The Development of a National Paediatric Psycho-Oncology Service.

Aims To investigate the psychological care provided to children and young adolescents with cancer and their families within the National Children's Cancer Service (NCCS), Ireland, in respect of the national and international standards of care. Methods A retrospective audit of 316 referrals made over 32 months by the NCCS to the psychology service in malignant haematology and oncology was performed. Results The audit revealed that out of 316 patients, a yearly average of 189 (50%) of urgently referred patients received psychological support within the NCCS between January 2013 and August 2016. Furthermore only 20 (22%) undergoing haematopoietic stem cell transplantation (HSCT), 14 (22%) referred to the paediatric palliative care team, and 84 (62%) of teenage patients received psychological input during this timeframe. Conclusion The audit revealed that the current psychology service provision is failing to meet the international standards of care. Due to the data provided by this audit, in conjunction with a clinical risk assessment of the service, funds for the post of principal psychologist have been secured. Further psychology posts (HSCT, late-effects and neuropsychology), and development of the psycho-oncology model of care are required to ensure equality of access and evidence-based psychological care for all children with cancer.

Changes in Multidisciplinary Tracheostomy Team Practice Over Time.

Aim Increasing numbers of tracheostomy patients are discharged from the Intensive Care Unit (ICU) to general hospital wards. There is evidence that a Multidisciplinary Tracheostomy Team (MTT) can have a positive impact on the care of tracheostomy patients discharged from the ICU. We compared tracheostomy management and patient outcome in two time periods, at the start of our MTT practice in 2009-2011 and again in 2017. Methods In a retrospective audit, we compared tracheostomy management and patient outcome in 117 patients who had a tracheostomy in 2009-2011 with 81 patients who had a tracheostomy in 2017. Results The duration of tracheostomy cannulation was significantly shorter (21 vs 31 days, p=0.0005) in 2017 compared to 2009-2011. A Mini-Trach was used after tracheostomy decannulation in 56 of the 81 (69%) tracheostomy patients in 2017. Conclusions The continued development of our MTT service over 8 years was associated with a significantly shorter duration of tracheostomy cannulation and the introduction of Mini-Trach use after tracheostomy decannulation. These results support the importance of maintaining an active MTT service to manage tracheostomy patients after discharge from the ICU.

Osteoarthritis-associated basic calcium phosphate crystals alter immune cell metabolism and promote M1 macrophage polarization.

OBJECTIVE: A number of studies have demonstrated that molecules called 'alarmins' or danger-associated molecular patterns (DAMPs), contribute to inflammatory processes in the OA joint. Metabolic reprogramming of immune cells, including macrophages, is emerging as a prominent player in determining immune cell phenotype and function. The aim of this study was to investigate if basic calcium phosphate (BCP) crystals which are OA-associated DAMPs, impact on macrophage phenotype and metabolism. METHODS: Human monocyte derived macrophages were treated with BCP crystals and expression of M1 (CXCL9, CXCL10) and M2 (MRC1, CCL13)-associated markers was assessed by real-time PCR while surface maturation marker (CD40, CD80 & CD86) expression was assessed by flow cytometry. BCP induced metabolic changes were assessed by Seahorse analysis and glycolytic marker expression (hexokinase 2(HK2), Glut1 and HIF1α) was examined using real-time PCR and immunoblotting. RESULTS: Treatment with BCP crystals upregulated mRNA levels of CXCL9 and CXCL10 while concomitantly downregulating expression of CCL13 and MRC1. Furthermore, BCP-treated macrophages enhanced surface expression of the maturation makers, CD40, CD80 and CD86. BCP-treated cells also exhibited a shift towards glycolysis as evidenced by an increased ECAR/OCR ratio and enhanced expression of the glycolytic markers, HK2, Glut1 and HIF1α. Finally, BCP-induced macrophage activation and alarmin expression was reduced in the presence of the glycolytic inhibitor, 2-DG. CONCLUSIONS: This study not only provides further insight into how OA-associated DAMPs impact on immune cell function, but also highlights metabolic reprogramming as a potential therapeutic target for calcium crystal-related arthropathies.

Growth plate extracellular matrix-derived scaffolds for large bone defect healing.

Limitations associated with demineralised bone matrix and other grafting materials have motivated the development of alternative strategies to enhance the repair of large bone defects. The growth plate (GP) of developing limbs contain a plethora of growth factors and matrix cues which contribute to long bone growth, suggesting that biomaterials derived from its extracellular matrix (ECM) may be uniquely suited to promoting bone regeneration. The goal of this study was to generate porous scaffolds from decellularised GP ECM and to evaluate their ability to enhance host mediated bone regeneration following their implantation into critically-sized rat cranial defects. The scaffolds were first assessed by culturing with primary human macrophages, which demonstrated that decellularisation resulted in reduced IL-1ß and IL-8 production. In vitro, GP derived scaffolds were found capable of supporting osteogenesis of mesenchymal stem cells via either an intramembranous or an endochondral pathway, demonstrating the intrinsic osteoinductivity of the biomaterial. Furthermore, upon implantation into cranial defects, GP derived scaffolds were observed to accelerate vessel in-growth, mineralisation and de novo bone formation. These results support the use of decellularised GP ECM as a scaffold for large bone defect regeneration.

Intra-articular basic calcium phosphate and monosodium urate crystals inhibit anti-osteoclastogenic cytokine signalling.

OBJECTIVE: Basic calcium phosphate (BCP) and monosodium urate (MSU) crystals are particulates with potent pro-inflammatory effects, associated with osteoarthritis (OA) and gout, respectively. Bone erosion, due to increased osteoclastogenesis, is a hallmark of both arthropathies and results in severe joint destruction. The aim of this study was to investigate the effect of these endogenous particulates on anti-osteoclastogenic cytokine signalling. METHODS: Human osteoclast precursors (OcP) were treated with BCP and MSU crystals prior to stimulation with Interleukin (IL-6) or Interferon (IFN-γ) and the effect on Signal Transducer and Activator of Transcription (STAT)-3 and STAT-1 activation in addition to Mitogen Activated Protein Kinase (MAPK) activation was examined by immunoblotting. Crystal-induced suppressor of cytokine signalling (SOCS) protein and SH-2 containing tyrosine phosphatase (SHP) expression was assessed by real-time polymerase chain reaction (PCR) in the presence and absence of MAPK inhibitors. RESULTS: Pre-treatment with BCP or MSU crystals for 1 h inhibited IL-6-induced STAT-3 activation in human OcP, while pre-treatment for 3 h inhibited IFN-γ-induced STAT-1 activation. Both crystals activated p38 and extracellular signal-regulated (ERK) MAPKs with BCP crystals also activating c-Jun N-terminal kinase (JNK). Inhibition of p38 counteracted the inhibitory effect of BCP and MSU crystals and restored STAT-3 phosphorylation. In contrast, STAT-1 phosphorylation was not restored by MAPK inhibition. Finally, both crystals potently induced the expression of SOCS-3 in a MAPK dependent manner, while BCP crystals also induced expression of SHP-1 and SHP-2. CONCLUSION: This study provides further insight into the pathogenic effects of endogenous particulates in joint arthropathies and demonstrates how they may contribute to bone erosion via the inhibition of anti-osteoclastogenic cytokine signalling. Potential targets to overcome these effects include p38 MAPK, SOCS-3 and SHP phosphatases.

A novel TLR2 agonist from Bordetella pertussis is a potent adjuvant that promotes protective immunity with an acellular pertussis vaccine.

Bordetella pertussis causes whooping cough, a severe and often lethal respiratory infection in infants. A recent resurgence of pertussis has been linked with waning or suboptimal immunity induced with acellular pertussis vaccines (Pa) that were introduced to most developed countries in the 1990s because of safety concerns around the use of whole-cell pertussis vaccines (Pw). Pa are composed of individual B. pertussis antigens absorbed to alum and promote strong antibody, T helper type 2 (Th2) and Th17 responses, but are less effective at inducing cellular immunity mediated by Th1 cells. In contrast, Pw, which include endogenous Toll-like receptor (TLR) agonists, induce Th1 as well as Th17 responses. Here we report the identification and characterization of novel TLR2-activating lipoproteins from B. pertussis. These proteins contain a characteristic N-terminal signal peptide that is unique to Gram-negative bacteria and we demonstrate that one of these lipoproteins, BP1569, activates murine dendritic cells and macrophages and human mononuclear cells via TLR2. Furthermore, we demonstrated that a corresponding synthetic lipopeptide LP1569 has potent immunostimulatory and adjuvant properties, capable of enhancing Th1, Th17, and IgG2a antibody responses induced in mice with an experimental Pa that conferred superior protection against B. pertussis infection than an equivalent vaccine formulated with alum.

Characteristics of epileptic episodes in UK dog breeds: an epidemiological approach.

In this study, previously unreported cohort characteristics and seizure patterns for canine epilepsy were identified from a series of UK-based epileptic dogs containing 1260 cases from 79 known pedigree breeds and a group of crossbreed dogs.

A nonlinear mixed effects IVIVC model for multi-release drug delivery systems.

The purpose of this analysis was the development of an IVIVC model, which involves a convolution step as described by O'Hara et al. and to describe a dual-release system: a controlled release formulation, which contains an initial immediate release element. Four formulations of Galantamine were used to test this modelling technique and a level A IVIVC, which meets the FDA criteria for internal and external validation, was successfully developed.

Gene expression profiles in HPV-infected head and neck cancer.

Epidemiological and laboratory evidence indicate that, in addition to tobacco and alcohol, human papillomaviruses (HPV) play an important aetiological role in a subset of head and neck squamous cell carcinoma (HNSCC). To evaluate the molecular pathogenesis of HPV-infected HNSCC, we compared gene expression patterns between HPV-positive and -negative HNSCC tumours using cDNA microarrays. Tumour tissue was collected from 42 histologically confirmed HNSCC patients from an inner-city area of New York. Total DNA and RNA were extracted and purified from frozen tumour samples and gene expression levels were compared to a universal human reference RNA standard using a 27 323 cDNA microarray chip. HPV detection and genotyping were performed using an MY09/11-PCR system and RT-PCR. HPV was detected in 29% of HNSCC tumours. Most harboured only HPV16 and expressed the HPV16-E6 oncogene. HPV prevalence was highest in pharyngeal tumours (45%). Gene expression patterns that differentiated HPV-positive from negative tumours were compared by supervised classification analysis, and a multiple-gene signature was found to predict HPV16 prevalence in primary HNSCC with a false discovery rate < 0.2. Focusing on never-smokers, we further identified a distinct subset of 123 genes that were specifically dysregulated in HPV16-positive HNSCC. Overexpressed genes in HPV-positive HNSCC tumours included the retinoblastoma-binding protein (p18), replication factor-C gene, and an E2F-dimerization partner transcription factor (TFDP2) that have also been found to be overexpressed in cervical cancer. An additional subset of genes involved in viral defence and immune response, including interleukins and interferon-induced proteins, was found to be down-regulated in HPV-positive tumours, supporting a characteristic and unique transcriptional profile in HPV-induced HNSCC.

Torsades de pointes and self-terminating ventricular fibrillation in a prescription methadone user.

Methadone is known to prolong the QT interval and precipitate torsades de pointes. A 54-year-old prescription methadone user with hypokalaemia was referred to Critical Care with acute confusion and respiratory distress. Alcohol withdrawal was the presumed precipitant. The real precipitant only became evident on analysis of a 24-h ECG (Holter monitor) attached to the patient at the time. The patient had suffered prolonged (10 min) ventricular arrhythmias including torsades de pointes and self-terminating ventricular fibrillation. The patient made a full recovery. Risk factors for acquired long QT syndrome and the treatment of torsades de pointes are discussed.

Malleostapedotomy: the Marburg experience.

BACKGROUND: The surgical procedure for patients with otosclerosis routinely is incus stapedotomy. In case of otosclerosis with incus necrosis or a bony fixation of the malleus and incus, malleostapedotomy is performed. PATIENTS AND METHODS: Between May 2002 and September 2003, malleostapedotomy was performed in 6 out of 34 patients with otosclerosis. In 2 primary cases, a middle ear dysplasia was found. The malleus was fixed in 2 further primary cases. Two revision surgeries were performed with incus necrosis present. A titanium piston was used, which was fixed at the malleus handle and introduced into an opening of the footplate. RESULTS: The preoperative air-bone gap was reduced from 36 dB(A) to 13 dB(A) after surgery for an average checkup time of 3 months. The length of the prostheses varied from 6.3 to 7.5 mm. No patient showed a hearing loss or vertigo after surgery. CONCLUSION: Malleostapedotomy is the technique of choice in case of an additional pathology of the ossicular chain in patients with otosclerosis. Larger numbers of patients and long-term investigations need to compare the results of malleostapedotomy with those of a conventional incus stapedotomy.

[State of the art of classification, diagnostics and therapy for cervicofacial hemangiomas and vascular malformations]. / "State of the Art" zur Klassifikation, Diagnostik und Therapie von zervikofazialen Hämangiomen und vaskulären Malformationen.

The successful treatment of vascular anomalies depends on profound knowledge of the biologic behavior of vascular lesions and their correct classification. On the base of the clinical course Mulliken and Glowacki developed a biologic classification that was accepted as official classification by the ISSVA (International Society for the Study of Vascular Anomalies). Based on an extended literature research, this manuscript will give an overview of different internationally accepted treatment concepts. Even if a wait-and-see strategy can be recommended in many cases of uneventful hemangiomas in infants the proliferative growth of such lesions requires an adequate treatment indication. Vascular malformations that persist lifelong require treatment in the majority of the cases, especially when clinical symptoms occur. Based on individual parameters such as the diameter, location or growth behavior, different therapeutic options as cryotherapy, corticosteroids, laser therapy, sclerotherapy, surgical intervention and/or embolisation can be performed successfully. None of those treatment concepts, however, represents the only treatment method of choice.

Teaching and assessment in otolaryngology and neurology: Does the timing of clinical courses matter?

Little is known about the effectiveness of clinical courses as a learning environment. To accurately assess performance in these courses, equal conditions for all candidates are required. We investigated the influence of the proximity of the course to the students test taking, the students' learning styles, and their self-motivation for learning in relation to performance success. One hundred and eleven students were randomized into eight groups, each attending a 2 week course in otolaryngology with a high proportion of patient-related teaching, and a 2 week long course in neurology with a low level of patient-related teaching. All students took multiple-choice end-of-term exams to assess their knowledge in both subjects. There was a different time interval between the course participation and the test taking for each of the groups. Performance success was correlated with the different groups, as well as with the type of learning style (LIST questionnaire) and with motivation for learning (study interest questionnaire). Explorative rank variance analysis showed a significant correlation between students' performance on the written exam and the time interval between completion of the neurology course and test-taking, with the shortest interval corresponding to highest scores (P = 0.002). There was no such effect on the success rate in otolaryngology (P = 0.28). Study motivation was not the major component for performance success, but a strong correlation between the use of strategic and deep learning styles and success in the exam was observed (R = 0.62; P < 0.001). The duration of time between a clinical course with little practical teaching and the students' taking of the exam plays a significant role on performance success; this effect does not occur in a course with a high proportion of practical patient-related teaching. More studies on clinical courses are needed to establish how students can be given adequate opportunities to develop necessary skills for patient care and for objective success on assessment. With such further information, the effectiveness of clinical courses as a learning experience might be enhanced.

Early supraglottic cancer: how extensive must surgical resection be, if used alone?

OBJECTIVES: Two centre based evaluations of oncologic results of endoscopic resection of supraglottic cancer without post-operative irradiation. PATIENTS AND METHODS: Twenty-six patients with clinical T1 (n=5) or T2 (n=21) primary squamous cell carcinomas of the supraglottic larynx and with N0 (n=24) or N1 (n=2) neck disease were treated by endoscopic supraglottic laryngectomy coupled with neck dissection(s). Endoscopic resection was standardized whereas neck dissections (NDs) varied from classical modified radical ND to selective ND of levels I to IV. RESULTS: Pathologically, three T2 patients were upstaged to T3, four N0 patients to N1 and one N2 patient down-staged to N1. Within an average of 42 months, there were no local failures and only one regional failure. CONCLUSIONS: Endoscopic resection of T1 and T2 supraglottic cancer without post-operative irradiation achieved good oncological results. No patients with lateralized primary cancers were found to have contralateral cancer on pathological evaluation from bilateral dissections.

Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients.

To assess the risk factor of capsular rupture for individual prognosis and potential therapeutic decision making, the present meta-analysis elaborated the prognostic significance of perinodal spread in a large group of patients suffering from head and neck squamous cell carcinomas (HNSCC). A review of the published literature was conducted, and fixed and random effects models were applied for estimation of the summarised odds ratio and 95% confidence intervals, including a test for homogeneity of the odds ratios. Study methodology allowed the enrollment of only nine studies of 115 published papers. Excluded studies lacked regarding primary tumour location, number and location of lymph node metastases, values on five-year survival, or adequate follow-up data. A summarised odds ratio of 2.7 leads to the conclusion that perinodal spread negatively impacts the five-year survival. The lower confidence limit of more than 2 also supports the concept that perinodal spread significantly reduces (doubled risk) the five-year-survival. These results support the conclusion that perinodal spread is a significant adverse risk factor for survival in patients with HNSCC.

Investigation of the medium-term effects of Olibratrade mark fat emulsion on food intake in non-obese subjects.

OBJECTIVE: To investigate the effect of Olibra fat emulsion on medium-term food intake and appetite in non-obese subjects. DESIGN: Double-blind, placebo-controlled, within-subject crossover. SETTING: University of Ulster, Coleraine. SUBJECTS: A total of 28 subjects (14 male, 14 female). INTERVENTIONS: Subjects were randomly assigned to receive either a 200 g portion of test (5 g of Olibra fat) or control (5 g milk fat) yoghurt for breakfast for 2 x 3 week 'study' phases, separated by a 3-week 'wash-out' phase. On days 1, 8 and 22 of the study phases, food intake 4 h post-consumption of the yoghurt was assessed by pre- and post-covert weighing at an ad libitum buffet-style test lunch. Throughout each of these study days, appetite was assessed using visual analogue scales (VAS) at regular intervals. For the remainder of the study days, and the following 24 h ('post-study days'), subjects reported their food intake using weighed dietary records. RESULTS: Consumption of the Olibra emulsion had no significant effect on mean energy, macronutrient or amounts of food consumed at the lunch 4 h post-consumption. Self-reported food intakes indicated that there was no significant effect of the emulsion on energy intakes for the remainder of each study day and post-study days. There was considerable individual variation in food intakes following consumption of the Olibra emulsion, with 46, 59 and 57% of subjects reducing their energy intakes at lunch on days 1, 8 and 22. There was no consistent effect of the emulsion on appetite ratings. CONCLUSIONS: In contrast to earlier studies, there was no evidence of a short- or medium-term effect of the Olibra emulsion on food intake or appetite. This could be owing to numerous confounding factors influencing eating behaviour and/or the different study design used in the present study.

Influence of matrix metalloproteinase 9 (MMP-9) on the metastatic behavior of oropharyngeal cancer.

BACKGROUND: The role of the single matrix metalloproteinases (MMPs) in the metastatic process of squamous cell carcinomas (SCC) is still obscure. MATERIALS AND METHODS: The MMP-9 expression was described immunohistochemically in 105 patients (40-79 years of age, mean: 57.84 years; 84 male, 21 female) suffering from orophatyngeal cancer (22x TI, 31x T2, 24x T3, 28x T4) with different neck stages (41x N0, 6x N1, 54x N2, 4x N3 neck). RESULTS: A significant correlation between MMP-9 expression and T stage (p < 0.05), N stage (r = 0.55, p < 0.01) and UICC stage (r = 0.55, p < 0.01) was revealed. Most remarkable was the high MMP-9 expression with simultaneously high UICC stages. CONCLUSION: The results give further indication that MMP-9 plays a role in the metastatic behavior of oropharyngeal SCC. It will be a project for the near future to create a standardized evaluation score of immuno-histological stainings to allow valid comparison of the results and published data.

Bipolar radiofrequency induced thermotherapeutic volumetric reduction of VX2 metastases in an animal model.

BACKGROUND: Radiofrequency-induced thermotherapy has shown promising results in the palliative treatment of various tumor entities. The purpose of this study was to investigate the effectiveness of bipolar radiofrequency volumetric tissue reduction (VTR) on lymph node (LN) metastases in the VX2 SCC model. MATERIALS AND METHODS: Six male New Zealand white rabbits, with palpable metastatic disease within the parotid lymph nodes, were treated using the Celon-ProSurge probe, needle length 10 mm, diameter of 2.3 mm. The animals were sacrificed on the 4th, 8th, 11th, 14th, 18th and 22nd postoperative days respectively. RESULTS AND CONCLUSION: Bipolar radiofrequency VTR could prevent progression of local metastatic disease in one-third of the animals compared to the control group of untreated VX2 carcinoma rabbits. These results encourage further studies, directed at whether this treatment modality could play a role in the palliative therapy of metastatic LN. Future studies should concentrate on the refinement of the treatment parameters and optimization of the treatment duration.

[Analysis of cost effectiveness of photodynamic therapy with Foscan (Foscan-PDT) in comparison with palliative chemotherapy in patients with advanced head-neck tumors in Germany]. / Eine Kosten-Effektivitäts-Analyse der photodynamischen Therapie mit Foscan (Foscan-PDT) im Vergleich zu einer palliativen Chemotherapie bei Patienten mit fortgeschrittenen Kopf-Halstumoren in Deutschland.

BACKGROUND: The purpose of this manuscript is to give a cost-effectiveness analysis of the photodynamic therapy by means of Foscan (Foscan-PDT) in Germany. The basis for this paper is provided by a study performed in Great Britain which analyses the costs of Foscan-PDT compared to the costs of palliative chemotherapy and to the option of no treatment in patients with advanced head and neck cancer. METHOD: In order to calculate the cost-effectiveness, an already published model developed on the base of English data was fed with German cost-data. For consideration of the different characteristics of cost-parameters as well as to minimize the over- or underestimation of the costs, sensitivity analyses were performed. RESULTS: The Foscan-PDT revealed the highest health-related effectiveness compared to all other above-mentioned options -- 129 additional days of life in comparison to no treatment or 48 days in comparison to four cycles of palliative chemotherapy. The costs per therapy of Foscan-PDT ( 8,761 euros) were lower than those of four cycles of palliative chemotherapy (11,600 euros). CONCLUSION: Foscan-PDT is a cost-effective treatment option for patients suffering from advanced head and neck cancer. For patients who up to now had only very limited treatment possibilities at their disposition, Foscan-PDT offers a chance for reduction of the tumor, remission, and a prolonged expectancy of life.

RT-PCR expression profiling of matrix metalloproteinases and their specific inhibitors in cell lines and fresh biopsies of squamous cell carcinomas of the head and neck.

The expressions of MMP2, -7, -9, -13 and TIMP1, -2, -3 were examined in biopsies and cell lines of head and neck squamous cell carcinomas (HNSCC) to determine the association between the expression profile and TNM-staging of the primary. The expressions of MMP2, -7, -9, -13 and TIMP1, -2, -3 were analyzed in 30 HNSCC biopsies, 7 HNSCC cell lines and 1 keratinocyte cell line using RT-PCR. Negative correlation was determined between N-status and MMP13-RNA expression [Kendall-tau-b -0.404 (p = 0.016), Spearman-rho -0.448 (p = 0.014)], histological grading [Kendall-tau-b -0.291 (p = 0.049), Spearman-rho -0,333 (p = 0.048)], and MMP7 and TIMP2 expression [Kendall-tau-b -0.318 (p = 0.045); Spearman-rho -0.353 (p = 0.045)]. Positive correlation was determined between M-status and MMP9-RNA expression [Kendall-tau-b 0.341 (p = 0.025), Spearman-rho 0.377 (p = 0.024)] and MMP13 and TIMP2 expression [Kendall-tau-b 0.727 (p = 0.037), Spearman-rho 0.850 (p = 0.016)]. The results point to a role of the tested MMPs and TIMPs in the metastatic spread of HNSCC.