Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy.

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.

Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 gene knockout rat model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease that leads to a wide range of motor and nonmotor deficits. Specifically, voice and swallow deficits manifest early, are devastating to quality of life, and are difficult to treat with standard medical therapies. The pathological hallmarks of PD include accumulation of the presynaptic protein α-synuclein (αSyn) as well as degeneration of substantia nigra dopaminergic neurons. However, there is no clear understanding of how or when this pathology contributes to voice and swallow dysfunction in PD. The present study evaluates the effect of loss of function of the phosphatase and tensin homolog-induced putative kinase 1 gene in rats (PINK1(-/-) ), a model of autosomal recessive PD in humans, on vocalization, oromotor and limb function, and neurodegenerative pathologies. Behavioral measures include ultrasonic vocalizations, tongue force, biting, and gross motor performance that are assayed at 2, 4, 6, and 8 months of age. Aggregated αSyn and tyrosine hydroxylase immunoreactivity (TH-ir) were measured at 8 months. We show that, compared with wild-type controls, PINK1(-/-) rats develop (1) early and progressive vocalization and oromotor deficits, (2) reduced TH-ir in the locus coeruleus that correlates with vocal loudness and tongue force, and (3) αSyn neuropathology in brain regions important for cranial sensorimotor control. This novel approach of characterizing a PINK1(-/-) genetic model of PD provides the foundational work required to define behavioral biomarkers for the development of disease-modifying therapeutics for PD patients.

Pembrolizumab With R-CHOP in Previously Untreated DLBCL: Sustained, High Efficacy, and Safety With Long-Term Follow-Up.

BACKGROUND: While generally ineffective in relapsed diffuse large B cell lymphoma (DLBCL), immune checkpoint inhibitors (ICIs) may hold greater promise in untreated, immunocompetent patients. We previously reported safety and early efficacy of pembrolizumab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (PR-CHOP) in a phase I trial of untreated DLBCL, noting responses in 90% of patients (complete response 77%) and a 2-year progression-free survival (PFS) of 83%. We herein report long-term safety and efficacy at 5-year follow up. PATIENTS AND METHODS: Adult patients with untreated DLBCL or grade 3b follicular lymphoma, intended to receive 6 cycles of R-CHOP were eligible. Patients (N = 30) were treated with pembrolizumab 200 mg IV and R-CHOP in 21-day cycles for 6 cycles. RESULTS: At median follow up of 4.8 years, 5-year PFS was 71% (CI, 54%-94%) and 5-year overall survival was 83% (CI, 71%-98%). Immune-related adverse events (IRAEs) occurred in 7 (23%) patients (10% grade 3/4). Three IRAEs (rash, thyroiditis, rheumatoid arthritis) occurred beyond 3 months of treatment completion. PD-L1 tumor expression was documented in 19 of 23 (83%) tested patients. None of the 19 patients who had any PD-L1 expression have relapsed, whereas 2 out of the 4 patients with no PD-L1 expression have relapsed. CONCLUSION: PR-CHOP has led to durable responses in most patients, with the best outcomes in PD-L1-expressing disease. Furthermore, the safety profile was manageable, with no consistent pattern of late events. These data support ongoing strategies incorporating ICIs in frontline DLBCL therapy and confirmation of predictive biomarkers including tumor PD-L1 expression.

Early identification and treatment of communication and swallowing deficits in Parkinson disease.

Parkinson disease (PD) is a complex, progressive, neurodegenerative disorder that leads to a wide range of deficits including fine and gross sensorimotor impairment, autonomic dysfunction, mood disorders, and cognitive decline. Traditionally, the focus for diagnosis and treatment has been on sensorimotor impairment related to dopamine depletion. It is now widely recognized, however, that PD-related pathology affects multiple central nervous system neurotransmitters and pathways. Communication and swallowing functions can be impaired even in the early stages, significantly affecting health and quality of life. The purpose of this article is to review the literature on early intervention for communication and swallowing impairment in PD. Overarching themes were that (1) studies and interpretation of data from studies in early PD are limited; (2) best therapy practices have not been established, in part due to the heterogeneous nature of PD; and (3) as communication and swallowing problems are pervasive in PD, further treatment research is essential.

Integrated waste management as a climate change stabilization wedge.

Anthropogenic sources of greenhouse gas emissions are known to contribute to global increases in greenhouse gas concentrations and are widely believed to contribute to climate change. A reference carbon dioxide concentration of 383 ppm for 2007 is projected to increase to a nominal 500 ppm in less than 50 years according to business as usual models. This concentration change is equivalent to an increase of 7 billion tonnes of carbon per year (7 Gt C year(-1)). The concept of a stabilization wedge was introduced by Pacala and Socolow (Science, 305, 968-972, 2004) to break the 7 Gt C year(- 1) into more manageable 1 Gt C year(- 1) reductions that would be achievable with current technology. A total of fifteen possible 'wedges' were identified; however, an integrated municipal solid waste (MSW) management system based on the European Union's waste management hierarchy was not evaluated as a wedge. This analysis demonstrates that if the tonnage of MSW is allocated to recycling, waste to energy and landfilling in descending order in lieu of existing 'business-as-usual' practices with each option using modern technology and best practices, the system would reduce greenhouse gas emissions by more than 1 Gt C year( -1). This integrated waste management system reduces CO(2) by displacing fossil electrical generation and avoiding manufacturing energy consumption and methane emissions from landfills.

Characterization of oromotor and limb motor dysfunction in the DJ1 -/- model of Parkinson disease.

Parkinson disease (PD) is devastating to sensorimotor function that includes cranial/oromotor and limb motor deficits. However, the onset, progression, and neural correlates of PD-related dysfunctions are poorly understood. To address this gap, we used a genetic rat model of PD, DJ1 -/-, and hypothesized that motor deficits would manifest early in the disease process, be progressive in nature, and be related to pathologies in brainstem structures associated with sensorimotor function. The present study compares homozygous DJ1 -/- male rats to age-matched wild type controls. Progressive cranial sensorimotor function (ultrasonic vocalizations and tongue motor performance) and limb motor function (tapered balance beam) was analyzed at 2, 4, 6, and 8 months of age. Additionally, tyrosine hydroxylase cell counts were performed in the locus coeruleus and correlated to behavioral measures. We found that compared to wild type controls, DJ1 -/- show deficits in ultrasonic vocalizations as well as oromotor (tongue) deficits that were progressive. Overtime, DJ1 -/- rats cross a tapered balance beam with significantly decreased speed of traversal. Additionally, in the DJ1 -/-, tyrosine hydroxylase positive cells in the locus coeruleus are significantly reduced and are negatively correlated to oromotor behaviors. Characterizing the DJ1 -/- model of PD provides important foundational work necessary to define behavioral and early-onset biomarkers that parallels early-stage PD pathology in humans.

Decreased approach behavior and nucleus accumbens immediate early gene expression in response to Parkinsonian ultrasonic vocalizations in rats.

Many individuals with Parkinson disease (PD) have difficulty producing normal speech and voice, resulting in problems with interpersonal communication and reduced quality of life. Translational animal models of communicative dysfunction have been developed to assess disease pathology. However, it is unknown whether acoustic feature changes associated with vocal production deficits in these animal models lead to compromised communication. In rodents, male ultrasonic vocalizations (USVs) have a well-established role in functional inter-sexual communication. To test whether acoustic deficits in USVs observed in a PTEN-induced putative kinase 1 (PINK1) knockout (KO) PD rat model compromise communication, we presented recordings of male PINK1 KO USVs and normal wild-type (WT) USVs to female rat listeners. We measured approached behavior and immediate early gene expression (c-Fos) in brain regions implicated in auditory processing and sexual motivation. Our results suggest that females show reduced approach in response to PINK1 KO USVs compared with WT. Moreover, females exposed to PINK1 KO USVs had lower c-Fos immunolabeling in the nucleus accumbens, a region implicated in sexual motivation. These results are the first to demonstrate that vocalization deficits in a rat PD model result in compromised communication. Thus, the PINK1 KO PD model may be valuable for assessing treatments aimed at restoring vocal communicative function.