Evaluation of Podoplanin Expression in Hepatocellular Carcinoma Using RNAscope and Immunohistochemistry - A Preliminary Report.

BACKGROUND: Podoplanin (PDPN), a mucin-type transmembrane glycoprotein, is expressed in a variety of human cancer types, and contributes to tumor progression. Our goal was to evaluate PDPN expression in hepatocellular carcinoma (HCC) using both immunohistochemistry (IHC) and RNAscope in situ hybridization. MATERIALS AND METHODS: Twenty patients with HCC who underwent partial hepatectomy with curative intent were retrospectively analyzed. RESULTS: IHC gave positive results in 11 cases, while RNAscope assay for PDPN detected amplification in 16 cases. A significant association was noted between PDPN protein expression and histological tumor grade (p=0.036). Four cases that had negative PDPN results by RNAscope were also negative by IHC, while the remaining five cases with negative results by IHC were positive by RNAscope. A positive relationship was found between PDPN mRNA protein expression (p<0.001). CONCLUSION: Our preliminary results suggest that PDPN contributes to the malignant potential of HCC. RNAscope proved to be a more sensitive and reliable method than IHC in PDPN detection.

Mast cells in breast cancer angiogenesis.

Mast cells, accumulate in the stroma surrounding certain tumors and take part to the inflammatory reaction occurring at the periphery of the tumor. Mast cell-secreted angiogenic cytokines facilitate tumor vascularization not only by a direct effect but also by stimulating other inflammatory cells of the tumor microenvironment to release other angiogenic mediators. An increased number of mast cells have been demonstrated in angiogenesis associated with solid tumors, including breast cancer. Mast cells might act as a new target for the adjuvant treatment of breast cancer through the selective inhibition of angiogenesis, tissue remodeling and tumor promoting molecules, allowing the secretion of cytotoxic cytokines and preventing mast cell mediated immune-suppression.

Identification of crucial parameters in a mathematical multiscale model of glioblastoma growth.

Glioblastomas are highly malignant brain tumours. Mathematical models and their analysis provide a tool to support the understanding of the development of these tumours as well as the design of more effective treatment strategies. We have previously developed a multiscale model of glioblastoma progression that covers processes on the cellular and molecular scale. Here, we present a novel nutrient-dependent multiscale sensitivity analysis of this model that helps to identify those reaction parameters of the molecular interaction network that influence the tumour progression on the cellular scale the most. In particular, those parameters are identified that essentially determine tumour expansion and could be therefore used as potential therapy targets. As indicators for the success of a potential therapy target, a deceleration of the tumour expansion and a reduction of the tumour volume are employed. From the results, it can be concluded that no single parameter variation results in a less aggressive tumour. However, it can be shown that a few combined perturbations of two systematically selected parameters cause a slow-down of the tumour expansion velocity accompanied with a decrease of the tumour volume. Those parameters are primarily linked to the reactions that involve the microRNA-451 and the thereof regulated protein MO25.

A novel method for simulating the extracellular matrix in models of tumour growth.

A novel hybrid continuum-discrete model to simulate tumour growth on a cellular scale is proposed. The lattice-based spatiotemporal model consists of reaction-diffusion equations that describe interactions between cancer cells and their microenvironment. The fundamental ingredients that are typically considered are the nutrient concentration, the extracellular matrix (ECM), and matrix degrading enzymes (MDEs). The in vivo processes are very complex and occur on different levels. This in turn leads to huge computational costs. The main contribution of the present work is therefore to describe the processes on the basis of simplified mathematical approaches, which, at the same time, depict realistic results to understand the biological processes. In this work, we discuss if we have to simulate the MDE or if the degraded matrix can be estimated directly with respect to the cancer cell distribution. Additionally, we compare the results for modelling tumour growth using the common and our simplified approach, thereby demonstrating the advantages of the proposed method. Therefore, we introduce variations of the positioning of the nutrient delivering blood vessels and use different initializations of the ECM. We conclude that the novel method, which does not explicitly model the matrix degrading enzymes, provides means for a straightforward and fast implementation for modelling tumour growth.

Biophysical modeling of brain tumor progression: from unconditionally stable explicit time integration to an inverse problem with parabolic PDE constraints for model calibration.

PURPOSE: A novel unconditionally stable, explicit numerical method is introduced to the field of modeling brain cancer progression on a tissue level together with an inverse problem (IP) based on optimal control theory that allows for automated model calibration with respect to observations in clinical imaging data. METHODS: Biophysical models of cancer progression on a tissue level are in general based on the assumption that the spatiotemporal spread of cancerous cells is determined by cell division and net migration. These processes are typically described in terms of a parabolic partial differential equation (PDE). In the present work a parallelized implementation of an unconditionally stable, explicit Euler (EE(⋆)) time integration method for the solution of this PDE is detailed. The key idea of the discussed EE(⋆) method is to relax the strong stability requirement on the spectral radius of the coefficient matrix by introducing a subdivision regime for a given outer time step. The performance is related to common implicit numerical methods. To quantify the numerical error, a simplified model that has a closed form solution is considered. To allow for a systematic, phenomenological validation a novel approach for automated model calibration on the basis of observations in medical imaging data is developed. The resulting IP is based on optimal control theory and manifests as a large scale, PDE constrained optimization problem. RESULTS: The numerical error of the EE(⋆) method is at the order of standard implicit numerical methods. The computing times are well below those obtained for implicit methods and by that demonstrate efficiency. Qualitative and quantitative analysis in 12 patients demonstrates that the obtained results are in strong agreement with observations in medical imaging data. Rating simulation success in terms of the mean overlap between model predictions and manual expert segmentations yields a success rate of 75% (9 out of 12 patients). CONCLUSIONS: The discussed EE(⋆) method provides desirable features for image-based model calibration or hybrid image registration algorithms in which the model serves as a biophysical prior. This is due to (i) ease of implementation, (ii) low memory requirements, (iii) efficiency, (iv) a straightforward interface for parameter updates, and (v) the fact that the method is inherently matrix-free. The explicit time integration method is confirmed via experiments for automated model calibration. Qualitative and quantitative analysis demonstrates that the proposed framework allows for recovering observations in medical imaging data and by that phenomenological model validity.

Devices used in cardiac arrest.

Even the best conventional manual cardiopulmonary resuscitation (CPR) is highly inefficient, producing only a fraction of normal cardiac output. Over the past several decades, many therapeutic devices have been designed to improve on conventional CPR during cardiac arrest and increase the probability of survival. This article reviews several adjuncts and mechanical alternatives to conventional CPR for use during cardiac arrest. Recent clinical studies comparing conventional resuscitation techniques with the use of devices during cardiac arrest are reviewed, with a focus on clinical implications and directions for future research.

A computational multiscale model of glioblastoma growth: regulation of cell migration and proliferation via microRNA-451, LKB1 and AMPK.

A new computational multiscale model of glioblastoma growth is introduced. This model combines an agent-based model for representing processes on the cellular level with a molecular interaction network for each cell on the subcellular scale. The network is based on recently published work on the interaction of microRNA-451, LKB1 and AMPK in the regulation of glioblastoma cell migration and proliferation. We translated this network into a mathematical description by the use of 17 ordinary differential equations. In our model, we furthermore establish a link from the molecular interaction network of a single cell to cellular actions (e.g. chemotactic movement) on the microscopic level. First results demonstrate that the computational model reproduces a tumor cell development comparable to that observed in in vitro experiments.

Steroids for patients in septic shock: the results of the CORTICUS trial.

CLINICAL QUESTION: What is the role of steroids in septic shock in the emergency department? ARTICLE CHOSEN: Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24. STUDY OBJECTIVE: To assess the safety and efficacy of low-dose hydrocortisone therapy for patients with septic shock and to compare outcomes based on response to corticotropin testing.

In-silico oncology: an approximate model of brain tumor mass effect based on directly manipulated free form deformation.

PURPOSE: The present work introduces a novel method for approximating mass effect of primary brain tumors. METHODS: The spatio-temporal dynamics of cancerous cells are modeled by means of a deterministic reaction-diffusion equation. Diffusion tensor information obtained from a probabilistic diffusion tensor imaging atlas is incorporated into the model to simulate anisotropic diffusion of cancerous cells. To account for the expansive nature of the tumor, the computed net cell density of malignant cells is linked to a parametric deformation model. This mass effect model is based on the so-called directly manipulated free form deformation. Spatial correspondence between two successive simulation steps is established by tracking landmarks, which are attached to the boundary of the gross tumor volume. The movement of these landmarks is used to compute the new configuration of the control points and, hence, determines the resulting deformation. To prevent a deformation of rigid structures (i.e. the skull), fixed shielding landmarks are introduced. In a refinement step, an adaptive landmark scheme ensures a dense sampling of the tumor isosurface, which in turn allows for an appropriate representation of the tumor shape. RESULTS: The influence of different parameters on the model is demonstrated by a set of simulations. Additionally, simulation results are qualitatively compared to an exemplary set of clinical magnetic resonance images of patients diagnosed with high-grade glioma. CONCLUSIONS: Careful visual inspection of the results demonstrates the potential of the implemented model and provides first evidence that the computed approximation of tumor mass effect is sensible. The shape of diffusive brain tumors (glioblastoma multiforme) can be recovered and approximately matches the observations in real clinical data.

Perceived barriers to therapeutic hypothermia for patients resuscitated from cardiac arrest: a qualitative study of emergency department and critical care workers.

OBJECTIVE: To identify the barriers to implementation of mild therapeutic hypothermia for adult survivors of cardiac arrest. Despite scientific evidence to support therapeutic hypothermia for resuscitated cardiac arrest patients, it is inconsistently and at times inadequately used. DESIGN: Qualitative study, using semistructured interviews. SETTING: A stratified random sample of 14 sites from an established network of 43 hospitals, including both community and tertiary care centers in Southern Ontario, Canada. PARTICIPANTS: Twenty-one intensive care unit and emergency department physicians and nurses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Purposive sampling was used to interview individuals who were most likely to be involved in the implementation and evaluation of the hypothermia protocol. All interviews were conducted by telephone by a clinician and a qualitative researcher. Interviews were recorded electronically and transcribed unless the participant declined to have the interview recorded. Untranscribed interviews were recorded as field notes and as direct quotations. New interviews were conducted until thematic saturation occurred. The analysis was completed through three phases of coding. Respondents identified lack of familiarity and availability of concrete therapeutic hypothermia protocols and process issues as the most frequent barriers. Process concerns included availability of equipment, equipment costs, and high workload demands for emergency nurses. Other barriers identified were variable nursing awareness, variable staff uptake, lack of agreement with supporting evidence, lack of interdisciplinary collaboration between the intensive care unit and emergency department, lack of interprofessional education between nurses and physicians, and challenges inherent in applying an intervention infrequently. CONCLUSIONS: This study demonstrated that the systematic adoption of a new intervention, therapeutic hypothermia, is met with interdependent generic, local, and individual barriers. A working awareness of the types of barriers that exist at multiple sites will assist in targeting specific knowledge translation strategies to improve adherence to evidence-based practice.

Revisiting the intrauterine contraceptive device in adolescents.

STUDY OBJECTIVE: The purpose of this study was to report on our experience with the intrauterine contraceptive device (IUCD) in a group of properly counseled adolescents and to determine whether traditional hesitation with use in this population should be reconsidered. DESIGN: Patients who had an IUCD inserted between April 1999 and March 2003 were identified using medical records and chart review. SETTING: A single Canadian University teaching hospital supervised by a single gynecologist. PARTICIPANTS: Twenty-eight patients, 21 years of age and under, were identified. Twenty agreed to participate in the study. INTERVENTIONS: Patients were contacted by mail to inform them of the study and subsequently interviewed using a 10-minute structured phone interview that contained seven primary questions with additional follow-up questions. MAIN OUTCOME MEASURES: Duration of use, reasons for removal, side effects experienced, satisfaction with use, prior contraception. RESULT: The average age at insertion was 18.7 years, the average time of use was 19.6 months and the average number of pregnancies prior to insertion was 1.4. Seven patients (35%) had discontinued use of their IUCD prior to the interview, with an average of 13.4 months between the time of insertion and removal. The most common reason for removal was increased bleeding. The most common side effect was increased cramping. Eighty-five percent (17/20) of users were either somewhat satisfied, satisfied or very satisfied with the IUCD. CONCLUSIONS: Following pre-insertion screening for STI-related cervicitis and with consistent follow-up following insertion, IUCDs are well-tolerated by properly selected and counseled adolescents who require an easy and effective long-term method of birth control.

Hysterectomy at a Canadian tertiary care facility: results of a one year retrospective review.

BACKGROUND: The purpose of this study was to investigate the indications for and approach to hysterectomy at Kingston General Hospital (KGH), a teaching hospital affiliated with Queen's University at Kingston, Ontario. In particular, in light of current literature and government standards suggesting the superiority of vaginal versus abdominal approaches and a high number of concurrent oophorectomies, the aim was to examine the circumstances in which concurrent oophorectomies were performed and to compare abdominal and vaginal hysterectomy outcomes. METHODS: A retrospective chart audit of 372 consecutive hysterectomies performed in 2001 was completed. Data regarding patient characteristics, process of care and outcomes were collected. Data were analyzed using descriptive statistics, t-tests and linear and logistic regression. RESULTS: Average age was 48.5 years, mean body mass index (BMI) was 28.6, the mean length of stay (LOS) was 5.2 days using an abdominal approach and 3.0 days using a vaginal approach without laparoscopy. 14% of hysterectomies were performed vaginally, 5.9% were laparoscopically assisted vaginal hysterectomies and the rest were abdominal hysterectomies. The most common indication was dysfunctional or abnormal uterine bleeding (37%). The average age of those that had an oophorectomy (removal of both ovaries) was 50.8 years versus 44.3 years for those that did not (p < .05). Factors associated with LOS included surgical approach, age and the number of concurrent procedures. CONCLUSIONS: A significant reduction in LOS was found using the vaginal approach. Both the patient and the health care system may benefit from the tendency towards an increased use of vaginal hysterectomies. The audit process demonstrated the usefulness of an on-going review mechanism to examine trends associated with common surgical procedures.