Basic activities of daily living measures are often supplemented by extended activities of daily living. We compared the Frenchay Activities Index (FAI) and Nottingham Extended Activities of Daily Living (NEADL) with the Barthel Index (BI) in terms of distribution of scores, concurrent validity, reliability, and their agreement and investigated the predictors of scales outcomes. Two hundred thirty-eight patients from the population-based South London Stroke Register were assessed with the BI, FAI, and NEADL 3 months after a first-ever stroke. The pairwise relationship was studied using correlations, fractional polynomial regression, and Bland and Altman plot; the baseline predictors, for example, sociodemography, case severity: National Institutes of Health Stroke Scale, and 7-day Abbreviated Memory Test, comorbidities, and acute treatments by negative binomial regression. The BI was highly affected by a ceiling effect (33% had the highest score), FAI was only affected by floor effect (19%), but NEADL was symmetrical with only 4% highest and lowest score. Despite high concurrent validity of the scales (r ≥0.80, P13) had 28% lower BI (79% lower FAI and 62% lower NEADL) score than nonsevere patients (P≤0.001). Cognitively intact patients (Abbreviated Memory Test: 8-10) had 2.3 times greater FAI values (65% higher NEADL) compared with impaired patients (P<0.001). The NEADL scale was symmetrical, concurrently valid with no floor and ceiling effects. It corresponded better with BI than FAI did confirming its basic activities of daily living properties, yet it is a more sensitive tool for extended activities of daily living without the floor and ceiling effects. Future functional status could be predicted by the acute stage National Institutes of Health Stroke Scale score, whereas only extended activities of daily living status could be predicted by the Abbreviated Memory Test score. Predicting future functional status at the acute stage may decrease unnecessary length of stay in acute care settings.

Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient. We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed. A total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions. We identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours’ phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation. European Clinical Trials Database(EudraCT): 2009-016675-29 , registered 17 March 2010; EudraCT: 2006-004511-21 , registered 09 March 2007; EudraCT: 2006-006491-38 , registered 22 December 2006.

Normal myoepithelial cells (MECs) play an important tumour-suppressor role in the breast but display an altered phenotype in ductal carcinoma in situ (DCIS), gaining tumour-promoter functions. Matrix metalloproteinase-8 (MMP-8) is expressed by normal MECs but is lost in DCIS. This study investigated the function of MMP-8 in MECs and the impact of its loss in DCIS. Primary normal and DCIS-associated MECs, and normal (N-1089) and DCIS-modified myoepithelial (β6-1089) cell lines, were used to assess MMP-8 expression and function. β6-1089 lacking MMP-8 were transfected with MMP-8 WT and catalytically inactive MMP-8 EA, and MMP-8 in N-1089 MEC was knocked down with siRNA. The effect on adhesion and migration to extracellular matrix (ECM), localisation of α6β4 integrin to hemidesmosomes (HD), TGF-β signalling and gelatinase activity was measured. The effect of altering MEC MMP-8 expression on tumour cell invasion was investigated in 2D and 3D organotypic models. Assessment of primary cells and MEC lines confirmed expression of MMP-8 in normal MEC and its loss in DCIS-MEC. Over-expression of MMP-8 WT but not MMP-8 EA in β6-1089 cells increased adhesion to ECM proteins and reduced migration. Conversely, knock-down of MMP-8 in N-1089 reduced adhesion and increased migration. Expression of MMP-8 WT in β6-1089 led to greater localisation of α6β4 to HD and reduced retraction fibre formation, this being reversed by MMP-8 knock-down in N-1089. Over-expression of MMP-8 WT reduced TGF-β signalling and gelatinolytic activity. MMP-8 knock-down enhanced TGF-β signalling and gelatinolytic activity, which was reversed by blocking MMP-9 by knock-down or an inhibitor. MMP-8 WT but not MMP-8 EA over-expression in β6-1089 reduced breast cancer cell invasion in 2D and 3D invasion assays, while MMP-8 knock-down in N-1089 enhanced cancer cell invasion. Staining of breast cancer cases for MMP-8 revealed a statistically significant loss of MMP-8 expression in DCIS with invasion versus pure DCIS (p = 0.001). These data indicate MMP-8 is a vital component of the myoepithelial tumour-suppressor function. It restores MEC interaction with the matrix, opposes TGF-β signalling and MMP-9 proteolysis, which contributes to inhibition of tumour cell invasion. Assessment of MMP-8 expression may help to determine risk of DCIS progression.

Galactomannan (GM) is widely used for detection of invasive aspergillosis in high-risk haemato-oncology patients. Recent publications have reported a lack of repeatability of GM detection. The objective of this retrospective study was to assess the repeatability of GM levels during storage of clinical samples. In a GM screening strategy, positive sera were repeat tested as per manufacturer’s recommendations. Short-term (ST) storage of samples was at +4 °C while long-term (LT) storage was at −80 °C. Bronchoalveolar (BAL) fluid was also repeating tested after ST storage and LT storage. Wilcoxon Signed Ranks Test was employed to assess the repeatability of GM levels. In a subset of 14 GM positive sera, repeat testing was performed on both the original serum and ethylenediaminetetraacetic acid (EDTA) pre-treated sample. There was a significant reduction in GM signals on repeat testing following ST storage (median GM index: 0.65 vs. 0.19; p < 0.001) and LT storage (median GM index: 0.56 vs. 0.10; p < 0.001) of serum samples. Of samples that were initially GM positive, an average GM index reduction of 50% was seen, with approximately two-thirds becoming GM negative on repeat testing of the same sample. In contrast, GM signal loss was not seen on repeat testing of BAL fluid following ST or LT storage. When GM positive serum samples were repeat tested using EDTA pre-treated serum from the first step of the testing protocol, all samples remained GM positive. In contrast, when the same samples were repeat tested from the original collected serum, 9 samples (64%) became GM negative. The significant reduction in GM signals during ST and LT storage of serum samples has implications for clinical management. Although the reasons for GM decline are unknown, they occur prior to the EDTA pre-treatment stage, indicating that the time from phlebotomy to testing should be minimized. BAL fluid GM index values remain stable.