Targeting the tumour microenvironment in platinum-resistant ovarian cancer.

Ovarian cancer typically presents at an advanced stage, and although the majority of cases initially respond well to platinum-based therapies, chemoresistance almost always occurs leading to a poor long-term prognosis. While various cellular autonomous mechanisms contribute to intrinsic or acquired platinum resistance, the tumour microenvironment (TME) plays a central role in resistance to therapy and disease progression by providing cancer stem cell niches, promoting tumour cell metabolic reprogramming, reducing chemotherapy drug perfusion and promoting an immunosuppressive environment. As such, the TME is an attractive therapeutic target which has been the focus of intense research in recent years. This review provides an overview of the unique ovarian cancer TME and its role in disease progression and therapy resistance, highlighting some of the latest preclinical and clinical data on TME-targeted therapies. In particular, it focuses on strategies targeting cancer-associated fibroblasts, tumour-associated macrophages, cancer stem cells and cancer cell metabolic vulnerabilities.

Patients with perianal Crohn's fistulas experience delays in accessing anti-TNF therapy due to slow recognition, diagnosis and integration of specialist services: lessons learned from three referral centres.

AIM: Crohn's anal fistula should be managed by a multidisciplinary team. There is no clearly defined 'patient pathway' from presentation to treatment. The aim of this study was to describe the patient route from presentation with symptomatic Crohn's anal fistula to starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Case note review was undertaken at three hospitals with established inflammatory bowel disease services. Patients with Crohn's anal fistula presenting between 2010 and 2015 were identified through clinical coding and local databases. Baseline demographics were captured. Patient records were interrogated to identify route of access, and clinical contacts during the patient pathway. RESULTS: Seventy-nine patients were included in the study, of whom 54 (68%) had an established diagnosis of Crohn's disease (CD). Median time from presentation to anti-TNF therapy was 204 days (174 vs 365 days for existing and new diagnosis of CD, respectively; P = 0.019). The mean number of surgical outpatient attendances, operations and MRI scans per patient was 1.03, 1.71 and 1.03, respectively. Patients attended a mean of 1.49 medical clinics. Seton insertion was the most common procedure, accounting for 48.6% of all operations. Where care episodes ('clinical events per 30 days') were infrequent this correlated with prolongation of the pathway (r = -0.87; P < 0.01). CONCLUSION: This study highlights two key challenges in the treatment pathway: (i) delays in diagnosis of underlying CD in patients with anal fistula and (ii) the pathway to anti-TNF therapy is long, suggesting issues with service design and delivery. These should be addressed to improve patient experience and outcome.

Causal entropic forces.

Recent advances in fields ranging from cosmology to computer science have hinted at a possible deep connection between intelligence and entropy maximization, but no formal physical relationship between them has yet been established. Here, we explicitly propose a first step toward such a relationship in the form of a causal generalization of entropic forces that we find can cause two defining behaviors of the human "cognitive niche"-tool use and social cooperation-to spontaneously emerge in simple physical systems. Our results suggest a potentially general thermodynamic model of adaptive behavior as a nonequilibrium process in open systems.

Relativistic statistical arbitrage.

Recent advances in high-frequency financial trading have made light propagation delays between geographically separated exchanges relevant. Here we show that there exist optimal locations from which to coordinate the statistical arbitrage of pairs of spacelike separated securities, and calculate a representative map of such locations on Earth. Furthermore, trading local securities along chains of such intermediate locations results in a novel econophysical effect, in which the relativistic propagation of tradable information is effectively slowed or stopped by arbitrage.

Assessment of quantitative computed tomographic cerebral perfusion imaging with H2(15)O positron emission tomography.

Assessment of quantitative cerebral blood flow on a conventional fast CT machine without the use of specialized equipment may be valuable in the investigation of acute stroke and head injury. We aimed to compare a single slice CT perfusion sequence with H2(15)O positron emission tomography using the sagittal sinus as an input function, a method that avoids unnecessary orbital irradiation. Eight patients were studied, two patients with gliomas, and six with arteriovenous malformations. The dynamic CT perfusion sequence was performed by acquiring the same 10 mm slice 10 times over 30 sec during a 50 ml bolus of intravenous contrast medium given at a rate of 7.5 ml sec-1 using a power injector. The CT perfusion studies were completed without complication. Co-registration was sub-optimal in one patient. Overall the correlation between the two methodologies was encouraging with an average r2 value of 0.524 for individual analyses. When two patients with high flow arteriovenous malformations were excluded the average r2 value increased to 0.640. The results of this CT perfusion methodology are encouraging. Having shown its feasibility, further studies in conditions with lower rates of cerebral blood flow are warranted.

Evaluation of carotid endarterectomy with sequential MR perfusion imaging: a preliminary 12-month follow up.

AIM: The clinical benefit of carotid endarterectomy is partially determined by peri-operative mortality and morbidity. Post-operative abnormalities in cerebral perfusion may be a risk factor for cerebral haemorrhage, and may be estimated from Bolus Arrival Time (BAT) as demonstrated by MR perfusion imaging. We aimed to use MR perfusion imaging to determine the temporal extent of these changes. MATERIALS AND METHODS: A single slice gradient recalled echo sequence was employed in five patients who underwent carotid endarterectomy. Sequential studies were undertaken pre-operatively, 3-5 days post carotid endarterectomy, and additionally at 3, 6 and 12 months. RESULTS: Asymmetric BATs were demonstrated in 3/5 patients, changes occurring as late as 6 to 12 months after carotid endarterectomy. These changes were not associated with either clinical or conventional MR morphological complications. CONCLUSIONS: MR perfusion imaging is able to demonstrate changes in BAT characteristics for up to 12 months after carotid endarterectomy. The clinical significance and underlying cause of these changes, including any association with post carotid endarterectomy hyperaemia, remains unknown.

Evaluation of carotid endarterectomy with sequential MR perfusion imaging: a preliminary report.

BACKGROUND AND PURPOSE: Current indications for carotid endarterectomy are determined by balancing the relative risks of surgery with the benefits of reduced risk of subsequent stroke. Our purpose was to use MR perfusion imaging to assess patients being considered for carotid endarterectomy and to monitor sequential changes in MR perfusion characteristics after surgery. In particular, we wished to determine whether this technique could be used to detect changes that might be related to post-carotid endarterectomy hyperemia. METHODS: We used a single-section gradient-recalled echo sequence to investigate 14 patients being examined before possible surgery for carotid artery disease. In the 12 patients in whom carotid endarterectomy was performed, sequential studies were performed 3 to 5 days after surgery and at 3 months. Analysis of bolus-arrival-time (BAT) images was performed. RESULTS: Significant delays in preoperative BAT images of 0.89 seconds (range, 0.05 to 3.22 seconds) were apparent between hemispheres. Excluding the two patients with contralateral internal carotid artery (ICA) occlusion, early arrival, possibly indicating postoperative hyperemia, was seen in five patients immediately after carotid endarterectomy but resolved within 3 to 5 months after surgery. CONCLUSION: MR perfusion imaging shows differences in BAT between hemispheres in patients with ICA stenosis. Changes in perfusion characteristics after carotid endarterectomy are complex, and early BAT on the operative side can occur soon after endarterectomy in over half those patients without an occluded contralateral vessel. The significance of these findings with regard to patient outcome and risk of postoperative hyperemia requires further investigation.

MR sialography. Work in progress.

PURPOSE: To develop a noninvasive method for demonstrating the main salivary gland duct systems. MATERIALS AND METHODS: The authors developed a magnetic resonance (MR) imaging protocol that uses a heavily T2-weighted (echo time, 750 msec), fat-suppressed pulse sequence and rapid acquisition with relaxation enhancement. The technique was optimized to depict fluid within a two-dimensional thick slab. A preliminary evaluation was performed by examining the major salivary gland ducts in 10 asymptomatic volunteers and three symptomatic patients with known salivary duct abnormalities. RESULTS: The main parotid gland ducts were clearly demonstrated in all volunteers. The submandibular ducts were visible in all cases, although not always on projection images. In the three patients, the MR technique clearly demonstrated bilateral sialectasis, a calculus obstructing the left submandibular duct, and a fluid-filled ranula, respectively. CONCLUSION: Preliminary work indicates that this MR technique can successfully demonstrate both normal and abnormal parotid and submandibular gland duct systems and has several advantages over conventional x-ray sialography.

Intelligence and the frontal lobe: the organization of goal-directed behavior.

Basic to the study of individual differences is the concept of 'general intelligence' or Spearman's g. In this article we suggest that g is largely a reflection of the control functions of the frontal lobe. A series of experiments investigates a phenomenon we call goal neglect: disregard of a task requirement event though it has been understood and remembered. Subjectively it is as though the neglected requirement "slips the subject's mind." Previously described in frontal patients, we show that goal neglect can also be seen in some members of the normal population. In line with conventional distinctions between controlled and automatic processing, eliciting conditions for goal neglect include novelty, weak error feedback, and multiple concurrent task requirements. Under these conditions neglect is linked closely to g and extremely common after frontal lesions. Following many other models, we suggest that behavior in any task is structured by a set of action constraints or requirements, derived in part from verbal instructions and specified at multiple levels of abstraction. A frontal process of constraint or requirement activation is fundamental to Spearman's g.

Neuroradiological findings in primary progressive aphasia: CT MRI and cerebral perfusion SPECT.

Primary progressive aphasia (PPA) is defined as progressive decline in language for 2 or more years with preservation of activities of daily living and general cognitive functions. Whereas the clinical features of this syndrome have been well documented, the neuroradiological findings have not been studied systematically. We studied 13 patients with PPA retrospectively: 10 underwent CT, 12 MRI and 12 cerebral perfusion studies using 99mTc-HMPAO SPECT.CT and MR images were scored for focal atrophy by two independent assessors. Initial qualitative assessment of SPECT images was confirmed by quantitative analysis. CT was normal in 5 patients. Focal atrophy, affecting predominantly the left temporal lobe, was seen in 4 of 10 patients on CT, and 10 of 12 on MRI. Atrophy was localised primarily to the superior and middle temporal gyri on MRI. All 12 patients who underwent SPECT had unilateral temporal lobe perfusion defects, in 2 patients of whom MRI was normal. CT is relatively insensitive to focal abnormalities in PPA; MRI and SPECT are the imaging modalities of choice. MRI allows accurate, specific localisation of atrophy within the temporal neocortex. SPECT may reveal a functional decrease in cerebral perfusion prior to establishment of structural change.

CT of a peripatetic intracranial foreign body.

We report the CT appearances of a low-velocity missile that lodged within the brain and which subsequently migrated spontaneously back along the entry path. We review the literature of similar instances of migration and draw conclusions about the presurgical radiological management.

Pictorial review: benign and malignant enlargement of the pterygo-masseteric muscle complex.

Seven cases of unilateral enlargement of the pterygoid and/or masseter muscles due to haemangioma (1), benign masseteric hypertrophy (2), rhabdomyosarcoma (2), leukaemic infiltration (1) and non-Hodgkin's lymphoma (1) are presented. The differential diagnosis of pterygo-masseteric muscle enlargement is outlined and the usefulness of computed tomography (CT) discussed.

Magnetic resonance imaging: when is one sequence sufficient?

We have studied 100 patients undergoing magnetic resonance imaging (MRI) in eight well-defined clinical problems. The relative values of the clinical details and the initial imaging sequence in reaching the final MR diagnoses were assessed. For each patient, two radiologists independently predicted the likely radiological findings from the clinical details. They then assessed the radiological appearances shown by the initial imaging sequence (which was chosen according to the clinical problem). Lastly, they made a final interpretation using all the available information. Prediction of likely radiological abnormalities from the clinical details proved unreliable. However, the radiological assessment of the initial imaging sequence was reliable for clinical problems related to the pituitary fossa, posterior fossa, internal auditory meatus and for suspected multiple sclerosis. In these patient groups additional sequences might be reserved for those with equivocal findings. Conversely, assessment of the initial imaging sequence proved unreliable compared with the full radiological assessment for clinical problems in the lumbar spine, the axilla and the knee. This study has led us to reduce the number of sequences performed for some clinical problems, with a commensurate increase in the throughput of patients.

Measurement of regional left ventricular function using labelled magnetic resonance imaging.

A technique for assessing regional left ventricular function using magnetic resonance imaging is described. Spatial modulation of magnetization (SPAMM) is effected immediately before images are obtained at various intervals during the cardiac cycle using a modified field echo even rephasing technique (FEER). By performing such modulation in two planes, a grid pattern of labelling can be produced across the image. On the resulting labelled short axis images of the left ventricle, the systolic increase in thickness (thickening) and decrease in length (shortening) of different regions of myocardium can then be measured. The findings in five normal volunteers are presented. Radial shortening was twice as great in the endocardium (mean 20.4%, standard deviation (SD) 5.7) than in the epicardium (mean 10.2%, SD 5.5) and appears to offer more promise as a marker of regional function than simple thickening (mean 9.8%, SD 13.6).

Localized in vivo proton spectroscopy of the human kidney.

In vivo 1H spectroscopy using the STEAM sequence for localization has been applied to the human kidney in normal volunteers and subjects with successful renal transplants. We show that, within the resolution of our measurements, trimethylamines are present in the spectra from some of the subjects and absent from others. The prominent peak seen at 5.8 ppm in the spectrum is identified as that from urea and not lipid, as previously suggested.

Radiology for cochlear implants.

One fifth of patients selected for cochlear implants have such bony irregularities in the cochlear duct that full insertion of a multichannel electrode array is impossible. Three cases of cochlear deafness are presented where pre- and post-operative radiology played an important part in the management. Standard CT at 2 mm cuts is compared with ultra high resolution CT at 1 mm cuts. The pitfall of poor definition is that the inexperienced surgeon may find himself unexpectedly drilling out an obliterated cochlear duct. Sections 30 degrees caudal to Reid's infra orbito-meatal base line at 1 mm intervals give maximum information for minimum radiation. Plain films show the placement of individual platinum electrode contacts in relation to the spiral 'frequency map' of the cochlea. This is vital information for the audiologist who has to route specific frequencies to specific sites within the ear for a good hearing result.

Magnetic resonance imaging of the head and spine: effective for the clinician or the patient?

OBJECTIVES: To test how the results of magnetic resonance imaging influence clinicians' diagnoses and management plans for patients with cranial and spinal problems and to assess changes in the quality of life of these patients. DESIGN: Survey of patients undergoing cranial and spinal magnetic resonance imaging with questionnaires about diagnoses and intended management plans before and after imaging and quality of life questionnaires at the time of imaging and again four months later. SETTING: Regional magnetic resonance imaging and spectroscopy unit. SUBJECTS: 100 consecutive patients referred for cranial imaging in early 1989; 100 similar patients referred for spinal imaging. MAIN OUTCOME MEASURES: Changes in clinicians' leading diagnoses after magnetic resonance imaging and their confidence in these diagnoses; changes in intended management plans; assessment of the contribution to the future management of the patient; changes in patients' quality of life. RESULTS: Magnetic resonance imaging altered the clinicians' leading diagnoses in 35 of 169 (21%) cases. The clinicians became more confident about their leading diagnoses in 90 of 167 (54%). There was a change in management plan in 113 of 182 (62%). The clinicians considered that magnetic resonance imaging made an important contribution to management in 119 of 162 (73%) patients. Overall, the patients' quality of life was unchanged at the four month assessment. CONCLUSIONS: Magnetic resonance imaging of patients with cranial and spinal problems influences clinicians' diagnoses and management plans, but the quality of life of these patients remains unchanged.

An audit of the clinical use of magnetic resonance imaging of the head and spine.

An audit was undertaken of the use of magnetic resonance imaging for clinical problems of the head and spine. Using a form of simulation, two consultant clinicians were asked to assess a sequential series of 200 patients referred for magnetic resonance. The clinicians considered that 200 magnetic resonance studies could replace about 330 other imaging and neurophysiology investigations; the cost of the alternative tests approximated the cost of magnetic resonance. However, there was considerable variation between cases in the costs of investigations potentially replaced by the procedure under audit, and this variation suggests ways in which magnetic resonance might be used more cost-effectively in the future.

Pituitary computed tomography: is contrast enhancement necessary?

Direct coronal computed tomography of the pituitary fossa, before and after enhancement with intravenous contrast medium, was performed on 25 consecutive patients with hyperprolactinaemia. The images were viewed separately by two independent observers and the pituitary height, width and contour, and the visibility of the infundibulum, optic chiasm and hypothalamus were assessed. The presence and size of any possible pituitary tumour was recorded. The administration of intravenous contrast medium made no significant difference to the pituitary measurements, the visibility of the infundibulum of hypothalamus, or the detection of possible pituitary tumours. There was an inconsistent improvement in the visibility of the optic chiasm following enhancement. The arguments against an unenhanced examination are discussed and refuted. It is proposed that routine administration of intravenous contrast medium is unnecessary when investigating moderate hyperprolactinaemia.