Pathway-based subnetworks enable cross-disease biomarker discovery

Surgical oncolog

Phantom breast syndrome: The effect of in situ breast carcinoma

Phantom breast syndrome (PBS) represents the experience of the continued presence of the breast, after mastectomy. Our aim was to assess PBS appearance by means of a structured questionnaire and to look into possible associations to disease and treatment parameters, in 105 women with breast cancer treated by mastectomy. PBS was recorded in 22.9% of the patients. In the majority of cases phantom experience had the size (88.9%), shape (76.5%) and weight (64.7%) of the normal breast and was localised in the entire breast (50%). Concerning disease parameters, no association with primary tumour size (T) or lymph node status was detected, but interestingly, in situ breast cancer (DCIS) was found to be more frequently associated with PBS, compared with invasive tumours. No significant associations of PBS with previous sensory experiences of the breast, radiotherapy or systemic treatment were assessed. The results are interpreted within the frame of Melzack's theory of a neuromatrix, assuming that PBS represents the continued existence, even after amputation, of a sensory engram of the breast. The absence of infiltration in primary tumour histology, probably through an unknown pathophysiological mechanism, might play a role for the significantly higher incidence of PBS in women undergoing mastectomy for DCIS. © 2009 Elsevier Ireland Ltd

In-vitro simulation of luminal conditions for evaluation of performance of oral drug products: Choosing the appropriate test media

Background Biorelevant media for evaluation of dosage form performance in the gastrointestinal lumen were first introduced in the late 1990s. Since then, a variety of additional media have been proposed, making it now possible to simulate most regions in the gastrointestinal tract in both prandial states. However, recent work suggests that the complexity and degree of biorelevance required to predict in-vivo release varies with the drug, dosage form and dosing conditions. Objective The aim of this commentary was to establish which levels of biorelevant media are appropriate to various combinations of active pharmaceutical ingredient(s), dosage form and dosing conditions. With regard to their application, a decision tree for the selection of the appropriate biorelevant medium/media is proposed and illustrative case scenarios are provided. Additionally, media to represent the distal small intestine in both prandial states are presented. Conclusion The newly proposed levels of biorelevance and accompanying decision tree may serve as a useful tool during formulation development in order to ensure high quality, predictive performance results without unnecessary complexity of media. In future work, further specific case examples will be evolved, which will additionally address the need to take gastrointestinal passage times and type and intensity of agitation into consideration. © 2015 Elsevier B.V. All rights reserved

The application of learning algorithms in the development of natural interaction

This paper argues that natural interaction with a machine can be realized and improved by using learning algorithms. Through the use of supervised and reinforcement learning algorithms, a robot was created that can be trained to perform actions using only verbal commands. The user has complete freedom in choosing preferred commands and what actions should be linked to these commands. The combination of supervised and reinforcement learning resulted in a fundamentally different way of interaction with a robot. The way this system was set up can be used as a framework for new projects, giving designers a new tool to improve human-machine interaction

Mechanistic investigation of the negative food effect of modified release zolpidem

Aims When administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmax and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods. Methods Pharmacokinetic profiles of zolpidem are presented from a bioavailability (8 mg intravenous; 10 mg immediate release Stilnox®; 10 mg and 12.5 mg modified release Ambien® CR) and from a food effect study (12.5 mg modified release Ambien® CR). The dissolution behavior of the 12.5 mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Qgut model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction. Results It was possible to simulate the mean plasma profiles using a “middle-out” approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values < 1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations. Conclusions The present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms. © 2017 Elsevier B.V

Sharing meaning and physical activity through a tangible interactive lighting object

This paper searches to explore the relation between designing for interaction and designing for systems by building an interactive lighting object as a part of a system for sharing meaning. The reflective transformative design process with extensive user involvement resulted in creation of an interactive lamp that expresses human-inspired behaviours that can be shared with another lighting object. Different from existing studies, the sharing of meaning was explored in the interaction between the human and the product instead of merely by observation. The preliminary tests showed that shared meaning through interactive lighting behaviours were difficult to interpret to be similar on cognitive (perceptual) level. On the level of experience the object promoted shared aesthetically pleasing responses and was intriguing for users to explore and create shared valu

Fournier's gangrene: Still highly lethal

Five patients with necrotizing soft tissue infections of the perineum and scrotum are presented. There were one female and four male patients, aged from 35 to 70 years. Portals of entry were perirectal abscesses in four cases and a scrotal abscess in one case. All patients required extensive surgical debridement and intravenous broad-spectrum antibiotics. Operative debridement involved the scrotum, the perineal and inguinal area, the upper thighs and the anterior abdominal wall. One patient required transverse loop colostomy and one loop sigmoidostomy. One patient was reoperated on after inadequate drainage of a perirectal abscess. Three patients were referred to our unit after some delay, while one patient did not seek medical care until after being febrile for 2 weeks. Despite aggressive debridement, this last patient died of fulminant sepsis. Fournier's gangrene, which is not so rare as is generally considered, is still associated with a high mortality, which can be reduced only by improving medical awareness and early treatment both of the primary cause and of necrotizing fasciitis

Rich interaction: issues

The topic of this paper is rich interaction. Rich interaction borrows from tangible interaction and the concept of affordances. This is achieved through integral design of form, interaction and function of products. It is applied to interactive consumer products. A digital camera with a rich user interface (RUI) was designed and compared in a user study to a digital camera with a more conventional user interface. Several issues concerning rich interfaces are discussed

Discordance between Immunohistochemistry and Erb-B2 Receptor Tyrosine Kinase 2 mRNA to Determine Human Epidermal Growth Factor Receptor 2 Low Status for Breast Cancer

Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization assay. However, current HER2 testing methods are designed to identify HER2-amplified tumors with high expression levels. The true definition of HER2-low expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. Erb-B2 receptor tyrosine kinase 2 (ERBB2) mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI, 0.36–0.57), 0.58 (95% CI, 0.26–0.70), and 0.32 (95% CI, −0.12 to 0.75) when comparing IHC 0+ without staining versus IHC 0+ with some staining, IHC 0+ with some staining versus IHC 1+, and IHC 1+ versus IHC 2+/fluorescence in situ hybridization–negative, respectively. The results showed immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggests a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response needs to be further evaluated by prospective clinical trials. © 2022 Association for Molecular Pathology and American Society for Investigative Patholog

The Nordic SentiMag trial: a comparison of super paramagnetic iron oxide (SPIO) nanoparticles versus Tc99 and patent blue in the detection of sentinel node (SN) in patients with breast cancer and a meta-analysis of earlier studies

The aim of the study is to compare the efficacy of SPIO as a tracer in sentinel node biopsy (SNB) in breast cancer with Tc and patent blue in a multicentre prospective study and perform a meta-analysis of all published studies. It also aims to follow skin discoloration after SPIO injection and describe when and how it resolves. Totally 206 patients with early breast cancer were recruited. Tc and patent blue were administered in standard fashion. Patients were injected with SPIO (Sienna+) preoperatively. SNB was performed and detection rates were recorded for both methods. Skin discoloration was followed and documented postoperatively. Data extraction and subsequent meta-analysis of all previous studies were also performed. SN detection rates were similar between standard technique succeeded and SPIO both per patient (97.1 vs. 97.6 %, p = 0.76) as well as per node (91.3 vs. 93.3 %, p = 0.34), something which was not affected by the presence of malignancy. Concordance rates were also consistently high (98.0 % per patient and 95.9 % per node). Discoloring was present in 35.5 % of patients postoperatively, almost exclusively in breast conservation. It fades slowly and is still detectable in 8.6 % of patients after 15 months. Meta-analysis depicted similar detection rates (p = 0.71) and concordance rates (p = 0.82) per patient. However, it seems that SPIO is characterized by higher nodal retrieval (p < 0.001). SPIO is an effective method for the detection of SN in patients with breast cancer. It is comparable to the standard technique and seems to simplify logistics. Potential skin discoloration is something of consideration in patients planned for breast conservation. © 2016, The Author(s)