Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model.

PURPOSE: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. METHODS: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. RESULTS: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. CONCLUSION: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

Effect of Platelet Parameters on Linezolid-Related Thrombocytopenia in Hospitalized Patients.

Background: Linezolid-induced thrombocytopenia incidence varies considerably. Linezolid-related thrombocytopenia in patients has received few studies which have investigated risk factors including platelet parameters except for platelet counts. The study aims to analyze the effect of platelet parameters, including mean platelet volume and platelet large cell ratio, on linezolid-related thrombocytopenia in patients. Methods: The effect of platelet parameters on linezolid-related thrombocytopenia was identified by univariate and multivariate logistic regressions. A Kaplan-Meier survival analysis was carried out to compare the survival of patients who developed linezolid-related thrombocytopenia with patients who did not. Results: Thrombocytopenia occurred at a rate of 41.5% (66/159) after linezolid therapy in hospitalized patients. Platelet parameters, including the difference in mean platelet volume (MPV/fL=0.08 (-1.2-0.9)vs-0.5 (-1.5-0.3), (OR, 0.459; P = 0.001), the difference in platelet large cell ratio (PLCR/fL=0.9 (-5.1-6.2)vs-3.8 (-8.6-2.4), (OR, 1.156; P = 0.001), baseline platelet counts (OR, 0.995; P = 0.006) and duration of linezolid therapy≥10d (OR, 1.346; P = 0.007), were significantly associated with linezolid-related thrombocytopenia in hospitalized patients. In addition, other risk factors which also are associated with linezolid-related thrombocytopenia include baseline red blood cells, co-medication with parecoxib and co-medication with caspofungin. Accumulated in-hospital mortality of patients with thrombocytopenia was significantly higher than that of patients without thrombocytopenia during linezolid treatment (19.7% vs 8.6%, P = 0.003). Conclusion: The difference in mean platelet volume, the difference in large platelet ratio, baseline platelet counts and duration of linezolid therapy≥10d significantly affected the development of linezolid-related thrombocytopenia in hospitalized patients.

Successful treatment with doxycycline monotherapy for human infection with Babesia venatorum (Babesiidae, Sporozoa) in China: a case report and proposal for a clinical regimen.

BACKGROUND: Human babesiosis is a worldwide disease caused by intraerythrocytic protozoa of the genus Babesia. It is transmitted by bites from ixodid ticks, and mechanically transmitted by blood transfusion. It is primarily treated with quinine and/or atovaquone, which are not readily available in China. In this study, we developed a novel treatment regimen involving doxycycline monotherapy in a patient with severe Babesia venatorum infection as an alternative therapeutic medication. The aim of our study is to provide a guidance for clinical practice treatment of human babesiosis. CASE PRESENTATION: A 73-year-old man who had undergone splenectomy and blood transfusion 8 years prior, presented with an unexplained fever, headache, and thrombocytopenia, and was admitted to the Fifth Medical Center of the PLA General Hospital. He was diagnosed with B. venatorum infection by morphological review of thin peripheral blood smears, which was confirmed by multi-gene polymerase chain reaction (PCR), and sequencing of the entire 18s rRNA and partial ß-tubulin encoding genes, as well as isolation by animal inoculation. The doxycycline monotherapy regimen (peros, 0.1 g bisindie) was administered following pharmacological guidance and an effective outcome was observed. The patient recovered rapidly following the doxycycline monotherapy. The protozoan load in peripheral blood samples decreased by 88% in hematocrit counts after 8 days, and negative PCR results were obtained after 90 days of follow-up at the hospital. The treatment lasted for 3 months without any side effects or sequelae. The nine-month follow-up survey of the patient did not reveal any signs of recrudescence or anti-babesial tolerance. CONCLUSIONS: We have reported a clinical case of successful doxycycline monotherapy for human babesiosis caused by B. venatorum, which provides an optional medical intervention for human babesiosis.

Withaferin A inhibits ferroptosis and protects against intracerebral hemorrhage.

Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage (ICH). Withaferin A (WFA), a natural compound, exhibits a positive effect on a number of neurological diseases. However, the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown. In this study, we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis. We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH. WFA was injected intracerebroventricularly at 0.1, 1 or 5 µg/kg once daily for 7 days, starting immediately after ICH operation. WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage. Through in vitro experiments, cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury. Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde, an oxidative stress marker, and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH. Western blot assay, quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling axis, promoted translocation of Nrf2 from the cytoplasm to nucleus, and increased HO-1 expression. Silencing Nrf2 with siRNA completely reversed HO-1 expression, oxidative stress and protective effects of WFA. Furthermore, WFA reduced hemin-induced ferroptosis. However, after treatment with an HO-1 inhibitor, the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened. MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell injury. Our findings reveal that WFA treatment alleviated ICH injury-induced ferroptosis and oxidative stress through activating the Nrf2/HO-1 pathway, which may highlight a potential role of WFA for the treatment of ICH.

A standard dose of linezolid puts patients with hepatic impairment at risk of overexposure.

PURPOSE: The purpose of this retrospective observational study conducted in patients with hepatic impairment was to assess the variability of linezolid trough concentrations, to determine the risk factors for linezolid overexposure, and to investigate the effect of linezolid overexposure on linezolid-induced thrombocytopenia. METHODS: All enrolled patients received a standard dose (600 mg every 12 h) of linezolid and underwent therapeutic drug monitoring. The Child-Pugh-Turcotte score was used to divide patients into three groups: mild, moderate, and severe hepatic impairment. The risk factors for linezolid overexposure (Cmin > 8 mg/L) and linezolid-induced thrombocytopenia were examined using logistic regression. And the Kaplan-Meier curve was used to describe the association between linezolid overexposure and linezolid-induced thrombocytopenia. RESULTS: Seventy-seven patients were included, 37 (48.1%) of whom experienced linezolid overexposure. Patients with severe hepatic impairment had a substantially higher median Cmin of linezolid than those with mild (20.7 mg/L vs 5.51 mg/L, P < 0.001) or moderate (20.7 mg/L vs 6.70 mg/L, P = 0.001) hepatic impairment. Severe hepatic impairment was significantly associated with linezolid overexposure (OR 7.037, 95%CI 1.426-34.727, P = 0.017). After linezolid treatment, linezolid-induced thrombocytopenia occurred in 32 (41.6%) patients, and Cmin > 8 mg/L was a significant predictor of linezolid-induced thrombocytopenia (OR 3.024, 95%CI 1.083-8.541, P = 0.035). CONCLUSION: Patients with hepatic impairment who received standard doses of linezolid are at greater risk of linezolid overexposure, which may lead to a higher incidence of linezolid-induced thrombocytopenia.

Antagonism of histamine H3 receptor promotes angiogenesis following focal cerebral ischemia.

Our previous study showed that H3 receptor antagonists reduced neuronal apoptosis and cerebral infarction in the acute stage after cerebral ischemia, but through an action independent of activation of histaminergic neurons. Because enhanced angiogenesis facilitates neurogenesis and neurological recovery after ischemic stroke, we herein investigated whether antagonism of H3R promoted angiogenesis after brain ischemia. Photothrombotic stroke was induced in mice. We showed that administration of H3R antagonist thioperamide (THIO, 10 mg·kg-1·d-1, i.p., from D1 after cerebral ischemia) significantly improved angiogenesis assessed on D14, and attenuated neurological defects on D28 after cerebral ischemia. Compared with wild-type mice, Hrh3-/- mice displayed more blood vessels in the ischemic boundary zone on D14, and THIO administration did not promote angiogenesis in these knockout mice. THIO-promoted angiogenesis in mice was reversed by i.c.v. injection of H3R agonist immepip, but not by H1 and H2 receptor antagonists, histidine decarboxylase inhibitor α-fluoromethylhistidine, or histidine decarboxylase gene knockout (HDC-/-), suggesting that THIO-promoted angiogenesis was independent of activation of histaminergic neurons. In vascular endothelial cells (bEnd.3), THIO (10-9-10-7 M) dose-dependently facilitated cell migration and tube formation after oxygen glucose deprivation (OGD), and H3R knockdown caused similar effects. We further revealed that H3R antagonism reduced the interaction between H3R and Annexin A2, while knockdown of Annexin A2 abrogated THIO-promoted angiogenesis in bEnd.3 cells after OGD. Annexin A2-overexpressing mice displayed more blood vessels in the ischemic boundary zone, which was reversed by i.c.v. injection of immepip. In conclusion, this study demonstrates that H3R antagonism promotes angiogenesis after cerebral ischemia, which is independent of activation of histaminergic neurons, but related to the H3R on vascular endothelial cells and its interaction with Annexin A2. Thus, H3R antagonists might be promising drug candidates to improve angiogenesis and neurological recovery after ischemic stroke.

Exploring factors influencing the retention of nurses in a religious hospital in Taiwan: a cross-sectional quantitative study.

BACKGROUND: Long-term deficits in the nursing labor force and high turnover rates are common in the Taiwanese medical industry. Little research has investigated the psychological factors associated with the retention of nursing staff. However, in practice, religious hospitals often provide nursing staff with education in medicine or the medical humanities to enhance their psychological satisfaction. The objective of this study was to explore factors influencing nursing staff retention in their work in relation to different levels of needs. A further objective was to investigate whether medical humanities education was associated with the retention of nursing staff. METHODS: This study used self-administrated questionnaires to survey nurses working in northern areas of Taiwan. The questionnaire design was based on the six levels of Maslow's hierarchy of needs. Participation was voluntary, and the participants signed informed consent documents. Self-administrated questionnaires were distributed to a total of 759 participants, and 729 questionnaires were returned (response rate 96.04%). Logistic regression analysis was used to estimate the impact of seniority on nurses' reported intention to stay after adjustment for nurse characteristics (gender and age). RESULTS: In the Pearson correlation analysis, nurses' willingness to stay was moderately correlated with "physical needs", "safety needs", "love and belonging needs", and "esteem needs" (r = 0.559, P < 0.001; r = 0.533, P < 0.001; r = 0.393, P < 0.001; and r = 0.476, P < 0.001, respectively). Furthermore, nurses' willingness to stay was highly correlated with "self-actualization needs", "beyond self-actualization needs" and "medical humanities education-relevant needs" (r = 0.707, P < 0.001; r = 0.728, P < 0.001; and r = 0.678, P < 0.001, respectively). We found that the odds ratios (ORs) of retention of nursing staff with less than 1 year (OR = 4.511, P = 0.002) or 1-3 years (OR = 3.248, P = 0.003) of work experience were significantly higher than that of those with 5-10 years of work experience. CONCLUSIONS: With regard to medical humanities education, we recommend adjusting training, as the compulsory activities included in the official programs are inadequate, and adjusting the number of required hours of medical humanities education. Tailoring different educational programs to different groups (especially nurses who have worked 3-5 years or 5-10 years in the case study hospital) might improve acceptance by nursing staff.

Coronavirus disease 2019 epidemic in impoverished area: Liangshan Yi autonomous prefecture as an example.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) had spread worldwide. Although the world has intensively focused on the epidemic center during this period of time, it is imperative to emphasize that more attention should also be paid to some impoverished areas in China since they are more vulnerable to disease outbreak due to their weak health service capacities. Therefore, this study took Liangshan Yi Autonomous Prefecture as an example to analyze the COVID-19 epidemic in the impoverished area, evaluate the control effect and explore future control strategies. METHODS: In this study, we collected information including age, gender, nationality, occupation, and address of all COVID-19 cases reported from 25 January 2020 to 23 April 2020 in Liangshan Prefecture from the Nationwide Notifiable Infectious Diseases Reporting Information System (NIDRIS), which were used under license and not publicly available. Additionally, we retrieved other information of cases through epidemiological investigation reports reviewing. Data were analyzed using the software Excel 2010 and SPSS 17.0. The geographic distribution of cases was mapped using ArcGIS10.2. RESULTS: By 23 April 2020, a total of 13 COVID-19 cases and two asymptomatic SARS-CoV-2 carriers were reported in Liangshan, in three family clusters. Among the cases, eight cases had a history of sojourning in Hubei Province (61.54%), of which six were related to Wuhan. Cases aged under 44 years accounted for 61.54%, with no child case. The delay of patients' hospital visiting, and the low degree of cooperation in epidemiological investigation are problems. CONCLUSIONS: During the study period, Liangshan was well under control. This was mainly contributed to strict preventive strategies aimed at local culture, inter-sectoral coordination and highly degree of public cooperation. Besides, some possible environmentally and culturally preventive factors (e.g., rapid air flow and family concept) would affect disease prevention and control. In the next step, the health education about COVID-19 should be strengthened and carried out according to the special culture of ethnic minorities to enhance public awareness of timely medical treatment.

A Hierarchical Model of Occupational Burnout in Nurses Associated With Job-Induced Stress, Self-Concept, and Work Environment.

BACKGROUND: Nurses may experience different levels of occupational burnout in different unit and hospital settings. However, pooling multilevel data in an analysis ignores independent, environmental, and sociocultural contexts of ecological validity. PURPOSE: This study aimed to explore a hierarchical model of occupational burnout that is associated with job-induced stress, nurse self-concept, and practice environment in nurses working in different units and hospitals. METHODS: A cross-sectional study was conducted, and 2,605 nurses were recruited from seven hospitals. The outcomes were measured using the Maslach Occupational Burnout Inventory-Human Services Survey, Nurses' Self-Concept Instrument, Nurse Stress Checklist, and Nursing Work Index-Revised. Hierarchical Linear Modeling 6.0 software was used to conduct hierarchical analysis on the study data. RESULTS: On the nurse level, job-induced stress was a significant factor affecting emotional exhaustion (ß = 0.608, p < .001) and depersonalization (ß = 2.439, p < .001), whereas nurse self-concept was a significant factor affecting emotional exhaustion (ß = -0.250, p < .001), depersonalization (ß = -1.587, p < .001), and personal accomplishment (ß = 4.126, p < .001). Furthermore, emotional exhaustion and depersonalization were significantly related to level of education (ß = 0.111, p < .01; ß = 0.583, p < .05). No significant unit-level associations were identified between occupational burnout and the factors of job-induced stress, nurse self-concept, and practice environment (p > .05). The intragroup correlation coefficient for emotional exhaustion was 2.86 (p < .001). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings of this study confirm that individual nurse characteristics are strong predictors of emotional exhaustion, depersonalization, and personal accomplishment as these relate to occupational burnout. In addition, nurse self-concept was identified as the most important predictor of all three aspects. In clinical practice, self-concepts about nursing may reduce occupational burnout. Nursing managers formulating new policies should consider nursing background and offer autonomous control over practice.

Single-Component Bismuth Nanoparticles as a Theranostic Agent for Multimodal Imaging-Guided Glioma Therapy.

Single-component nanomaterials such as bismuth (Bi) based on nanoparticles (NPs) intrinsically having both diagnostic and therapeutic capabilities are widely needed in biomedical fields. However, their design and fabrication still face enormous challenges. Here, a kind of pure Bi NPs with ultrahigh X-ray attenuation coeffcient was developed and evaluated as a simple but powerful theranostic nanomaterals and potent light-to-heat conversion efficiency for photoacuostic imaging (PAI)/photothermal therapy (PTT) in this study. The prepared pure Bi NPs showed excellent photothermal performance and the temperature of NPs solution (1 mg/mL) increased to 70 °C under near-infrared light irradiation within 4 min. The pure Bi NPs showed obvious enhancement effect both in X-ray computed tomography (CT) and PA imaging modalities in vivo. In addition, the glioma growth was efficiently suppressed by the pure Bi NPs after 808 nm laser irradiation, while maintained the biosafety and low toxicity. Thus, it is notable that this type of Bi nanomaterial has great potential in multi-imaging guided cancer treatment.

Molecular response of Vibrio parahaemolyticus to the sanitizer peracetic acid.

Peracetic acid (PAA) is a common oxidative sanitizer that is used in the food industry against various microorganisms. Limited information on the response of bacteria to this biocide is available. This study investigates the molecular response of the prevalent seafood-borne pathogenic Vibrio parahaemolyticus to PAA using mutants of peroxide scavenging genes. Among katE1, katE2, katG1, katG2, ahpC1 and ahpC2, and their regulator oxyR gene mutants, oxyR and katE mutants were highly susceptible to PAA. The growth and lethality of V. parahaemolyticus were harmed by 15 ppm of PAA in the △katE1E2 double mutant, and were significantly ameliorated in the presence of the katE1 gene in the wild-type strain and the gene-complementary strains that were pre-adapted in 2 ppm of PAA or 100 µM hydrogen peroxide. The application of PAA to these strains induced the accumulation of reactive oxygen species. The reduction of the level of hydrogen peroxide and gene expression during this treatment was influenced by the presence of katE genes. This investigation confirmed the major role of katE1 and a compensatory role of katE2 in the resistance of V. parahaemolyticus to PAA, and demonstrated some minor differences in the responses of this bacterium against PAA and hydrogen peroxide.

Exercises improve body composition, cardiovascular risk factors and bone mineral density for menopausal women: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Menopause has been considered as an aggravating factor for developing cardiovascular diseases and the metabolic syndromes for women. Exercise might be an effective intervention for reducing such threats. OBJECTIVE: The purpose of this study was to evaluate the exercise effects on body composition, cardiovascular risk factors, and bone mineral density of menopausal women. METHODS: Two reviewers did a complete search of five electronic database (Medline, PubMed, Cochrane Central Register of Controlled Trials, CINAHL, and the Chinese Electronic Periodical Service) records up to January 31, 2014. Randomized controlled trials (RCTs) that compared female menopausal participants with exercises, and those without exercise or with placebo were included. Risk of bias was classified based on the Cochrane Collaboration tool, the meta-analysis was conducted using Comprehensive Meta-Analysis Version 2.2. The study selection, data extraction, and validation were performed independently by the 2 reviewers. RESULTS: A total of 17 RCTs with 792 participants were included for meta-analysis. Among the eight RCTs (247 participants), a moderate effect size of exercise on body fat was found (SMD=-0.34, 95% CI: -0.60 to -0.08). In five RCTs (195 participants), a moderate effect size of exercise on waist circumference (SMD=-0.39, 95% CI: -0.68 to -0.09), in seven RCTs (162 participants), a moderate effect size on triglyceride level (SMD=-0.37, 95% CI: -0.62 to -0.11), and in five RCTs (311 participants), a moderate effect size on bone mineral density (SMD=0.38, 95% CI: 0.08-0.68). Subgroup analysis revealed a significant effect of aerobic exercise on body fat (SMD=-0.29, 95% CI: -0.53 to -0.06), and a short-term exercise on body fat (SMD=-0.50, 95% CI: -0.89 to -0.11) and on triglycerides (SMD=-0.42, 95% CI: -0.79 to -0.04). The trials included in this meta-analysis were small and some had methodologic limitations. CONCLUSIONS: This study provides evidences to clinical practice for menopause women that exercise, compared with nonexercise or placebo exerted significant benefits on body fat, waist circumference, triglyceride level, and lumbar spine bone mineral density. Particularly, aerobic exercise did help menopausal women improve their body fat. A short-term exercise intervention had a benefit on not only body fat but also triglyceride level. However, well-designed, well-executed RCTs, and a detailed long-term clinical research should be needed in the future.

Gadolinium-chelate functionalized bismuth nanotheranostic agent for in vivo MRI/CT/PAI imaging-guided photothermal cancer therapy.

Multifunctional nanomaterials with simple structure and good biosafety, integrating multimodal imaging and therapeutic functions, can facilitate the development of clinical cancer treatments. Here, a simple but powerful pure bismuth based nanoparticle (Gd-PEG-Bi NPs) was developed from pure Bi NPs and gadolinium-diethylenetriaminepentaacetic acid-bis-tetradecylamide, which not only shows high quality MRI/CT/PAI triple-modal imaging, but can also be a potent photothermal therapy agent under the guidance of the triple-modal imaging. The Gd-PEG-Bi NPs showed good stability and excellent biocompatibility. In vitro and in vivo study demonstrated that Gd-PEG-Bi NPs have ultrahigh X-ray attenuation coefficient, short T1 relaxation time in MRI, and strong PAI signal. Following the imaging diagnosis, the excellent light-to-heat conversion efficiency of Gd-PEG-Bi NPs was capable of suppressing the tumor growth effectively under near-infrared laser radiation in vivo. Such multifunctional nanoparticles were ideal candidates for cancer diagnosis and treatment.

Role of post-chemotherapy radiation in the management of children and adolescents with primary advanced malignant mediastinal germ cell tumors.

OBJECTIVE: Primary malignant mediastinal germ cell tumors (MMGCTs) are rare in children and adolescents and have a poorer prognosis than their gonadal counterparts. We report a single institutional experience of a 10-year period of primary advanced MMGCTs treated with chemotherapy, followed by radiotherapy in those who had residual mass. METHODS: Children and adolescents with primary advanced MMGCTs between 2005 and 2014 were identified from the Cancer Center, Sun Yat-Sen University. Medical records were reviewed for clinicopathological characteristics, treatments, and outcomes. RESULTS: Twenty-four children and adolescents with either stage III or IV primary advanced MMGCTs met the inclusion criteria. There were 23 males and one female with a median age of 16 (range 10-18). Seven cases were seminomas (29.2%); four (16.7%) yolk sac tumors (YST); three (12.5%) choriocarcinomas; and ten (41.6%) nonteratomatous combined germ cell tumors (CGCTs). All patients were treated with first-line cisplatin-based chemotherapy regimens (PEB: 19, VIP: 5). Thirteen (54.2%) and Twelve (50%) patients received surgery and radiotherapy, respectively. With a median follow-up of 46.2 months (range 9.6-124.8 months), a total of five (20%) patients died of disease progression; the five-year overall survival (OS) and disease-free survival (DFS) rates were 82.3% and 64.9%, respectively.-Seven patients with seminoma GCTs received post-chemotherapy irradiation were alive with sustained CR (5-year OS and DFS, 100%, respectively). Five patients with NSGCTs were administered irradiation and one relapsed 35 months later and died of metastasis (5-year OS, 100%; 5-year DFS 66.7%). Univariate analysis identified histology and stage were prognostic factors. CONCLUSION: Multimodality treatment approach of chemotherapy followed by radiation consolidation ensured long-term survival in primary advanced MMGCTs. Further research is warranted to improve the prognosis of children with primary advanced MMGCTs.

Near-infrared light-triggered theranostics for tumor-specific enhanced multimodal imaging and photothermal therapy.

The major challenge in current clinic contrast agents (CAs) and chemotherapy is the poor tumor selectivity and response. Based on the self-quench property of IR820 at high concentrations, and different contrast effect ability of Gd-DOTA between inner and outer of liposome, we developed "bomb-like" light-triggered CAs (LTCAs) for enhanced CT/MRI/FI multimodal imaging, which can improve the signal-to-noise ratio of tumor tissue specifically. IR820, Iohexol and Gd-chelates were firstly encapsulated into the thermal-sensitive nanocarrier with a high concentration. This will result in protection and fluorescence quenching. Then, the release of CAs was triggered by near-infrared (NIR) light laser irradiation, which will lead to fluorescence and MRI activation and enable imaging of inflammation. In vitro and in vivo experiments demonstrated that LTCAs with 808 nm laser irradiation have shorter T1 relaxation time in MRI and stronger intensity in FI compared to those without irradiation. Additionally, due to the high photothermal conversion efficiency of IR820, the injection of LTCAs was demonstrated to completely inhibit C6 tumor growth in nude mice up to 17 days after NIR laser irradiation. The results indicate that the LTCAs can serve as a promising platform for NIR-activated multimodal imaging and photothermal therapy.

MRI-guided tumor chemo-photodynamic therapy with Gd/Pt bifunctionalized porphyrin.

Porphyrin derivatives have been widely applied in MR imaging and photodynamic cancer therapy. We here report a novel Gd/Pt bifunctionalized porphyrin derivative (Gd/Pt-P1) for MRI-guided chemo-photodynamic cancer therapy. Gd/Pt-P1 was prepared from tetra(4-pyridyl) porphyrin (P1) via step by step coordination to cisplatin and gadolinium (Gd(iii)). Gd/Pt-P1 showed a particularly high synergetic chemo-photodynamic antitumor effect in vivo with a tumor inhibition rate (TIR) of 96.6% and excellent MR imaging performance.

Involvement of IL-10 and TGF-ß in HLA-E-mediated neuroblastoma migration and invasion.

Human leukocyte antigen (HLA)-E is highly expressed in a variety of tumors and, in addition to immune escape, may promote tumor growth via other mechanisms. However, the role of HLA-E in neuroblastoma (NB) migration and invasion is unknown. In the present study, HLA-E expression in human NB tumors was measured by immunohistochemistry. The effect of HLA-E on NB cell migration and invasion was studied in vitro and in vivo, as well as the effect of HLA-E on natural killer (NK)-cell cytotoxicity. HLA-E was expressed in 70.2% of the NB tumor tissues examined. HLA-E expression by NB cells inhibited NK-cell cytotoxicity and induced the release of interleukin (IL)-10 and transforming growth factor (TGF)-ß1. HLA-E and the released cytokines enhanced the ability of NB cells migration and invasion. NK cell infusion did not inhibit the growth of NB cells with high HLA-E expression but instead increased the number of metastatic cells in the bone marrow. Taken together, the results indicate that IL-10 and TGF-ß are involved in HLA-E-mediated NB migration and invasion. Thus, HLA-E may be a new treatment target in NB.

Effect of chemotherapy alone with adult chemotherapy regimens on prognosis of children and adolescents with Hodgkin's disease.

OBJECTIVE: A current focus on the treatment of children and adolescents with Hodgkin's disease is identification of subgroups of patients for whom radiotherapy can be omitted without compromising clinical outcome. We evaluated the feasibility of using adult chemotherapy regimens alone to treat children and adolescents with Hodgkin's disease. METHODS: Recruitment inclusion criteria were children and adolescents ≤18 years old who were newly diagnosed as Hodgkin's disease. Chemotherapy comprised four cycles of ABVD, six cycles of ABVD or COPP/ABV and six cycles of BEACOPP/ABVD chemotherapy regimens in the low-, intermediate- and high-risk groups, respectively. Radiotherapy was omitted for patients with low-risk, nonbulky disease who had achieved complete remission after chemotherapy and patients who failed to undergo the scheduled radiotherapy due to various reasons beyond the disease. RESULTS: Seventy-five children and adolescents were recruited, including 28, 24 and 23 patients in the low-, intermediate- and high-risk groups, respectively. With a median follow-up of 48 months, 4-year event-free survival and 4-year overall survival were 77.6% ± 5% and 95.3% ± 3%, respectively, in the whole cohort. The 4-year event-free survival in the low-, intermediate- and high-risk groups were 88.2% ± 6%, 78.1% ± 9% and 66.2% ± 11%, respectively (P = 0.062). Sixteen patients (21.3%) relapsed and four died from tumor progression. CONCLUSIONS: Over three-quarters of children and adolescents with Hodgkin's disease achieved long-term event-free survival after receiving chemotherapy alone with adult chemotherapy regimens, and radiotherapy-related toxicity was avoided.

Long-Term Outcomes of Nasopharyngeal Carcinoma in 148 Children and Adolescents.

The aim of this study was to investigate the survival and long-term morbidities of nasopharyngeal carcinoma (NPC) in children and adolescents.We retrospectively reviewed children and adolescents with NPC treated at Sun Yat-sen University Cancer Center from February 1991 to October 2010, where the prognostic factors and long-term effects of therapy were analyzed.A total of 148 patients were identified. The median age was 15 years old (range, 5-18 years) and the male to female ratio was 3.6:1. Most of the tumor histopathology was undifferentiated nonkeratinizing carcinoma (97.3%). The number of patients staged with IVa, IVb, IVc, III, and II were 45 (30.4%), 12 (8.1%), 5 (3.4%), 70 (47.3%), and 16 (10.8%), respectively. For the whole series with a median follow-up of 81 months (range, 6-282 months), the 5-year overall survival (OS) and disease-free survival (DFS) ratios were 79.3% and 69.7%, respectively. We observed significant differences in the 5-year OS (81.1% vs 25.0%, P = 0.002) and the DFS rates (72.2% vs 0.0%, P = 0.000) between patients with stage II to IVb disease and stage IVc disease. For patients with stage II, III, IVa, and IVb disease, we found a high radiation dose (dose > 66 Gy to the primary lesion) would not significantly improve the survival compared to the sub-high radiation dose group (dose = 60-66 Gy to the primary lesion), even considering the type of radiation therapy technologies. However, the incidences of sequelae (grades I-IV) in patients with high radiation dose were apparently higher than those in patients with low radiation dose.Considering the late sequelae, a dose of 60 to 66 Gy to the primary lesions seems to be enough for children and adolescents with NPC.