Simultaneous automatic scoring and co-registration of hormone receptors in tumour areas in whole slide images of breast cancer tissue slides

Aims: Automation of downstream analysis may offer many potential benefits to routine histopathology. One area of interest for automation is in the scoring of multiple immunohistochemical markers in order to predict the patient's response to targeted therapies. Automated serial slide analysis of this kind requires robust registration to identify common tissue regions across sections. We present an automated method for co-localised scoring of Estrogen Receptor and Progesterone Receptor (ER/PR) in breast cancer core biopsies using whole slide images. Methods and Results: Regions of tumour in a series of fifty consecutive breast core biopsies were identified by annotation on H&E whole slide images. Sequentially cut immunohistochemical stained sections were scored manually, before being digitally scanned and then exported into JPEG 2000 format. A two-stage registration process was performed to identify the annotated regions of interest in the immunohistochemistry sections, which were then scored using the Allred system. Overall correlation between manual and automated scoring for ER and PR was 0.944 and 0.883 respectively, with 90% of ER and 80% of PR scores within in one point or less of agreement. Conclusions: This proof of principle study indicates slide registration can be used as a basis for automation of the downstream analysis for clinically relevant biomarkers in the majority of cases. The approach is likely to be improved by implantation of safeguarding analysis steps post registration

Standard classification of expense

Adopted November 11th, 1920. The basic costs to be ascertained were warehouse, direct shipment and indirect shipment. The total expense of doing business includes all three of these factors. The Committee discussed at length the advisability of following the plan of some cost systems which start with the invoiced unit cost, and then load this with the burden of expense incurred during transit through the various processes involved in filling an order. In following such a procedure, overhead is naturally assessed on a basis of price per pound or some similar unit, but we found the units in a paper warehouse differed so in character that it would be impracticable to follow such a plan. For instance, it developed that some paper warehouses handled not only the various kinds of paper, but ice cream cones, butter dishes, clothes lines, matches, hammocks, automobile tires, etc. For this reason, and also because the majority of houses kept no record of sales and purchases on a tonnage basis, it was found impracticable to operate the system in its initial stages on a price per pound basis. Therefore the only easy, workable method was to operate on a percentage of sales, and the system was devised along this line. Original item in Box no. 040

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Improving trial recruitment through improved communication about patient and public involvement : an embedded cluster randomised recruitment trial

Background: Evidence is emerging that patient and public involvement in research (PPIR) may improve recruitment into randomised controlled trials, but the best methods to achieve improvement are unclear. Although many trials use PPIR to improve design and conduct, many do not communicate their use of PPIR clearly to potential participants. Directly communicating PPIR might encourage participation through increased patient confidence and trust in a trial. We aimed to develop and evaluate the impact on recruitment an intervention communicating PPIR in a trial to potential participants. Methods: This study was embedded in EQUIP, a cluster randomised controlled trial which allocated mental health teams in England to either a training intervention group to improve service user and carer involvement in care planning, or to a control group (no training). We conducted a cluster randomised trial of a recruitment intervention communicating PPIR, embedded within the EQUIP trial. The principles underlying the intervention were informed by a systematic review and a workshop that included mental health service users and trialists. Working with EQUIP PPIR partners (service users and carers) we developed the intervention using a leaflet to advertise the nature and function of the PPIR. Professional graphic design optimised readability and impact. Patients identified as potentially eligible for EQUIP were randomised to receive the leaflet or not, alongside the standard trial information. The primary outcome was the proportion of participants enrolled in EQUIP. The secondary outcome was the proportion expressing interest in taking part. Results: 34 clusters (mental health teams) were recruited, and 8182 potential participants were randomised. Preliminary analyses show that for the primary outcome, 4% of patients receiving the PPIR leaflet were enrolled vs. 5.3% in the control group. For the secondary outcome 7.3% of potential participants receiving the PPIR leaflet responded positively to the invitation to participate, vs. 7.9% in the control group. Future analyses will be by intention-to-treat and use logistic regression to estimate between-group odds ratios (ORs) and corresponding 95% confidence intervals. A planned secondary analysis will explore whether the impact of the intervention is moderated by age and gender. Conclusion: In preliminary analysis of this large trial, communicating PPIR demonstrated no benefits for improving the numbers of potential participants expressing interest in the trial, and reduced trial enrolment. Our findings contrast with the literature suggesting PPIR benefits recruitment. We will discuss the potential reasons for this finding, along with implications for future recruitment practice and research

Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study

© The Author(s), 2018. Background: Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Objective: Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. Methods: In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). Results: A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24—end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. Conclusion: Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged

Design of a Pseudo-Holographic Distributed Time-of-Flight Sonar Range-Imaging System

The design of an audible sonar distributed sensor time-of-flight range imaging system is investigated, sonar being chosen as a substitute for optical range imaging due to cost and simplicity of implementation. The distributed range imaging system proposed is based on the holographic principle where the sensors detect the self interference of the reflected sound from the scene, and the Fourier analysis computes the reflected object profile. An approximate linearised model used in related holographic imaging techniques is found to be inappropriate for the design, and qualitative assessment of simulations show that removing the linearisation dramatically improves image reconstruction. Quantitatively the nonlinear reconstruction improves the RMSE by a factor of 1.3-2.1 times. The full nonlinear reconstruction is slow, and mathematical development lead to 15 fold reduction in computation time

Feature integration in natural language concepts

Two experiments measured the joint influence of three key sets of semantic features on the frequency with which artifacts (Experiment 1) or plants and creatures (Experiment 2) were categorized in familiar categories. For artifacts, current function outweighed both originally intended function and current appearance. For biological kinds, appearance and behavior, an inner biological function, and appearance and behavior of offspring all had similarly strong effects on categorization. The data were analyzed to determine whether an independent cue model or an interactive model best accounted for how the effects of the three feature sets combined. Feature integration was found to be additive for artifacts but interactive for biological kinds. In keeping with this, membership in contrasting artifact categories tended to be superadditive, indicating overlapping categories, whereas for biological kinds, it was subadditive, indicating conceptual gaps between categories. It is argued that the results underline a key domain difference between artifact and biological concepts

Antibody to aquaporin-4 in the long-term course of neuromyelitis optica

Neuromyelitis optica (NMO) is a severe inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the spinal cord and optic nerves. Recently, a highly specific serum reactivity to CNS microvessels, subpia and Virchow–Robin spaces was described in patients with NMO [called NMO–IgG (NMO–immunoglobulin G)]. Subsequently, aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Strong support for a pathogenic role of the antibody would come from studies demonstrating a correlation between AQP4-Ab (AQP4-antibody) titres and the clinical course of disease. In this study, we determined AQP4-Ab serum levels in 96 samples from eight NMO–IgG positive patients (median follow-up 62 months) in a newly developed fluorescence-based immunoprecipitation assay employing recombinant human AQP4. We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates. Our results demonstrate a strong relationship between AQP4-Abs and clinical state, and support the hypothesis that these antibodies are involved in the pathogenesis of NMO