Comparative Outcomes of Single-Stage versus Two-Stage Laparoscopic Fowler-Stephens Orchidopexy: A Systematic Review snd Meta-Analysis.

INTRODUCTION: Intra-abdominal testis (IAT) remains a challenging and controversial subset within the management of cryptorchidism. While Fowler-Stephens orchidopexy (FSO) is still being advocated as the gold standard for the treatment of this entity, there is new and conflicting evidence on the comparative outcomes between single- or two-stage laparoscopic FSO (LFSO). The aim of the study is to investigate whether staging has benefits in children receiving LFSO. METHODS: We searched the PubMed, Medline, Embase, and Cochrane Trials databases for studies comparing single- with two-stage LFSO in children from January 1, 1995 to December 31, 2023. We assessed the identified studies for quality and performed a systematic review and meta-analysis in accordance with the Preferred Reporting of Systematic Reviews and Meta-Analyses. The main outcome measures examined were success rate (in terms of the scrotal position of the testis) and testicular atrophy, which were analyzed using fixed effect models. RESULTS: We included 17 eligible studies that involved a total of 499 operated testes. The overall success rates of single- and two-stage LFSO were 79.4 and 90.3%, respectively. The overall testicular atrophy rates of single- and two-stage LFSO were 17.3 and 11%, respectively. Fixed effect model analysis showed that two-stage LFSO is significantly superior to single-stage LFSO in overall success rate (odds ratio [OR: 2.57]; 95% confidence interval [CI]: 1.50-4.39, p = 0.0006) and testicular atrophy rate (OR: 0.48; 95% CI: 0.28-0.79, p = 0.004). There is no heterogeneity in the reports, and the funnel plot showed no publication bias. CONCLUSIONS: Two-stage LFSO remains the first choice of operation for children with a high IAT, with a significantly higher success rate and a lower testicular atrophy rate.

Return to work after injury in Hong Kong: prospective multi-center cohort study.

PURPOSE: Trauma remains a major cause of morbidity and disability worldwide; however, reliable data on the health status of an urban Asian population after injury are scarce. The aim was to evaluate 1-year post-trauma return to work (RTW) status in Hong Kong. METHODS: This was a prospective, multi-center cohort study involving four regional trauma centers from 2017 to 2019 in Hong Kong. Participants included adult patients entered into the trauma registry who were working or seeking employment at the time of injury. The primary outcome was the RTW status up to 1 year. The Extended Glasgow Outcome Scale, 12-item Short Form (SF-12) survey and EQ5D were also obtained during 1-, 3-, 6-, 9-, and 12-month follow-ups. Multivariable Cox proportional hazards regression analysis was used for analysis. RESULTS: Six hundred and seven of the 1115 (54%) recruited patients had RTW during the first year after injury. Lower physical requirements (p = 0.003, HR 1.51) in pre-injury job nature, higher educational levels (p < 0.001, HR 1.95), non-work-related injuries (p < 0.001, HR 1.85), shorter hospital length of stay (p = 0.007, HR 0.98), no requirement for surgery (p = 0.006, HR 1.34), and patients who could be discharged home (p = 0.006, HR 1.43) were associated with RTW within 12 months post-injury. In addition, 1-month outcomes including extended Glasgow Outcome Scale ≥ 6 (p = 0.001, HR 7.34), higher mean SF-12 physical component summary (p = 0.002, HR 1.02) and mental component summary (p < 0.001, HR 1.03), and higher EQ5D health index (p = 0.018, HR 2.14) were strongly associated with RTW. CONCLUSIONS: We have identified factors associated with failure to RTW during the first year following in Hong Kong including socioeconomic factors, injury factors and treatment-related factors and 1-month outcomes. Future studies should focus on the interventions that can impact on RTW outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03219424.

Seven-year excess mortality, functional outcome and health status after trauma in Hong Kong.

PURPOSE: The purpose was to investigate long-term health impacts of trauma and the aim was to describe the functional outcome and health status up to 7 years after trauma. METHODS: We conducted a prospective, multi-centre cohort study of adult trauma patients admitted to three regional trauma centres with moderate or major trauma (ISS ≥ 9) in Hong Kong (HK). Patients were followed up at regular time points (1, 6 months and 1, 2, 3, 4, 5, 6, and 7 years) by telephone using extended Glasgow Outcome Scale (GOSE) and the Short-Form 36 (SF36). Observed annual mortality rate was compared with the expected mortality rate estimated using the HK population cohort. Linear mixed model (LMM) analyses examined the changes in SF36 with subgroups of age ≥ 65 years, ISS > 15, and GOSE ≥ 5 over time. RESULTS: At 7 years, 115 patients had died and 48% (138/285) of the survivors responded. The annual mortality rate (AMR) of the trauma cohort was consistently higher than the expected mortality rate from the general population. Forty-one percent of respondents had upper good recovery (GOSE = 8) at 7 years. Seven-year mean PCS and MCS were 45.06 and 52.06, respectively. LMM showed PCS improved over time in patients aged < 65 years and with baseline GOSE ≥ 5, and the MCS improved over time with baseline GOSE ≥ 5. Higher mortality rate, limited functional recovery and worse physical health status persisted up to 7 years post-injury. CONCLUSION: Long-term mortality and morbidity should be monitored for Asian trauma centre patients to understand the impact of trauma beyond hospital discharge.

RISC II is superior to TRISS in predicting 30-day mortality in blunt major trauma patients in Hong Kong.

PURPOSE: Hong Kong (HK) trauma registries have been using the Trauma and Injury Severity Score (TRISS) for audit and benchmarking since their introduction in 2000. We compare the mortality prediction model using TRISS and Revised Injury Severity Classification, version II (RISC II) for trauma centre patients in HK. METHODS: This was a retrospective cohort study with all five trauma centres in HK. Adult trauma patients with Injury Severity Score (ISS) > 15 suffering from blunt injuries from January 2013 to December 2015 were included. TRISS models using the US and local coefficients were compared with the RISC II model. The primary outcome was 30-day mortality and the area under the receiver operating characteristic curve (AUC) for tested models. RESULTS: 1840 patients were included, of whom 1236/1840 (67%) were male. Median age was 59 years and median ISS was 25. Low falls were the most common mechanism of injury. The 30-day mortality was 23%. RISC II yielded a superior AUC of 0.896, compared with the TRISS models (MTOS: 0.848; PATOS: 0.839; HK: 0.858). Prespecified subgroup analyses showed that all the models performed worse for age ≥ 70, ASA ≥ III, and low falls. RISC II had a higher AUC compared with the TRISS models in all subgroups, although not statistically significant. CONCLUSION: RISC II was superior to TRISS in predicting the 30-day mortality for Hong Kong adult blunt major trauma patients. RISC II may be useful when performing future audit or benchmarking exercises for trauma in Hong Kong.

COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade.

Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins. We evaluated the prevalence of TIGIT and its cognate ligand, PVR (CD155), in human cancers by assessing their expression in a large set of solid tumors. TIGIT is expressed on CD4+ and CD8+ TILs and is upregulated in tumors compared to normal tissues. PVR is expressed on tumor cells and tumor-associated macrophages from multiple solid tumors. We explored the therapeutic potential of targeting TIGIT by generating COM902, a fully human anti-TIGIT hinge-stabilized IgG4 monoclonal antibody that binds specifically to human, cynomolgus monkey, and mouse TIGIT, and disrupts the binding of TIGIT with PVR. COM902, either alone or in combination with a PVRIG (COM701) or PD-1 inhibitor, enhances antigen-specific human T cell responses in-vitro. In-vivo, a mouse chimeric version of COM902 in combination with an anti-PVRIG or anti-PD-L1 antibody inhibited tumor growth and increased survival in two syngeneic mouse tumor models. In summary, COM902 enhances anti-tumor immune responses and is a promising candidate for the treatment of advanced malignancies.

PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function.

Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8+ T-cell cytokine production and cytotoxic activity. The inhibitory effect of PVRL2 was mediated by PVRIG and not TIGIT, demonstrating that the PVRIG-PVRL2 pathway is a nonredundant signaling node. A combination of PVRIG blockade with TIGIT or PD-1 blockade further increased T-cell activation. In human tumors, PVRIG expression on T cells was increased relative to normal tissue and trended with TIGIT and PD-1 expression. Tumor cells coexpressing PVR and PVRL2 were observed in multiple tumor types, with highest coexpression in endometrial cancers. Tumor cells expressing either PVR or PVRL2 were also present in numbers that varied with the cancer type, with ovarian cancers having the highest percentage of PVR-PVRL2+ tumor cells and colorectal cancers having the highest percentage of PVR+PVRL2- cells. To demonstrate a role of PVRIG and TIGIT on tumor-derived T cells, we examined the effect of PVRIG and TIGIT blockade on human tumor-infiltrating lymphocytes. For some donors, blockade of PVRIG increased T-cell function, an effect enhanced by combination with TIGIT or PD-1 blockade. In summary, we demonstrate that PVRIG and PVRL2 are expressed in human cancers and the PVRIG-PVRL2 and TIGIT-PVR pathways are nonredundant inhibitory signaling pathways.See related article on p. 244.

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.

ILDR2 Is a Novel B7-like Protein That Negatively Regulates T Cell Responses.

The B7-like protein family members play critical immunomodulatory roles and constitute attractive targets for the development of novel therapies for human diseases. We identified Ig-like domain-containing receptor (ILDR)2 as a novel B7-like protein with robust T cell inhibitory activity, expressed in immune cells and in immune-privileged and inflamed tissues. A fusion protein, consisting of ILDR2 extracellular domain with an Fc fragment, that binds to a putative counterpart on activated T cells showed a beneficial effect in the collagen-induced arthritis model and abrogated the production of proinflammatory cytokines and chemokines in autologous synovial-like cocultures of macrophages and cytokine-stimulated T cells. Collectively, these findings point to ILDR2 as a novel negative regulator for T cells, with potential roles in the development of immune-related diseases, including autoimmunity and cancer.

Endoscopic injection for primary vesicoureteric reflux: Predictors of resolution and long term efficacy.

AIM: We investigated the efficacy of endoscopic-Deflux-injection in treating primary-vesicoureteric-reflux (VUR) and identified factors to predict resolution. MATERIALS AND METHODS: Records of children treated with Deflux for primary-VUR from 1995 to 2016 were reviewed, and outcomes were investigated. RESULTS: Eighty-eight ureters (35 bilateral, 18 unilateral) in 53 children underwent 124 injections. Thirty-five (66%) patients had single injection (13 unilateral, 22 bilateral). Fifteen (28%), two (37%), and one (2%) patients had two, three, and four injections, respectively. Overall success rate by ureters was 57% after single injection. Complete resolution occurred in 65% of ureters with VUR below grade III, 63% of grade III, 40% of grade IV, and 70% of grade V VUR. Four patients had reimplantation. The median follow up duration was 60months (range 20-216months). Univariate analysis showed that lower VUR grade (p=0.03) and absent renal scars (p=0.04) were statistically significant predictors of resolution. In multivariate analysis, absent renal scars were statistically significant (p=0.01). CONCLUSION: We demonstrated efficacy of endoscopic-Deflux-injection as the first line treatment for primary-VUR. Absent renal scar and lower VUR grade were statistically significant predictors of resolution after single injection. TYPE OF STUDY: Case-Control / Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III.

Outcomes of Re-Intervention for Laparoscopic Transperitoneal Pyeloplasty in Children.

BACKGROUND: There is no consensus for the management of failed laparoscopic pyeloplasty in pediatric surgical patients, and only limited publications are available. We evaluated here the clinical outcomes of re-intervention for failed laparoscopic transperitoneal pyeloplasty in infants and children. MATERIALS AND METHODS: Retrospective review of all children who had undergone laparoscopic transperitoneal dismembered Anderson-Hynes pyeloplasty for ureteropelvic junction obstruction from 2002 to 2013 was performed. Patients' demographics, indications, operative details, and outcomes for primary operation as well as re-intervention were studied. RESULTS: There were 42 patients with a median age of 20 months (range, 3-192 months) and a median body weight of 12 kg (range, 6-56 kg) who underwent a total of 46 laparoscopic transperitoneal pyeloplasties during the study period. The median operative time and blood loss were 193 minutes (range, 115-480 minutes) and trace amount (range, trace amount to 400 mL), respectively. No conversion was reported. Ten cases (22%) required re-intervention. No statistically significant risk factor for failed pyeloplasty was identified. Indications for re-intervention included deterioration of differential renal function (n = 6), progressive hydronephrosis (n = 1), urinary ascites (n = 2), and urosepsis (n = 1). Median time of re-intervention was 6.5 ± 38 months postpyeloplasty. Re-intervention was categorized into the redo pyeloplasty group (n = 6) and the urinary diversion group (n = 4) (insertion of double-J ureteral stent or endopyelotomy) with success rates of 50% and 25%, respectively. Among the redo pyeloplasty group, 3 patients underwent redo laparoscopic pyeloplasty, and all of them had drainage restored with a median improvement in differential renal function of 11%. The mean follow-up duration was 77 ± 38 months. CONCLUSIONS: Laparoscopic transperitoneal pyeloplasty is safe and feasible in children. Redo pyeloplasty is a more favorable re-intervention compared with urinary diversion in our series. Redo laparoscopic pyeloplasty has been shown to improve differential renal function.

Performance of a prehospital trauma diversion system in Hong Kong, China.

PURPOSE: To evaluate the performance of a prehospital trauma diversion system in Hong Kong, China. METHODS: A retrospective analysis of prospectively collected data in the trauma registry of Queen Mary Hospital, Hong Kong from 1 January 2009 to 31 December 2013 was done. All adult patients aged 18 years or above, either primarily or secondarily diverted to Queen Mary Hospital according to the trauma patient diversion protocol, were recruited. Need for trauma center level of care was based on a consensus-based criterion standard published in 2014. Performance of the protocol in terms of over- diversion and under-diversion was determined. RESULTS: A total of 209 patients were included for analysis. About 30% of the patients required trauma center level of care. The most common reason was the need for vascular, neurologic, abdominal, thoracic, pelvic, spine or limb-conserving surgery within 24 h of presentation. The over-diversion rate and under- diversion rate were 69.6% and 19.7% respectively. CONCLUSION: The trauma patient diversion protocol currently in use in Hong Kong is not accurate enough. Further revision and refinement is needed.

Identification and characterization of distinct IL-17F expression patterns and signaling pathways in chronic lymphocytic leukemia and normal B lymphocytes.

Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of B lymphocytes. T cell abnormalities are a common feature of CLL and contribute to impaired immune function in these patients. T cells are ineffective in eliminating the leukemic clone and may actually promote tumor growth and survival. Previous work from our laboratory documented elevated circulating levels of IL-17A-producing Th17 cells in CLL patients as compared to healthy age-matched control subjects. These high circulating Th17 levels associated with better prognostic markers and significantly longer overall survival, even among patients whose clones used unmutated IGHVs (U-CLL). Recent studies suggest that Th17 cells are heterogeneous, expressing different profiles of cytokines, and that different subsets of Th17s mediate different biological functions. In the present study, we found significantly higher levels of IL-17F-expressing CD4(+) T cells in CLL versus healthy peripheral blood mononuclear cells following in vitro stimulation in the presence of Th17-promoting cytokines. Furthermore, the differentiation of IL-17F-expressing Th17 cells was significantly enhanced when purified CD4(+) T cells from CLL patients were cultured in the presence of autologous CLL B cells. Lastly, single-cell network profiling revealed that IL-17F triggers NFκB phosphorylation in T and B cells from patients with CLL, but not age-matched healthy controls. Taken together, our data suggest that the phenotype of Th17 cells in CLL patients is distinct from healthy individuals, expressing higher levels of IL-17F, and that B and T cells from CLL patients are particularly responsive to IL-17F, as compared to healthy age-matched control individuals.

Management of tracheobronchial obstruction in infants using metallic stents: long-term outcome.

INTRODUCTION: Tracheobronchial obstruction, although uncommon in the pediatric age group, remains a challenging problem. We review the long-term outcome of endoscopic metallic stenting in infants with tracheobronchial obstruction. MATERIALS AND METHODS: Medical records of all pediatric surgical patients who underwent tracheobronchial metallic stenting in our center were reviewed retrospectively from 1996 to 2014. Patients' demographic data, including etiology, associated anomalies and nature of obstruction were reviewed. Outcome measures include complications such as re-stenosis, granulation tissue, stent migration, fractured stent, maximal tracheal diameter achieved, weaning of ventilator and growth at interval follow-up. RESULTS: Twelve balloon-expandable metallic stents were placed in the trachea (n = 10) and/or bronchi (n = 2) of 5 patients with a median age of 13 months (range 5-30 months). Etiology of the airway obstruction included congenital tracheal stenosis (n = 4), giant cervical and superior mediastinal lymphatic malformation with tracheobronchomalacia (n = 1). Seven complications were reported (3 patients developed granulation tissue, 2 patients had re-stenosis, 1 stent migrated, 1 stent fractured). All patients survived and were in good condition with a median follow-up of 16 years (range 11-18 years). Three patients weaned off ventilator and oxygen. CONCLUSIONS: Endoscopic stenting with metallic stent has satisfactory long-term outcome in treating infants with tracheobronchial obstruction.

Laparoscopic Nissen fundoplication for gastro-oesophageal reflux disease in infants.

INTRODUCTION: Data on laparoscopic Nissen fundoplication for gastro-oesophageal reflux disease (GERD) in infants remain limited. We describe our experience with this operation in children and in particular, infants younger than 12 months old. MATERIALS AND METHODS: Medical records of all paediatric patients who had laparoscopic fundoplication done for GERD from 1998 to 2013 were reviewed. Patients were divided into two groups based on age: group I: 0-12 months, and group II >12 months. Data on indications, patient's demographics, operative time, blood loss, conversions, complications, recurrences and duration of hospitalization were studied. RESULTS: A total of 86 patients were reviewed (group I, n = 21; group II, n = 65). While the mean age and body weight for group I were 8 ± 2.99 months and 6 ± 1.96 kg, the values for group II were 98 ± 65 months and 18 ± 9.6 kg, respectively. All patients had concurrent laparoscopic gastrostomy for feeding difficulties. The mean operative time was shorter in group I (157 ± 55 vs 169 ± 52 min, p = 0.66). Both groups had minimal blood loss only. The surgical outcomes in both groups were comparable in terms of recurrence (0 vs 3 %, p = 0.105) and complications (9.5 vs 6 %, p = 0.275). The median follow-up duration for group I and group II was 23 and 40 months, respectively. Sixteen (76 %) patients in group I and 45 (67 %) patients in group II did not develop pneumonia post fundoplication. CONCLUSION: Laparoscopic Nissen fundoplication can be safely performed in infants with outcomes comparable to older patients and a shorter operative duration. Low recurrence rate (up to 3 %) is shown by our long term follow-up data. We recommend laparoscopic Nissen fundoplication to be considered in managing infants with GERD.

Quantitative measurement of alterations in DNA damage repair (DDR) pathways using single cell network profiling (SCNP).

BACKGROUND: Homologous recombination repair (HRR) pathway deficiencies have significant implications for cancer predisposition and treatment strategies. Improved quantitative methods for functionally characterizing these deficiencies are required to accurately identify patients at risk of developing cancer and to identify mechanisms of drug resistance or sensitivity. METHODS: Flow cytometry-based single cell network profiling (SCNP) was used to measure drug-induced activation of DNA damage response (DDR) proteins in cell lines with defined HRR pathway mutations (including ATM-/-, ATM+/-, BRCA1+/-, BRCA2-/-) and in primary acute myeloid leukemia (AML) samples. Both non-homologous end joining (NHEJ) and HRR pathways were examined by measuring changes in intracellular readouts (including p-H2AX, p-ATM, p-DNA-PKcs, p-53BP1, p-RPA2/32, p-BRCA1, p-p53, and p21) in response to exposure to mechanistically distinct genotoxins. The cell cycle S/G2/M phase CyclinA2 marker was used to normalize for proliferation rates. RESULTS: Etoposide induced proliferation-independent DNA damage and activation of multiple DDR proteins in primary AML cells and ATM +/+but not ATM -/- cell lines. Treatment with the PARPi AZD2281 +/- temozolomide induced DNA damage in CyclinA2+ cells in both primary AML cells and cell lines and distngiushed cell lines deficient (BRCA2-/-) or impaired (BRCA1+/-) in HRR activity from BRCA1+/+ cell lines based on p-H2AX induction. Application of this assay to primary AML samples identified heterogeneous patterns of repair activity including muted or proficient activation of NHEJ and HRR pathways and predominant activation of NHEJ in a subset of samples. CONCLUSIONS: SCNP identified functional DDR readouts in both NHEJ and HRR pathways, which can be applied to identify cells with BRCA1+/- haploinsuffiency and characterize differential DDR pathway functionality in primary clinical samples.

Management of the low-flow head and neck vascular malformations in children: the sclerotherapy protocol.

AIM: Image-guided sclerotherapy is becoming the preferred treatment for low-flow vascular malformations in head and neck region. The authors review the management protocol for this condition and evaluate its clinical outcomes. METHODS: Children with low-flow vascular malformations in head and neck region undergoing sclerotherapy from 2010 to 2013 were reviewed. All patients were assessed by pediatric surgeons and interventional radiologists in the multidisciplinary vascular anomalies clinic. Ultrasonography and intravenous contrast enhanced magnetic resonance imaging were performed preoperatively. Under general anesthesia with endotracheal intubation, sclerotherapy were performed with ultrasonographic and fluoroscopic guidance. Sodium tetradecryl sulfate (STS) foam or ethanolamine was used for venous malformation and doxycycline for lymphatic malformations as primary sclerosants, whereas 98% ethanol was reserved as an adjuvant sclerosant in selected cases of repeated procedures. Perioperative dexamethasone 0.2 mg/kg thrice daily was administered to decrease postsclerotherapy swelling and single dose intravenous mannitol 0.5 g/kg was given to minimize thromboembolic complications. Postoperatively, patients were admitted to intensive care unit for mechanical ventilation under deep sedation for airway protection. RESULTS: Overall 13 children (8 male and 5 female) with a mean age of 25 months (range, 2 mo-11 y) underwent a total of 25 sessions of image-guided staged sclerotherapy. There were five venous and eight lymphatic malformations. Location wise there were eight cervical, one lingual, one parotid, one lip, one facial, and one palatal lesions. Six patients had obstructive airway symptoms. Five patients required staged sclerotherapies from two to six sessions. There were no airway and thromboembolic complications. One patient had bleeding while another had recurrent swelling following sclerotherapy for lymphatic malformations and they were treated by aspiration. Significant size reductions of more than 50% volume were achieved in all patients. All patients with obstructive symptoms showed improvement. CONCLUSION: Sclerotherapy is a safe and effective treatment for head and neck vascular malformations in children. Routine perioperative protocol is essential to reduce airway and thromboembolic complications. Size reduction and functional improvement occurred in all patients undergoing sclerotherapy.

AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.

Gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a calicheamicin-γ(1) derivative, induces remissions and improves survival in a subset of patients with acute myeloid leukemia (AML). As the mechanisms underlying GO and calicheamicin-γ(1) resistance are incompletely understood, we herein used flow cytometry-based single cell network profiling (SCNP) assays to study cellular responses of primary human AML cells to GO. Our data indicate that the extent of DNA damage is quantitatively impacted by CD33 expression and drug efflux activity. However, although DNA damage is required for GO-induced cytotoxicity, it is not sufficient for effective cell kill, suggesting that downstream anti-apoptotic pathways may function as relevant resistance mechanisms. Supporting this notion, we found activated PI3K/AKT signaling to be associated with GO resistance in vitro in primary AML cells. Consistently, the investigational AKT inhibitor MK-2206 significantly sensitized various human AML cells to GO or free calicheamicin-γ(1) with particularly pronounced effects in otherwise GO or free calicheamicin-γ(1)-resistant cells. Likewise, MK-2206 also sensitized primary AML cells to calicheamicin-γ(1). Together, our findings illustrate the capacity of SCNP assays to discover chemotherapy-related biological pathways and signaling networks relevant to GO-induced genotoxic stress. The identification of AKT signaling as being associated with GO resistance in vitro may provide a novel approach to improve the in vivo efficacy of GO/calicheamicin-γ(1) and, by extrapolation, other DNA damage-based therapeutics.

Multiple atherosclerosis-related biomarkers associated with short- and long-term mortality after stroke.

OBJECTIVES: We investigated the relationships of biomarkers of various pathophysiologic pathways including high-sensitivity C-reactive protein (hs-CRP), lipocalin-2 (LCN2), myeloperoxidase (MPO) and matrix metalloproteinases 9 (MMP9) with mortality in stroke patients. DESIGN AND METHODS: hs-CRP, LCN2 and MPO concentrations in 92 patients were determined using enzyme-linked immunosorbent assays. MMP9 mRNA concentrations were determined using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Twelve patients (13.0%) died at 6 months and 34 patients (37.0%) died at 5 years. The independent predictors for 6-month mortality were hs-CRP (adjusted OR=16.0) and LCN2 (adjusted OR=16.9), while for 5-year mortality was hs-CRP (adjusted OR=5.56). For patients with hs-CRP >3.4 mg/L, an increase in LCN2 was associated with 2.5-fold higher 6-month mortality, while an increase in normalized MMP9 mRNA was associated with 5.8-fold higher 6-month and 1.5-fold higher 5-year mortality. CONCLUSION: hs-CRP was the most significant independent predictor of both short- and long-term mortality after stroke, with LCN2 and MMP9 mRNA each adding further to the risk stratification.

Zic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells.

Aberrant activation of Hedgehog (Hh) signalling has been implicated in the pathogenesis of human cancers. However, the cognate molecular mechanisms contributing to this disregulated pathway are incompletely understood. In this study, we showed that Zic2 was frequently over-expressed and associated with high-grade cervical cancer (p = 0.032), high levels of Gli1 (p < 0.001) and CyclinD1 (p < 0.001) by immunohistochemical and quantitative RT-PCR analyses. Further biochemical studies using luciferase reporter, co-immunoprecipitation, subcellular fractionation and immunofluorescence analyses demonstrated that Zic2 can physically interact with Gli1 and retain it in the nucleus, which in turn increases Gli-mediated transcriptional activity. Gain- and loss-of-function analyses of Zic2 showed that Zic2 could increase Hh signalling activity, cell proliferation and anchorage-independent growth ability in cervical cancer cells. Conversely, deletion of the zinc finger domain at C-terminus of Zic2 significantly abrogated its interaction with Gli1, the retention of Gli1 in the nucleus, effects on Hh signalling activity and oncogenic properties in cervical cancer cells. Our findings suggest that Zic2 is a positive modulator increasing Gli1 transcriptional and oncogenic activity by retaining Gli1 in the nucleus of cervical cancer cells.

CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo.

CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.