Protein expression differences between lung adenocarcinoma and squamous cell carcinoma with brain metastasis

AIM: We investigated tissue biomarkers in non-small cell lung cancer (NSCLC) to find indicators of brain metastasis and peritumoral brain edema.

PATIENTS AND METHODS: Fifty-two cases were studied out of which 26 had corresponding brain metastatic tissue. Clinicopathological characteristics of tumors were correlated with biomarkers of cell adhesion, cell growth, cell cycle and apoptosis regulation that were previously immunohistochemically studied but never analyzed separately according to histological subgroups, gender and smoking history.

RESULTS: Increased collagen XVII in adenocarcinoma (ADC) and increased caspase-9, CD44v6, and decreased cellular apoptosis susceptibility protein (CAS) and Ki-67 in squamous cell carcinoma (SCC) correlated significantly with brain metastasis. Increased β-catenin, E-cadherin and decreased caspase-9 expression in primary SCC, and decreased CD44v6 expression in brain metastatic SCC tissues showed a significant correlation with the extent of peritumoral brain edema. Positive correlation between smoking and biomarker expression could be observed in metastatic ADCs with p16 and caspase-8, while-negative correlation was found in SCC without brain metastasis with caspase-3, and in SCC with brain metastasis with p27.

CONCLUSION: Our results highlight the importance of separate analysis of biomarker expression in histological subtypes of NSCLC.

The progress in understanding and treatment of diabetic retinopathy

In most countries, diabetic retinopathy is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss globally. Its etiology and pathology have been extensively studied for half a century, yet there are disappointingly few therapeutic options. Although some new treatments have been introduced for diabetic macular edema (DME) (e.g. intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') and new steroids), up to 50% of patients fail to respond. Furthermore, for people with proliferative diabetic retinopathy (PDR), laser photocoagulation remains a mainstay therapy, even though it is inherently a destructive procedure. This review summarizes the clinical features of diabetic retinopathy and its risk factors. It describes details of retinal pathology and the cell culture approaches and animal models that are used to mimic its key components, advance understanding of its pathogenesis, and enable identification of new therapeutic targets. We emphasise that although there have been significant advances, there is still a pressing need for a better understanding basic mechanisms to enable development of reliable and robust means to identify patients at highest risk, and to intervene effectively before vision loss occurs.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

Effect of accelerated rehabilitation on function after ankle sprain:randomised controlled trial

OBJECTIVE: To compare an accelerated intervention incorporating early therapeutic exercise after acute ankle sprains with a standard protection, rest, ice, compression, and elevation intervention.

DESIGN: Randomised controlled trial with blinded outcome assessor.

SETTING: Accident and emergency department and university based sports injury clinic.

PARTICIPANTS: 101 patients with an acute grade 1 or 2 ankle sprain.

INTERVENTIONS: Participants were randomised to an accelerated intervention with early therapeutic exercise (exercise group) or a standard protection, rest, ice, compression, and elevation intervention (standard group).

MAIN OUTCOME MEASURES: The primary outcome was subjective ankle function (lower extremity functional scale). Secondary outcomes were pain at rest and on activity, swelling, and physical activity at baseline and at one, two, three, and four weeks after injury. Ankle function and rate of reinjury were assessed at 16 weeks.

RESULTS: An overall treatment effect was in favour of the exercise group (P=0.0077); this was significant at both week 1 (baseline adjusted difference in treatment 5.28, 98.75% confidence interval 0.31 to 10.26; P=0.008) and week 2 (4.92, 0.27 to 9.57; P=0.0083). Activity level was significantly higher in the exercise group as measured by time spent walking (1.2 hours, 95% confidence interval 0.9 to 1.4 v 1.6, 1.3 to 1.9), step count (5621 steps, 95% confidence interval 4399 to 6843 v 7886, 6357 to 9416), and time spent in light intensity activity (53 minutes, 95% confidence interval 44 to 60 v 76, 58 to 95). The groups did not differ at any other time point for pain at rest, pain on activity, or swelling. The reinjury rate was 4% (two in each group).

CONCLUSION: An accelerated exercise protocol during the first week after ankle sprain improved ankle function; the group receiving this intervention was more active during that week than the group receiving standard care.

TRIAL REGISTRATION: Current Controlled Trials ISRCTN13903946.

Meningeal alveolar soft part sarcoma confirmed by characteristic ASPCR1-TFE3 fusion

Sarcoma metastatic to the brain is uncommon and rarely occurs as the initial manifestation of tumor. Alveolar soft part sarcoma (ASPS) is a rare but well-studied subtype of sarcoma. A 39-year-old man presented with seizures due to a left temporal meningeal-enhancing lesion with striking brain edema on MRI. The patient underwent neurosurgical resection for suspected meningioma. Histology showed large tumor cells clustering and forming small nests, in places with pseudoalveolar pattern. Diastase-resistant periodic acid-Schiff revealed very rare granular and rod-like cytoplasmic inclusions. Immunohistochemistry showed convincing positivity only with vimentin and smooth muscle actin. The histological features were strongly suggestive of ASPS. At the molecular level RT-PCR and sequencing analysis demonstrated ASPCR1-TFE3 fusion confirming the histological diagnosis of ASPS. There was no evidence of primary extracranial tumor by physical examination and on chest and abdominal CT scan 11 months after presentation. ASPS typically arise from the soft tissues of the extremities and develop multiple metastatic deposits usually with a long clinical course. This case may represent primary meningeal ASPS although metastatic deposit from an undiscovered primary site cannot be entirely excluded.