Trauma team activation criteria and outcomes of geriatric trauma: 10 year single centre cohort study.

BACKGROUND: With the aging population, the number of older patients with multiple injuries is increasing. The aim of this study was to understand the patterns and outcomes of older patients admitted to a major trauma centre in Hong Kong from 2006 to 2015, and investigate the performance of the trauma team activation (TTA) criteria for these elderly patients. METHODS: This was a retrospective cohort study from a university hospital major trauma centre in Hong Kong from 2006 to 2015. Patients aged 55 or above who entered the trauma registry were included. Patients were divided into those aged 55-70, and above 70. To test the performance of the TTA criteria, we defined injured patients with severe outcomes as those having any of the following: death within 30 days; the need for surgery; or the need for intensive care unit (ICU) care. RESULTS: 2218 patients were included over the 10 year period. The 30-day mortality was 7.5% for aged 55-70 and 17.7% for those aged above 70. The sensitivity of TTA criteria for identifying severe outcomes for those aged 55 or above was 35.6%, with 91.6% specificity. The under-triage rate was 59% for age 55-70, and 69.1% for those aged above 70. CONCLUSION: There is a need to consider alternative TTA criteria for our geriatric trauma population, and to more clearly define the process and standards of care in Hong Kong.

Comprehensive care programme for patients with chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: There have been no randomised controlled trials that specifically evaluate the effect of a comprehensive programme with multidisciplinary input on patients who have just been discharged from hospital after treatment of acute exacerbation of COPD (AECOPD). The aim of this study was to assess whether a comprehensive care programme would decrease hospital readmissions and length of hospital stay (LOS) for patients with COPD. METHODS: Patients discharged from hospital after an episode of AECOPD were randomised to an intervention group (IG) or usual care group (UG). The IG received a comprehensive, individualised care plan which included education from a respiratory nurse, physiotherapist support for pulmonary rehabilitation, 3-monthly telephone calls by a respiratory nurse over 1 year, and follow-up at a respiratory clinic with a respiratory specialist once every 3 months for 1 year. The UG were managed according to standard practice. The primary outcome was hospital readmission rate at 12 months. RESULTS: 180 patients were recruited (IG, N=90; UG, N=90; mean±SD age 74.7±8.2 years, 172 (95.6%) men; mean±SD FEV1 45.4±16.6% predicted). At 12 months, the adjusted relative risk of readmission was 0.668 (95% CI 0.449 to 0.995, p=0.047) for the IG compared with the UG. At 12 months, the IG had a shorter LOS (4.59±7.16 vs 8.86±10.24 days, p≤0.001), greater improvement in mean Modified Medical Research Council Dyspnoea Scale (-0.1±0.6 vs 0.2±0.6, p=0.003) and St George's Respiratory Questionnaire score (-6.9±15.3 vs -0.1±13.8, p=0.003) compared with the UG. CONCLUSIONS: A comprehensive COPD programme can reduce hospital readmissions for COPD and LOS, in addition to improving symptoms and quality of life of the patients. TRIAL REGISTRATION NUMBER: NCT 01108835, Results.

Strategies and solutions to alleviate access block and overcrowding in emergency departments.

OBJECTIVES: Access block refers to the delay caused for patients in gaining access to in-patient beds after being admitted. It is almost always associated with emergency department overcrowding. This study aimed to identify evidence-based strategies that can be followed in emergency departments and hospital settings to alleviate the problem of access block and emergency department overcrowding; and to explore the applicability of these solutions in Hong Kong. DATA SOURCES: A systematic literature review was performed by searching the following databases: CINAHL, Cochrane Database of Systematic Reviews, EMBASE, MEDLINE (OVID), NHS Evidence, Scopus, and PubMed. STUDY SELECTION: The search terms used were "emergency department, access block, overcrowding". The inclusion criteria were full-text articles, studies, economic evaluations, reviews, editorials, and commentaries. The exclusion criteria were studies not based in the emergency departments or hospitals, and abstracts. DATA EXTRACTION: Abstracts of identified papers were screened, and papers were selected if they contained facts, data, or scientific evidence related to interventions that aimed at improving outcome measures for emergency department overcrowding and/or access block. Papers identified were used to locate further references. DATA SYNTHESIS: All relevant scientific studies were evaluated for strengths and weaknesses using appraisal tools developed by the Critical Appraisal Skills Programme. We identified solutions broadly classified into the following categories: (1) strategies addressing emergency department overcrowding: co-locating primary care within the emergency department, and fast-track and emergency nurse practitioners; and (2) strategies addressing access block: holding units, early discharge and patient flow, and political action--management and resource priority. CONCLUSION: Several evidence-based approaches have been identified from the literature and effective strategies to overcome the problem of access block and overcrowding of emergency departments may be formulated.

Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas.

Genomic imprinting plays a role in influencing the parental origin of genes involved in cancer-specific rearrangements. We have analysed 22 neuroblastomas with N-myc amplification to determine the parental origin of the amplified N-myc allele and the allele that is deleted from chromosome 1p. We analysed DNA from neuroblastoma patients and their parents, using four polymorphisms for 1p and three for the N-myc amplicon. We determined that the paternal allele of N-myc was preferentially amplified (12 out of 13 cases; P = 0.002). However, the paternal allele was lost from 1p in six out of ten cases, consistent with a random distribution (P > 0.2). These results suggest that parental imprinting influences which N-myc allele is amplified in neuroblastomas, but it does not appear to affect the 1p allele that is deleted in the cases that we have examined.

Expression profile of oestrogen receptors and oestrogen-related receptors is organ specific and sex dependent: the Japanese medaka Oryzias latipes model.

Gene expression of all known subtypes of oestrogen receptor (ER) and oestrogen-related receptor (ERR) in multiple organs and both sexes of the Japanese medaka Oryzias latipes was profiled and systematically analysed. As revealed by statistical analyses and low-dimensional projections, the expressions of ERRs proved to be organ and sex dependent, which is in contrast with the ubiquitous nature of ERs. Moreover, expressions of specific ERR isoforms (ERRγ1, ERRγ2) were strongly correlated with that of all ERs (ERα, ERß1 and ERß2), suggesting the existence of potential interactions. Findings of this study shed light on the co-regulatory role of particular ERRs in oestrogen-ERs signalling and highlight the potential importance of ERRs in determining organ and sex-specific oestrogen responses. Using O. latipes as an alternative vertebrate model, this study provides new directions that call for collective efforts from the scientific community to unravel the mechanistic action of ER-ERR cross-talks, and their intertwining functions, in a cell and sex-specific manner in vivo.

Open-access colonoscopy: outcomes of referrals from the emergency department.

AIM: The study investigated the diagnostic outcome of colonoscopy referrals from the emergency department (ED) via an open-access system. METHOD: A retrospective cohort study over two years was performed on all patients under 65 years referred for open-access colonoscopy by the ED in a hospital with an annual ED attendance of 140,000. Patient characteristics and presenting symptoms were retrieved. Waiting times from presentation to colonoscopy were recorded. RESULTS: Over a 2-year period, 266 patients were referred, of whom 37 defaulted, leaving 229 patients who had a colonoscopy. The mean age was 48.3 ± 11.3 (SD) and the female/male ratio was 229/125. The most frequent presenting symptoms included: rectal bleeding (n = 142, 62%), change of bowel habit (n = 47, 20.5%) and abdominal pain (n = 40, 17.5%). The median waiting time from presentation to colonoscopy was 17 (range 1-69) days. A positive colonoscopic finding was recorded in 45.4%, including colorectal cancer in 12 (5.2%). CONCLUSION: The rate of a positive diagnoses from the ED-based colonoscopy referral service was comparable to that of the general Hong Kong population. This approach may help to reduce the waiting time for colonoscopy in a specialist colorectal clinic.

Phagocytosis of tumor cells by human monocytes cultured in recombinant macrophage colony-stimulating factor.

Macrophages and cultured human monocytes can mediate efficient antibody-dependent cytotoxicity (ADCC) against human tumor cells using monoclonal antibodies (mAbs). The mechanism of this killing is usually assumed to involve secreted factors (reactive oxygen intermediates, tumor necrosis factor, or other cytotoxic factors) leading to target cell lysis. In this study, we present evidence that phagocytosis of intact target cells is the principal mechanism of antitumor cytotoxicity in our in vitro model of ADCC by cultured monocytes. Human monocytes cultured in recombinant human macrophage colony-stimulating factor ingested up to 100% of fluorochrome-labeled melanoma and neuroblastoma target cells, in the presence of an appropriate antitumor mAb. Electron microscopy demonstrated phagocytosis of intact tumor cells by cultured monocytes during ADCC. All of the radionuclide in radiolabeled target cells was taken up by monocytes during phagocytosis. By preventing the release of radioisotope tracers, phagocytosis thus prevents the detection of this very efficient form of cytotoxicity by most conventional assays.

Antibody-dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. Induction of efficient antibody-mediated antitumor cytotoxicity not detected by isotope release assays.

Macrophage colony-stimulating factor (M-CSF) is known to stimulate proliferation of monocyte/macrophage progenitors and enhance in vitro antitumor cytotoxicity by murine macrophages. In this paper we have shown that recombinant human M-CSF causes human peripheral blood monocytes to differentiate in culture into metabolically active macrophage-like cells. These cells mediate very efficient antibody-dependent cellular cytotoxicity (ADCC) against human melanoma and neuroblastoma cell lines in the presence of two murine IgG3 mAbs (3F8 and R24). They also mediate antibody-independent cytotoxicity (or cytostasis) to a lesser extent. Human serum had an inconsistent effect on ADCC, but often induced similar high levels of ADCC. Cytotoxicity was measured using a novel ELISA to detect surviving tumor cells after ADCC. Two conventional isotope-release assays (51Cr and [3H]TdR) underestimated or entirely failed to detect ADCC by M-CSF-activated monocytes. Optimal activation occurred with 100-300 U/ml of M-CSF, and required 9-11 d for completion. Most of the M-CSF cultured monocytes expressed the low-affinity Fc receptor (CD16). ADCC by cells of the monocyte/macrophage lineage using murine IgG3 mAbs may have significance for the immunotherapy of human malignancies.

GD2 oligosaccharide: target for cytotoxic T lymphocytes.

Carbohydrate antigens rarely provide target epitopes for cytotoxic T lymphocytes (CTL). Disialoganglioside GD2 is a glycolipid expressed at high levels in human tumors and a small group of murine lymphomas (EL4, RBL5, RMA, RMA-S, A13, and BALBRVE). Immunization of C57B1/6 mice with irradiated EL4 cells stimulated a specific CTL response and protected these animals from engraftment of EL4 lymphoma. The CTL activity resided in the CD4-CD8+ population, was dependent on T cell receptor alpha/beta, and was not removed by anti-natural killer cell immunoabsorption, but was restricted to GD2 and H-2b bearing targets. CTL activity could be completely inhibited by GD2-oligosaccharide-specific monoclonal antibodies and their F(ab')2 fragments, but not by immunoglobulin G3 myelomas or antibodies against GD3 or GM2. Soluble GD2 did not inhibit specific tumor lysis. RMA-S lymphoma cells (GD2+H-2b-TAP2 deficient) were resistant to GD2-specific CTL. Sialic acid-containing peptides eluted from EL4 lymphoma cells could (a) stabilize H-2 molecules on RMA-S cells and (b) sensitize them for GD2-specific CTL. Control peptides (derived from vesicular stomatitis virus nucleoprotein peptide and GD2-negative lymphomas) could also stabilize H-2 on RMA-S, but were resistant to GD2-specific CTL. These H-2-binding peptides could be purified by anti-GD2 affinity chromatography. We postulate a new class of naturally occurring epitopes for T cells where branched-chain oligosaccharides are linked to peptides with anchoring motifs for the major histocompatibility complex class I pocket. While analogous to the haptens trinitrophenyl and O-beta-linked acetyl-glucosamine, the potential implications of natural carbohydrates as antigenic epitopes for CTL in biology are considerable.

Immune suppression in vivo with antigen-modified syngeneic cells. I. T-cell-mediated suppression to the terpolymer poly-(Glu, Lys, Phe)n.

The palmitoyl derivative of the linear polypeptide of poly-(L-Glu-L-Lys-L-Phe)n (GLphi) can be coupled to spleen cells directly. The intravenous administration of 2 X 10(5)--3 X 10(7) GLphi-coupled syngeneic spleen cells induces GL-phi-specific suppressor T cells in C57BL/6 nonresponder mice. The suppression is antigen specific and can be detected by the inhibition of the primary GLphi plaque-forming cell response to challenge with GLphi-fowl gamma globulin. The number of inducer cells required for suppression carry less than 0.1 microgram of antigen. Spleen cells from tolerized mice can transfer suppression to normal syngeneic recipients. The suppression is cyclophosphamide sensitive and the suppressor cells bear the Thy 1.2 marker. This method of inducing antigen-specific suppressor cells may be generally applicable to other antigen systems.

Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes.

Most tumor cells function poorly as antigen-presenting cells in part because they do not express costimulatory molecules. To provide costimulation to T lymphocytes that recognize tumor cells, we constructed a CD28-like receptor specific for GD2, a ganglioside overexpressed on the surface of neuroblastoma, small-cell lung carcinoma, melanoma, and other human tumors. Recognition of GD2 was provided by a single-chain antibody derived from the GD2-specific monoclonal antibody 3G6. We demonstrate that the chimeric receptor 3G6-CD28 provides CD28 signaling upon specific recognition of the GD2 antigen on tumor cells. Human primary T lymphocytes retrovirally transduced with 3G6-CD28 secrete interleukin 2, survive proapoptotic culture conditions, and selectively undergo clonal expansion in the presence of an antiidiotypic antibody specific for 3G6-CD28. Polyclonal CD8(+) lymphocytes expressing 3G6-CD28 are selectively expanded when cultured with cells expressing allogeneic major histocompatibility complex class I together with GD2. Primary T cells given such an antigen-dependent survival advantage should be very useful to augment immune responses against tumor cells.

Trajectory of functional outcome and health status after moderate-to-major trauma in Hong Kong: A prospective 5 year cohort study.

BACKGROUND: Trauma care systems in Asia have been developing in recent years, but there has been little long-term outcome data from injured survivors. This study aims to evaluate the trajectory of functional outcome and health status up to five years after moderate to major trauma in Hong Kong. METHODS: We report the five year follow up results of a multicentre, prospective cohort from the trauma registries of three regional trauma centres in Hong Kong. The original cohort recruited 400 adult trauma patients with ISS ≥ 9. Telephone follow up was conducted longitudinally at seven time points, and the extended Glasgow Outcome Scale (GOSE) and Short-Form 36 (SF36) were tracked. RESULTS: 119 out of 309 surviving patients (39%) completed follow up after 5 years. The trajectory of GOSE, PCS and MCS showed gradual improvements over the seven time points. 56/119 (47.1%) patients reported a GOSE = 8 (upper good recovery), and the mean PCS and MCS was 47.8 (95% CI 45.8, 49.9) and 55.8 (95% CI 54.1, 57.5) respectively at five years. Univariate logistic regression showed change in PCS - baseline to 1 year and 1 year to 2 years, and change in MCS - baseline to 1 year were associated with GOSE = 8 at 5 years. Linear mixed effects model showed differences in PCS and MCS were greatest between 1-month and 6-month follow up. CONCLUSIONS: After injury, the most rapid improvement in PCS and MCS occurred in the first six to 12 months, but further recovery was still evident for MCS in patients aged under 65 years for up to five years.

Decay-accelerating factor protects human tumor cells from complement-mediated cytotoxicity in vitro.

The disialoganglioside GD2 is expressed on a wide spectrum of human tumor types, including neuroblastomas and melanomas. Upon binding of 3F8, a murine monoclonal antibody (MAb) specific for GD2, neuroblastomas and some melanomas are sensitive to killing by human complement, whereas some melanomas are not. To investigate the mechanism underlying these differences in complement mediated cytotoxicity, complement-insensitive melanoma cell lines were compared with respect to expression of the decay-accelerating factor (DAF), a membrane regulatory protein that protects blood cells from autologous complement attack. While DAF was undetectable among neuroblastomas, it was present in complement-insensitive melanomas. When the function of DAF was blocked by anti-DAF MAb, C3 uptake and complement-mediated lysis of the insensitive melanoma lines were markedly enhanced. F(ab')2 fragments were as effective in enhancing lysis as intact anti-DAF MAb. The DAF-negative and DAF-positive melanoma cell lines were comparably resistant to passive lysis by cobra venom factor-treated serum. The data suggest that in some tumors, DAF activity accounts for their resistance to complement-mediated killing. The ability to render these cells complement-sensitive by blocking DAF function may have implications for immunotherapy.

Do trauma teams make a difference? A single centre registry study.

OBJECTIVE: To evaluate the association between trauma team activation according to well-established protocols and patient survival. METHODS: Single centre, registry study of data collected prospectively from trauma patients (who were treated in a trauma resuscitation room, who died or who were admitted to ICU) of a tertiary referral trauma centre Emergency Department (ED) in Hong Kong. A 10-point protocol was used to activate rapid trauma team response to the ED. The main outcome measures were mortality, need for ICU care, or operation within 6h of injury. RESULTS: Between 1 January 2001 and 31 December 2005, 2539 consecutive trauma patients were included in our trauma registry, of which 674 patients (mean age 43 years, S.D. 22; 71% male; 94% blunt trauma) met trauma call criteria. Four hundred and eighty two (72%) correctly triggered a trauma call, and 192 (28%) were not called ('undercall'). Patients were less likely to have a trauma call despite meeting criteria if they were aged over 64 years, had sustained a fall, had a respiratory rate <10 or >29 per minute, a systolic blood pressure between 60 and 89 mm Hg, or a GCS of 9-13. In a sub-group of moderately poor probability of survival (probability of survival, P(s), 0.5-0.75), the odds ratio for mortality in the undercall group compared with the trauma call group was 7.6 (95% CI, 1.1-33.0). CONCLUSIONS: In our institution, undercalls account for 28% of patients who meet trauma call criteria and in patients with moderately poor probability of survival undercall is associated with decreased survival. Although trauma team activation does not guarantee better survival, better compliance with trauma team activation protocols optimises processes of care and may translate into improved survival.

Small molecule nerve growth factor analogs image receptors in vivo.

The in vivo targeting efficacy of small molecule analogs of nerve growth factor (NGF) that bind the NGF receptor p140 TrkA was evaluated and compared with that of a high-affinity anti-TrkA monoclonal antibody (Mab 5C3). Nuclear imaging studies were done after the injection of 99mTc-labeled compounds in nude mice bearing tumors. Kinetics of tumor targetting, blood clearance, and bioavailability of NGF mimics were equivalent or better than Mab 5C3. Tumors that do not express TrkA were not targeted, demonstrating the specificity of NGF mimics in vivo. This comparative biodistribution study demonstrates that receptor-specific small molecule analogs designed from large polypeptides may be more useful than antibodies and may be effective agents for the detection, diagnosis, and possible treatment of neoplasias involving overexpressed oncogenic receptors such as TrkA.

Acute myeloid leukemia targets for bispecific antibodies.

Despite substantial gains in our understanding of the genomics of acute myelogenous leukemia (AML), patient survival remains unsatisfactory especially among the older age group. T cell-based therapy of lymphoblastic leukemia is rapidly advancing; however, its application in AML is still lagging behind. Bispecific antibodies can redirect polyclonal effector cells to engage chosen targets on leukemia blasts. When the effector cells are natural-killer cells, both antibody-dependent and antibody-independent mechanisms could be exploited. When the effectors are T cells, direct tumor cytotoxicity can be engaged followed by a potential vaccination effect. In this review, we summarize the AML-associated tumor targets and the bispecific antibodies that have been studied. The potentials and limitations of each of these systems will be discussed.

Vascularized Tissue-Engineered Model for Studying Drug Resistance in Neuroblastoma.

Neuroblastoma is a vascularized pediatric tumor derived from neural crest stem cells that displays vasculogenic mimicry and can express a number of stemness markers, such as SOX2 and NANOG. Tumor relapse is the major cause of succumbing to this disease, and properties attributed to cancer stem-like cells (CSLC), such as drug-resistance and cell plasticity, seem to be the key mechanisms. However, the lack of controllable models that recapitulate the features of human neuroblastoma limits our understanding of the process and impedes the development of new therapies. In response to these limitations, we engineered a perfusable, vascularized in vitro model of three-dimensional human neuroblastoma to study the effects of retinoid therapy on tumor vasculature and drug-resistance. METHODS: The in vitro model of neuroblastoma was generated using cell-sheet engineering and cultured in a perfusion bioreactor. Firstly, we stacked three cell sheets containing SKNBE(2) neuroblastoma cells and HUVEC. Then, a vascular bed made of fibrin, collagen I and HUVEC cells was placed onto a collagen-gel base with 8 microchannels. After gelling, the stacked cell sheets were placed on the vascular bed and cultured in the perfusion bioreactor (perfusion rate: 0.5 mL/min) for 4 days. Neuroblastoma models were treated with 10µM isotretionin in single daily doses for 5 days. RESULTS: The bioengineered model recapitulated vasculogenic mimicry (vessel-like structure formation and tumor-derived endothelial cells-TECs), and contained CSLC expressing SOX2 and NANOG. Treatment with Isotretinoin destabilized vascular networks but failed to target vasculogenic mimicry and augmented populations of CSLCs expressing high levels of SOX2. Our results suggest that CSLCs can transdifferentiate into drug resistant CD31+-TECs, and reveal the presence of an intermediate state STEC (stem tumor-derived endothelial cell) expressing both SOX2 and CD31. CONCLUSION: Our results reveal some roles of SOX2 in drug resistance and tumor relapse, and suggest that SOX2 could be a therapeutic target in neuroblastoma.

Targeted drug distribution in tumor extracellular fluid of GD2-expressing neuroblastoma patient-derived xenografts using SN-38-loaded nanoparticles conjugated to the monoclonal antibody 3F8.

Neuroblastoma is a pediatric solid tumor with high expression of the tumor associated antigen disialoganglioside GD2. Despite initial response to induction therapy, nearly 50% of high-risk neuroblastomas recur because of chemoresistance. Here we encapsulated the topoisomerase-I inhibitor SN-38 in polymeric nanoparticles (NPs) surface-decorated with the anti-GD2 mouse mAb 3F8 at a mean density of seven antibody molecules per NP. The accumulation of drug-loaded NPs targeted with 3F8 versus with control antibody was monitored by microdialysis in patient-derived GD2-expressing neuroblastoma xenografts. We showed that the extent of tumor penetration by SN-38 was significantly higher in mice receiving the targeted nano-drug delivery system when compared to non-targeted system or free drug. This selective penetration of the tumor extracellular fluid translated into a strong anti-tumor effect prolonging survival of mice bearing GD2-high neuroblastomas in vivo.

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system.

We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m2/day, x 4 days; thiotepa 300 mg/m2/day, x 3 days; and carboplatin approximately 500 mg/m2/day, x 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cis-retinoic acid, +/-oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.+/-8%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day +9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.