Efficacy of perioperative 2% dorzolamide ophthalmic solution for reduction of postoperative ocular hypertension in dogs following routine phacoemulsification surgery: A prospective clinical trial.

OBJECTIVE: To evaluate the efficacy of 2% dorzolamide ophthalmic solution for reduction of postoperative ocular hypertension (POH) following routine phacoemulsification surgery in dogs. ANIMALS STUDIED: Thirty one dogs (53 eyes) with naturally occurring cataracts undergoing routine phacoemulsification surgery. PROCEDURE(S): A prospective, double-masked, randomized, placebo-controlled study design was utilized. Dogs received 2% dorzolamide ophthalmic solution or saline 1 h prior to surgery then three times daily for 21 days postoperatively in the operated eye(s). Intraocular pressure (IOP) was recorded 1 h prior to surgery and 3 h, 7 h, 22 h, 1 week and 3 weeks postoperatively. Statistical analyses were performed using chi-squared and Mann-Whitney U test with a significance level of p < .05. RESULTS: Postoperative ocular hypertension (IOP ≥25 mmHg, <24 h after surgery) occurred in 28/53 (52.8%) eyes. There was significant reduction in the incidence of POH for eyes receiving dorzolamide (10/26 (38.4%) eyes) versus eyes receiving placebo (18/27 (66.7%) eyes) (p = .0384). Animals were followed for a median of 163 days after surgery. Thirty-seven (37/53 (69.8%)) eyes were visual at final examination and 3/53 (5.7%) globes were enucleated postoperatively. At last follow-up, there was no difference in visual status (p = .9280), need for topical IOP lowering medication (p = .8319) or incidence of glaucoma (p = .5880) based on treatment group. CONCLUSIONS: Perioperative administration of topical 2% dorzolamide reduced the incidence of POH after phacoemulsification in the dogs studied. However, this was not associated with differences in visual outcome, incidence of glaucoma or need for IOP-lowering medications.

Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma.

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Endoglin in the Spotlight to Treat Cancer.

A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFß pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy.

Improved guidance is needed to optimise diagnostics and treatment of patients with thyroid cancer in Europe.

Although thyroid cancer (TC) is generally associated with a favourable prognosis, there are certain high-risk groups with a clear unmet therapeutic need. Unravelling the genomic landscape of TC has recently led to the development of novel effective targeted treatments. To date, these treatments have mostly been evaluated in non-randomised single-arm phase II clinical trials and are consequently non-reimbursed in several countries. Furthermore, most of these agents must be tailored to individual patient molecular characteristics, a context known as personalised cancer medicine, necessitating a requirement for predictive molecular biomarker testing. Existing guidelines, both in Europe and internationally, entail mostly therapeutic rather than molecular testing recommendations. This may reflect ambiguity among experts due to lack of evidence and also practical barriers in availability of the preferred molecular somatic screening and/or targeted treatments. This article reviews existing European recommendations regarding advanced/metastatic TC management with a special focus on molecular testing, and compares findings with real-world practice based on a recent survey involving TC experts from 18 European countries. Significant disparities are highlighted between theory and practice related to variable access to infrastructure, therapies and expertise, together with the insufficient availability of multidisciplinary tumour boards. In particular, practitioners' choice of what, how and when to test is shown to be influenced by the expertise of the available laboratory, the financing source and the existence of potential facilitators, such as clinical trial access. Overall, the need of a collaborative initiative among European stakeholders to develop standardised, accessible molecular genotyping approaches in TC is underscored.

Are infections in children with juvenile idiopathic arthritis more frequent than in healthy children? A prospective multicenter observational study.

Background: Children with juvenile idiopathic arthritis (JIA) might be at a higher risk of infection. Our objectives are to describe and compare infection rates in patients with JIA vs. healthy patients. Methods: A prospective, multicenter observational study was performed in Spain from January 2017 to June 2019. Patients with JIA from 7 participating hospitals and children without JIA (siblings of patients with JIA, and non-JIA children from primary health centers) were followed up with quarterly questionnaires to record infection episodes. Tuberculosis, herpes zoster, and infections requiring hospital admission were considered severe infections. Rates of infection (episodes/patient/year) were compared using a generalized estimating equations model. Results: A total of 371 children (181 with and 190 without JIA) were included. The median age was 8.8 years (IQR 5.5-11.3); 75% of the patients with JIA received immunosuppressive treatment (24% methotrexate, 22% biologic, 26% both). A total of 667 infections were recorded; 15 (2.2%) were considered severe. The infection rate was 1.31 (95%CI 1.1-1.5) in JIA and 1.12 (95%CI 0.9-1.3) in non-JIA participants (p = 0.19). Age <4 years increased the infection rate by 2.5 times (2.72 vs. 1.12, p < 0.001) in both groups. The most frequent infection sites were upper respiratory (62.6% vs. 74.5%) and gastrointestinal (18.8% vs. 11.4%). There were no differences in severe infections (2.5% vs. 2%, p = 0.65) between the groups. In children with JIA, younger age and higher disease activity (JADAS71) were associated with a higher infection rate. Conclusion: We found no differences in the infection rate or infection severity between patients with and without JIA. Most infections were mild. An age younger than 4 years increased the infection risk in both groups. Higher disease activity was associated with a higher infection rate.

Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma.

PURPOSE: Endoglin (ENG; CD105) is a coreceptor of the TGFß family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFß, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease. EXPERIMENTAL DESIGN: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma. RESULTS: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts in a dose-dependent manner. CONCLUSIONS: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.

Preservation of Neisseria gonorrhoeae: should swabs be refrigerated or not?: Neisseria gonorrhoeae preservation.

Although molecular diagnosis has replaced culture as the reference technique in gonococcal infection, conventional culture is still performed. The aim was to compare the survival of Neisseria gonorrhoeae (NG) in transport swabs at room temperature (RT) and at 4°C. Fifty-four NG isolates were tested. A 1.5×108CFUmL-1 suspension was prepared for each strain, in which two swabs (Amies liquid medium with flocked swabs) were absorbed; one was preserved at RT and the other at 4°C. At 24 and 48h, 150µL of Amies medium were plated in Thayer Martin agar. The recovery percentage was significantly higher for the swabs kept at 4°C than for those kept at RT, both at 24h (94.4% vs. 16.7%), and at 48h (37% vs. 0%). This study clearly demonstrates the higher survival of NG when transport swabs are kept refrigerated. Modifying the guidelines could greatly improve the efficiency of microbiological diagnosis of the gonococcal infection.

Incidence and Risk Factors for Infection When Teicoplanin Is Included for Prophylaxis in Patients with Hip Fracture.

BACKGROUND: Surgical site infection (SSI) rate after surgery for hip fracture is about 4%. The aim of the present study was to review the efficacy of dual prophylaxis using teicoplanin plus cefuroxime and risk factors for SSI. PATIENTS: Operations for hip fracture from 2012 to 2013 were retrospectively reviewed. Relevant information was gathered: Demographics, comorbidities, ASA score, laterality, type of fracture, type of surgery, d from admission to surgery, length of surgery, hemoglobin value at admission, urinary or respiratory infections, and the need for pre-operative, intra-operative, and post-operative red blood cell (RBC) transfusion. Prophylaxis consisted of cefuroxime and teicoplanin during the induction of anesthesia. U.S. Centers for Disease Control and Prevention (CDC) criteria for superficial and deep SSI were applied. Univariate and multivariable analysis were performed. RESULTS: Six hundred fifty-seven patients were included in the study. Thirteen (2.0%) SSI were identified, six superficial (0.9%), and seven deep (1.1%). Staphylococcus aureus was isolated in two infections (one superficial and one deep). The SSI rate was 2.4% in intra-medullary nails (n = 334), 1.4% in prostheses (n = 211), and 1.8% in other synthesis (n = 112). Parameters independently associated with SSI were: Intra-operative RBC transfusion (OR: 11.6, p = 0.002), length of surgery >120 min (OR: 4.5, p = 0.02), and having a urinary infection (OR: 4.28, p = 0.02). CONCLUSION: Dual prophylaxis including cefuroxime and teicoplanin was associated with a 2% rate of SSI. Staphylococcus aureus caused only two SSIs. Reducing SSI is of utmost importance for patients' quality of life and to avoid additional cost of surgical procedures. Therefore, more experience with dual prophylaxis is needed to confirm our results.

[Neurofibromatosis type 2 and its head and neck manifestations: literature review and population study in the Community of Cantabria and the province of Las Palmas]. / Neurofibromatosis tipo ii y sus manifestaciones en cabeza y cuello: revisión bibliográfica y estudio poblacional en la Comunidad de Cantabria y la provincia de Las Palmas.

INTRODUCTION AND OBJECTIVES: Neurofibromatosis type 2 (NF2) is an infrequent autosomal dominant disease characterised by the appearance of viii nerve schwannomas, meningiomas and ocular abnormalities. Incidence of 1:25,000 and prevalence above 1:80,000 are estimated in general. The objectives of our study were to determine current prevalence of NF2 in the Community of Cantabria and the province of Las Palmas, and its head and neck manifestations. MATERIAL AND METHODS: This was a population-based, retrospective study in 3 tertiary hospitals. RESULTS: The study population showed prevalence of 1:600,000 in the Community of Cantabria and 1:280,000 in the province of Las Palmas. The most frequently diagnosed tumour was acoustic neuroma (n=15), followed by trigeminal neurinoma (n=2) and vagus (n=1). CONCLUSIONS: Cases of NF2 are infrequent in Cantabria and Las Palmas, lower than that reported in the literature. The most frequently described head and neck tumour in the literature is acoustic neuroma, followed by schwannoma of cranial nerves v and x. Other tumours such as nasal, laryngeal, chorda tympani or cranial nerve vii schwannomas are also described. The most frequent ENT manifestation is hearing loss, especially unilateral, followed by cervical mass, tinnitus and headache. Early diagnosis and multidisciplinary management in specialised centres could improve life expectancy and quality of life for these patients.

Prosthetic joint infections due to Staphylococcus aureus and coagulase-negative staphylococci.

PURPOSES: To evaluate the specific characteristics, outcome, and predictors of failure of prosthetic joint infections (PJI) due to S. aureus and coagulase-negative staphylococci (CNS) treated with open debridement and retention of the implant. METHODS: PJI due to S. aureus or CNS prospectively registered in a database from 1999 to 2009 were retrospectively reviewed. During the study period, 106 patients met the inclusion criteria. The mean follow-up period was 3.8 years and for at least 2 years in all patients. The failure rate was 23.6% (25 out of 106). The only variable significantly associated with failure in the global cohort was polymicrobial infection (38.7% vs. 17.3%, p = 0.024). Fifty-seven (53.8%) patients had an infection due to S. aureus and 49 (46.2%) due to CNS. Among S. aureus infections, 95% corresponded to primary arthroplasties while 98% of PJIs due to CNS were after revision arthroplasties (p<0.001). C-reactive protein was significantly higher in PJI due to S. aureus (9.5 mg/dl vs. 4.9 mg/dl, p = 0.007). The rate of methicillin-resistance (8.8% vs. 59.2%, p<0.001) and fluoroquinolone-resistance (15.8% vs. 34.7%, p = 0.005) was significantly higher in CNS infections. The global failure rate was higher in S. aureus infections (28% vs. 18.3. p = 0.26). In S. aureus infections, patients diagnosed within the first 15 days after joint arthroplasty (p = 0.031) and with bacteremia (p = 0.046) had poor pro-gnosis. In CNS infections only the location of the prosthesis (knee 27.6% vs. hip 5%, p = 0.045) was associated with failure. CONCLUSIONS: PJIs due to S. aureus were mainly in primary arthroplasties; they had a higher inflammatory response; and the strains were more susceptible to fluoroquinolones and methicillin than CNS infections. S. aureus infections had a higher failure rate than CNS infections, however, the difference was not statistically significant. There were few factors associated with failure and they were different in S. aureus and CNS infections.

Less invasive fixation of an interthrocanteric fracture in an ankylosed hip with cannulated screws: a case report.

A 68-year-old woman presented following a road accident with an undisplaced intertrochanteric fracture affecting an ankylosed hip and an ipsilateral calcaneal fracture. The interthrocanteric fracture was fixed with four 7.0 mm cannulated screws. The calcaneal fracture was fixed with K wires and immobilized in a plaster. Because of this combination of injuries, although she was allowed to mobilize non weight bearing from the first week, sitting and progressive weight bearing were not permitted for six weeks. Radiographs taken at the one year showed consolidation of the hip fracture without complications. Final functional indices showed an EQ-5D VAS score of 40, EQ-5D health state index adapted to Spanish value sets of 0.493 and an Oxford Hip Score of 31. Screw fixation of an undisplaced intertrochanteric fracture in an ankylosed hip may be sufficient in some instances provided the patient remains non weight bearing for long enough.