Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BackgroundA previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak.MethodsIn order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).ResultsOf the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available.ConclusionOff-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies

Three-dimensional hydrodynamic and sediment transport modeling to test the sediment focusing hypothesis in upland lakes

Palaeolimnological studies rely on assumptions regarding the distribution and completeness of lake deposits that are not always fully supported by observations. In particular, the assumption that “focusing” of suspended sediments leads to preferential deposition in the deepest part of a lake is not always justified, especially in upland lakes subject to energetic wind forcing. Few studies have investigated the hydrodynamic controls on lake sediment focusing, especially the importance of wind-driven currents in deep water. We combine a three-dimensional numerical hydrodynamic and suspended sediment model (FVCOM) with a semi-empirical wind wave model to investigate the potential mobility of bottom sediments in a small oligotrophic upland lake (Llyn Conwy, north Wales, UK). Exploratory simulations of wave- and current-generated bottom stress and suspended sediment dynamics confirm the expected importance of wave-generated bottom stresses in shallower waters (< 3 m depth) around the shore. Field survey shows that lake sediments are largely absent from this zone. This is consistent with peripheral wave action as a sediment focusing mechanism. In deeper water, wind-driven currents become the dominant contributor to bottom stress. Strong wind forcing events drive an energetic circulation with peak bottom stresses that intermittently exceed any realistic erosion threshold over a large proportion of the lake at depths far below those at which waves can be effective. The spatial distribution of lake sediments, and the completeness of the sediment record, is thus determined by a complex interaction between wind-driven circulation and bathymetry, rather than by bathymetry alone. Although our sediment dynamics simulations are purely exploratory, the results are consisted with survey results that show a patchy distribution of deep-water accumulation. Some implications of these results for the selection of sediment coring locations and the interpretation of sediment records are considered

Duramycin-porphyrin conjugates for targeting of tumour cells using photodynamic therapy

Duramycin, through binding with phosphatidylethanolamine (PE), has been shown to be a selective molecular probe for the targeting and imaging of cancer cells. Photodynamic therapy aims to bring about specific cytotoxic damage to tumours through delivery of a photosensitising agent and light irradiation. Conjugation to biological molecules that specifically target cancer has been shown to increase photosensitiser (PS) selectivity and decrease damage to surrounding normal tissue. The aim of this study was to target tumour cells with a PE-specific PS therefore duramycin was conjugated to a porphyrin based PS which was achieved via direct reaction with the ε-amino group on the lysine residue near duramycin's N-terminal. The compound was subsequently purified using RP-HPLC and confirmed using mass spectrometry. Binding of the conjugate to ovarian and pancreatic cancer cell lines was assessed by flow cytometry. Light irradiation with a light fluence of 7.5 J/cm2 was delivered to conjugate treated cancer cells and cell proliferation analysed by MTT assay. The conjugate detected PE on all 4 cancer cell lines in a concentration dependent manner and conjugate plus irradiation effectively reduced cell proliferation at concentrations ≥0.5 μM, dependent on cancer cell line. Reduction in cell proliferation by the irradiated conjugate was enhanced over unconjugated duramycin in A2780, AsPC-1 and SK-OV-3 (p b 0.05). In this study we have shown that a duramycin-porphyrin conjugate retained good binding affinity for its target and, following irradiation, reduced cell proliferation of pancreatic and ovarian cancer cell lines

Effects of Vagus Nerve Stimulation on Progressive Myoclonus Epilepsy of Unverricht-Lundborg Type

Purpose : A 34-year-old woman with progressive myoclonus epilepsy of Unverricht-Lundborg type was considered for vagus nerve stimulation (VNS) therapy. Methods : After demonstration of intractability to multiple antiepileptic regimens and progressive deterioration in cerebellar function, the patient was implanted with a vagus nerve stimulator and followed for 1 year. Neurological status, seizure frequency, and parameter changes were analyzed. Results : VNS therapy resulted in reduction of seizures (more than 90%) and a significant improvement in cerebellar function demonstrated on neurological examination. The patient reported improved quality of life based in part on her ability to perform activities of daily living. Conclusions : VNS therapy may be considered a treatment option for progressive myoclonus epilepsy. The effects of VNS on seizure control and cerebellar dysfunction may provide clues to the underlying mechanism(s) of action.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65549/1/j.1528-1157.2000.tb00293.x.pd

Human helminth therapy to treat inflammatory disorders - where do we stand?

Parasitic helminths have evolved together with the mammalian immune system over many millennia and as such they have become remarkably efficient modulators in order to promote their own survival. Their ability to alter and/or suppress immune responses could be beneficial to the host by helping control excessive inflammatory responses and animal models and pre-clinical trials have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, MS, asthma and atopy. Thus, helminth therapy has been suggested as a possible treatment method for autoimmune and other inflammatory disorders in humans

All Optical Implementation of Multi-Spin Entanglement in a Semiconductor Quantum Well

We use ultrafast optical pulses and coherent techniques to create spin entangled states of non-interacting electrons bound to donors (at least three) and at least two Mn2+ ions in a CdTe quantum well. Our method, relying on the exchange interaction between localized excitons and paramagnetic impurities, can in principle be applied to entangle a large number of spins.Comment: 17 pages, 3 figure

Survey of the needs of patients with spinal cord injury: impact and priority for improvement in hand function in tetraplegics\ud

Objective: To investigate the impact of upper extremity deficit in subjects with tetraplegia.\ud \ud Setting: The United Kingdom and The Netherlands.\ud \ud Study design: Survey among the members of the Dutch and UK Spinal Cord Injury (SCI) Associations.\ud \ud Main outcome parameter: Indication of expected improvement in quality of life (QOL) on a 5-point scale in relation to improvement in hand function and seven other SCI-related impairments.\ud \ud Results: In all, 565 subjects with tetraplegia returned the questionnaire (overall response of 42%). Results in the Dutch and the UK group were comparable. A total of 77% of the tetraplegics expected an important or very important improvement in QOL if their hand function improved. This is comparable to their expectations with regard to improvement in bladder and bowel function. All other items were scored lower.\ud \ud Conclusion: This is the first study in which the impact of upper extremity impairment has been assessed in a large sample of tetraplegic subjects and compared to other SCI-related impairments that have a major impact on the life of subjects with SCI. The present study indicates a high impact as well as a high priority for improvement in hand function in tetraplegics.\ud \u

Selective inhibition of T suppressor-cell function by a monosaccharide

Interactions between regulatory T lymphocytes and other cells are assumed to occur at the level of the cell surface. T cells which suppress the generation of specifically effector cells have been described as having antigenic, idiotypic, allotypic and I-region specificity1−4. Other T suppressor cells generated by in vitro cultivation with or without mitogenic stimulation5,6 have suppressive activity for T and B cells but no specificity can be assigned to them. These T suppressor cells (Ts) inhibit various lymphoid functions—this either reflects their polyclonal origin or indicates that the structures recognized by the Ts receptors must be common for many cell types. Carbohydrates on cell membrane-inserted glycoproteins or glycolipids might function as specific ligands for recognition by cellular receptors or soluble factors. Almost all cell-surface proteins of mammalian cells are glycosylated. There is evidence for lectin-like carbohydrate binding proteins not only in plants7 but also in toxins8, viruses9, prokaryotic cells10 and even mammalian cells, including T cells11. A functional role for these lectin-like proteins has been described for slime moulds and suggested for the selective association of embryonic cells12,13. We report here that addition of a monosaccharide can counteract the effect of T suppressor cells during the generation of alloreactive cytotoxic T cells (CTLs) in vitro

Inter-rater reliability of the Dysexecutive Questionnaire (DEX): comparative data from non-clinician respondents – all raters are not equal

Primary objective: The Dysexecutive Questionnaire (DEX) is used to obtain information about executive and emotional problems after neuropathology. The DEX is self-completed by the patient (DEX-S) and an independent rater such as a family member (DEX-I). This study examined the level of inter-rater agreement between either two or three non-clinician raters on the DEX-I in order to establish the reliability of DEX-I ratings. Methods and procedures: Family members and/or carers of 60 people with mixed neuropathology completed the DEX-I. For each patient, DEX-I ratings were obtained from either two or three raters who knew the person well prior to brain injury. Main outcomes and results: We obtained two independent-ratings for 60 patients and three independent-ratings for 36 patients. Intra-class correlations revealed that there was only a modest level of agreement for items, subscale and total DEX scores between raters for their particular family member. Several individual DEX items had low reliability and ratings for the emotion sub-scale had the lowest level of agreement. Conclusions: Independent DEX ratings completed by two or more non-clinician raters show only moderate correlation. Suggestions are made for improving the reliability of DEX-I ratings.</p