Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402.

The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub-study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B-cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31-49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.

Comparing Acute Effects of a Nano-TiO2 Pigment on Cosmopolitan Freshwater Phototrophic Microbes Using High-Throughput Screening.

Production of titanium-dioxide nanomaterials (nano-TiO2) is increasing, leading to potential risks associated with unintended release of these materials into aquatic ecosystems. We investigated the acute effects of nano-TiO2 on metabolic activity and viability of algae and cyanobacteria using high-throughput screening. The responses of three diatoms (Surirella angusta, Cocconeis placentula, Achnanthidium lanceolatum), one green alga (Scenedesmus quadricauda), and three cyanobacteria (Microcystis aeruginosa, Gloeocapsa sp., Synechococcus cedrorum) to short-term exposure (15 to 60 min) to a common nano-TiO2 pigment (PW6; average crystallite size 81.5 nm) with simulated solar illumination were assessed. Five concentrations of nano-TiO2 (0.5, 2.5, 5, 10, and 25 mg L-1) were tested and a fluorescent reporter (fluorescein diacetate) was used to assess metabolic activity. Algae were sensitive to nano-TiO2, with all showing decreased metabolic activity after 30-min exposure to the lowest tested concentration. Microscopic observation of algae revealed increased abundance of dead cells with nano-TiO2 exposure. Cyanobacteria were less sensitive to nano-TiO2 than algae, with Gloeocapsa showing no significant decrease in activity with nano-TiO2 exposure and Synechococcus showing an increase in activity. These results suggest that nanomaterial contamination has the potential to alter the distribution of phototrophic microbial taxa within freshwater ecosystems. The higher resistance of cyanobacteria could have significant implications as cyanobacteria represent a less nutritious food source for higher trophic levels and some cyanobacteria can produce toxins and contribute to harmful algal blooms.

Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402.

PURPOSE: In low-tumor burden follicular lymphoma (FL), maintenance rituximab (MR) has been shown to improve progression-free survival when compared with observation. It is not known whether MR provides superior long-term disease control compared with re-treatment rituximab (RR) administered on an as-needed basis. E4402 (RESORT) was a randomized clinical trial designed to compare MR against RR. PATIENTS AND METHODS: Eligible patients with previously untreated low-tumor burden FL received four doses of rituximab, and responding patients were randomly assigned to either RR or MR. Patients receiving RR were eligible for re-treatment at each disease progression until treatment failure. Patients assigned to MR received a single dose of rituximab every 3 months until treatment failure. The primary end point was time to treatment failure. Secondary end points included time to first cytotoxic therapy, toxicity, and health-related quality of life (HRQOL). RESULTS: A total of 289 patients were randomly assigned to RR or MR. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years for patients receiving RR and 4.3 years for those receiving MR (P = .54). Three-year freedom from cytotoxic therapy was 84% for those receiving RR and 95% for those receiving MR (P = .03). The median number of rituximab doses was four patients receiving RR and 18 for those receiving MR. There was no difference in HRQOL. Grade 3 to 4 toxicities were infrequent in both arms. CONCLUSION: In low-tumor burden FL, a re-treatment strategy uses less rituximab while providing disease control comparable to that achieved with a maintenance strategy.

Algal exudates and stream organic matter influence the structure and function of denitrifying bacterial communities.

Within aquatic ecosystems, periphytic biofilms can be hot spots of denitrification, and previous work has suggested that algal taxa within periphyton can influence the species composition and activity of resident denitrifying bacteria. This study tested the hypothesis that algal species composition within biofilms influences the structure and function of associated denitrifying bacterial communities through the composition of organic exudates. A mixed population of bacteria was incubated with organic carbon isolated from one of seven algal species or from one of two streams that differed in anthropogenic inputs. Pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) revealed differences in the organic composition of algal exudates and stream waters, which, in turn, selected for distinct bacterial communities. Organic carbon source had a significant effect on potential denitrification rates (DNP) of the communities, with organics isolated from a stream with high anthropogenic inputs resulting in a bacterial community with the highest DNP. There was no correlation between DNP and numbers of denitrifiers (based on nirS copy numbers), but there was a strong relationship between the species composition of denitrifier communities (as indicated by tag pyrosequencing of nosZ genes) and DNP. Specifically, the relative abundance of Pseudomonas stutzeri-like nosZ sequences across treatments correlated significantly with DNP, and bacterial communities incubated with organic carbon from the stream with high anthropogenic inputs had the highest relative abundance of P. stutzeri-like nosZ sequences. These results demonstrate a significant relationship between bacterial community composition and function and provide evidence of the potential impacts of anthropogenic inputs on the structure and function of stream microbial communities.

Effects of anthropogenic inputs on the organic quality of urbanized streams.

Due to arid conditions, population growth, and anthropogenic impacts from agricultural and urban development, wastewater effluent makes up an increasingly large percentage of surface water supplies promoting concerns about the potential ecological and human health effects associated with the organic quality of surface waters receiving treated wastewater discharge. Anthropogenic inputs alter the quality and quantity of organic carbon and also affect the ability of aquatic ecosystems to retain or transform carbon and other nutrients. In this paper, we use pyrolysis-GC/MS (Py-GC/MS) as a tool to examine whether the dissolved organic carbon (DOC) in suburban streams influenced by anthropogenic inputs displays an organic signature that is structurally different from natural organic material (NOM). Py-GC/MS was not only able to differentiate among stream sites that received discharge from upstream wastewater treatment plants and those that did not, but also distinguished stream sites influenced significantly by storm water. Distinct organic signatures were evident in stream waters with upstream wastewater treatment plant discharges regardless of the distance from effluent discharge, indicative of the persistent nature of effluent-derived organic material (EfOM). The pyrolysis fragments of 3-methyl-pyridine, 2-methyl-pyridine, pyrrole, and acetamide were identified as indicators of EfOM, supporting previous research that has suggested that protein and aminosugar derivitives are possible wastewater markers. Furthermore, pyrolysis fragments associated with soil polycarboxylic acids correlated highly with stream sites having the least anthropogenic influences.

Development of associations between microalgae and denitrifying bacteria in streams of contrasting anthropogenic influence.

We compared the development of microalgal and bacterial-denitrifier communities within biofilms over 28 days in a restored-prairie stream (RP) and a stream receiving treated wastewater effluent (DER). Inorganic nutrient concentrations were an order of magnitude greater in DER, and stream waters differed in the quality of dissolved organics (characterized via pyrolysis-GC/MS). Biofilm biomass and the densities of algae and bacteria increased over time in both systems; however, algal and denitrifier community composition and the patterns of development differed between systems. Specifically, algal and denitrifier taxonomic composition stabilized more quickly in DER than RP, whereas the rates of algal and denitrifier succession were more closely coupled in RP than DER. We hypothesize that, under unenriched conditions, successional changes in algal assemblages influence bacterial denitrifiers due to their dependence on algal exudates, while under enriched conditions, this relationship is decoupled. Between-system differences in organic signatures supported this, as RP biofilms contained more labile, aliphatic compounds than DER. In addition, potential denitrification rates (DNP) were negatively correlated with the percentage of aromatic compounds within the biofilm organic signatures, suggesting a significant relationship between algal exudate composition and denitrification. These results are significant because anthropogenic factors that affect biofilm community composition may alter their capacity to perform critical ecosystem services.

Influence of algal community structure on denitrification rates in periphyton cultivated on artificial substrata.

We conducted a field survey of periphyton cultivated on benthic mesh installations in freshwater aquatic systems, including two constructed wetlands and a pond, and also studied periphyton grown on a benthic mesh in laboratory mesocosms. The objectives of this study were to (1) determine if periphyton cultivated on benthic mesh denitrifies at higher rates than the underlying sediments and (2) determine if denitrification rates within periphyton vary with characteristics such as algal and bacterial community structure and biomass. We measured denitrification potential rates of field and laboratory periphyton by the acetylene inhibition method. We characterized algal community composition by algal identification and bacterial community composition by terminal restriction fragment length polymorphisms. Periphyton collected on benthic mesh from our field sites denitrified at significantly higher rates than the underlying sediments, regardless of sampling site or season. Results from both our field survey and laboratory studies indicated a significant, positive correlation between diatom presence and denitrification rate. In our laboratory studies, we found that periphyton with the highest diatom abundance showed the highest denitrification rates as well as a distinct bacterial community composition. These results suggest a synergistic relationship between diatoms and denitrifying bacteria that warrants further study.

Influence of flow conditions and system geometry on nitrate use by benthic biofilms: implications for nutrient mitigation.

The effects of substratum geometry and overlying velocity on nitrate use by periphyton were assessed. Periphyton was cultivated at an average current velocity of 0.5 cm s(-1) in laboratory mesocosms (120 cm long, 60 cm wide) on polyethylene nets of three different geometries, "1-lay er", "3-layer", and "bedform" structures, overlaying a thin bed of sand. Bulk nitrate use was then measured as the reduction of nitrate concentration in the overlying water under average velocities of 0.005, 0.05, and 0.5 cm s(-1). Periphyton structural characteristics were quantified as algal/bacterial biomass, algal species composition, and bacterial densities. Accrual of microbial biomass increased monotonically with increasing benthic net surface area, with upper sections of structures supporting the highest biomass. Maximum rates of nitrate removal were measured in the bedform geometry at intermediate velocity (173 mg NO3-N m(-2) d(-1)), and the lowest was measured with 1-layer geometry at the fastest velocity (11 mg NO3-N m(-2) d(-1)). Oxygen microprofiles within biofilms demonstrated that hydrodynamic conditions and benthic structure both play a key role in the regulation of microbial processing of nitrate delivered from the water column by promotion of denitrification in downstream sections of bedform substrata. Interactions between hydrodynamic conditions and substratum geometry are expected to regulate microbial activity in all surficial natural and engineered environments and must be parameterized to forecast long-term average biochemical transformation rates in rivers and other dynamic aquatic systems.

Follicular lymphoma: management options in the era of targeted therapy.

For the vast majority of patients diagnosed with follicular lymphoma, the disease is never cured. As a result, it becomes a "chronic disease" that must be managed over many years. A wide array of management options exist, and it is difficult to claim that one strategy is better than another. It remains to be proven that a particular initial therapy or a particular sequence of therapies is superior, if one defines "superior" as affecting survival. It also remains to be proven that immediate treatment is superior to a "watch and wait" approach in patients with low tumor burden. However, newer targeted approaches to treatment are providing additional treatment options, and they generally have more favorable side-effect profiles than traditional cytotoxic therapies. The challenge is determining how to best incorporate such targeted therapies into traditional treatment. Additionally, determining the true impact of newer therapies is not entirely straightforward, as selection bias often confounds trial results in follicular lymphoma. A new follicular lymphoma prognostic index should aid in the interpretation of future clinical trials.

Combined modality treatment for central nervous system malignancies.

This review summarizes the current status and future prospects for combined modality treatment of primary and metastatic central nervous system malignancies. The laboratory and clinical basis for multimodality therapy, including surgery, ionizing radiation, and drug therapy, are outlined and critically reviewed. The central nervous system diseases discussed include: glioma (low and high grade), brain metastases, and primary central nervous system lymphoma. Collectively, these data suggest a shift favoring combined modality approaches in several of these diseases; however, the incremental gains are indeed modest. The individual practitioner must weigh these with the additional toxicities before making a therapeutic decision for a particular patient. The future direction of combined modality therapy in these diseases will likely revolve around the increased use of molecular diagnostics resulting in the application of targeted therapy. Clearly, such promising innovations must be delineated in the context of continued preclinical studies and controlled clinical trials.

Stream permanence influences microalgal food availability to grazing tadpoles in arid-zone springs.

Primary production in many ephemeral waters peaks soon after inundation, but the extent to which the algal biomass generated by this process is immediately available to aquatic herbivores as a food source has not been extensively studied. To examine this, we exposed natural epilithon from two permanent and two recently rewetted temporary reaches of an intermittent stream to grazing by small, presumably newly hatched, Limnodynastes tasmaniensis tadpoles and compared the algal content of tadpole feces to that of the assemblages on which they grazed. Rocks from the temporary sites, one colonized by tadpoles and one not, supported relatively flocculent, diatom-rich (79.7-85.7%) epilithon of similar biomass and taxonomic content. Epilithon from the permanent sites (one with and one without tadpoles) were more cohesive, contained fewer diatoms (57.0-60.7%), and differed in species composition from that of the temporary sites, and from one another. Feces and epilithon were more taxonomically similar when epilithon originated from temporary reaches than from permanent sites. This implies that grazing tadpoles accessed a greater percentage of the algal assemblages from recently rewetted sites. Algal species differed in susceptibility to ingestion by small tadpoles, but these differences were not consistent among habitats; susceptibility to ingestion was not predictable based solely on species growth habit, but was likely also affected by physiognomic differences in mat structure among habitats. A large percentage of algal cells ingested by tadpoles survived gut passage. `Live' cells (those with full chloroplasts) comprised 43.8-66.6% of all diatoms from epilithic samples and 27.4-42.7% of those in feces of small tadpoles. In contrast, only 12.8-14.9% of the diatoms in feces produced by large L. tasmaniensis tadpoles collected from the two tadpole-colonized sites contained full chloroplasts, suggesting higher digestion efficiency in large tadpoles than in small ones. Distinct, gut-passage-induced transitions from `live' diatoms to empty frustules or single diatom valves (`dead' cells) were evident when grazed material originated from temporary reaches. In contrast, `live' diatoms in epilithon from permanent sites were more likely to emerge in tadpole feces with reduced or fragmented chloroplasts. Thus, algae from temporary reaches appeared to be more efficiently digested than those from permanent reaches. While digestibility of individual taxa varied among sites, some algae (e.g., Synedra ulna) were clearly more digestible than others. Our results suggest that temporary stream reaches in arid-zone catchments are important sources of readily digestible autotrophic biomass for anuran species in these regions.

Mechanisms of benthic algal recovery following spates: comparison of simulated and natural events.

We conducted a manipulative field experiment to examine individual and interactive effects of scour and short-term nutrient enrichment (4 h exposure) on postspate recovery of benthic algae in a desert stream. We then compared recovery from these simulated-spate conditions to algal recovery patterns following a natural spate that increased water-column nutrient levels for 2 weeks. That event differentially scoured communities on artificial substrata in place for a long-term experiment, significantly reducing biomass in 49-day-old communities but causing no significant reduction of biomass in older, 133-day-old communities. Thus, we were able to examine recovery of scoured and non-scoured benthic algal communities under natural post-spate conditions. Both natural and simulated spates reduced actual and relative abundances of diatoms within communities. In the manipulative experiment, scoured communities accrued biomass more rapidly than those not subjected to scour, but short-term enrichment had not effect. Accrual of diatoms and green algae was stimulated by the scour manipulations, while cyanobacteria maintained equal rates of growth in all treatments. Following the natural spate, diatom and green-algal densities increased in scoured communities, but recovery of algal biomass was slow on both scoured and non-scoured substrata, primarily because cyanobacteria, the dominant algal group on all tiles, did not increase under exposure to highly nitrate-enriched waters. Rates of algal cell accrual were inversely correlated with the amount of algal biomass present at the start of a recovery sequence. Algal immigration rates measured immediately after the natural spate and during an interflood period in the same season did not differ, indicating that the algal drift pool was not augmented by disturbance. Benthic algal recovery following spates is strongly influenced by the degree of scour generated by the event, but recovery patterns are also affected by the length of post-spate enrichment and the taxonomic composition of the affected community.