Molecular markers for urothelial bladder cancer prognosis: Toward implementation in clinical practice

ObjectivesTo summarize the current status of clinicopathological and molecular markers for the prediction of recurrence or progression or both in non–muscle-invasive and survival in muscle-invasive urothelial bladder cancer, to address the reproducibility of pathology and molecular markers, and to provide directions toward implementation of molecular markers in future clinical decision making.Methods and materialsImmunohistochemistry, gene signatures, and FGFR3-based molecular grading were used as molecular examples focussing on prognostics and issues related to robustness of pathological and molecular assays.ResultsThe role of molecular markers to predict recurrence is limited, as clinical variables are currently more important. The prediction of progression and survival using molecular markers holds considerable promise. Despite a plethora of prognostic (clinical and molecular) marker studies, reproducibility of pathology and molecular assays has been understudied, and lack of reproducibility is probably the main reason that individual prediction of disease outcome is currently not reliable.ConclusionsMolecular markers are promising to predict progression and survival, but not recurrence. However, none of these are used in the daily clinical routine because of reproducibility issues. Future studies should focus on reproducibility of marker assessment and consistency of study results by incorporating scoring systems to reduce heterogeneity of reporting. This may ultimately lead to incorporation of molecular markers in clinical practice.     

Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET

Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [(11)C]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [(11)C]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [(11)C]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [(11)C]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [(11)C]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [(11)C]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.     

The Target for Statins,HMG-CoA Reductase,Is Expressed in Ductal Carcinoma-In Situ and May Predict Patient Response to Radiotherapy

Background

Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benefit from radiotherapy is warranted. Statins have been suggested to exert radio-sensitizing effects. The target for cholesterol-lowering statins is HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. The aim of this study was to examine HMGCR expression in DCIS and study its treatment predictive value.

Methods

A population-based cohort including 458 women diagnosed with primary DCIS between 1986 and 2004 were followed until November 2011 to study long-term survival. Tumor tissue microarrays were constructed, and immunohistochemical analyses were performed to detect cytoplasmic protein expression of HMGCR. The association between DCIS HMGCR expression and invasive breast cancer recurrence-free survival (RFS_inv) and overall survival (OS) was analyzed by Kaplan–Meier curves, log rank test, and Cox proportional hazard analysis.

Results

HMGCR was strongly expressed in 24 % of the assessed DCIS samples, moderately expressed in 46 %, and weakly expressed in 23 %; no expression was detected in 7 % of the samples. During the follow-up time (median 13.8 years), 61 patients were diagnosed with an invasive breast cancer recurrence, and 80 patients died. A crude analysis showed no survival benefit from radiotherapy. However, patients with strong HMGCR expression showed an improved RFS_inv (log rank, p = 0.03) and OS (log rank, p = 0.04) after radiotherapy. No statistically significant interaction was observed for HMGCR and radiotherapy (RFS_inv p = 0.69 and OS p = 0.29).

Conclusions

This study demonstrates HMGCR expression in DCIS and suggests HMGCR as a predictive marker of response to postoperative radiotherapy in DCIS, although the test for interaction was nonsignificant. Future DCIS studies addressing the potential of statin treatment targeting HMGCR are warranted.     

Visual field findings after a ruptured intracranial aneurysm

Background

Visual field defects (VFDs) negatively affect activities of daily living and rehabilitation following aneurysmal subarachnoid haemorrhage (aSAH). The aim here was to assess VFDs in patients with aSAH and their associations with age, gender, aSAH severity, and clinical outcome.

Methods

Patients admitted to Helsinki University Central Hospital and treated during 2011 were participants in this prospective study. Findings obtained with the Octopus 900 perimeter (Haag-Streit Inc, Koenic, Switzerland), the Goldmann perimeter (Haag-Streit Inc, Bern, Switzerland), or the confrontation visual field test on admission and 3 days, 14 days, 2 to 4 months, and 6 months postoperatively were assigned to 16 classes. Associations between post-chiasmal VFDs and relevant clinical, radiological, and demographic data were analysed with uni- and multivariate logistic regression.

Results

Of 105 survivors at 6 months, 20 (19 %) had VFDs occurring for aneurysm- or operation-related reasons; homonymous hemianopias or quadrantanopias were the most common finding, occurring in 16 patients (15 %). Posterior ischaemic optic neuropathy presented in two patients (2 %). Ten survivors (10 %) no longer fulfilled visual field requirements for driving licences. Significant associations emerged between VFDs at 6 months and the Hunt and Hess (H&H), World Federation of Neurosurgical Societies (WFNS), and Fisher grades on admission, presence of intracerebral haemorrhage (ICH), hydrocephalus, or postoperative infarction, and higher modified Rankin Scale scores at 6 months. Multivariate logistic regression showed the H&H grade and presence of ICH to independently predict VFDs.

Conclusions

Assessing VFDs is advisable, especially among patients with poor-grade aSAH (H&H grade IV or V) and ICH.     

Primärversorgung penetrierender Verletzungen

Blast injuries may result from a variety of causes but the biomechanical impact and pathophysiological consequences do not differ between domestic or industrial accidents or even terrorist attacks. However, this differentiation relevantly affects the tactical procedures of the rescue teams. Focusing on further detonations, top priority is given to the personal safety of all rescue workers. The rareness of blast injuries in a civilian setting results in a lack of experience on the one hand but on the other hand the complexity of blast injuries to the human body places high demands on the knowledge and skills of the entire rescue team for competent treatment. The purpose of this article is to explain the physicochemical principles of explosions and to convey tactical and medical knowledge to emergency medical services.     

Friedrich Berthold Reinke (1862–1919)

The 95th anniversary of the anatomist Friedrich Berthold Reinke’s death is 19 May 2014. This an excellent moment to remember his anatomical research. Two structures which he discovered and first described continue to be associated with his name: Reinke crystals of testicular Leydig cells and Reinke’s space in the larynx. Reinke’s crystals are crystalline protein aggregates within interstitial Leydig cells which are probably associated with testosterone production. They are pathognomonic for Leydig cell tumours.     

Training of goal directed arm movements with motion interactive video games in children with cerebral palsy – A kinematic evaluation

Objective: The main aim of this study was to evaluate the quality of goal-directed arm movements in 15 children with cerebral palsy (CP) following four weeks of home-based training with motion interactive video games. A further aim was to investigate the applicability and characteristics of kinematic parameters in a virtual context in comparison to a physical context.

Method: Kinematics and kinetics were captured while the children performed arm movements directed towards both virtual and physical targets.

Results: The children’s movement precision improved, their centre of pressure paths decreased, as did the variability in maximal shoulder angles when reaching for virtual objects. Transfer to a situation with physical targets was mainly indicated by increased movement smoothness.

Conclusion: Training with motion interactive games seems to improve arm motor control in children with CP. The results highlight the importance of considering both the context and the task itself when investigating kinematic parameters.