low-affinity immunoglobulin G receptor FcγRIIa to drive thrombosis and thrombocytopenia. Functional assays are important for VITT diagnosis, as not all detectable anti-PF4 antibodies are pathogenic, and immunoassays have varying sensitivity. Combination of ligand binding of G protein-coupled receptors (protease-activated receptor-1) and immunoreceptor tyrosine-based activation motif-linked receptors (FcγRIIa) synergistically induce procoagulant platelet formation, which supports thrombin generation. Here, we describe a flow cytometry-based procoagulant platelet assay using cell death marker GSAO and P-selectin to diagnose VITT by exposing donor whole blood to patient plasma in the presence of a protease-activated receptor-1 agonist. Consecutive patients triaged for confirmatory functional VITT testing after screening using PF4/heparin ELISA were evaluated. In a development cohort of 47 patients with suspected VITT, plasma from ELISA-positive patients (n = 23), but not healthy donors (n = 32) or individuals exposed to the ChAdOx1 nCov-19 vaccine without VITT (n = 24), significantly increased the procoagulant platelet response. In a validation cohort of 99 VITT patients identified according to clinicopathologic adjudication, procoagulant flow cytometry identified 93% of VITT cases, including ELISA-negative and serotonin release assay-negative patients. The in vitro effect of intravenous immunoglobulin (IVIg) and fondaparinux trended with the clinical response seen in patients. Induction of FcγRIIa-dependent procoagulant response by patient plasma, suppressible by heparin and IVIg, is highly indicative of VITT, resulting in a sensitive and specific assay that has been adopted as part of a national diagnostic algorithm to identify vaccinated patients with platelet-activating antibodies.

Absolute energies and emission line shapes of the L x-ray transitions of lanthanide metals.

We use an array of transition-edge sensors, cryogenic microcalorimeters with 4 eV energy resolution, to measure L x-ray emission-line profiles of four elements of the lanthanide series: praseodymium, neodymium, terbium, and holmium. The spectrometer also surveys numerous x-ray standards in order to establish an absolute-energy calibration traceable to the international system of units for the energy range 4 keV to 10 keV. The new results include emission line profiles for 97 lines, each expressed as a sum of one or more Voigt functions; improved absolute energy uncertainty on 71 of these lines relative to existing reference data; a median uncertainty on the peak energy of 0.24 eV, four to ten times better than the median of prior work; and six lines that lack any measured values in existing reference tables. The 97 lines comprise nearly all of the most intense L lines from these elements under broad-band x-ray excitation. The work improves on previous measurements made with a similar cryogenic spectrometer by the use of sensors with better linearity in the absorbed energy and a gold x-ray absorbing layer that has a Gaussian energy-response function. It also employs a novel sample holder that enables rapid switching between science targets and calibration targets with excellent gain balancing. Most of the results for peak energy values shown here should be considered as replacements for the currently tabulated standard reference values, while the line shapes given here represent a significant expansion of the scope of available reference data.

Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study.

BACKGROUND: Grade 3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) origin with Ki-67 indices <55% do not respond well to platinum-based chemotherapy. The combination of capecitabine and temozolomide (CAPTEM) has shown favorable responses in grade 1-2 NENs, but has rarely been studied in patients with grade 3 NENs. PATIENTS AND METHODS: This open-label, single-arm phase II trial included patients with unresectable or metastatic grade 3 NENs of GEP origin with Ki-67 indices <55% enrolled between June 2017 and July 2020. Patients received oral capecitabine 750 mg/m2 twice daily on days 1 to 14 and oral temozolomide 200 mg/m2 once daily on days 10 to 14 every 4 weeks. Histologic findings were centrally reviewed after the completion of enrollment. The primary endpoint was overall response rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Of the 30 patients included in the full analysis set, 1 (3.3%) achieved complete response, 8 (26.7%) had partial responses, and 14 (46.7%) had stable disease, making the overall response rate 30.0%. At a median follow-up of 19.2 months, the median PFS was 5.9 months and the median OS was not reached. Patients with well-differentiated NENs showed significantly better median PFS (9.3 months versus 3.5 months, P = 0.005) and median OS (not reached versus 6.2 months, P = 0.004) than patients with poorly differentiated tumors. Expression of O6-methyl-guanine methyltransferase protein did not correlate with clinical outcomes. The most common grade 3-4 adverse events were thrombocytopenia (10%), anemia (6.7%), and nausea (6.7%). CONCLUSIONS: CAPTEM was effective and well tolerated in patients with grade 3 GEP-NENs with Ki-67 indices <55%, with superior efficacy outcomes compared with the historical controls receiving platinum-based chemotherapy.

Surgical outcomes of second primary lung cancer after the extrapulmonary malignancy.

OBJECTIVE: To study the surgical outcomes of patients with a second primary lung cancer after the extrapulmonary malignancy. MATERIALS AND METHODS: Patients who underwent surgical resection for lung cancers between January 2005 and December 2014 were reviewed. Clinical data, imaging characteristics of tumors, surgical approaches, and outcomes were analyzed with a mean follow-up of 97 months. RESULTS: Of 1075 patients, 166 (15.4%) had a second primary lung cancer after extrapulmonary malignancy. There were no differences in overall 5-year survival rates (81.8% for the group of lung cancer vs. 72.9% for the second primary lung cancer group, p = 0.069) and 5-year disease-free survival (70.1% for the lung cancer group vs. 70.3% for the second primary lung cancer group, p = 0.863) between the two groups. Gender, performance status, tumor size, and maximum standard uptake value (SUVmax) were significantly different between the two groups. After propensity-score matching analysis, patients in the group with lung cancers had better 5-year overall survival (88.1% vs. 72.1% for the group with second primary lung cancers, p = 0.016) and 5-year disease-free survival (80.6% vs. 70.3% for the group with second primary lung cancers; p = 0.054). In the second primary lung cancer group, the patients with preceding breast or thyroid cancers had better prognoses than did those with other extrapulmonary malignancy. CONCLUSIONS: Second primary lung cancers following extrapulmonary malignancies were not uncommon. Surgical resection is considered for early stage secondary primary lung cancer after meticulous work up and result in fair outcome.

Long noncoding RNA MIRG induces osteoclastogenesis and bone resorption in osteoporosis through negative regulation of miR-1897.

OBJECTIVE: To investigate the expression of long noncoding RNA (LncRNA) MIRG and its potential functions in regulating osteoclastogenesis and bone resorption function through modulating miR-1897 in bone marrow macrophages (BMMs). MATERIALS AND METHODS: qRT-PCR was performed to detect the expressions of MIRG and its co-expression mRNA NFATc1 at different stages during osteoclastogenesis. The CCK-8 assay was performed to evaluate cell proliferation and differentiation. The correlation between miR-1897 and MIRG was detected by statistical analysis. Bioinformatics and luciferase assay were performed to explore the interaction and binding site of MIRG and miR-1897. We also cloned the mice NFATc1 3'-UTR into the luciferase reporter vector and constructed miR-1897 binding mutants to validate the inhibited regulation of miR-1897 to the expression of NFATc1. RESULTS: Results showed that expressions of MIRG and NFATc1 were upregulated during osteoclastogenesis. qRT-PCR and CCK-8 assay showed that MIRG expression is associated with osteoclastogenesis and bone resorption. The bioinformatics prediction and luciferase assay suggested that by interacting with miR-1897, MIRG acts as a molecular sponge for the miR-1897 target NFATc1, to partly modulate the inhibitory effect of miR-1897 on NFATc1. CONCLUSIONS: We found that lncRNA-MIRG was upregulated in osteoclasts, which could promote osteoclastogenesis and bone resorption function as a molecular sponge by modulating the inhibitory effect of miR-1897 on NFATc1.

Multicentre study of perioperative versus adjuvant chemotherapy for resectable colorectal liver metastases.

Background: It is not known whether perioperative chemotherapy, compared with adjuvant chemotherapy alone, improves disease-free survival (DFS) in patients with upfront resectable colorectal liver metastases (CLM). The aim of this study was to estimate the impact of neoadjuvant 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) on DFS in patients with upfront resectable CLM. Methods: Consecutive patients who presented with up to five resectable CLM at two Japanese and two French centres in 2008-2015 were included in the study. Both French institutions favoured perioperative FOLFOX, whereas the two Japanese groups systematically preferred upfront surgery plus adjuvant chemotherapy. Inverse probability of treatment weighting (IPTW) and Cox regression multivariable models were used to adjust for confounding. The primary outcome was DFS. Results: Some 300 patients were included: 151 received perioperative chemotherapy and 149 had upfront surgery plus adjuvant chemotherapy. The weighted 3-year DFS rate was 33·5 per cent after perioperative chemotherapy compared with 27·1 per cent after upfront surgery plus adjuvant chemotherapy (hazard ratio (HR) 0·85, 95 per cent c.i. 0·62 to 1·16; P = 0·318). For the subgroup of 165 patients who received adjuvant FOLFOX successfully (for at least 3 months), the adjusted effect of neoadjuvant chemotherapy was not significant (HR 1·19, 0·74 to 1·90; P = 0·476). No significant effect of neoadjuvant chemotherapy was observed in multivariable regression analysis. Conclusion: Compared with adjuvant chemotherapy, perioperative FOLFOX does not improve DFS in patients with resectable CLM, provided adjuvant chemotherapy is given successfully.

Antecedentes: Se desconoce si la quimioterapia perioperatoria en comparación con la quimioterapia adyuvante sola mejora la supervivencia libre de enfermedad (disease­free survival, DFS) en pacientes con metástasis hepáticas de origen colorrectal (colorectal liver metastases, CLM) resecables de inicio. El objetivo de este estudio fue estimar el impacto de la neoadyuvancia con 5­fluorouracilo, leucovorina y oxaliplatino (FOLFOX) sobre la DFS en pacientes con CLM resecables desde el principio. Métodos: Se incluyeron pacientes consecutivos que presentaban hasta cinco CLM resecables en dos centros japoneses y dos centros franceses entre 2008 a 2015. Ambas instituciones francesas favorecían FOLFOX perioperatorio, mientras que los dos grupos japoneses utilizaban sistemáticamente la cirugía de entrada y quimioterapia adyuvante. Se utilizaron la probabilidad inversa del tratamiento ponderado (Inverse Probability of Treatment Weighting, IPTW) y el modelo multivariable de regresión de Cox para ajustar por factores de confusión. El resultado primario fue la DFS. Resultados: Se incluyeron 300 pacientes (grupo de quimioterapia perioperatoria n = 151 y grupo de cirugía de entrada más quimioterapia adyuvante n = 149). La DFS a los 3 años ponderada fue del 33% después de quimioterapia perioperatoria versus 27% tras cirugía de entrada (cociente de riesgos instantáneos, hazard ratio HR: 0,85; i.c. del 95% (0,62­1,16); P = 0,32). Cuando se consideró el subgrupo de pacientes que (n = 165) de manera efectiva (al menos 3 meses) recibieron FOLFOX adyuvante, el efecto ajustado de la quimioterapia neoadyuvante no fue significativo (HR: 1,19 (0,74­1,90); P = 0,48). No se observó un efecto significativo de la quimioterapia neoadyuvante en el análisis de regresión multivariable. Conclusión: En comparación con la quimioterapia adyuvante, el FOLFOX perioperatorio no mejora la DFS en CLM resecables siempre y cuando la quimioterapia adyuvante se administre de forma efectiva.

Effect of different doses of ketamine with low-dose rocuronium on intubation conditions in children: prospective randomized double blind trial.

OBJECTIVE: The effect of ketamine on intubation condition, when used as an induction agent with low-dose rocuronium, is unknown. This study aimed to compare the effects of three doses of ketamine used with 0.3 mg/kg rocuronium and 1 µg/kg fentanyl on intubation conditions in children undergoing short elective surgery. PATIENTS AND METHODS: The study was performed as a prospective, randomized double-blind clinical trial. A total of 60 children aged 2 to 12 years, who were scheduled for inguinal herniorrhaphy under general anesthesia, were randomly allocated into three groups on the basis of ketamine dose: 1 mg/kg (Group K1, n = 20), 1.5 mg/kg (Group K1.5, n = 20), and 2 mg/kg (Group K2, n = 20). The primary outcome was the intubation condition. Other assessments included hemodynamic data, recovery profile, adverse events in the postanesthetic care unit (PACU) and use of fentanyl as a rescue analgesic in the PACU were also assessed. RESULTS: The occurrence of a clinically acceptable intubation condition increased with the use of an increased dose (≥ 1.5 mg/kg) (K1/K1.5/K2: 30%/65%/65%; p=0.038, for trends p=0.028). Hemodynamic data, recovery profile and adverse events in PACU showed no difference among groups. Fentanyl dose used in the PACU was higher in K1 than K2 and the number of patients requiring rescue analgesics in the PACU decreased in accordance with the dose of ketamine (K1/K1.5/K2: 30%/15%/0%; p=.031, for trends p=0.013). CONCLUSIONS: Different intubation conditions were observed on the basis of ketamine dose used in conjunction with 0.3 mg/kg rocuronium and fentanyl 1 µg/kg. Ketamine dose ≥ 1.5 mg/kg with low-dose rocuronium should be used to improve intubation conditions in pediatrics.

A Robust Principal Component Analysis for Outlier Identification in Messy Microcalorimeter Data.

A principal component analysis (PCA) of clean microcalorimeter pulse records can be a first step beyond statistically optimal linear filtering of pulses toward a fully nonlinear analysis. For PCA to be practical on spectrometers with hundreds of sensors, an automated identification of clean pulses is required. Robust forms of PCA are the subject of active research in machine learning. We examine a version known as coherence pursuit that is simple and fast and well matched to the automatic identification of outlier records, as needed for microcalorimeter pulse analysis.

Folding a small protein using harmonic linear discriminant analysis.

Many processes of scientific importance are characterized by time scales that extend far beyond the reach of standard simulation techniques. To circumvent this impediment, a plethora of enhanced sampling methods has been developed. One important class of such methods relies on the application of a bias that is a function of a set of collective variables specially designed for the problem under consideration. The design of good collective variables can be challenging and thereby constitutes the main bottle neck in the application of these methods. To address this problem, recently we have introduced Harmonic Linear Discriminant Analysis, a method to systematically construct collective variables as linear combinations of a set of descriptors. The method uses input information that can be gathered in short unbiased molecular dynamics simulations in which the system is trapped in the metastable states. Here, to scale up our examination of the method's efficiency, we applied it to the folding of chignolin in water. Interestingly, already before any biased simulations were run, the constructed one-dimensional collective variable revealed much of the physics that underlies the folding process. In addition, using it in metadynamics, we were able to run simulations in which the system goes from the folded state to the unfolded one and back, where to get fully converged results, we combined metadynamics with parallel tempering. Finally, we examined how the collective variable performs when different sets of descriptors are used in its construction.

Prognostic Value of the Metabolic and Volumetric Parameters of 11C-Methionine Positron-Emission Tomography for Gliomas: A Systematic Review and Meta-Analysis.

BACKGROUND: Several studies have demonstrated that 11C-methionine positron-emission tomography provides information on prognosis. PURPOSE: We performed a systematic review and meta-analysis of the prognostic value of the metabolic and volumetric parameters of 11C-methionine-PET for gliomas. DATA SOURCES: A systematic search was performed using the following combination of keywords: "methionine," "PET," "glioma," and "prognosis." STUDY SELECTION: The inclusion criteria were the use of 11C-methionine-PET as an imaging tool, studies limited to gliomas, studies including metabolic parameters (tumor-to-normal ratio) and/or volumetric parameters (metabolic tumor volume), and studies reporting survival data. The electronic search first identified 181 records, and 14 studies were selected. DATA ANALYSIS: Event-free survival and overall survival were the outcome measures of interest. The effect of the tumor-to-normal ratio and metabolic tumor volume on survival was determined by the effect size of the hazard ratio. Hazard ratios were extracted directly from each study when provided or determined by analyzing the Kaplan-Meier curves. DATA SYNTHESIS: The combined hazard ratios of the tumor-to-normal ratio for event-free survival was 1.74 with no significance and that of the tumor-to-normal ratio for overall survival was 2.02 with significance. The combined hazard ratio of the metabolic tumor volume for event-free survival was 2.72 with significance and that of the metabolic tumor volume for overall survival was 3.50 with significance. LIMITATIONS: The studies selected were all retrospective, and there were only 4 studies involving the metabolic tumor volume. CONCLUSIONS: The present meta-analysis of 11C-methionine-PET suggests that the tumor-to-normal ratio for overall survival and the metabolic tumor volume for event-free survival and overall survival are significant prognostic factors for patients with gliomas.

Single-Center Experience Using Marginal Liver Grafts in Korea.

BACKGROUND: Liver transplantation (LT) is an established therapeutic modality for patients with end-stage liver disease. The use of marginal donors has become more common worldwide due to the sharp increase in recipients, with a consequent shortage of suitable organs. We analyzed our single-center experience over the last 8 years in LT to evaluate the outcomes of using so-called "marginal donors." METHODS: We retrospectively analyzed the database of all LTs performed at our institution from 2009 to 2017. Only patients undergoing deceased-donor LTs were analyzed. Marginal grafts were defined as livers from donors >60 years of age, livers from donors with serum sodium levels >155 mEq, graft steatosis >30%, livers with cold ischemia time ≥12 hours, livers from donors who were hepatitis B or C virus positive, livers recovered from donation after cardiac death, and livers split between 2 recipients. Patients receiving marginal grafts (marginal group) were compared with patients receiving standard grafts (standard group). RESULTS: A total of 106 patients underwent deceased-donor LT. There were 55 patients in the standard group and 51 patients in the marginal group. There were no significant differences in terms of age, sex, Model for End-Stage Liver Disease score, underlying liver disease, presence of hepatocellular carcinoma, and hospital stay between the 2 groups. Although the incidence of acute cellular rejection, cytomegalovirus infection, and postoperative complications was similar between the 2 groups, the incidence of early allograft dysfunction was higher in the marginal group. With a median follow-up of 26 months, the 1-, 3-, and 5-year overall and graft (death-censored) survivals in the marginal group were 85.5%, 75%, and 69.2% and 85.9%, 83.6%, and 77.2%, respectively. Patient overall survival and graft survival (death-censored) were significantly lower in the marginal group (P = .023 and P = .048, respectively). On multivariate analysis, receiving a marginal graft (hazard ratio [HR], 4.862 [95% confidence interval (CI), 1.233-19.171]; P = .024) and occurrence of postoperative complications (HR, 4.547 [95% CI, 1.279-16.168]; P = .019) were significantly associated with worse patient overall survival. Also, when factors associated with marginal graft were analyzed separately, graft steatosis >30% was independently associated with survival (HR, 5.947 [95% CI, 1.481-23.886]; P = .012). CONCLUSIONS: Patients receiving marginal grafts showed lower but acceptable overall survival and graft survival. However, because graft steatosis >30% was independently associated with worse survival, caution must be exercised when using this type of marginal graft by weighing the risk and benefits.

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy.

Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.