The chemokine, CXCL12, is an independent predictor of poor survival in ovarian cancer.

BACKGROUND: The chemokine CXCL12 and its cognate receptor, CXCR4, have been implicated in numerous tumour types where expression promotes tumour growth, angiogenesis, metastasis and suppresses tumour immunity. METHODS: Using a tissue microarray of 289 primary ovarian cancers coupled to a comprehensive database of clinicopathological variables, the expression of CXCL12 and CXCR4 was assessed by immunohistochemistry and its impact in terms of survival and clinicopathological variables was determined. RESULTS: Patients whose tumours expressed high levels of CXCL12 had significantly poorer survival (P=0.026) than patients whose tumours failed to produce this chemokine. Lack of CXCL12 expression within tumours was associated with a 51-month survival advantage for patients when compared with patients whose tumours expressed high levels of CXCL12. FIGO stage, adjuvant chemotherapy and the absence of macroscopic disease after surgery were all shown to predict prognosis independently of each other in this cohort of patients. CXCL12 was independently predictive of prognosis on multivariate analysis (P=0.016). There was no correlation between CXCL12 and any clinicopathological variable. CONCLUSION: The chemokine CXCL12 is an independent predictor of poor survival in ovarian cancer. High expression of CXCL12 was seen in only 20% of the tumours, suggesting a role for anti-CXCL12/CXCR4 therapy in the management of these patients.

Superimposed vibration confers no additional benefit compared with resistance training alone.

Eighteen participants (22-43 years) were randomly allocated to one of two groups: resistance training combined with vibration (VIB; five males, four females) or resistance training alone (CON; five males, four females). Each participant trained three sessions per week (three sets of 10 seated calf raises against a load, which was increased progressively from 75% of one repetition maximum (1RM) to 90% 1RM for 4 weeks. For the VIB group, a vibratory stimulus (30 Hz, 2.5 mm amplitude) was applied to the soles of the feet by a vibration platform. The two groups did not differ significantly with respect to the total amount of work performed during training. Both groups showed a significant increase in maximum voluntary contraction and 1RM (P<0.01) with training. There were no significant changes in measures that assessed the rate at which force was developed. Countermovement jump height increased for the CON (P<0.01) but not for the VIB group. Comparisons between the groups revealed that they did not differ significantly from one another with respect to any measure of performance, before or following training. It appears that vibration superimposed upon resistance training does not alter or augment the increase in strength induced by resistance training alone.

Improvement in condition-specific and generic quality of life outcomes in patients with knee osteoarthritis following single-injection Synvisc: results from the LOBRAS study.

OBJECTIVE: To evaluate the effectiveness of viscosupplementation with single-injection hylan G-F20 (Synvisc-One) in knee osteoarthritis (OA), during routine clinical care, in a 52 week observational study. RESEARCH DESIGN AND METHODS: The LOBRAS study involved a 1 year long, multi-center, quasi-experimental, repeated measures, observational study. Consenting patients in Australia fulfilling inclusion/exclusion criteria under the care of a medical specialist in routine clinical practice were enrolled. Prior to, and for 52 weeks following, intra-articular single-injection hylan G-F20, patients were repeatedly evaluated using the WOMAC NRS4.1 Index and the SF-36 questionnaire. The WOMAC NRS4.1 was administered by mobile phone (with paper back-up), and the SF-36 was administered on paper. Patients were monitored for adverse events. MAIN OUTCOME MEASURES: Western Ontario and McMaster (WOMAC) OA Index, and the Short Form 36 questionnaire (SF-36 v2). RESULTS: A total of 131 patients with knee OA were enrolled, of whom 119 provided both pre- and post-intervention WOMAC data. Statistically significant improvements (with a maximum of p ≤ .025) from baseline to Week 12, Month 6 and Week 52 were detected, by intention-to-treat (ITT) and per-protocol (PP) analyses, in WOMAC Pain, Stiffness, Function, PGA, and Total Score, SF-36 PCS, and WOMAC-derived HUI3. Adverse event (AE) monitoring detected treatment-related AEs in 5.3% of patients. CONCLUSIONS: The effectiveness of single-injection hylan G-F20 in routine clinical care is supported by the detection of statistically significant, clinically important improvements in WOMAC Pain, Stiffness, Function, Total, and PGA outcomes, and statistically significant improvements in SF-36 PCS and WOMAC-derived HUI3 outcomes at multiple time points. Limitations of this study include lack of a control group or blinding. No predictive indicators of the response to treatment were identified. In general single-injection hylan G-F20 was well tolerated with very few patients experiencing any treatment-related adverse events. Collectively, these observations attest to the effectiveness of single-injection hylan G-F20 and complement previous observations in routine clinical care.

Immune Checkpoint Inhibitors in Lung Cancer - An Unheralded Opportunity?

Lung cancer remains the leading cause of cancer-related death worldwide, with non-small cell lung cancer accounting for 85% of the disease. Over 70% of patients present with locally advanced, non-resectable or metastatic disease and despite improvements in chemoradiotherapy regimens and the development of molecularly targeted agents, 5 year survival rates remain poor, with acquired resistance to novel targeted therapies becoming a growing concern. Currently there remains an unmet need in effectively treating and inducing durable responses in advanced disease. Targeting the immune system has, however, recently given hope of improving therapeutic outcomes for these patients. The notion that the immune system is capable of recognising and eliminating cancer cells is now a widely accepted phenomenon and growing evidence suggests lung cancer is an attractive target for such intervention. Recent success targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis of immune checkpoint inhibition suggests a major immunotherapeutic advance in treating lung cancer and unheralded opportunity for such approaches to further improve outcome for patients. Currently there is considerable interest in combining anti-PD-1 or PD-L1 monoclonal antibodies with established standard of care therapies such as radiotherapy. Radiotherapy is known to be immunostimulatory and efforts are underway to combine and augment the efficacy of the immune checkpoint inhibitors further. This review outlines the interaction between lung cancer and the immune system, summarises current evidence supporting the use of monoclonal antibodies targeting the PD-1 axis in lung cancer and explores the potential of combining radiotherapy with immunotherapy to augment anti-tumour immune responses.

A new illusion demonstrates long-range processing.

In the Fraser phase-illusion [Popple & Sagi. Vision Research, 40 (2000) 873-878] rows of Gabor patches appear tilted because successive elements are shifted in phase. We measured this bias in global orientation judgment, while varying the number of patches in each row, and their separation. We found that illusory tilt increases with the number of patches, at least up to ten patches for a separation of four carrier periods. This finding implies that the visual system is able to integrate information over large (>10 degrees ) strips of the central visual field. Our model shows that the tilt illusion might be the result of averaging the activity of oriented filters.

A Fraser illusion without local cues?

In the well-known Fraser illusion, a line composed of tilted elements itself appears tilted. The standard explanation of this illusion has been that the global orientation of the line is in some way influenced by the local orientation of the elements. The illusion was recreated using a texture composed of collinear Gabor stimuli, which were vertical. There was no local tilt. The illusory tilt was produced by gradually shifting the phase of the successive Gabors along each line. Although the 2D Fourier transform of this global pattern peaks at off-vertical orientations, the local energy of the patches is predominantly vertical. How does the visual system nevertheless pick up this global information? This can be explained by elongated linear filters, or a phase-tuned second-stage mechanism. We examined the first theory using a stereoscopic demonstration. When lines of opposite tilt are presented in the two eyes, they combine binocularly to produce stereoscopic slant. We tested whether the illusory tilts in the phase-shifted Gabors texture give stereoscopic slant, when opposite tilts are presented to the two eyes. They do not. Instead, stereoscopic depth is dominated by the local phase-disparity of the individual patches. This indicates that the illusion is not present at the stage of linear filters, which are input to stereo, but must involve second-stage interactions or collators.

The area of spatial integration for initial horizontal disparity vergence.

We investigated over what central area disparity in a random dot stereogram is integrated to stimulate an initial vergence response. Vergence was measured subjectively, with a forced choice dichoptic nonius vernier task following a brief (230 msec) stimulus presentation. Stimuli were random-dot stereograms showing a central circular disc of 12.5 min arc crossed retinal disparity in front of, and occluding, a same density fixation plane surround. The size of the disc was varied. All ten observers responded to the brief stimulus. Initial vergence increased with increasing disc diameter and, for nine out of ten subjects, reached a maximum with the disc ca 6 deg, suggesting this is the extent of the spatial integration region. Below 6 deg diameter, surround and target disparities were averaged together. Initial horizontal vergence responds automatically to a cyclopean target presented in the centre of gaze by pooling disparities within a limited but surprisingly large area.

Using clinicopathological analysis of general practitioner skin surgery to determine educational requirements and guidelines.

OBJECTIVE: To study the impact of skin surgery in general practice on the workload of a pathology laboratory and to identify what further training might be helpful. DESIGN: Analysis of skin biopsy specimens from general practitioners before and after their new contract to determine numbers of specimens, changes in diagnoses, adequacy of treatment of malignant tumours, and areas of low diagnostic accuracy. SETTING: District general hospital. SUBJECTS: All 1017 skin biopsy specimens from general practice for 15 months before and 12 months after the new general practitioner contract. RESULTS: The number of pathology specimens received increased from 16 to 65 per month (median = 6 submitted by each general practitioner in the post-contract year). The proportion of the more common pathological diagnoses was unchanged between the two periods, but the proportion of correctly diagnosed naevi, cysts, and seborrhoeic keratoses increased in the second. Although few diagnoses were overtly incorrect, accurate diagnosis of dermatofibromas and malignancies decreased after the contract, and the overall correct diagnosis rate for seborrhoeic keratoses, dermatofibromas, rashes, and malignancies was below 30%. Only nine out of 21 squamous cell carcinomas were adequately excised with tumour free margins, and follow up of malignant tumours may have been inadequate. CONCLUSIONS: Skin surgery in general practice has advantages but matters of concern are the increase in laboratory workload, the excision of some benign lesions, and the inappropriateness of biopsy of rashes. Squamous cell carcinoma and other malignant tumours submitted for pathological examination were often unsuspected and inadequately excised, and heightened suspicion is recommended. Pathology request forms may need redesigning to encourage provision of clinical details.

Sudden unexpected cardiac death--a practical approach to the forensic problem.

Sudden cardiac death can usually be resolved by the pathologist into ischaemic heart disease, non-vascular cardiac disease such as aortic stenosis or hypertrophic obstructive cardiomyopathy and infrequently a morphologically normal heart on naked eye examination. When ischaemic heart disease is present one third of cases have a recent occlusive coronary artery thrombosis. Two thirds of patients have coronary stenosis only; the minimum degree of disease reasonably associated with sudden death is one area of 85% stenosis. The majority of patients, however, have multiple areas of stenosis. The predominant causes of non-ischaemic sudden death are severe LV hypertrophy, hypertrophic obstructive cardiomyopathy and the prolapsing mitral valve syndrome. Where the heart and coronary arteries are morphologically normal, review of any previous ECG's, a family history and histological examination of the myocardium and conduction system may reveal a cause or at least allow a reasonable assumption of cardiac arrhythmia to be made. Sudden unexpected death where the circumstances strongly suggest a cardiac cause may pose problems for the pathologist. Ischaemic heart disease (coronary atherosclerosis) is undoubtedly the most frequent cause but even when this is so the detailed pathology is controversial. It is when coronary artery disease is conspicuously absent, often in young individuals previously in good health, that a problem exists. Sudden death in infancy (cot death) is a different entity with its own problems and is not here discussed further.

Amblyopes see true alignment where normal observers see illusory tilt.

Amblyopia ("lazy eye") is an impairment in visual acuity resulting from abnormal neural development in the visual cortex. We tested the responses of ten amblyopic and six normal observers to illusions of perceived orientation in textures of Gabor patches: the "Fraser illusion," the "phase illusion," and a "tilted chain" illusion. The illusory tilt of the stimulus rows was matched by actual tilt in the opposite direction by using the method of constant stimuli. Amblyopes showed a significant increase in the Fraser illusion, a decrease in the phase illusion, and a reversal of the tilted chain illusion. Amblyopic performance could be simulated in normal observers by reducing the length of the rows. These results can be modeled by a theory which places the neural abnormality in amblyopia at the level of second stage grouping processes. Additionally, the illusions might be useful in the early diagnosis of amblyopia without the need for prior refractive correction.

Collinear effects on 3-Gabor alignment as a function of spacing, orientation and detectability.

Our ability to align three Gabor patches depends upon their internal carrier orientation; we are better at aligning vertical or horizontal patches than oblique patches (Keeble and Hess, 1998). However, the tuning of alignment to patch orientation has not studied in detail. We measured the alignment of a vertical target with reference patches varying in orientation and found it tuned to vertical (collinear) patches at centre-to-centre separation of three carrier periods, with a steep increase for oblique references and slight downturn for horizontal (orthogonal) references. Next, we increased separation between the patches, testing collinear, side-by-side, orthogonal and oblique configurations. Surprisingly, we found that the tuning for collinear patches was preserved. All ten observers tested had lower alignment thresholds for collinear patches. This effect extended to an inter-patch separation of 10 carrier periods (20 envelope standard deviations). Additionally, we measured contrast detection thresholds for the reference patches using the same stimuli. The collinear facilitation of alignment was even greater than the collinear facilitation of detection.

Persistent erythema and pruritus, with a confluent histiocytic skin infiltrate, following the use of a hydroxyethylstarch plasma expander.

A 40-year-old woman developed a persistent pruritus with erythema of the head and upper trunk, which started within 2 weeks of a hydroxyethylstarch (HES) infusion and was still present 2 years later. Histological examination demonstrated a striking dermal infiltrate of KP1-positive foamy macrophages which had electron-lucent vacuoles. The timing of the onset, the body site distribution, the exclusion of other possibilities and an appropriate history of high dosage HES infusion, suggested that this was the cause of the eruption. Staining with periodic acid-Schiff (PAS) surprisingly was negative but we could not stain HES in vitro with this histochemical stain, and we postulate that the unique extent of the infiltrate and the negative PAS stain in our patient may indicate an impaired ability to degrade this chemical. This may be an important factor in the poorly understood pathogenesis of persistent pruritus induced by HES.

Right ventricular outflow tract obstruction secondary to small intestinal lymphoma.

A 71-year-old man developed symptoms and signs of right ventricular outflow obstruction. After angiography, which showed multiple lobulated and well-defined filling defects in the right ventricular outflow tract, endomyocardial biopsy disclosed infiltration of the myocardium by a poorly differentiated malignant neoplasm. At necropsy he was found to have a small intestinal lymphoma.

'Coarse-to-fine' cyclopean processing.

Previously (Popple et al, 1998 Vision Research 38 319-326) we found, using random-dot stereograms, that initial vergence increases with the size of a cyclopean disc. A corresponding improvement in stereoacuity within the disc was predicted, because disparities in the disc would be brought closer to the plane of current fixation. In the present experiment, we looked at the effect of the spatial extent of a briefly presented (< or = 500 ms) cyclopean depth pedestal on stereoacuity thresholds. Observers were required to judge the depth of a small, 1.7 deg, central disc relative to a larger surrounding disc in a random-pattern stereogram. The larger disc was set, initially, at a pedestal disparity of +/- 24 min of arc against a fixation-plane surround. The size of the larger disc was varied from 2.6 to 8.0 deg. As predicted, stereoacuity thresholds fell significantly with increasing pedestal disc size. Next, the disparity of the pedestal disc was varied. When pedestal disparity was reduced to +/- 2.4 min of arc, a disparity too small to demand vergence, the size effect disappeared except when the pedestal boundary was within 30 min of arc of the test disc boundary. We argue from this result that the effect was largely due to vergence and not cyclopean integration alone. However, the effect of pedestal size was found to persist with stimuli too brief to permit vergence (< or = 100 ms) suggesting that factors other than vergence may also play a role.

Jaccoud's arthropathy. A case report and necropsy study.

We present a case of Jaccoud's arthropathy in a 59-year-old woman. She developed painless correctable ulnar deviation at the metacarpophalangeal joints of both hands following 4 attacks of rheumatic fever. Radiology did not show the hook lesions previously described, but we do not consider this sign essential for the diagnosis. There was no clinical evidence of rheumatoid arthritis. We were able to examine 3 complete joints from the left little finger at necropsy. Pathological examination of this kind has been possible only once before. The histological findings were fibrous thickening of the joint capsule, secondary degenerative changes, presumably due to longstanding joint deformity, and no evidence of significant synovial pathology.

Amyloid deposition in basal cell carcinoma: a cause of apparent lack of sensitivity to radiotherapy.

We describe a patient with a large nodular basal cell carcinoma (BCC), which was excised following apparent failure to respond to radiotherapy. Histological examination of the fully excised lesion demonstrated a solid mass of amyloid, which stained positively for cytokeratins, but there was no residual BCC.

A reticulate vascular abnormality in patients with lymphoedema: observations in eight patients.

We describe eight patients with lymphoedema who had prominent compressible ridges of tissue in a reticulate pattern, situated predominantly on the upper part of the lower leg. In five patients the lymphoedema was primary, two patients had circumferential venous ulceration, and one had marked venous disease with a small ulcer. One patient had a squamous cell carcinoma of the medial thigh and dysplastic keratoses in the distribution of the reticulate ridges. In three of the four cases in whom histological examination of the ridges was performed, the skin at these areas was demonstrated to contain grossly dilated angular vessels in the mid-dermis, many with valves visible. The vessel walls had a single layer of endothelial cells (anti-factor VIII-related antigen positive) and a basement membrane containing type IV collagen. Abnormal elastic tissue in these biopsies was similar to that in erythema ab igne. Indirect lymphography in one case did not demonstrate dilated lymphatic vessels. The body site distribution and clinical pattern of the abnormality appeared to be similar to erythema ab igne but associated with an underlying abnormality of lymphatic rather than blood vasculature. We propose that our cases may represent 'lymphoedema ag igne'.

An experimental assessment of macroscopic enzyme techniques for the autopsy demonstration of myocardial infarction.

Experimental cardiac infarction produced in dogs by coronary artery ligation has been used to investigate the value of macroscopic histochemical enzyme loss in the diagnosis of myocardial infarction at post-mortem. Creative phosphokinase and non-specific dehydrogenase methods gave the best results but became positive only 5-6 hr after infarction. It is concluded that the method is of limited value in autopsy practice.