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.

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.

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.

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.

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.

ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.

The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2 immunotherapy and isotretinoin: a prospective Phase II study.

Relapse of high-risk neuroblastoma (HR-NB) is deemed invariably fatal yet increasing numbers of HR-NB patients achieve a second complete/very good partial remission (CR/VGPR), hence the urgency to find a successful consolidative therapy. Identifying efficacy in patients without assessable disease, however, is problematic. We report the first study providing outcome data for this group of patients with poor prognosis. To prevent another relapse, HR-NB patients in second or later CR/VGPR received the anti-GD2 murine antibody 3F8 plus granulocyte-macrophage colony-stimulating factor plus isotretinoin in a Phase II trial. Upon meeting the target aim for progression-free survival (PFS) in the initial cohort of 33 patients, the trial was amended to allow patients who developed human anti-mouse antibody (HAMA) to receive rituximab to ablate HAMA with or without low-dose maintenance chemotherapy until immunotherapy could resume. For the total of 101 study patients, 5-year PFS and overall survival (OS) rates were 33% ± 5% and 48% ± 5%, respectively. Among the 33 long-term progression-free survivors, 19 had MYCN amplification, 19 had previously received anti-GD2 immunotherapy plus isotretinoin (as first-line therapy), and 15 never received maintenance chemotherapy. In a multivariate analysis of prognostic factors, only absence of minimal residual disease in bone marrow after 2 cycles of immunotherapy and before initiation of isotretinoin or anti-HAMA therapy was significantly favorable for both PFS and OS. Therefore, long-term PFS is possible for HR-NB patients who achieve at least a second CR/VGPR and receive consolidation that includes anti-GD2 immunotherapy plus isotretinoin, even if the patients received these biological treatments before relapse. Results from this prospective study will aid in the development of future Phase II studies for this growing ultra high-risk patient population.

Human derived dimerization tag enhances tumor killing potency of a T-cell engaging bispecific antibody.

Bispecific antibodies (BsAbs) have proven highly efficient T cell recruiters for cancer immunotherapy by virtue of one tumor antigen-reactive single chain variable fragment (scFv) and another that binds CD3. In order to enhance the antitumor potency of these tandem scFv BsAbs (tsc-BsAbs), we exploited the dimerization domain of the human transcription factor HNF1α to enhance the avidity of a tsc-BsAb to the tumor antigen disialoganglioside GD2 while maintaining functional monovalency to CD3 to limit potential toxicity. The dimeric tsc-BsAb showed increased avidity to GD2, enhanced T cell mediated killing of neuroblastoma and melanoma cell lines in vitro (32-37 fold), exhibited a near 4-fold improvement in serum half-life, and enhanced tumor ablation in mouse xenograft models. We propose that the use of this HNF1α-derived dimerization tag may be a novel and effective strategy to increase the potency of T-cell engaging antibodies for clinical cancer immunotherapy.

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.

Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential.

WT1126 (RMFPNAPYL) is a human leukocyte antigen-A2 (HLA-A2)-restricted peptide derived from Wilms tumor protein 1 (WT1), which is widely expressed in a broad spectrum of leukemias, lymphomas and solid tumors. A novel T-cell-receptor (TCR)-like single-chain variable fragment (scFv) antibody specific for the T-cell epitope consisting of the WT1/HLA-A2 complex was isolated from a human scFv phage library. This scFv was affinity-matured by mutagenesis combined with yeast display and structurally analyzed using a homology model. This monovalent scFv showed a 100-fold affinity improvement (dissociation constant (KD)=3 nm) and exquisite specificity towards its targeted epitope or HLA-A2(+)/WT1(+) tumor cells. Bivalent scFv-huIgG1-Fc fusion protein demonstrated an even higher avidity (KD=2 pm) binding to the T-cell epitope and to tumor targets and was capable of mediating antibody-dependent cell-mediated cytotoxicity or tumor lysis by chimeric antigen receptor-expressing human T- or NK-92-MI-transfected cells. This antibody demonstrated specific and potent cytotoxicity in vivo towards WT1-positive leukemia xenograft that was HLA-A2 restricted. In summary, T-cell epitopes can provide novel targets for antibody-based therapeutics. By combining phage and yeast displays and scFv-Fc fusion platforms, a strategy for developing high-affinity TCR-like antibodies could be rapidly explored for potential clinical development.

Large traumatic pneumatocele in a 2-year-old child.

Traumatic pneumatoceles are a rare complication of blunt chest trauma in children. Although they characteristically present as small, regular shaped lesions which can be safely treated nonoperatively, larger traumatic pneumatoceles pose diagnostic and management difficulties for clinicians. This case study reports one of the largest traumatic pneumatoceles reported to date in the paediatric population, which resulted in aggressive surgical intervention for both diagnostic and treatment reasons. This case adds further evidence to the current literature that significantly large traumatic pneumatoceles with failure of initial conservative management warrant surgical exploration and management to optimise recovery and prevent complications.

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.

Seatbelt: a double-edged sword.

Intra-abdominal vascular injury due to blunt trauma is unusual in children. Due to its rarity, detailed reports dealing with its management are scarce in paediatric literature. Diagnosis of these injuries is challenging, and a high degree of awareness is necessary for rapid identification and treatment of these injuries. We report the case of a child with seatbelt sign and mesenteric vein injury due to blunt trauma to the abdomen during a motor vehicle accident where the seatbelt was incorrectly placed. She also sustained cervical vertebral injury. The pattern of injuries in children in these situations may differ from that found in adults. While seatbelts have undoubtedly saved many lives, awareness about correct placement of these restraints is extremely necessary.

Retargeting NK92 cells using an HLA-A2-restricted, EBNA3C-specific chimeric antigen receptor.

Advances in adoptive cell immunotherapy have led to several promising options for cancer patients. Single-chain variable fragments (scFvs) were isolated from a human phage display library by panning on recombinant human leukocyte antigen (HLA)-A2-peptide complexes. A scFv (EBNA Clone 315) specific for HLA-A2 carrying a 10 amino acid peptide (LLDFVRFMGV) derived from the Epstein-Barr virus latent protein EBNA3C was fully characterized. EBNA Clone 315 displayed exquisite specificity toward its targeted T-cell epitope (TCE) and did not cross-react with the free peptide, HLA-A2 complexes, which carried irrelevant peptides, or HLA-A2(-) cells. Furthermore, after engineering into a scFv-Fc fusion protein, we were able to determine its affinity, detection sensitivity, and ability to induce antibody-dependent cellular cytotoxicity (ADCC). As a proof-of-principle, a chimeric antigen receptor (CAR) version of EBNA Clone 315 was used to reprogram NK92MI cells. CAR-expressing NK92MI cells showed highly specific and potent cytotoxicity toward the targeted TCE, with detection sensitivity of approximately 25 molecules and cytolytic capacity threefold greater than scFv-Fc-mediated ADCC. For the first time, we show the successful reprogramming of non-T cells toward a specific TCE using a CAR.

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.

Bicycle related injuries presenting to a trauma centre in Hong Kong.

BACKGROUND: Bicycle riding is a popular leisure activity and an important means of transportation in Hong Kong. Young cyclists' riding behaviour causes injury patterns which may differ from older riders. The aim of this study is firstly to describe bicycle related injuries presenting to a regional trauma centre in Hong Kong, and secondly to compare patients aged > 15 years with those patients aged < or = 15 years. METHODS: This retrospective observational study examined all bicycle related injury patients presenting to the ED of the Prince of Wales Hospital (PWH) in 2006. RESULTS: Results showed that bicycle helmet use was low in Hong Kong suggesting that the wearing of helmets when cycling should be promoted. Bicycle related injuries were common in children but the injuries in adults were more serious. Head and limb injuries were common and limbs on the left side were 2.5 times more likely to be injured than those on the right. The older group were more likely to be involved in a motor vehicle collision and sustained more severe injuries than the younger group. They had more serious head and neck, face, thorax and abdominal injuries compared to the younger group. CONCLUSION: Prevention strategies should include more widespread helmet use and increasing bicycle lane provision to enable traffic separation in Hong Kong. The three 'E' approaches (education, enforcement and environment) should be implemented to prevent bicycle injuries in Hong Kong.

High risk trauma in older adults in Hong Kong: a multicentre study.

BACKGROUND: Trauma is the eighth leading cause of death in Hong Kong. In 2002, 18.5% of the population of Hong Kong was aged 55 years or above, which increased to 22.1% in 2006. The increasing older population in Hong Kong presents a challenge to the health care system yet there is little local data on older trauma patients. The objectives of this study are firstly to describe the epidemiology of high risk trauma in older patients in Hong Kong, and secondly to identify predictors of trauma mortality. METHOD: Retrospective analysis of prospectively collected data from a centralised trauma database; data collected from 2002 to 2004 from four trauma centres in Hong Kong. RESULTS: Between 2002 and 2004, the four trauma centres had a total of 2,124,175 emergency department attendances of which 376,021 (17.7%) were trauma patients, and 80,827 (3.8%) were aged 55 years or older. 810 injured older patients met the inclusion criteria for this study. 380 (46.9%) patients had co-morbidity at the time of injury. Common causes of injury were falls (50.0%, 405/810) and motor vehicle crashes (33.6%, 272/810) of which (77.2%, 210/272) were pedestrians. Mortality was 24.4% (198/810) and increased with advancing age (p<0.0001). 53.5% (433/810) of patients had major trauma (ISS>15). Head injury contributed to 80.3% (159/198) of deaths. 38.4% (311/810) of patients required operations. Most patients were discharged home (40.5%, 328/810) and one-third (270/810) required rehabilitation. Significant predictors of mortality included co-morbidity, injury severity score, age and decreasing Glasgow Coma Score. CONCLUSION: Pedestrians struck by motor vehicles and falls are the principal causes of trauma in older patients in Hong Kong. Mortality increased with advancing age. The independent indicators of trauma mortality in older patients are co-morbidity, age, ISS and GCS.