A Safe Framework for Quantitative In Vivo Human Evaluation of Image Guidance.

Goal: We present a new framework for in vivo image guidance evaluation and provide a case study on robotic partial nephrectomy. Methods: This framework (called the "bystander protocol") involves two surgeons, one who solely performs the therapeutic process without image guidance, and another who solely periodically collects data to evaluate image guidance. This isolates the evaluation from the therapy, so that in-development image guidance systems can be tested without risk of negatively impacting the standard of care. We provide a case study applying this protocol in clinical cases during robotic partial nephrectomy surgery. Results: The bystander protocol was performed successfully in 6 patient cases. We find average lesion centroid localization error with our IGS system to be 6.5 mm in vivo compared to our prior result of 3.0 mm in phantoms. Conclusions: The bystander protocol is a safe, effective method for testing in-development image guidance systems in human subjects.

Simultaneous implementation of unrelated tumour sites on the MR Linac: A review of the commissioning process from a radiographer perspective and lessons learned.

INTRODUCTION: This work reports on a systematic approach to select MRI sequences, quantify inter-observer image registration variation and determine patient positioning for the clinical implementation of MR-guided adaptive radiotherapy (MRgRT) in patients with oropharyngeal (H&N) and lung cancer. METHODS: A total of 30 participants (N=10 H&N and N=10 lung cancer patients and N=10 healthy participants) were scanned on the Elekta Unity Magnetic Resonance Linear Accelerator (MRL). Participant experience questionnaires were used to determine the most appropriate positioning device for lung treatments and tolerability of H&N immobilization devices within the confined MR Linac environment. Visual guided assessments (VGAs) completed by three observers (one oncologist and two radiographers) were used to determine the most suitable tissue weighting (using vendor-provided 3D T1w and T2w sequences) for online image registration. Offline MRI to CT and MRI to MRI rigid registrations were undertaken by nine radiographers using bony and soft tissue matching. Single-factor ANOVA and paired t-tests were utilized to determine the interobserver variation. RESULTS: Based on oncologist and patient feedback, lung cancer patients would be treated in a vac-bag with their arms by their sides, while H&N cancer patients would be immobilized using a 5-point fixation device and 5-point personalized thermoplastic shell. There was no clear preference for T1w or T2w images in the H&N cohort. However, observers preferred T2w sequences for tumour and organ at risk (OAR) visualization in the lung images. When a bony match was conducted, single-factor ANOVA tests showed no statistically significant differences between all H&N image registration types (p=0.09). For the soft-tissue registrations, T1w-CT and T1w-T1w registrations showed a statistically significant (p=0.01) reduction in inter-observer variability over T2w-CT registrations. Paired t-tests showed no statistically significant differences for bony or soft tissue matches using T1w or T2w sequences to the planning CT in the lung cohorts (p=0.63 and p=0.52, respectively). CONCLUSION: We describe the systematic approach to the selection of strategies for imaging, immobilization, and online image registration we used for H&N and lung cancer treatments on the MRL. This has facilitated the selection of the most appropriate adaptive MRgRT strategies for treating these sites at our institution.

Targeting Epilepsy Through the Foremen Ovale: How Many Helical Needles are Needed?

Laser ablation of the hippocampus offers medically refractory epilepsy patients an alternative to invasive surgeries. Emerging commercial solutions deliver the ablator through a burr hole in the back of the head. We recently introduced a new access path through the foremen ovale, using a helical needle, which minimizes the amount of healthy brain tissue the needle must pass through on its way to the hippocampus, and also enables the needle to follow the medial axis of the hippocampus more closely. In this paper, we investigate whether helical needles should be designed and fabricated on a patient-specific basis as we had previously proposed, or whether a small collection of pre-defined needle shapes can apply across many patients. We propose a new optimization strategy to determine this needle set using patient data, and investigate the accuracy with which these needles can reach the the medial axis of the hippocampus. We find that three basic tube shapes (mirrored as necessary for left vs. right hippocampi) are all that is required, across 20 patient datasets (obtained from 10 patient CT scans), to reduce worst-case maximum error below 2 mm.

Toward Practical and Accurate Touch-Based Image Guidance for Robotic Partial Nephrectomy.

Partial nephrectomy involves removing a tumor while sparing surrounding healthy kidney tissue. Compared to total kidney removal, partial nephrectomy improves outcomes for patients but is underutilized because it is challenging to accomplish minimally invasively, requiring accurate spatial awareness of unseen subsurface anatomy. Image guidance can enhance spatial awareness by displaying a 3D model of anatomical relationships derived from medical imaging information. It has been qualitatively suggested that the da Vinci robot is well suited to facilitate image guidance through touch-based registration. In this paper we validate and advance this concept toward real-world use in several important ways. First, we contribute the first quantitative accuracy evaluation of touch-based registration with the da Vinci. Next, we demonstrate real-time touch-based registration and display of medical images for the first time. Lastly, we perform the first experiments validating use of touch-based image guidance to improve a surgeon's ability to localize subsurface anatomical features in a geometrically realistic phantom.

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway.

Deleted in bladder cancer 1 (DBC1) is a candidate gene for the bladder tumour suppressor locus at 9q33.1. The function of the gene is currently unknown but a cross-species sequence comparison suggests an important role, as it is highly evolutionarily conserved. Here, we transfected a nonexpressing human bladder cancer cell line with a set of human DBC1 cDNA constructs. The effect on global expression patterns was assessed using cDNA microarrays. The cell clone with the lowest level of DBC1 expression showed induced expression of 26 genes including plasminogen activator inhibitor 2 (SERPINB5; 4.6-fold), heparin-binding EGF-like growth factor precursor (DTR; 4.2-fold), small proline-rich protein 2B (SPRR2B; 3.6-fold), metallothionein 1 isoforms (MT1B/MT1A/MT-1F; from 2.9- to 3.2-fold), tissue-type plasminogen activator precursor (PLAT; 2.8-fold) and urokinase-type plasminogen activator precursor (PLAU; 2.7-fold). In clustering analysis, both PLAT and PLAU clustered with the functionally related urokinase plasminogen activator surface receptor (PLAUR; 1.9-fold). Furthermore, 14 human bladder tumours were analysed by real-time quantitative PCR using gene-specific primers for selected (n=20) genes. The expression levels of SERPINB5, PLAU, PLAUR and MT1 correlated with the DBC1 levels, suggesting previously unknown involvement of DBC1 in the urokinase-plasminogen pathway.

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway.

The CDKN2A locus is frequently inactivated in urothelial cell carcinoma (UCC), yet how this alteration contributes to bladder tumorigenesis is not known. Although most UCC express telomerase, inactivation of the p16/Rb pathway is generally required for in vitro immortalisation. This and the involvement of p16 in senescence of normal human urothelial cells (NHUC) suggest that CDKN2A deletion may aid bypass of senescence and allow immortalisation. CDKN2A encodes p16 and p14ARF and therefore inactivation of this locus can disrupt both the Rb and p53 tumour suppressor pathways. Retrovirus-mediated transduction was used to specifically modulate the p16/Rb and/or p53 tumour suppressor pathways in NHUC and to express human telomerase reverse transcriptase (hTERT). Expression of hTERT bypassed Rb and p53 pathway-dependent barriers to proliferation and immortalised NHUC. TERT-NHUC had normal karyotypes, were non-tumorigenic and unexpectedly retained CDKN2A. Thus, the phenotypic significance of inactivation of CDKN2A in UCC may not be solely related to bypass of senescence. Phenotypic assays in human urothelial cells have relied on cell strains derived from invasive tumours or NHUC immortalised by expression of SV40-large T. The production of genetically normal but immortal NHUC lines now provides a valuable platform for experiments to examine the timing and combination of events necessary for UCC tumorigenesis.

Optimization of Curvilinear Needle Trajectories for Transforamenal Hippocampotomy.

BACKGROUND: The recent development of MRI-guided laser-induced thermal therapy (LITT) offers a minimally invasive alternative to craniotomies performed for tumor resection or for amygdalohippocampectomy to control seizure disorders. Current LITT therapies rely on linear stereotactic trajectories that mandate twist-drill entry into the skull and potentially long approaches traversing healthy brain. The use of robotically-driven, telescoping, curved needles has the potential to reduce procedure invasiveness by tailoring trajectories to the curved shape of the ablated structure and by enabling access through natural orifices. OBJECTIVE: To investigate the feasibility of using a concentric tube robot to access the hippocampus through the foramen ovale to deliver thermal therapy and thereby provide a percutaneous treatment for epilepsy without drilling the skull. METHODS: The skull and both hippocampi were segmented from dual CT/MR image volumes for 10 patients. For each of the 20 hippocampi, a concentric tube robot was designed and optimized to traverse a trajectory from the foramen ovale to and through the hippocampus from head to tail. RESULTS: Across all 20 cases, the mean distances (error) between hippocampus medial axis and backbone of the needle were 0.55 mm, 1.11 mm, and 1.66 mm for best, mean, and worst case, respectively. CONCLUSION: These curvilinear trajectories would provide accurate transforamenal delivery of an ablation probe to typical hippocampus volumes. This strategy has the potential to both decrease the invasiveness of the procedure and increase the completeness of hippocampal ablation.

Removal of C-spine protection by A&E triage nurses: a prospective trial of a clinical decision making instrument.

OBJECTIVE: To investigate if triage nurses could safely apply a set of clinical criteria, removing hard collars and spinal boards at initial triage assessment. METHODS: The Nexus clinical decision rules were applied by trained triage nurses to patients who attended the department with cervical collars and/or on spinal boards. Patients were excluded if they were felt to be in need of immediate medical assessment. Data were collected on the time to nursing assessment, time to medical assessment and time spent restrained. Patients were followed up until discharge and their radiological diagnosis confirmed. Hospital records were checked to ensure that no patients re-presented with injuries that had been missed at initial assessment. RESULTS: In total, 112 patients were included in the study. Clinical criteria were met in 59 patients and their collar removed at triage assessment. For low risk patients, this reflects a mean reduction in time spent restrained of 23.3 minutes (p<0.005; 95% confidence interval 20.18 to 26.54). No patient who had a collar removed was found to have a significant injury. CONCLUSIONS: Simple criteria can be applied by accident and emergency triage nurses to allow safe removal of cervical collars and spinal boards. The reduced time patients spent immobilised represents an important improvement in patient care.

High fidelity, low cost moulage as a valid simulation tool to improve burns education.

Simulation allows the opportunity for repeated practice in controlled, safe conditions. Moulage uses materials such as makeup to simulate clinical presentations. Moulage fidelity can be assessed by face validity (realism) and content validity (appropriateness). The aim of this project is to compare the fidelity of professional moulage to non-professional moulage in the context of a burns management course. Four actors were randomly assigned to a professional make-up artist or a course faculty member for moulage preparation such that two actors were in each group. Participants completed the actor-based burn management scenarios and answered a ten-question Likert-scale questionnaire on face and content validity. Mean scores and a linear mixed effects model were used to compare professional and non-professional moulage. Cronbach's alpha assessed internal consistency. Twenty participants experienced three out of four scenarios and at the end of the course completed a total of 60 questionnaires. Professional moulage had higher average ratings for face (4.30 v 3.80; p=0.11) and content (4.30 v 4.00; p=0.06) validity. Internal consistency of face (α=0.91) and content (α=0.85) validity questions was very good. The fidelity of professionally prepared moulage, as assessed by content validity, was higher than non-professionally prepared moulage. We have shown that using professional techniques and low cost materials we can prepare quality high fidelity moulage simulations.

Negative regulation of G(1)/S transition by the candidate bladder tumour suppressor gene DBCCR1.

Deletion of all or part of chromosome 9q is the most common genetic alteration in all stages and grades of bladder cancer. DBCCR1 (deleted in bladder cancer chromosome region candidate 1) maps to the chromosome region 9q32-33, a candidate tumour suppressor locus for bladder cancer. Although no mutations of DBCCR1 have been detected in bladder tumours, expression of DBCCR1 is silenced by promoter hypermethylation in 50% of bladder cancer cell lines analysed. Here we sought to provide functional evidence to authenticate DBCCR1 as a tumour suppressor using gene-transfer methods. Exogenous expression of DBCCR1 protein or an HA epitope-tagged fusion protein, HA-DBCCR1 in NIH3T3 cells and human bladder tumour cell lines resulted in suppression of proliferation. Cell cycle analyses in NIH3T3 cells revealed that DBCCR1-mediated growth inhibition was due to an increase in the number of cells in the G(1) phase of the cell cycle. The levels of apoptosis were not altered. These results demonstrate a role for DBCCR1 in cell cycle control, thereby supporting the hypothesis that this is the tumour suppressor gene targeted by 9q32-33 deletion in bladder cancer.

Prediction of outcome in acute renal failure by discriminant analysis of clinical variables.

To define factors of prognostic importance in patients with acute renal failure, we studied 23 clinical variables (including preexisting conditions, the acute clinical setting, and complications) by univariate and multivariate analysis in 148 patients. Ten variables contributed to discrimination in the overall analysis. Using a function derived by stepwise discriminant analysis, death could be predicted with a positive predictive value of 100% and a sensitivity of 58%. The performance of this discriminant score was validated in a subsequent group of 113 patients with a positive predictive value of 100% and a sensitivity of 26%. Thus, a fatal outcome of acute renal failure can be accurately predicted in a considerable proportion of patients by a weighted evaluation of clinical variables. The discriminant score may be useful in comparing the severity of illness among series of patients with acute renal failure.

Prehospital care in Indonesia.

BACKGROUND: Indonesia is a huge, diverse, and developing country that until recently had no public ambulance service let alone a system of prehospital care. It commonly experiences many natural disasters, manmade conflicts, and violence as well as the daily emergencies seen worldwide. CURRENT SYSTEM: Hospitals of varying standards are widespread but have no system of emergency ambulance or patient retrieval. Indonesia's only public emergency ambulance service, 118, is based in five of the biggest cities and is leading the way in paramedic training and prehospital care. CHALLENGES AND DEVELOPMENTS: There are many challenges faced including the culture of acceptance, vast geographical areas, traffic, inadequate numbers of ambulances, and access to quality training resources. Recently there have been a number of encouraging developments including setting up of a disaster response brigade, better provision of ambulances, and development of paramedic training. CONCLUSIONS: An integrated national regionalised hospital and prehospital system may seem fantastic but with the enthusiasm of those involved and perhaps some help from countries with access to training resources it may not be an unrealistic goal.

Abnormal brachial artery flow-mediated vasodilation in young adults with major depression.

Depressive illness in patients without traditional risk factors for coronary artery disease is associated with striking abnormalities of endothelial function and elevation of circulating markers of atherosclerosis propensity. Further studies are needed to define the mechanisms that underlie these observations.

The use of corticosteroids encapsulated in erythrocytes in the treatment of adjuvant induced arthritis in the rat.

Corticosteroid esters have been encapsulated into intact erythrocytes and used as an intravenous treatment for adjuvant induced arthritis in the rat. The treatment consisted of injections of the encapsulated steroids with the effects monitored for up to 14 days. On an equivalent weight basis both encapsulated cortisol-21-phosphate and prednisolone-21-sodium hemisuccinate proved superior to the free steroid esters administered in solution by injection.

Encapsulation of drugs in intact erythrocytes: an intravenous delivery system.

A number of drugs and the plasma antiprotease alpha 1-antitrypsin has been encapsulated in intact erythrocytes after hypotonic swelling, using a technique designed to preserve the viability of the cells. By labelling the cells with fluorescein isothiocyanate it has been shown that the cells survive exceptionally well when returned to the animal's circulation. Cell survival has been demonstrated in the rat, rabbit and guinea-pig. With encapsulation of cortisol-21-phosphate and methotrexate it was found that blood levels of the drug were maintained for a longer period than when the free drug was administered. Cortisol-21-phosphate was hydrolysed enzymatically by acid phosphatase located primarily in the erythrocyte membrane. An in vitro test involving the interaction or erythrocytes with phagocytes was developed to determine the viability or erythrocytes after being subjected to the encapsulation process. Preparations which did not interact with phagocytes survived when returned to the animal's circulation. The encapsulation procedure increased the fragility of the cell membrane compared to that of normal cells as measured by the leakage of haemoglobin after thermal treatment but it was found that encapsulated cortisol-21-phosphate in cells actually stabilized the membrane. The electrical charge on the membrane of encapsulating cells was the same as that of the normal cells. The charge on reformed ghosts was lower than that of normal cells. Reformed ghosts were rapidly removed when introduced into the circulation. The encapsulation procedure and its possible applications are discussed.

Assessment of the Glycotronic C blood glucose meter.

The performance of the Glycotronic C blood glucose meter, a pocket sized glucose strip meter, was assessed on the ward and in the laboratory. Theoretically there is a relation between blood glucose concentration, plasma glucose concentration and haematocrit when glucose is measured using conventional methods. The Glycotronic C meter would yield results about 20% greater than those of a conventional instrument when used to measure plasma glucose and about 15% less than a conventional instrument when used to measure the blood glucose concentration of a neonate. The Glycotronic C is easy to use and gives an acceptable performance for near patient use; it compares well with its current British competitors.

Effects of long-chain fatty acids on human urothelial cells in organ culture.

It has been suggested that tumour-derived cells are differentially sensitive to the anti-proliferative and cytotoxic effects of long chain n-3 and n-6 polyunsaturated fatty acids (PuFAs). We have previously shown that PuFAs are also growth suppressive to highly proliferative normal human urinary bladder uro-epithelial (NHU) cells grown in monolayer culture. To determine if the effects on NHU cells are directly related to the proliferative index, we have studied the effects of long chain fatty acids in a bladder organ culture system, where proliferation and differentiation of the urothelium is under homeostatic control. A 50 microM concentration of fatty acids was chosen as this concentration of PuFA was profoundly growth inhibitory to NHU cells in monolayer culture. In organ culture, 50 microM PuFAs had no detectable effect on the proliferation or on the preservation of urothelial differentiated histioarchitecture, as assessed using a panel of phenotypic markers. These results suggest that the effects of PuFA may be modulated by the tissue microenvironment.

A comparison of four commercial systems used to measure whole-body electrical impedance.

Four commercial whole-body impedance measuring systems (Holtain, RJL, Bodystat and EZcomp) were compared on two separate occasions for a group of normal subjects. The first set of readings in 21 subjects demonstrated a significant difference of approximately 6% between the Holtain measurement and the higher readings from the Bodystat or RJL systems. The differences between the RJL and Bodystat readings were much less (mean difference 0.6%). Similar differences between the Holtain and EZcomp or Bodystat measurements were demonstrated on a second occasion for a group of 11 subjects. Given that these devices operate by supplying a constant current, the differences may be explained by the results from a series of measurements on a whole-body resistance simulator in which it appears that for skin contact resistance > 200 omega the Holtain device is unable to sustain a constant current and therefore records a lower impedance than the true value.