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Objectives This study investigated the safety, clinical activity and patient-reported outcomes of patients with diffuse-type tenosynovial giant-cell tumour (dTGCT) of the soft tissue who were treated with emactuzumab, a humanised anti-colony stimulating factor 1 receptor (CSF1R) monoclonal antibody and were followed up for up to 2 years after the start of treatment. Methods In this open-label phase 1 study ( ClinicalTrials.gov NCT01494688 ), patients received intravenous (IV) emactuzumab from 900 to 2000 mg every two weeks in the dose-escalation phase and at the optimal biological dose of 1000 mg with different schedules in the dose-expansion phase. Adverse event (AE) rates and biomarker assessments from tumour biopsies were analysed. Quality of life was assessed using a standard questionnaire (EuroQol-5D-3L) and the WOMAC® 3.1 Osteoarthritis Index. Tumour responses were determined with magnetic resonance imaging. Results Altogether, 63 patients were enrolled into the study. The most frequently reported AEs were pruritus, asthenia and oedema. In 36 patients for whom biopsy tissue was available a substantial decrease of CSF1R-positive and CD68/CD163-positive macrophages was detected. The independently reviewed best overall objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors version 1.1) was 71%. Responses were durable, and an ORR of 70% and 64% was determined after one or two years after enrolment into the study. Clinical activity was accompanied by an improvement in EuroQol-5D-3L and particularly the joint disorder–specific WOMAC score. Conclusions Systemic therapy of dTGCT patients with emactuzumab resulted in pronounced and durable responses associated with symptomatic improvement and a manageable safety profile.

BackgroundThis phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).MethodsEmactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.ResultsOverall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.ConclusionEmactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Background Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. Patients and methods This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3weeks, as monotherapy or in combination with paclitaxel 80mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. Results No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000mg administered every 2weeks. Conclusions Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688)

Background Selicrelumab is a human IgG2 agonistic anti-CD40 monoclonal antibody. Binding of the antibody to CD40 expressed on antigen-presenting cells results in T- cell priming and T-cell dependent anti-tumor activity. In response to T-cell activation, tumor cells express programmed-death ligand 1 (PD-L1) that can suppress effector T-cells. Atezolizumab interrupts this feedback loop by blocking PD-L1, thereby supporting the combination with selicrelumab. Methods This phase Ib open-label, multicenter, dose escalation (DE)/expansion clinical study (NCT02304393) investigated safety, pharmacokinetic (PK), pharmacodynamics (PD) and efficacy of selicrelumab in combination with atezolizumab in unselected patients with advanced/metastatic solid tumors, not amenable to standard therapy. In DE cohorts, a single dose of selicrelumab was given, either by intravenous (IV) infusion at a 16 mg fixed dose or subcutaneously (SC) at a range from 1 to 64 mg/dose. In dose-expansion cohorts (small bowel and colorectal cancer, head and neck squamous cell carcinoma [HNSCC] and non-small cell lung carcinoma), patients received multiple doses of selicrelumab SC at a dose of 16 mg. In all treatment cohorts, patients received atezolizumab at a fixed dose of 1200 mg IV Q3W. Results In this study, 140 patients were treated. This included 95 patients in DE cohorts (6 patients in the IV cohort, 89 patients in the SC cohorts) and 45 patients in dose-expansion cohorts. In the IV cohort, infusion related reaction was the most frequent treatment-related adverse event (TRAE; 50%), while Grade ≥ 3 TRAE occurred in 1 patient (16.7%). In this cohort one dose-limiting toxicity (DLT) was reported (Grade 3 pancytopenia). In the SC cohorts, the most frequent TRAE was injection site reaction (ISR; 92%). Four DLTs were reported in four patients: three Grade 3 ISR and one Grade 3 transaminase increase. Grade ≥ 3 TRAE were reported in 22 patients (16.4%). Anti-tumor activity was observed across cohorts receiving SC selicrelumab (dose range 1 to 36 mg). Eight of 80 evaluable patients in DE cohorts experienced objective responses (9% ORR). In the dose-expansion HNSCC cohort, three of 16 evaluable patients responded (15.8% ORR). There were no objective responses in the IV cohort. Treatment with selicrelumab resulted in significant peripheral B-cell depletion and activation and CD8+ T cell proliferation. Conclusions Treatment with selicrelumab in combination with atezolizumab was well tolerated in patients with advanced solid tumors. Signals of clinical and PD activity were observed. However, efficacy of the combination in this unselected population was limited, when compared to monotherapy efficacy of atezolizumab. Trial Registration NCT02304393 Ethics Approval This study was approved by the local IRB at each participating study site.

Colony-stimulating factor 1 receptor (CSF1R) blockade abates tumor-associated macrophage (TAM) infiltrates and provides marked clinical benefits in diffuse-type tenosynovial giant cell tumors. However, facial edema is a common adverse event associated with TAM elimination in patients. In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix–remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in the mice. In patients, edema developed at doses well below the established optimal biological dose for emactuzumab, a CSF1R dimerization inhibitor. Patients who developed edema in response to emactuzumab had elevated HA in peripheral blood. Our findings indicate that an early increase of peripheral HA can serve as a pharmacodynamic marker for edema development and suggest potential interventions based on MMP inhibition for relieving periorbital edema in patients treated with CSF1R inhibitors.

More and more research data, models and software are being made accessible. This should, in principle, be of real value to the scientific community as well as decision makers, industry and wider society.However, too often the data is not particularly easy to Find, users can be left confused about terms, conditions and licences, therefore limiting Access. If a user actually manages to identify usable data that is Interoperable with other relevant datasets and services they too often report that the process is not as easy they would like it to be. All of this results in valuable, accessible data remaining unused never mind Re-used.Taking inspiration from the product design industries and applying the techniques of Service Design and User eXperience (UX) to develop user centric solutions would result in more intuitive, user relevant services that maximise the impact of making data and tools Open and FAIR.This talk will present three use cases:UK Geoenergy Observatories: a complex and challenging programme of work to develop the digital infrastructure necessary to open up all research findings from two new Geoenergy testbeds in the UK. CAMELLIA rain garden calculator: a community engagement and co-design project in which rapid software prototyping led to local residents of a South London housing estate being able to co-design a new green space with environmental scientists and funding bodies. Geospatial Commission - Data Discoverability project: an evaluation of the current geospatial data portal landscape, involving user research and a UX evaluation of exiting portals. Resulting in a report on future improvements to geospatial data portals being submitted to the UK Government Cabinet Office. This user centric, design led approach has provided developers with greater clarity on user requirements, resulting in more iterative and rapid deployments of digital services. End users, such as scientists, project managers and other stakeholders, reported a greater sense of ownership and investment in projects in which they are were throughout the research, design and development process.

The continued globalization of pharmaceutics has increased the demand for companies to know and understand the regulations that exist across the globe. One hurdle facing pharmaceutical and biotechnology companies developing new drug candidates is interpreting the current regulatory guidance documents and industry publications associated with bioanalytical method validation (BMV) from each of the different agencies throughout the world. The objective of this commentary is to provide our opinions on the best practices for reference standards and key reagents, such as metabolites and internal standards used in the support of regulated bioanalysis based on a review of current regulatory guidance documents and industry white papers for BMV.

OBJECTIVE To study the long-term recurrence rate of cholesteatoma with autoclaved incus autograft. STUDY DESIGN Prospective observational study between 1994 and 2009. The incus remnants were autoclaved at 134°C for 24 minutes at 205 kPa. The mean follow-up duration was 65.5 months, with a minimum follow-up duration of 31 months and a maximum follow-up duration of 186 months. SETTING Secondary referral center in a district general hospital. PATIENTS Thirty-seven cases of cholesteatoma treated with canal wall down mastoidectomy with primary ossicular reconstruction with autoclaved incus autograft were included. The age range of the patients was from 11 years to 67 years. The mean age was 38 years. Fifty-four percent was male, and 46% was female. INTERVENTIONS Therapeutic and rehabilitative--to treat and improve the patients' hearing loss secondary to cholesteatoma by using autoclaved autologous incus. MAIN OUTCOME MEASURES Primary end point is the recurrence rate of cholesteatoma with a mean follow-up period of more than 5 years. Secondary end point is the audiometric outcome with air-bone gap (ABG) and air conduction improvement. RESULTS No recurrence of cholesteatoma was observed. No graft extrusion was seen. Preoperative mean ABG was 29.8 dB. Postoperative mean ABG was 25.6 dB at the final review, with the air conduction improvement at final review at 4.2 dB. CONCLUSION Autoclaving the incus remnant harvested from cholesteatomatous middle ear cleft is a safe and effective method to prepare an incus autograft for primary ossicular reconstruction.

Objective: 1) To evaluate the relationship between cholesteatoma and the degree of mastoid pneumatization. 2) To assess the relationship between the location of cholesteatoma and mastoid pneumatization.Method: A prospective analysis on all patients undergoing mastoid exploration for cholesteatoma during 1993-2011 was performed. The degree of mastoid pneumatization and the site of cholesteatoma were recorded. All patients were operated on and graded by the same surgeon. Revision surgery and atticotomy, where pneumatization could not be assessed, were excluded.Results: A total of 393 (222: male, 171: female) patients underwent surgery for cholesteatoma; 203 were left sided, and 190 were right sided. The mean age of the patients was 37 years (range 6-79). Pneumatization of the mastoid was: sclerotic 23% (90), diploic 16.7% (66), and cellular 60.3% (237, P < .001), respectively. Attico-antral cholesteatoma was present in 88.9% sclerotic, 95.4% diploic, and 91.1% cellular mastoids. Middle ear (ie, sinus tympan...

Spontaneous temporal meningoencephaloceles are rare entities and diagnostic difficulties can occur. We present two cases whose presentation was atypical and diagnosis delayed by the presence of dual pathology.

Senior registrars in otolaryngology were asked to complete a questionnaire about the opportunities for training and research offered by their current post. Trainees were asked whether, in their opinion, the post complied with the SAC requirements for a training post. Completed replies were received from 53 (66%) trainees. Most trainees were fairly satisfied with their post but 26% considered that it did not meet with the ideals of a training post as laid down by the SAC. Large variations were noted between posts in the exposure to specialist clinics, own operating lists and research opportunities. Outpatient experience and, in particular, whether the trainee was able to follow up their own post-operative cases adequately appeared to be an important determinant in whether or not trainees were satisfied with their current post.

The nasal airway resistance of 15 patients with unilateral chronic otitis media and 15 controls was measured by anterior active rhinomanometry. Airway resistance was measured on each side before and after decongestion to differentiate resistance due to structural abnormality from that due to mucosal swelling. The nasal resistance was significantly greater (P less than 0.01) on the side of the affected ear in patients with unilateral chronic otitis media before decongestion, but following decongestion the difference was not significant. Nasal obstruction is a significant determinant in unilateral chronic otitis media and although septal displacement may be the underlying cause, the major component of the obstruction appears to be due to an associated mucosal oedema.

A case is described of osteochondroma of the tongue and the literature on osteomata, chondromata and osteochondromata of the tongue is reviewed. The tendency for these tumours to arise in the region of the foramen caecum has been noted in previous reports as has the female preponderance. It has been suggested that they arise from remnants of branchial arch cartilage. The variation in the duration and age at presentation of the lesion has not been explained and an alternative theory is suggested.

Unilateral secretory otitis media is a well recognized presenting feature of nasopharyngeal tumours. In the case described the underlying cause was of oncocytic metaplasia arising in the nasopharynx.

Ossicular necrosis is often associated with chronic adhesive otitis media. An unusual abnormality discovered in an incus removed during tympanoplasty is reported. The long process appears to have been grooved by pressure from the chorda tympani. An alternative theory to explain the vulnerability of the long process of the incus is suggested.

Methods of evaluation used to measure the effect of a training sequence designed to develop skilled family planning assistants and the problems inherent in training and evaluation are described. 8 American registered nurse volunteers being trained at the University of Kentucky Center for Developmental Change as Peace Corps family planning extension workers in India were taught factual knowledge of the anatomy physiology and elementary pathology of reproduction. They acquired specific technical skills in taking obstetrical and gynecological histories in performing pelvic examinations in recognizing normal and abnormal pelvic conditions and in transmitting technical information to others in a foreign language. Along with attending formal lectures the nurses examined patients at the outpatient obstetrics and gynecology clinic of the University of Kentucky Medical School and did pelvic examinations and took Papanicolaou smears of patients in State chronic disease hospitals. They spent 1 week working with the staff of the Frontier Nursing Service. To evaluate the success of the 3 months training the nurses were tested on their factual knowledge and language skills before and after the program. Teaching skills and clinical competence were subjectively rated by evaluators. The value of the training in the subsequent experiences in India was explored by an attitude questionnaire administered 3 months after they began field work in the Punjab. The evaluations indicated partial success in achieving the goal of producing medical assistants skilled in specific tasks.(AUTHORS MODIFIED)