1,721,041 research outputs found
Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis
Full text linkPURPOSE To assess the efficacy and tolerability of bortezomib with or without dexamethasone and to define prognostic factors for patients with primary systemic light chain (AL) amyloidosis treated with bortezomib or both. PATIENTS AND METHODS Ninety-four patients from three centers were analyzed: 19% received the combination as first-line treatment, 81% had a median of two previous therapies, and 69% had refractory disease, while most patients had symptomatic heart involvement or elevated serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Results A hematologic response was achieved in 71% within a median of 52 days, including 25% complete responses (CRs). Previously untreated patients had a 47% CR rate. Age 65 years or younger (P = .043) and twice weekly administration of bortezomib (P = .041) were associated with higher response rates. A cardiac response was documented in 29% of patients, in most as sustained improvement of functional class and less often as a decrease in wall thickness. Hematologic responses were associated with a cardiac response and NT-proBNP reduction. After a median follow-up of 12 months, 29% of patients had organ progression and 27% had hematologic progression. Median survival has not been reached and the 1-year survival rate is 76%. Baseline NT-proBNP was independently associated with survival (P = .001), while in a landmark analysis, survival was associated with NT-proBNP reduction of > or = 30% (P = .006) and achievement of hematologic response (P = .001). Toxicity was manageable and mostly consisted of neuropathy, orthostasis, peripheral edema, and constipation or diarrhea. CONCLUSION Bortezomib with or without dexamethasone is active in AL amyloidosis and induces rapid responses and high rates of hematologic and organ responses. Serial measurement of cardiac biomarkers is a powerful predictor of outcome
Amyloidosis: Diagnostic investigations, clinical categories, prognosis and management
Full text linkBACKGROUND: Amyloidosis is a very rare disorder of protein misfolding characterised by the deposition of certain proteins in an abnormal fibrillary form within the extracellular space, which disrupts the normal structure and function of organs throughout the body. Amyloid deposition may be systemic or localised, though there have been few systematic clinical studies of the latter. Treatment depends on the respective amyloid fibril type, and comprises chemotherapy regimens derived from myeloma for the most prevalent systemic monoclonal immunoglobulin light chain (AL) type. The clinical features of systemic AL amyloidosis are protean, commonly including a variety of poorly understood coagulation abnormalities and fatigue symptoms of uncertain cause. Measurement of serum free light chains (FLC) has been a very important advance in guiding treatment of systemic AL amyloidosis. Novel treatment approaches include the serum amyloid P component (SAP) depleting drug ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2 carboxylic acid which has shown promise in a pilot study in patients with hereditary fibrinogen amyloidosis. AIMS: To compare the performance of two commercially available serum free light chain assays and study the prognostic utility of each in systemic AL amyloidosis. To investigate the underlying bleeding and coagulation abnormalities, associated prognostic implications, endothelial dysfunction and implications for the possibility of light chain toxicity. To explore the sleep disordered breathing morbidity in amyloidosis. To investigate the incidence, patient characteristics and survival outcomes in patients with localised AL amyloidosis. To explore a subgroup of localised amyloidosis: tracheobronchial and laryngeal amyloidosis from a clinical and proteomic perspective. To examine two types of treatment in systemic amyloidosis: the use of lenalidomide based chemotherapy with prior use of Thalidomide/Bortezomib treatment in systemic AL amyloidosis and CPHPC treatment. RESULTS AND CONCLUSIONS: Both FreeliteTM and N Latex assays have high sensitivity for detecting abnormal FLC in patients with systemic light chain amyloidosis, showing an excellent correlation between the assays for identifying the abnormal light chain subtype but with discordance in the absolute values. Coagulation abnormalities in systemic AL amyloidosis were frequent and included the following abnormalities: elevated concentration of fibrinogen in 42 (56.8%), elevated FVIII 67 (90.5%) and vWF Ag 67 (90.5%). Kaplan Meier estimates showed that vWF Ag (p=0.039) and FVIII (p=0.01) thresholds greater than 280IU associated with a significant survival disadvantage. A fall in the vWF Ag levels following chemotherapy in those achieving a clonal response suggests potential light chain toxicity implications. Albumin concentration lower than 25g/L correlated with coagulation factors which are prothrombotic, implying that anticoagulation may be an important consideration in newly diagnosed systemic AL. Thus these findings suggest the potential prognostic utility of vWF Ag levels and thrombotic risks associated with newly diagnosed systemic AL patients. Recurrent overnight oxygen desaturations proved to be frequent in patients with cardiac and/or soft tissue amyloidosis, although the occurrence of sleep disordered breathing (SDB) needs confirmation with formal polysomnography. Patients with poor right heart ventricular systolic function score high with SDB questionnaires, which was associated with adverse outcome in newly diagnosed cardiac AL amyloidosis. Localised AL amyloidosis is a very different disease from systemic AL amyloidosis, with a far superior prognosis. Local surgical resection is adequate in most patients with localised amyloidosis in whom treatment is needed, and radiotherapy can have a useful role in some patients whose disease cannot be controlled by local measures. Progression to systemic AL amyloidosis is extremely rare except among patients with lymph node involvement. Patients with lymph node involvement and those with isotypic specific circulating free light chains warrant closer follow up for development of systemic amyloidosis. Most patients with localised AL have excellent long term outcomes. Laryngeal and tracheobronchial amyloidosis is a subtype of localised amyloidosis, in which hoarseness and dyspnoea are the predominant symptoms, the 2 year OS 93% and 90% respectively. Proteomic analysis of amyloid dissected from biopsies showed the presence of the amyloid signature proteins, apolipoprotein A1 (in greater amounts protein) and insulin-like growth factor binding protein complex in all samples compared with patients with systemic AL or transthyretin amyloidosis. Of interest, apolipoprotein A1 has been described within the respiratory tract and insulin growth factor has been postulated to play a role in inflammation, which may be relevant with respect to the pathogenesis and effects of airways amyloidosis. Lenalidomide and dexamethasone combination treatment following prior proteasome inhibitor based therapy produced an overall haematologic response rate of 61%, including 20% complete responses. Renal responses among patients who received prolonged treatment were surprisingly frequent; twenty one out of 38 (55%) evaluable patients achieved a renal response (40% on an ITT basis) – 7 (18%) at 6 months, 7 (18%) at 12 months and an additional 7 (18%) patients at 18 months by long term follow up. This raises the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits. CPHPC depletes circulating Serum amyloid P (SAP) component as a treatment for systemic amyloidosis.1 Our study of 10 patients suggested a significant reduction in the natural progression of renal decline and renal survival along with an excellent safety profile; this was supported by our QoL assessments using SFv36 questionnaires. The work in this thesis has thus contributed to improved characterisation and clinical management of various types of amyloidosis, and has identified several avenues of therapy that merit further investigation in larger populations and randomised clinical trials
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
