Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single-agent bendamustine in patients with rituximab-refractory, ...indolent B-cell lymphoma.
Eligible patients (N = 100, ages 31-84 years) received bendamustine at a dose of 120 mg/m(2) by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0-6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression-free survival (PFS).
An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria version 3.0.19. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).
Single-agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab-refractory indolent B-cell lymphoma.
Aim: Reducing the impacts of feral cats (Felis catus) is a priority for conservation managers across the globe, and success in achieving this aim requires a detailed understanding of the species' ...ecology across a broad spectrum of climatic and environmental conditions. We reviewed the diet of the feral cat across Australia and on Australian territorial islands, seeking to identify biogeographical patterns in dietary composition and diversity, and use the results to consider how feral cats may best be managed. Location: Australia and its territorial islands. Methods: Using 49 published and unpublished data sets, we modelled trophic diversity and the consumption of eight food groups against latitude, longitude, mean temperature, precipitation, environmental productivity and climate-habitat regions. Results: We recorded 400 vertebrate species that feral cats feed on or kill in Australia, including 28 IUCN Red List species. We found evidence of continental-scale prey-switching from rabbits to small mammals, previously recorded only at the local scale. The consumption of arthropods, reptiles, rabbits, rodents and medium-sized native mammals varied with different combinations of latitude, longitude, mean annual precipitation, temperature and environmental productivity. The frequency of rodents and dasyurids in cats' diets increased as rabbit consumption decreased. Main conclusions: The feral cat is an opportunistic, generalist carnivore that consumes a diverse suite of vertebrate prey across Australia. It uses a facultative feeding strategy, feeding mainly on rabbits when they are available, but switching to other food groups when they are not. Control programmes aimed at culling rabbits could potentially decrease the availability of a preferred food source for cats and then lead to greater prédation pressure on native mammals. The interplay between cat diet and prey species diversity at a continental scale is complex, and thus cat management is likely to be necessary and most effective at the local landscape level.
Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with ...relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab.
Patients received rituximab 375 mg/m(2) intravenously on day 1 and bendamustine 90 mg/m(2) intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs.
Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%).
Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.
Several neurodegenerative diseases associated with protein misfolding (Alzheimer's and Parkinson's disease) exhibit oxidative and nitrergic stress following initiation of neuroinflammatory pathways. ...Associated nitric oxide (NO)-mediated posttranslational modifications impact upon protein functions that can exacerbate pathology. Nonenzymatic and irreversible glycation signaling has been implicated as an underlying pathway that promotes protein misfolding, but the direct interactions between both pathways are poorly understood. Here we investigated the therapeutic potential of pharmacologically suppressing neuroinflammatory NO signaling during early disease progression of prion-infected mice. Mice were injected daily with an NO synthase (NOS) inhibitor at early disease stages, hippocampal gene and protein expression levels of oxidative and nitrergic stress markers were analyzed, and electrophysiological characterization of pyramidal CA1 neurons was performed. Increased neuroinflammatory signaling was observed in mice between 6 and 10 wk postinoculation (w.p.i.) with scrapie prion protein. Their hippocampi were characterized by enhanced nitrergic stress associated with a decline in neuronal function by 9 w.p.i. Daily in vivo administration of the NOS inhibitor L-NAME between 6 and 9 w.p.i. at 20 mg/kg prevented the functional degeneration of hippocampal neurons in prion-diseased mice. We further found that this intervention in diseased mice reduced 3-nitrotyrosination of triose-phosphate isomerase, an enzyme involved in the formation of disease-associated glycation. Furthermore, L-NAME application led to a reduced expression of the receptor for advanced glycation end-products and the diminished accumulation of hippocampal prion misfolding. Our data suggest that suppressing neuroinflammatory NO signaling slows functional neurodegeneration and reduces nitrergic and glycation-associated cellular stress.
New data are reported from analyses of stomach contents from 114 long-finned pilot whales mass-stranded at four locations around Tasmania, Australia from 1992-2006. Identifiable prey remains were ...recovered from 84 (74%) individuals, with 30 (26%) individuals (17 females and 13 males) having empty stomachs. Prey remains comprised 966 identifiable lower beaks and 1244 upper beaks, belonging to 17 families (26 species) of cephalopods. Ommastrephidae spp. were the most important cephalopod prey accounting for 16.9% by number and 45.6% by reconstructed mass. Lycoteuthis lorigera was the next most important, followed by Ancistrocheirus lesueurii. Multivariate statistics identified significant differences in diet among the four stranding locations. Long-finned pilot whales foraging off Southern Australia appear to be targeting a diverse assemblage of prey (≥10 species dominated by cephalopods). This is compared to other similar studies from New Zealand and some locations in the Northern Hemisphere, where the diet has been reported to be primarily restricted to ≤3 species dominated by cephalopods. This study emphasises the importance of cephalopods as primary prey for Southern long-finned pilot whales and other marine vertebrates, and has increased our understanding of long-finned pilot whale diet in Southern Ocean waters.
Summary Background Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated ...pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. Methods In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov , number NCT00967382 , and with Current Controlled Trials, number ISRCTN87441504. Findings Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 17·1%; 95% CI 11·4–24·2% vs no dalteparin 27/143 18·9%; 95% CI 12·8–26·3%; risk difference −1·8% 95% CI −10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 19·6% vs no dalteparin 24/141 17·0%; risk difference +2·6% 95% CI −6·4 to 11·6%). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 19·6%) than in the no dalteparin group (13/141 9·2%; risk difference 10·4%, 95% CI 2·3–18·4; p=0·01). Interpretation Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
Civic participation in news production has been a trend under academic scrutiny for at least two decades. The prevalence of digital communication and the dominance of proprietary platforms are two ...combining forces that disrupt the established journalistic norms. In this article, we investigate news participation and make three grand statements regarding: 1) the holistic definition of participation, 2) the network structure of participation delineating the power dynamics of different media actors, and 3) the transnational context of participation exhibiting the structural constraints within nation-state sovereignty. It is our argument that news participation as a civic act in the digital, globalized age has not fundamentally democratized the information flow as early optimists predicted. Instead, a group of “information elite” have risen to power due to their access to institutional resources, their advantageous positioning in the media ecology, and their entrenchment in the dominant ideology. Participation on proprietary platforms can be easily co-opted to serve the interest of the new information elite.
Bendamustine hydrochloride is an alkylating agent with novel mechanisms of action. This phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell ...non-Hodgkin's lymphoma (NHL) refractory to rituximab.
Patients received bendamustine 120 mg/m(2) intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression-free survival, and safety.
Seventy-six patients, ages 38 to 84 years, with predominantly stage III/IV indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 months), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded 1 year. The most frequent nonhematologic adverse events included nausea and vomiting, fatigue, constipation, anorexia, fever, cough, and diarrhea. Grade 3 or 4 reversible hematologic toxicities included neutropenia (54%), thrombocytopenia (25%), and anemia (12%).
Single-agent bendamustine produced durable objective responses with acceptable toxicity in heavily pretreated patients with rituximab-refractory, indolent NHL. These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population.
Patients with hematological malignancies have an increased risk of serious outcomes following COVID-19 infection, suggesting broader protection is needed beyond vaccination. Monoclonal antibodies ...such as sotrovimab, casirivimab–imdevimab, and bamlanivimab have provided valuable options for the treatment of COVID-19 disease. More recently, monoclonal antibodies have been examined for the prevention of COVID-19 infection. The monoclonal antibody combination, tixagevimab–cilgavimab, was recently approved by Health Canada as pre-exposure prophylaxis against COVID-19 in individuals who are immunocompromised or where vaccination is not recommended. Prophylactic approaches such as the use of tixagevimab–cilgavimab, in addition to COVID-19 vaccination, may provide additional protection for patients with hematological malignancies who are at greater risk of serious outcomes from COVID-19 infection.
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