Erlotinib in patients with previously irradiated, recurrent brain metastases from non-small cell lung cancer: Two case reports

Background: With the current improvements in primary lung care, the long-term control of brain metastases becomes a clinical challenge. No established therapeutic approaches exist for cranial relapse after response to previous radiotherapy and systemic therapy. Tyrosine kinase inhibitors like erlotinib with its proven activity in non-small cell lung cancer may provide clinical benefits in such patients. Patients and Methods: Two case reports are presented illustrating the efficacy of erlotinib in patients with recurrent brain metastases and parallel thoracic progression. Results: Both patients showed lasting partial remissions in the brain and lung, and clinical symptom improvement. Conclusion: The observed survival times of above 18 and 15 months, respectively, since occurrence of cranial disease manifestation in line with the achieved progression-free survival times of 9 and 6 months by the erlotinib third-line therapy are remarkable. The use of targeted therapies after whole-brain irradiation should be investigated more systematically in prospective clinical trials

Preoperative automated fibre quantification predicts postoperative seizure outcome in temporal lobe epilepsy

Approximately one in every two patients with pharmacoresistant temporal lobe epilepsy will not be rendered completely seizure-free after temporal lobe surgery. The reasons for this are unknown and are likely to be multifactorial. Quantitative volumetric magnetic resonance imaging techniques have provided limited insight into the causes of persistent postoperative seizures in patients with temporal lobe epilepsy. The relationship between postoperative outcome and preoperative pathology of white matter tracts, which constitute crucial components of epileptogenic networks, is unknown. We investigated regional tissue characteristics of preoperative temporal lobe white matter tracts known to be important in the generation and propagation of temporal lobe seizures in temporal lobe epilepsy, using diffusion tensor imaging and automated fibre quantification. We studied 43 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis and 44 healthy controls. Patients underwent preoperative imaging, amygdalohippocampectomy and postoperative assessment using the International League Against Epilepsy seizure outcome scale. From preoperative imaging, the fimbria-fornix, parahippocampal white matter bundle and uncinate fasciculus were reconstructed, and scalar diffusion metrics were calculated along the length of each tract. Altogether, 51.2% of patients were rendered completely seizure-free and 48.8% continued to experience postoperative seizure symptoms. Relative to controls, both patient groups exhibited strong and significant diffusion abnormalities along the length of the uncinate bilaterally, the ipsilateral parahippocampal white matter bundle, and the ipsilateral fimbria-fornix in regions located within the medial temporal lobe. However, only patients with persistent postoperative seizures showed evidence of significant pathology of tract sections located in the ipsilateral dorsal fornix and in the contralateral parahippocampal white matter bundle. Using receiver operating characteristic curves, diffusion characteristics of these regions could classify individual patients according to outcome with 84% sensitivity and 89% specificity. Pathological changes in the dorsal fornix were beyond the margins of resection, and contralateral parahippocampal changes may suggest a bitemporal disorder in some patients. Furthermore, diffusion characteristics of the ipsilateral uncinate could classify patients from controls with a sensitivity of 98%; importantly, by co-registering the preoperative fibre maps to postoperative surgical lacuna maps, we observed that the extent of uncinate resection was significantly greater in patients who were rendered seizure-free, suggesting that a smaller resection of the uncinate may represent insufficient disconnection of an anterior temporal epileptogenic network. These results may have the potential to be developed into imaging prognostic markers of postoperative outcome and provide new insights for why some patients with temporal lobe epilepsy continue to experience postoperative seizures

Minimization of free radical damage by metal catalysis of multivitamin/multimineral supplements

Multivitamin/multimineral complexes are the most common dietary supplements. Unlike minerals in foods that are incorporated in bioorganic structures, minerals in dietary supplements are typically in an inorganic form. These minerals can catalyze the generation of free radicals, thereby oxidizing antioxidants during digestion. Here we examine the ability of a matrix consisting of an amino acid and non-digestible oligosaccharide (AAOS) to blunt metal-catalyzed oxidations. Monitoring of ascorbate radical generated by copper shows that ascorbate is oxidized more slowly with the AAOS matrix than with copper sulfate. Measurement of the rate of oxidation of ascorbic acid and Trolox® by catalytic metals confirmed the ability of AAOS to slow these oxidations. Similar results were observed with iron-catalyzed formation of hydroxyl radicals. When compared to traditional forms of minerals used in supplements, we conclude that the oxidative loss of antioxidants in solution at physiological pH is much slower when AAOS is present

Experiences of enhanced recovery after surgery in general gynaecology patients: An interpretative phenomenological analysis.

There is little qualitative research exploring non-cancer gynaecology patients’ experiences of enhanced recovery after surgery (ERAS) protocols. Seven women participated in audio-recorded interviews, discussing their experiences of enhanced recovery after surgery for gynaecological surgery. Data were transcribed and analysed using interpretative phenomenological analysis. Three themes were identified: meeting informational needs, taking control of pain, and mobilising when feeling fragile. Control emerged as a key element throughout the themes and was supported by provision of factual information. While participants were generally satisfied with their experience, topics such as concerns about analgesic use, the informal role of staff in mobilisation, and the expressed desire for more experiential information for participants require further research.N/

Discovery and application of immune biomarkers for hematological malignancies

Introduction: Haematological malignancies originate and progress in primary and secondary lymphoid organs, where they establish a uniquely immune-suppressive tumour microenvironment. Although high-throughput transcriptomic and proteomic approaches are being employed to interrogate immune surveillance and escape mechanisms in patients with solid tumours, and to identify actionable targets for immunotherapy, our knowledge of the immunological landscape of haematological malignancies, as well as our understanding of the molecular circuits that underpin the establishment of immune tolerance, is not comprehensive. Areas covered: This article will discuss how multiplexed immunohistochemistry, flow cytometry/mass cytometry, proteomic and genomic techniques can be used to dynamically capture the complexity of tumour-immune interactions. Moreover, the analysis of multi-dimensional, clinically annotated data sets obtained from public repositories such as Array Express, TCGA and GEO is crucial to identify immune biomarkers, to inform the rational design of immune therapies and to predict clinical benefit in individual patients. We will also highlight how artificial neural network models and alternative methodologies integrating other algorithms can support the identification of key molecular drivers of immune dysfunction. Expert comment: High-dimensional technologies have the potential to enhance our understanding of immune-cancer interactions and will support clinical decision making and the prediction of therapeutic benefit from immune-based interventions

Prospects for seasonal forecasting of iceberg distributions in the North Atlantic

An efficient approach to ocean–iceberg modelling provides a means for assessing prospects for seasonal forecasting of iceberg distributions in the northwest Atlantic, where icebergs present a hazard to mariners each spring. The stand-alone surface (SAS) module that is part of the Nucleus for European Modelling of the Ocean (NEMO) is coupled with the NEMO iceberg module (ICB) in a “SAS-ICB” configuration with horizontal resolution of 0.25°. Iceberg conditions are investigated for three recent years, 2013–2015, characterized by widely varying iceberg distributions. The relative simplicity of SAS-ICB facilitates efficient investigation of sensitivity to iceberg fluxes and prevailing environmental conditions. SAS-ICB is provided with daily surface ocean analysis fields from the global Forecasting Ocean Assimilation Model (FOAM) of the Met Office. Surface currents, temperatures and height together determine iceberg advection and melting rates. Iceberg drift is further governed by surface winds, which are updated every 3 h. The flux of icebergs from the Greenland ice sheet is determined from engineering control theory and specified as an upstream flux in the vicinity of Davis Strait for January or February. Simulated iceberg distributions are evaluated alongside observations reported and archived by the International Ice Patrol. The best agreement with observations is obtained when variability in both upstream iceberg flux and oceanographic/atmospheric conditions is taken into account. Including interactive icebergs in an ocean–atmosphere model with sufficient seasonal forecast skill, and provided with accurate winter iceberg fluxes, it is concluded that seasonal forecasts of spring/summer iceberg conditions for the northwest Atlantic are now a realistic prospect

Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

A parsimonious 3-gene signature predicts clinical outcomes in an acute myeloid leukemia multicohort study

Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy with variable responses to chemotherapy. Although recurring cytogenetic abnormalities and gene mutations are important predictors of outcome, 50% to 70% of AMLs harbor normal or risk-indeterminate karyotypes. Therefore, identifying more effective biomarkers predictive of treatment success and failure is essential for informing tailored therapeutic decisions. We applied an artificial neural network (ANN)–based machine learning approach to a publicly available data set for a discovery cohort of 593 adults with nonpromyelocytic AML. ANN analysis identified a parsimonious 3-gene expression signature comprising CALCRL, CD109, and LSP1, which was predictive of event-free survival (EFS) and overall survival (OS). We computed a prognostic index (PI) using normalized gene-expression levels and β-values from subsequently created Cox proportional hazards models, coupled with clinically established prognosticators. Our 3-gene PI separated the adult patients in each European LeukemiaNet cytogenetic risk category into subgroups with different survival probabilities and identified patients with very high–risk features, such as those with a high PI and either FLT3 internal tandem duplication or nonmutated nucleophosmin 1. The PI remained significantly associated with poor EFS and OS after adjusting for established prognosticators, and its ability to stratify survival was validated in 3 independent adult cohorts (n = 905 subjects) and 1 cohort of childhood AML (n = 145 subjects). Further in silico analyses established that AML was the only tumor type among 39 distinct malignancies for which the concomitant upregulation of CALCRL, CD109, and LSP1 predicted survival. Therefore, our ANN-derived 3-gene signature refines the accuracy of patient stratification and the potential to significantly improve outcome prediction