Bendamustine and rituximab (BR) versus dexamethasone,rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia

The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. We compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients’ MYD88^L265P mutation status. Of 160 consecutive patients, 60 received BR (43 with relapsed/refractory WM) and 100 received DRC (50 had relapsed/refractory WM). In the treatment-naïve setting, overall response rate (ORR) was 93% with BR versus 96% with DRC (p?=?0.55). Two-year progression-free survival (PFS) with BR and DRC was 88 and 61%, respectively (p?=?0.07). In salvage setting, ORR was 95% with BR versus 87% with DRC, p?=?0.45; median PFS with BR was 58 versus 32 months with DRC (2-year PFS was 66 versus 53%; p?=?0.08). Median disease-specific survival was not reached with BR versus 166 months with DRC (p?=?0.51). The time-to-event endpoints and depth of response were independent of the MYD88 mutation status. Grade ≥?3 adverse events of both regimens were comparable. A trend for longer PFS was observed with BR although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients’ MYD88 mutation status.     

Clinical, morphological, and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma

We reviewed the clinical and morphological findings in 43 cases of monoclonal gammopathy of undetermined significance (MGUS), 9 of smoldering multiple myeloma (SMM), and 23 of overt multiple myeloma (MM). In all cases, the patients' physicians had requested a bone marrow examination because of the possibility of MM. In all 75 cases, 3H-thymidine labeling indices were performed. The plasma cell labeling index correctly classified 62 of the 75 cases (83%). A linear discriminant function combining the labeling index and percentage of plasma cells improved the accuracy to 92% (69/75), or to 95% (71/75) if patients in whom MM developed within 6 mo were considered to have MM. The labeling index was most critical for the differential diagnosis of MM from SMM (p less than 0.001). Serum or urine M-protein level, percentage of plasma cells or lymphocytes in the bone marrow, and plasma cell grade, asynchrony, and nucleolar size failed to discriminate the group with SMM from the group with MM. In patients with MGUS or SMM, a plasma cell labeling index greater than 0.4% warned of impending MM. The plasma cell labeling index is a reliable diagnostic test when applied in cases of monoclonal gammopathy, especially when differentiation from MM is difficult using standard clinical criteria.     

Genetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic tests

Rising costs of antimalarial agents are increasing the demand for accurate diagnosis of malaria. Rapid diagnostic tests (RDTs) offer great potential to improve the diagnosis of malaria, particularly in remote areas. Many RDTs are based on the detection of Plasmodium falciparum histidine-rich protein (PfHRP) 2, but reports from field tests have questioned their sensitivity and reliability. We hypothesize that the variability in the results of PfHRP2-based RDTs is related to the variability in the target antigen. We tested this hypothesis by examining the genetic diversity of PfHRP2, which includes numerous amino acid repeats, in 75 P. falciparum lines and isolates originating from 19 countries and testing a subset of parasites by use of 2 PfHRP2-based RDTs. We observed extensive diversity in PfHRP2 sequences, both within and between countries. Logistic regression analysis indicated that 2 types of repeats were predictive of RDT detection sensitivity (87.5% accuracy), with predictions suggesting that only 84% of P. falciparum parasites in the Asia-Pacific region are likely to be detected at densities < or = 250 parasites/microL. Our data also indicated that PfHRP3 may play a role in the performance of PfHRP2-based RDTs. These findings provide an alternative explanation for the variable sensitivity in field tests of malaria RDTs that is not due to the quality of the RDTs.     

Novel oral anticoagulants for heparin-induced thrombocytopenia

To review the use of the novel oral anticoagulant (NOAC) agents for the treatment of heparin-induced thrombocytopenia (HIT) from relevant clinical trial data. A MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google-Scholar searches (1966–March 2016) were conducted using the keywords: thrombocytopenia, NOACs, dabigatran, apixaban, rivaroxaban, edoxaban, Xa inhibitor, direct thrombin inhibitor. Articles evaluating the new oral anticoagulants for thrombocytopenia published in English and using human subjects were selected. Eight clinical trials were identified. References cited in identified articles were used for additional citations. Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. HIT, an immune-mediated, prothrombotic adverse reaction is a potential complication of heparin therapy. As a result, heparin products must be immediately withdrawn and replaced by alternative anticoagulants to compensate for the thrombotic risk associated with HIT. Limitations exist with the only currently FDA approved heparin alternative, argatroban. NOACs have been considered as potential alternatives to traditional agents based on their pharmacologic activity. Case reports have indicated positive results in patients, with clinical outcomes and tolerability supporting the use of the NOACs as alternative agents in the treatment of HIT. Positive results have been reported for the use of NOACs in the treatment of HIT. Further robust studies are needed for definitive decision making by clinicians.     

Recombinant human megakaryocyte growth and development factor stimulates thrombocytopoiesis in normal nonhuman primates

Megakaryocyte growth and development factor (MGDF) is a novel cytokine that binds to the c-mpl receptor and stimulates megakaryocyte development in vitro and in vivo. This report describes the ability of recombinant human (r-Hu) MGDF to affect megakaryocytopoiesis in normal nonhuman primates. r-HuMGDF was administered subcutaneously to normal, male rhesus monkeys once per day for 10 consecutive days at dosages of 2.5, 25, or 250 micrograms/kg of body weight. Bone marrow and peripheral blood were assayed for clonogenic activity and peripheral blood counts were monitored. Circulating platelet counts increased significantly (P < .05) for all doses within 6 days of r-HuMGDF administration and reached maximal levels between day 12 and day 14 postcytokine administration. The 2.5, 25.0, and 250.0 micrograms/kg/d doses elicited peak mean platelet counts that were 592%, 670%, and 449% of baseline, respectively. Bone marrow-derived clonogenic data showed significant increases in the concentration of megakaryocyte (MEG)- colony-forming unit (CFU) and granulocyte-erythroid-macrophage- megakaryocyte (GEMM)-CFU, whereas that of granulocyte-macrophage (GM)- CFU and burst-forming unit-erythroid (BFU-e) remained unchanged during the administration of r-HuMGDF. These data show that r-HuMGDF is a potent stimulator of thrombocytopoiesis in the normal nonhuman primate.     

Drivers of fatal bird collisions in an urban center

Millions of nocturnally migrating birds die each year from collisions with built structures, especially brightly illuminated buildings and communication towers. Reducing this source of mortality requires knowledge of important behavioral, meteorological, and anthropogenic factors, yet we lack an understanding of the interacting roles of migration, artificial lighting, and weather conditions in causing fatal bird collisions. Using two decades of collision surveys and concurrent weather and migration measures, we model numbers of collisions occurring at a large urban building in Chicago. We find that the magnitude of nocturnal bird migration, building light output, and wind conditions are the most important predictors of fatal collisions. The greatest mortality occurred when the building was brightly lit during large nocturnal migration events and when winds concentrated birds along the Chicago lakeshore. We estimate that halving lighted window area decreases collision counts by 11× in spring and 6× in fall. Bird mortality could be reduced by ∼60% at this site by decreasing lighted window area to minimum levels historically recorded. Our study provides strong support for a relationship between nocturnal migration magnitude and urban bird mortality, mediated by light pollution and local atmospheric conditions. Although our research focuses on a single site, our findings have global implications for reducing or eliminating a critically important cause of bird mortality.

North America has lost nearly one-third of its birdlife in the last half-century, with migratory species experiencing particularly acute declines (1). Fatal collisions with built structures represent a major source of direct, human-caused bird mortality across North America, second only to predation by domestic cats (2). Estimates indicate that between 365 million and 988 million birds die annually in collisions with buildings in the United States, with another 16 million to 42 million annual deaths in Canada (2, 3). Birds may collide with glass windows because they reflect the surrounding environment or allow birds to perceive a seemingly open pathway to the interior of the building (4). For the billions of birds that migrate at night, outdoor lighting (e.g., streetlights and floodlights) and interior lighting from buildings may be disorienting and draw birds into built-up areas, at high risk to collide with infrastructure (5–8). Light pollution not only alters nocturnal migratory behavior on a large scale (5, 7), but is also an acute conservation concern. Nocturnal collisions with well-lit communication towers alone are estimated to kill appreciable percentages of the populations of sensitive species (9).Avian collisions with lighted structures have been documented in the scientific literature as early as the 19th century (10–12). In recent decades, this link between collisions and light pollution has been the subject of detailed investigation (8, 13–16). Observers of bird–building collisions and tower kills have long remarked on the apparent influence of meteorological factors such as cloud ceiling, fog, frontal passage, and abrupt changes in conditions, all of which have been associated with large mortality events (10, 13, 17–24). Steady-burning lights may be particularly hazardous (25). Due to high building density and intensity of artificial lighting, cities are of particular concern. Reports of mass collisions at lighted buildings in urban areas are frequent in both the popular and scientific press (13, 19–21, 26).Understanding, predicting, and preventing collision mortality are areas of active scientific inquiry and priorities for policymakers (1, 13). Collisions occur more frequently during migration seasons and impact numerous species of migratory birds (29), and recent work suggests that nocturnal migratory movements can be useful for predicting bird–window collisions (30). Lights-out programs, which encourage the public to extinguish outdoor lighting to protect migratory birds, are receiving increasing attention (13). The act of extinguishing lighting allows birds to immediately return to normal, safe behavior (7) and reduces mortality at lighted buildings (13). Presently, advisories are generally issued for a given time period (e.g., peak migration periods) or on specific nights when weather conditions are favorable for large migratory movements [e.g., using migration forecasting, (31, 32)].Here, we integrate meteorological, migration-intensity, and window-radiance data to understand how these factors interact to cause bird collisions. We use a 21-y dataset of fatal collisions recorded at a single large building (McCormick Place Lakeside Center) in Chicago, IL (Fig. 1), to understand the behavioral, environmental, and anthropogenic drivers of these mortality events. Chicago poses the greatest potential risk from light pollution to migrating birds of all cities in the United States (33), and over 40,000 dead birds have been recovered from McCormick Place alone since 1978 (Figs. 2 and ​and3).3). Since 2000, we have recorded the number of birds and the lighting status of each window bay during dawn collision monitoring. Nocturnal lighting at McCormick Place correlates positively with bird collisions in many songbird species (34), but this association has not been quantified in the context of other important factors, including migration intensity and weather conditions. We estimate the effect of window lighting on collision counts and assess how the intensity of nocturnal bird migration mediates this relationship. We also test whether wind and weather conditions may magnify these associations. Finally, we investigate the spatiotemporal scales at which weather and migration data best explain collision mortality, identifying the times of night and areas of airspace associated with these events.Open in a separate windowFig. 1.Location of McCormick Place along the Chicago lakefront. The Lakeside Center building monitored in this study is highlighted in red in a three-dimensional rendering.Open in a separate windowFig. 2.Summary of collisions recorded at McCormick Place and regional bird migration between 2000 and 2020. (Upper) Individual years are drawn in different colors. Dates are given for mortality events totaling more than 50 birds. Pie charts show the family (fam.) composition of collected birds, with families representing less than 5% of total collisions merged into a single “other” category. (Lower) Summed annual migration passage at the KLOT radar in estimated number of individual birds (years colored). (Lower, Inset) Summed seasonal passage totals in estimated number of birds crossing a 75-km transect, with each point representing a year. Estimates are based on methods from ref. 35.Open in a separate windowFig. 3.Recorded collisions by year and window lighting. (A) Collisions recorded at McCormick Place between 1982 and 2020 for spring (light gray) and fall (dark gray) seasons. Horizontal lines with numeric labels show average seasonal collision totals before and after the window-lighting regime changed from fully lighted to partially lighted in 1999. The year 1997 is not shown because construction limited access to the site during that year. (B) Mean recorded daily collisions by window-lighting status from 2000 to 2020.     

The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism,vascular function,cell proliferation,and tumor growth

Background

Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer.

Methods

Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments.

Results

Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors’ avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor’s vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia.

Conclusion

The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident.