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Background: Relapsed and refractory Diffuse large B cell lymphoma (DLBCL) can be successfully treated with axicabtagene ciloleucel (axi-cel), a CD19-directed autologous chimeric antigen receptor T cell (CAR-T) therapy. Diagnostic image-based features could help identify the patients who would clinically respond to this advanced immunotherapy. Purpose: The aim of this study was to establish a radiomic image feature-based signature derived from positron emission tomography/computed tomography (PET/CT), including metabolic tumor burden, which can predict a durable response to CAR-T therapy in refractory/relapsed DLBCL. Methods: We conducted a retrospective review of 155 patients with relapsed/refractory DLBCL treated with axi-cel CAR-T therapy. The patients' disease involvement was evaluated based on nodal or extranodal sites. A sub-cohort of these patients with at least one nodal lesion (n=124) was assessed, while an overlapping sub-cohort (n=94) had at least one extranodal lesion. The lesion regions were characterized using 306 quantitative imaging metrics for PET images and CT images independently. Principal component (PC) analysis was performed to reduce the dimensionality in feature-based functional categories: size (n=38), shape (n=9), and texture (n=259). The selected features were used to build prediction models for survival at 1 year and tested for prognosis to overall/progression-free survival (OS/PFS) using a Kaplan-Meier (KM) plot. Results: The Shape-based PC features of the largest extranodal lesion on PET were predictive of 1-year survival (AUC 0.68 [0.43,0.94]) and prognostic of OS/PFS (p<0.018). Metabolic tumor volume (MTV) was an independent predictor with an area under the curve (AUC) of 0.74 [0.58, 0.87]. Combining these features improved the predictor performance (AUC of 0.78 [0.7, 0.87]). Additionally, the Shape-based PC features were unrelated to total MTV (Spearman's ρ of 0.359, p≤ 0.001). Conclusion: Our study found that shape-based radiomic features on PET imaging were predictive of treatment outcome (1-year survival) and prognostic of overall survival. We also found non-size-based radiomic predictors that had comparable performance to MTV and provided complementary information to improve the predictability of treatment outcomes. [ABSTRACT FROM AUTHOR]

Ketamine, an N -methyl-D-aspartate (NMDA)-receptor antagonist, is a recently revitalized treatment for pain and depression, yet its actions at the molecular level remain incompletely defined. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription in a pharmacokinetically controlled fashion. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Cellular level gene localization was performed with multiplex fluorescent in situ hybridization. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9–12 significant genes per brain region, p < 0.01 per gene) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling (Nuclear Factor Erythroid-Derived 2-Like 2) containing 12–25 increasing genes (p < 0.01) per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. At the cellular level, in situ hybridization localized up-regulation of the plasticity-associated gene Bdnf, and the transcription factors Nr4a1 and Fos, in cortical layers III and V. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine. [ABSTRACT FROM AUTHOR]

Summary: Axicabtagene ciloleucel (axi‐cel) is an autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed or refractory large B‐cell lymphoma (R/R LBCL). To reduce axi‐cel–related toxicity, several exploratory safety management cohorts were added to ZUMA‐1 (NCT02348216), the pivotal phase 1/2 study of axi‐cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti‐CD19 CAR T cells/kg after conditioning chemotherapy. Forty‐one patients received axi‐cel. Incidences of any‐grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone‐equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA‐1 cohorts. With a median follow‐up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi‐cel. [ABSTRACT FROM AUTHOR]

Summary: ZUMA‐1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi‐cel), an autologous CD19‐directed chimaeric antigen receptor (CAR)‐T cell therapy, in refractory large B‐cell lymphoma. To reduce treatment‐related toxicity, several exploratory safety management cohorts were added to ZUMA‐1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end‐points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days −5 through −3), 2 × 106 CAR‐T cells/kg (day 0) and once‐daily oral dexamethasone [10 mg, day 0 (before axi‐cel) through day 2]. Forty patients received axi‐cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty‐eight per cent of patients did not experience CRS or NEs within 72 h of axi‐cel. With a median follow‐up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population. [ABSTRACT FROM AUTHOR]

Interoceptive and exteroceptive signals, and the corresponding coordinated control of internal organs and sensory functions, including pain, are received and orchestrated by multiple neurons within the peripheral, central and autonomic nervous systems. A central aim of the present report is to obtain a molecularly informed basis for analgesic drug development aimed at peripheral rather than central targets. We compare three key peripheral ganglia: nodose, sympathetic (superior cervical), and dorsal root ganglia in the rat, and focus on their molecular composition using next-gen RNA-Seq, as well as their neuroanatomy using immunocytochemistry and in situ hybridization. We obtained quantitative and anatomical assessments of transmitters, receptors, enzymes and signaling pathways mediating ganglion-specific functions. Distinct ganglionic patterns of expression were observed spanning ion channels, neurotransmitters, neuropeptides, G-protein coupled receptors (GPCRs), transporters, and biosynthetic enzymes. The relationship between ganglionic transcript levels and the corresponding protein was examined using immunohistochemistry for select, highly expressed, ganglion-specific genes. Transcriptomic analyses of spinal dorsal horn and intermediolateral cell column (IML), which form the termination of primary afferent neurons and the origin of preganglionic innervation to the SCG, respectively, disclosed pre- and post-ganglionic molecular-level circuits. These multimodal investigations provide insight into autonomic regulation, nodose transcripts related to pain and satiety, and DRG-spinal cord and IML-SCG communication. Multiple neurobiological and pharmacological contexts can be addressed, such as discriminating drug targets and predicting potential side effects, in analgesic drug development efforts directed at the peripheral nervous system. [ABSTRACT FROM AUTHOR]

The spatial distribution of metals reflects, and can be used to constrain, the processes of chemical enrichment and mixing. Using PHANGS-MUSE optical integral field spectroscopy, we measure the gas-phase oxygen abundances (metallicities) across 7138 H  ii regions in a sample of eight nearby disc galaxies. In Paper I, we measure and report linear radial gradients in the metallicities of each galaxy, and qualitatively searched for azimuthal abundance variations. Here, we examine the 2D variation in abundances once the radial gradient is subtracted, Δ(O/H), in order to quantify the homogeneity of the metal distribution and to measure the mixing scale over which H  ii region metallicities are correlated. We observe low (0.03–0.05 dex) scatter in Δ(O/H) globally in all galaxies, with significantly lower (0.02–0.03 dex) scatter on small (<600 pc) spatial scales. This is consistent with the measurement uncertainties, and implies the 2D metallicity distribution is highly correlated on scales of ≲600 pc. We compute the two-point correlation function for metals in the disc in order to quantify the scale lengths associated with the observed homogeneity. This mixing scale is observed to correlate better with the local gas velocity dispersion (of both cold and ionized gas) than with the star formation rate. Selecting only H  ii regions with enhanced abundances relative to a linear radial gradient, we do not observe increased homogeneity on small scales. This suggests that the observed homogeneity is driven by the mixing introducing material from large scales rather than by pollution from recent and on-going star formation. [ABSTRACT FROM AUTHOR]

Recent analyses of Lee et al. (2018, 2019) have confirmed that Galactic bulge consists of stellar populations originated from Milky Way globular clusters (MWGCs). Motivated by this, here we present the evolutionary population synthesis (EPS) for the Galactic bulge and early-type galaxies (ETGs) with the realistic treatment of individual variations in light elements observed in the MWGCs. We have utilized our model with GC-origin populations to explain the CN spread observed in ETGs, and the results show remarkable matches with the observations. We further employ our model to estimate the age of ETGs, which are considered as good analogs for the MW bulge. We find that, without the effect of our new treatments, EPS models will almost always underestimate the true age of ETGs. Our analysis indicates that the EPS with GC-origin populations is an essential constraint in determining the ETG formation epoch and is closely related to understanding the evolution of the Universe. [ABSTRACT FROM AUTHOR]

In order to investigate the origin of multiple populations in globular clusters (GCs), we have constructed new chemical evolution models for proto-GCs where the supernova blast waves undergo blowout without expelling the ambient gas. Chemical enrichments in our models are then dictated by the winds of massive stars together with the asymptotic-giant-branch stars ejecta. We find that the observed Na-O anti-correlation can be reproduced when multiple episodes of starburst and enrichment are allowed to continue in proto-GCs. The "mass budget problem" is mostly resolved by our models without ad-hoc assumptions on star formation efficiency, initial mass function, and significant loss of first-generation stars. Interestingly, ages and chemical abundances predicted by this chemical evolution model are in good agreements with those independently obtained from our stellar evolution model for the horizontal-branch. We also discuss observational evidence for the GC-like multiple populations in the Milky Way bulge. [ABSTRACT FROM AUTHOR]

Recent investigations of multiple stellar populations in globular clusters (GCs) suggest that the horizontal-branch (HB) morphology and mean period of type ab RR Lyrae variables are mostly sensitive to helium abundance, while the star formation timescale has the greatest effect on our chemical evolution model constructed to reproduce the Na-O anti-correlation of GCs. Therefore, by combining the results from synthetic HB model with those from chemical evolution model, we could put better constraints on star formation history and chemical evolution in GCs with multiple populations. From such efforts made for four GCs, M4, M5, M15, and M80, we find that consistent results can be obtained from these two independent models. [ABSTRACT FROM AUTHOR]

Purpose: Studies suggested the existence of a 'trial effect,' in which for a given treatment, participation in a clinical trial is associated with a better outcome. Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). We aimed to study the effect of clinical trial participation on the outcome of mRCC patients treated with sunitinib, which at present, is poorly defined. Materials and Methods: The records of mRCC patients treated with sunitinib between 2004-2013 in 7 centers across 2 countries were reviewed. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS), between clinical trial participants (n=49) and a matched cohort of non-participants (n=49) who received standard therapy. Each clinical trial participant was individually matched with a non-participant by clinicopathologic factors. PFS and OS were determined by Cox regression. Results: The groups were matched by age (median, 64), sex (male, 67%), Heng risk (favorable, 25%; intermediate, 59%; poor, 16%), prior nephrectomy (92%), RCC histology (clear cell 86%), pre-treatment neutrophil to lymphocyte ratio (> 3 in 55%, n=27), sunitinib induced hypertension (45%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non-participants, RR was partial response/stable disease 80% (n=39) versus 74% (n=36), and progressive disease 20% (n=10) versus 26% (n=13) (p=0.63; odds ratio, 1.2). The median PFS was 10 versus 11 months (hazard ratio [HR], 0.96; p=0.84), and the median OS 23 versus 24 months (HR, 0.97; p=0.89). Conclusion: In mRCC patients treated with sunitinib, the outcome of clinical trial participants was similar to that of non-participants who received standard therapy. [ABSTRACT FROM AUTHOR]

Background It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients. Objective To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT). Design, setting, and participants Patients ( n = 2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses ( n = 1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non–clear cell RCC (nccRCC) patients, respectively. Outcome measurements and statistical analysis The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). Results and limitations All patients with LNM had worse PFS ( p = 0.001) and OS ( p < 0.001) compared to those without LNM. Compared to patients without LNM (PFS 8.8 mo; OS 25.1 mo), any SBD LNM involvement was associated with worse PFS (SBD, 6.8 mo; p = 0.003; SPD+/SBD+, 5.5 mo; p < 0.001) and OS (SBD, 16.2 mo; p < 0.001; SPD+/SBD+, 11.5 mo; p < 0.001). Both SBD and SPD+/SBD+ LNM were retained as independent prognostic factors in multivariate analyses (MVA) for PFS ( p = 0.006 and p = 0.022, respectively) and OS (both p < 0.001), while SPD LNM was not an independent risk factor. Likewise, in ccRCC, SBD LNM (19.8 mo) and SPD+/SBD+ LNM (12.85 mo) patients had the worst OS. SPD+/SBD+ LNM ( p = 0.006) and SBD LNM ( p = 0.028) were independent prognostic factors for OS in MVA, while SPD LNM was not significant ( p = 0.301). The study is limited by its retrospective design and the lack of pathologic evaluation of LNM in all cases. Conclusions The metastatic spread of RCC to SBD lymph nodes is associated with poor prognosis in mRCC patients treated with TT. Patient summary The presence of lymph node metastases below the diaphragm is associated with shorter survival outcome when metastatic renal cell carcinoma (mRCC) patients are treated with targeted therapies. Clinical trials should evaluate whether surgical removal of regional lymph nodes at the time of nephrectomy may improve outcomes in high-risk RCC patients. [ABSTRACT FROM AUTHOR]

Background The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy. Objective To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies. Design, setting, and participants Retrospective data from patients with synchronous mRCC ( n = 1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not. Outcome measurements and statistical analysis OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria. Results and limitations Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo ( p < 0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52–0.69; p < 0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively. Conclusions CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials. Patient summary We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors. [ABSTRACT FROM AUTHOR]

Examines the importance of cryptic site proteolytic exposure within collagen type IV on angiogenesis and tumor growth. Regulation of biochemical and cellular processes; Role of growth factors and integrin receptors on angiogenesis; Components of the vascular basement membrane.

In the SCHOLAR-1 retrospective analysis of pts with refractory LBCL, the objective response rate (ORR) was 26% and the complete response (CR) rate was 7% with available salvage therapies in the pre-chimeric antigen receptor (CAR) T cell therapy era (Crump M, et al. Blood. 2017). These results served as a benchmark for novel therapies. ZUMA-1 (NCT02348216) is the pivotal Phase 1/2 study evaluating axi-cel, an autologous anti-CD19 CAR T cell therapy, in refractory LBCL. At a median follow-up of 27.1 mo, the ORR in ZUMA-1 was 83% and the CR rate was 58% (Locke FL, et al. Lancet Oncol. 2019). Here, we describe comparative analyses of outcomes in ZUMA-1 and SCHOLAR-1 after adjusting for refractory status. Pts in both studies had refractory LBCL defined as stable disease of ≤ 6 mo with ≥ 4 cycles of frontline or ≥ 2 cycles of later-line therapy, progressive disease as best response, or relapse ≤ 12 mo post-autologous stem cell transplant (SCT). To address potential imbalances between studies, standardized analyses were performed that equally weighted the proportions of pts by refractory categorization (primary refractory, refractory to ≥ 2nd-line therapy, or relapse after SCT) and presence of post-refractory SCT in each study. Stratified Cochran-Mantel-Haenszel (CMH) tests and Cox models were used to compare the odds ratio (OR) for response and hazard ratio (HR) for survival between ZUMA-1 and SCHOLAR-1. P values were not adjusted for multiplicity. In Phase 2 of ZUMA-1, 101 pts received axi-cel. In SCHOLAR-1, 508 and 497 pts were evaluable for response and survival, respectively. The median follow-up in ZUMA-1 was 2.3 y, and the median follow-up from the overall SCHOLAR-1 study ranged from 7.6-14.8 y across different cohorts. Compared with SCHOLAR-1, ZUMA-1 had higher proportions of pts who received ≥ 3 lines of therapy (69% vs 23%) and pts refractory to 2nd- or later-line therapy (76% vs 62%). Fewer pts in ZUMA-1 were classified as primary refractory vs those in SCHOLAR-1 (26% vs 45%), and relapse rates within 1 y of SCT were similar between studies (21% vs 18%). The standardized ORR and CR rate in ZUMA-1 vs SCHOLAR-1 were 72% and 54% vs 22% and 7%, respectively. The OR for ORR and CR rate were 7.2-fold and 11.5-fold higher, respectively in ZUMA-1 vs SCHOLAR-1 (CMH test; P <.0001 for both ORR and CR rate). The standardized 2-year survival rate was 50% (95% CI, 40-59) in ZUMA-1 and 12% (95% CI, 9-15) in SCHOLAR-1, yielding a 73% reduction in the risk of death (HR, 0.27; P <.0001). This standardized analysis of ZUMA-1 and SCHOLAR-1 indicates that treatment with axi-cel in this selected population increased odds of CR and reduced the risk of death versus standard salvage regimens in an unselected population. Although limited by retrospective evaluation and cross-study comparisons, these results support axi-cel as a highly effective treatment option for pts with refractory LBCL. [ABSTRACT FROM AUTHOR]