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We discovered a new type of dendritic spine. It is found on space-specific neurons in the barn owl inferior colliculus, a site of experience-dependent plasticity. Connectomic analysis revealed dendritic protrusions of unusual morphology including topological holes, hence termed "toric" spines (n = 76). More significantly, presynaptic terminals converging onto individual toric spines displayed numerous active zones (up to 49) derived from multiple axons (up to 11) with incoming trajectories distributed widely throughout 3D space. This arrangement is suited to integrate input sources. Dense reconstruction of two toric spines revealed that they were unconnected with the majority (∼84%) of intertwined axons, implying a high capacity for information storage. We developed an ex vivo slice preparation and provide the first published data on space-specific neuron intrinsic properties, including cellular subtypes with and without toric-like spines. We propose that toric spines are a cellular locus of sensory integration and behavioral learning.

Summary: The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi‐arm randomized phase II trial evaluating novel salvage therapies compared with R‐GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)‐eligible patients with relapsed/refractory diffuse large B‐cell lymphoma (RR‐DLBCL). This component of the LY.17 trial evaluated a dose‐intensive chemotherapy approach using a single cycle of inpatient R‐DICEP (rituximab, dose‐intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol‐specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R‐DICEP or to 3 cycles of R‐GDP. The overall response rate (ORR) was 65.6% for R‐DICEP and 48.6% for R‐GDP. The ASCT rate was 71.9% versus 54.3%, and 1‐year progression‐free survival rate was 42% versus 32%, respectively, for R‐DICEP versus R‐GDP. Although the improvement in ORR for R‐DICEP versus R‐GDP exceeded the pre‐specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3–5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents. [ABSTRACT FROM AUTHOR]

Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1·8 to 22·8 months and 11·8 to 26·3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhoea (61·1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P

BackgroundCurrent treatment of diffuse-large-B-cell lymphoma (DLBCL) includes rituximab, an expensive drug, combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Economic models have predicted rituximab plus CHOP (RCHOP) to be a cost-effective alternative to CHOP alone as first-line treatment of DLBCL, but it remains unclear what its real-world costs and cost-effectiveness are in routine clinical practice.MethodsWe performed a population-based retrospective cohort study from 1997 to 2007, using linked administrative databases in Ontario, Canada, to evaluate the costs and cost-effectiveness of RCHOP compared to CHOP alone. A historical control cohort (n = 1,099) with DLBCL who received CHOP before rituximab approval was hard-matched on age and treatment intensity and then propensity-score matched on sex, comorbidity, and histology to 1,099 RCHOP patients. All costs and outcomes were adjusted for censoring using the inverse probability weighting method. The main outcome measure was incremental cost per life-year gained (LYG).ResultsRituximab was associated with a life expectancy increase of 3.2 months over 5 years at an additional cost of $16,298, corresponding to an incremental cost-effectiveness ratio of $61,984 (95% CI $34,087-$135,890) per LYG. The probability of being cost-effective was 90% if the willingness-to-pay threshold was $100,000/LYG. The cost-effectiveness ratio was most favourable for patients less than 60 years old ($31,800/LYG) but increased to $80,600/LYG for patients 60-79 years old and $110,100/LYG for patients ≥ 80 years old. We found that post-market survival benefits of rituximab are similar to or lower than those reported in clinical trials, while the costs, incremental costs and cost-effectiveness ratios are higher than in published economic models and differ by age.ConclusionsOur results showed that the addition of rituximab to standard CHOP chemotherapy was associated with improvement in survival but at a higher cost, and was potentially cost-effective by standard thresholds for patients

Summary: The treatment pattern and outcomes in patients with indolent B‐cell lymphoma treated during the coronavirus disease 2019 (COVID‐19) pandemic period compared to the prepandemic period are unclear. This was a retrospective population‐based study using administrative databases in Ontario, Canada (follow‐up to 31 March 2022). The primary outcome was treatment pattern; secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization) and SARS‐CoV‐2 outcomes. Adjusted hazard ratios (aHR) from Cox proportional hazards models were used to estimate associations. We identified 4143 patients (1079 pandemic, 3064 prepandemic), with a median age of 69 years. In both time periods, bendamustine (B) + rituximab (BR) was the most frequently prescribed regimen. During the pandemic, fewer patients received R maintenance or completed the full 2‐year course (aHR 0.81, 95% CI 0.71–0.92, p = 0.001). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p < 0.0001; hospitalization aHR 0.81, 95% CI 0.70–0.94, p = 0.0067) and complications (infection aHR 0.69, 95% CI 0.57–0.82, p < 0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47–0.94, p = 0.020), with no difference in death. Independent of vaccination, active rituximab use was associated with a higher risk of COVID‐19 complications. Despite similar front‐line regimen use, healthcare utilization and admissions for infection were less in the pandemic cohort. [ABSTRACT FROM AUTHOR]

The streams and rivers of the Ozark Plateaus are an unrivaled natural resource for the region. They provide habitat to some of the North America’s most abundant and rich biodiversity, while also serving as water sources for human drinking, agricultural, and recreational needs. The Nature Conservancy (TNC) has identified several priority watersheds through its Ozarks Ecoregional Conservation Assessment of 2003, where it focuses its on-the ground conservation planning and implementation efforts.Sedimentation from unpaved roads is a primary threat to water quality in Ozark streams. TNC has partnered with various organizations including the US Forest Service (USFS), the Watershed Conservation Resource Center (WCRC), and others to develop a multi-phased approach to address the impacts of unpaved roads on these priority watersheds.The first step in the approach utilizes advanced GIS/GPS technologies to develop a detailed vehicle-based road inventory of the target watershed or subwatershed. Sub-meter differential GPS with customized data dictionaries are used to characterize the location and function of sediment-producing and conveying features of the road infrastructure, including the road surface, prism and slope, ditches, bars, lead-offs, culverts, crossings, and outlets. The road inventory yields a comprehensive geodatabase and map series of the mapped features.A stratified random sample of the inventoried road network is then measured to generate sediment yield predictions on ten percent of the road network. Detailed field measurements are collected with differential GPS and customized data dictionaries. The data are entered into the Water Erosion Prediction Project (WEPP) model, a process-based erosion prediction model developed by multiple federal agencies over the past 20 years. With sediment yields predicted for sample sites, erosion predictions are then extrapolated for the entire study watershed using the road inventory geodatabase.Once sedimentation yields are predicted for each road segment in the entire study area, priority sub-watersheds are identified in the GIS using watershed sediment accumulation tools. These sub-watersheds with high potential for sediment yield may be compared to species inventory data, stream bank erosion surveys, and other land use information to set priorities for conservation planning and prioritization efforts. Priority infrastructure maintenance improvements are also identified through features that were flagged in the road inventory geodatabase as needing repair or replacement.Road maintenance workshops are held with USFS engineers, county road crews, and other partners to transfer the inventory information, present the findings of the study and to demonstrate best management practices for road maintenance.Since 2004, TNC and its partners in the Arkansas have worked in three priority Ozark watersheds to inventory over 600 miles of unpaved roads and 3000 associated point features in an area greater than 900 square miles. The area comprises over thirty 6th level (12-digit) HUCs.