Absolute and relative temporal order memory for performed activities following stroke

Reconstructing the temporal order of events is a crucial part of episodic memory. The temporal dimension, however, is often discarded in clinical settings, and measurements of true temporal aspects of episodic memory are scarce. The present study assessed temporal memory in stroke patients and in age- and education-matched healthy controls. Both groups underwent a standardized neuropsychological examination. We asked participants afterwards to reconstruct the order of tests they had performed, measured in absolute temporal order (event placed on correct moment in sequence) and relative temporal order (event placed correctly relative to directly preceding and following events). The aim of the study was to examine how serial-position curve effects (measuring absolute temporal order anchored in exact time) and how relative temporal order memory (anchored to other events) may differ in a group of cerebral stroke patients. Another aim was to link temporal order memory deficits with established neuropsychological measures of cognitive functioning. Although item identification was comparable in both groups, absolute temporal order memory was impaired in patients: A total of 43% of the patients lacked the expected primacy and recency effects (serial position effect). In addition, relative temporal order memory was affected in this group as well, F(1, 70) = 4.08, p < .05; 25% of the patients were impaired in reconstructing the relative temporal order (p = .019, Fisher’s Exact Test). Both absolute and relative temporal order memory performance related to the domains of executive functioning and memory. Our results suggest that it is important to test both absolute and relative temporal order memory, especially because these types of memory depend on different anchors, either on time or on adjacent events.     

Cost-Effectiveness of Everolimus for Second-Line Treatment of Metastatic Renal Cell Carcinoma in Serbia

Background

New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had progressed on sunitinib and/or sorafenib. The only targeted therapy for mRCC currently reimbursed in Serbia is sunitinib.

Objective

The aim of this study was to estimate the cost-effectiveness and the budget impact of the introduction of everolimus in Serbia in comparison to best supportive care, for mRCC patients refractory to sunitinib.

Methods

A Markov model was designed corresponding with Serbian treatment protocols. A health care payer perspective was taken, including direct costs only. Treated and untreated cohorts were followed up over 18 cycles, each cycle lasting 8 weeks, which covered the lifetime horizon of mRCC patients refractory to the first-line treatment. Annual discounted rates of 1.5% for effectiveness and 3% for costs were applied. Transitions between health states were modeled by time-dependent probabilities extracted from published Kaplan-Meier curves of PFS and overall survival (OS). Utility values were obtained from the appraisals of other mRCC treatments. One-way and probabilistic sensitivity analyses were done to test the robustness and uncertainty of the base–case estimate. Lastly, the potential impacts of everolimus on the overall health care expenditures on annual and 4-year bases were estimated in the budget-impact analysis.

Results

The incremental cost-effectiveness ratio for everolimus was estimated at €86,978 per quality-adjusted life-year. Sensitivity analysis identified the hazard multiplier, a statistical approximator of OS gain, as the main driver of everolimus cost-effectiveness. Furthermore, probabilistic sensitivity analyses revealed a wide 95% CI around the base–case incremental cost-effectiveness ratio estimate (€32,594–€425,258 per quality-adjusted life-year). Finally, an average annual budgetary impact of everolimus in first 4 years after its potential reimbursement would be around €270,000, contributing to <1% of the total budget in Serbian oncology.

Conclusions

Everolimus as a second-line treatment of mRCC is not likely to be a cost-effective option under the present conditions in Serbia, with a relatively limited impact on its budget in oncology. A major constraint on the estimation of the cost-effectiveness of everolimus relates to the uncertainty around the everolimus effect on extending OS. However, prior to a final decision on the acceptance/rejection of everolimus, reassessment of the whole therapeutic group might be needed to construct an economically rational treatment strategy within the mRCC field.     

Fludarabine: a new agent with major activity against chronic lymphocytic leukemia

Fludarabine was used to treat 68 patients with previously treated chronic lymphocytic leukemia (CLL). Nine (13%) patients achieved a complete remission and 30 (44%) a partial remission. The response rates for Rai stages 0 to 2, 3, and 4 were 64%, 58%, and 50% respectively. Seventeen (43%) of the 40 Rai stage 1 to 3 patients and four (19%) of the Rai stage 4 patients returned to Rai stage 0. Survival was strongly correlated with the final Rai stage achieved. The survival of the 11 partial responders with residual disease consisting only of residual bone-marrow nodules was similar to the complete responders (36+ months) and superior to the other partial response patients (16 months). The response to fludarabine was rapid, with 36 (92%) of the 39 responders having achieved at least a partial response following the first three courses. Complete responses occurred in the blood, liver, spleen, and lymph nodes in 48% to 69% of the patients. Eradication of all disease in the bone marrow occurred in only 13% of the cases. Neutropenia and thrombocytopenia occurred in 56% and 25% of evaluable courses. Major infections occurred in 9% of evaluable courses and fevers of unknown origin or minor infections in 12% of courses respectively. Myelosuppression and infection were more common in patients with initial Rai stages 3 and 4 and in nonresponding patients. Other toxicity was mild. No CNS toxicity was noted.     

Interruption from irrelevant auditory and visual onsets even when attention is in a focused state

The common view on the interplay between exogenous and endogenous orienting holds that abrupt onsets are not capable of attracting attention when they occur outside the current focus of attention. Does this also apply to sudden irrelevant auditory onsets and when irrelevant visual onsets occur far in the periphery? In addition, does focused attention also reduce the alerting effect of auditory onsets, or vice versa, do highly alerting stimuli distort the attentional state? Crossmodal and unimodal variants of the Posner paradigm were examined in two experiments with targets and irrelevant onsets occurring at 28.3 and 19.3° from fixation. Either centrally presented arrows indicated the forthcoming position of visual targets to be discriminated, or warning cues signaled the likely moment of target occurrence. The targets could be preceded by peripheral auditory or visual onsets that were to be ignored. Crossmodal and unimodal exogenous orienting effects of these irrelevant onsets were observed while participants focused at the relevant side. In addition, no evidence was found that the alerting effect of auditory onsets was dependent on focused attention. Our findings indicate that, at least under the current conditions, neither crossmodal nor unimodal orienting effects of peripheral events dissipate when attention is in a focused state.     

Differential expression and distribution of epithelial adhesion molecules in non-small cell lung cancer and normal bronchus

BACKGROUND: Changes in epithelial cell interactions have been implicated in carcinogenesis, tumour invasion and metastasis. AIM: To screen for altered expression of epithelial adhesion genes in lung cancer development. METHODS: Gene expression profiles were assessed with cDNA expression arrays in eight non-small cell lung cancer (NSCLC) and eight normal bronchi obtained from the same patient. Immunohistochemistry (IHC) and RNA in situ hybridisation (ISH) were used to confirm the most prominently expressed adhesion molecules and to investigate their distribution at protein and mRNA levels. RESULTS: 43 differentially expressed cancer-related genes were identified in adenocarcinoma, squamous cell carcinoma (SCC) and normal bronchus. Five of these genes are related to epithelial adhesion-that is, integrin alpha3 (ITGA3), integrin beta4 (ITGB4), desmoplakin I and II (DSP), plakoglobin, and desmocollin 3 (DSC3). ITGA3 and ITGB4, showing predominantly cell-matrix staining, were up regulated in adenocarcinoma and SCC, respectively. ITGB4 also showed strong staining in SCC with IHC and ISH. Components of the desmosome adhesion complex DSP, plakoglobin and DSC3 were strongly up regulated in SCC and showed a distinct cell-cell staining pattern. DSP and plakoglobin were predominantly present at central, more differentiated tumour cells, whereas DSC3 showed a stronger staining in the peripheral basal cells of SCC tumour areas. CONCLUSIONS: Lack of cellular adhesion may have an important role in the metastatic potency of a primary tumour. A possible association of strong presence and normal-distributed desmosomal molecules in SCC with the less frequent and late pattern of metastasis in SCC as compared with adenocarcinoma is suggested.