Traits linked to sensory processing sensitivity mediate the relationship between externally oriented thinking and fantasizing.

Introduction: Alexithymia is characterized by difficulties identifying and describing feelings but expression of externally oriented thinking (EOT) and difficulty fantasizing is more variable. In two studies, we investigated whether links between EOT and fantasizing are mediated by sensory processing sensitivity (SPS). Methods: University students completed measures of alexithymia, SPS, and fantasizing. Results: In Study 1 (N = 700) we identified two clusters of SPS traits: a positive facet (sensitivity to subtle stimuli) and a negative facet (sensitivity to uncomfortable stimuli). In the 499 participants who completed the fantasy measure, low EOT scores predicted stronger SPS positive and negative traits, which predicted a stronger tendency to mentally project oneself into the lives of characters in books, movies, and plays. In Study 2 (N = 600), the link between EOT and this same fantasizing tendency was again mediated by features of SPS-in this case fantasy proneness and emotional reactivity. Discussion: We suggest that, whereas individuals who score high on EOT have an impoverished fantasy life, those who score relatively low on EOT and turn their attention inward are able to maintain stronger representations of imagined events in working memory (enhancing the likelihood that they will be recalled) and react more strongly to these events (enhancing their salience). Stronger expression of these features of SPS, in turn, increases the likelihood that one will develop a cognitive style that involves the application of imagery-based strategies to support deep processing of the thoughts and feelings of characters depicted in narratives.

An Event-Related Potential (ERP) Examination of the Neural Responses to Emotional and Movement-Related Images.

Previous research has suggested that the perception of emotional images may also activate brain regions related to the preparation of motoric plans. However, little research has investigated whether these emotion-movement interactions occur at early or later stages of visual perception. In the current research, event-related potentials (ERPs) were used to examine the time course of the independent - and combined - effects of perceiving emotions and implied movement. Twenty-five participants viewed images from four categories: 1) emotional with implied movement, 2) emotional with no implied movement, 3) neutral with implied movement, and 4) neutral with no implied movement. Both emotional stimuli and movement-related stimuli led to larger N200 (200-300 ms) waveforms. Furthermore, at frontal sites, there was a marginal interaction between emotion and implied movement, such that negative stimuli showed greater N200 amplitudes vs. neutral stimuli, but only for images with implied movement. At posterior sites, a similar effect was observed for images without implied movement. The late positive potential (LPP; 500-1000 ms) was significant for emotion (at frontal sites) and movement (at frontal, central, and posterior sites), as well as for their interaction (at parietal sites), with larger LPPs for negative vs. neutral images with movement only. Together, these results suggest that the perception of emotion and movement interact at later stages of visual perception.

Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial.

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

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.

Genomic analyses indicate resilience of a commercially and culturally important marine gastropod snail to climate change.

Genomic vulnerability analyses are being increasingly used to assess the adaptability of species to climate change and provide an opportunity for proactive management of harvested marine species in changing oceans. Southeastern Australia is a climate change hotspot where many marine species are shifting poleward. The turban snail, Turbo militaris is a commercially and culturally harvested marine gastropod snail from eastern Australia. The species has exhibited a climate-driven poleward range shift over the last two decades presenting an ongoing challenge for sustainable fisheries management. We investigate the impact of future climate change on T. militaris using genotype-by-sequencing to project patterns of gene flow and local adaptation across its range under climate change scenarios. A single admixed, and potentially panmictic, demographic unit was revealed with no evidence of genetic subdivision across the species range. Significant genotype associations with heterogeneous habitat features were observed, including associations with sea surface temperature, ocean currents, and nutrients, indicating possible adaptive genetic differentiation. These findings suggest that standing genetic variation may be available for selection to counter future environmental change, assisted by widespread gene flow, high fecundity and short generation time in this species. We discuss the findings of this study in the content of future fisheries management and conservation.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023.

Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Alexithymia and sensory processing sensitivity account for unique variance in the prediction of emotional contagion and empathy.

Introduction: Empathy-the ability to identify and share another person's emotional state-is an important socio-emotional process arising, in part, from emotional contagion. In the current study, we assessed unique variance in emotional contagion and other empathy-related constructs accounted for by two personality traits, alexithymia and sensory processing sensitivity (SPS), when controlling for childhood emotional abuse and current depressed mood. Methods: A sample of 305 adults (M age = 20.1 years) watched brief film clips chosen to induce various emotional states. After each film, the participants rated how strongly they experienced each of nine different emotions. They then completed self-report measures of alexithymia, SPS, empathy-related constructs, childhood emotional abuse, and current mood. Results: Those scoring high (vs. low) on SPS reported stronger primary emotions and a larger range of emotions when watching the films and were more apt to believe that their emotions matched those of the individuals featured in the films. They also scored higher on both self-oriented processes (such as the tendency to feel personal distress in tense situations) and other-oriented processes (such as perspective taking and empathic concern) related to empathy. Individuals scoring high (vs. low) on alexithymia reported feeling a larger range of emotions while watching the films but scored lower on other-oriented processes related to empathy. After controlling for SPS and alexithymia, current depressed mood predicted experiencing less varied reactions to mixed valence films that elicited strong feelings of embarrassment/humiliation, and less amusement when watching positive films. Childhood emotional abuse did not emerge as a predictor of emotional contagion or empathy. Discussion: We propose that the strong and nuanced feelings elicited in those scoring high on SPS by observing others support their personal view that they are highly empathic. In contrast, by failing to closely examine their own mixed reactions to others, individuals with alexithymia may find it difficult to connect with, understand, and respond to others' feelings.

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

A multiplexed assay for quantifying immunomodulatory proteins supports correlative studies in immunotherapy clinical trials.

Introduction: Immunotherapy is an effective treatment for a subset of cancer patients, and expanding the benefits of immunotherapy to all cancer patients will require predictive biomarkers of response and immune-related adverse events (irAEs). To support correlative studies in immunotherapy clinical trials, we are developing highly validated assays for quantifying immunomodulatory proteins in human biospecimens. Methods: Here, we developed a panel of novel monoclonal antibodies and incorporated them into a novel, multiplexed, immuno-multiple reaction monitoring mass spectrometry (MRM-MS)-based proteomic assay targeting 49 proteotypic peptides representing 43 immunomodulatory proteins. Results and discussion: The multiplex assay was validated in human tissue and plasma matrices, where the linearity of quantification was >3 orders of magnitude with median interday CVs of 8.7% (tissue) and 10.1% (plasma). Proof-of-principle demonstration of the assay was conducted in plasma samples collected in clinical trials from lymphoma patients receiving an immune checkpoint inhibitor. We provide the assays and novel monoclonal antibodies as a publicly available resource for the biomedical community.

Concurrent pembrolizumab with AVD for untreated classic Hodgkin lymphoma.

Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles. Twelve patients experienced grade 3 or 4 nonhematologic adverse events (AEs), most commonly febrile neutropenia and infection/sepsis. Grade 3 or 4 immune-related AEs, including alanine aminotransferase elevation and aspartate aminotransferase elevation were observed in 3 patients. One patient experienced an episode of grade 2 colitis and arthritis. Six patients missed at least 1 dose of pembrolizumab because of AEs, primarily grade 2 or higher transaminitis. Among 29 response-evaluable patients, the best overall response rate was 100% and the complete response rate was 90%. With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who has withheld or discontinued pembrolizumab because of toxicity has progressed. Clearance of circulating tumor DNA (ctDNA) was associated with superior PFS when measured after cycle 2 and at the end of treatment (EOT). None of the 4 patients with persistent uptake by fluorodeoxyglucose positron emission tomography (PET) at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy but may yield spurious PET findings in some patients. This trial was registered at www.clinicaltrials.gov as #NCT03331341.

Structural differences in the cortex of individuals who experience the autonomous sensory meridian response.

BACKGROUND AND PURPOSE: The autonomous sensory meridian response (ASMR) is a multimodal perceptual phenomenon in which specific sensory triggers evoke tingling sensations on the scalp, neck, and shoulders; these sensations are accompanied by a positive and calming affective state. Previous functional neuroimaging research has shown that ASMR experiences involve medial prefrontal and sensorimotor brain areas. The purpose of the current study was to examine whether there are structural differences in the cortex of individuals who experience ASMR. METHODS: Seventeen individuals with ASMR and 17 matched control participants completed an MPRAGE structural MRI scan. These data were analyzed to determine if group differences were present for measures of cortical thickness, cortical complexity, sulcal depth, and gyrification. RESULTS: ASMR was associated with reduced cortical thickness in a number of regions including the left precuneus, precentral gyrus, and insula, and the right orbitofrontal cortex, superior frontal cortex, and paracentral lobule. Reduced thickness was observed bilaterally in the supramarginal gyrus. Individuals with ASMR also showed less cortical complexity in the pars opercularis and pars triangularis. CONCLUSIONS: The differences in cortical thickness and complexity were in brain areas whose functions relate to the ASMR experience. These differences include neural regions related to phonological processing, sensorimotor functions, and attention.

Efficacy, safety, and molecular response predictors of oral ixazomib and short-course rituximab in untreated iNHL.

Patients with indolent B-cell non-Hodgkin lymphoma (iNHL) generally require treatment but experience normal survival, emphasizing the need for simpler, safer therapies. Proteasome inhibitors target aberrant signaling pathways within iNHL and have manageable toxicities. We evaluated the oral proteasome inhibitor ixazomib as initial monotherapy, and combined with rituximab, for first-line treatment of iNHL. Treatment-naïve patients with iNHL needing therapy received oral ixazomib 4 mg weekly until progressive disease or unacceptable adverse events. A 4-week course of rituximab was added during month 7. The primary end point was overall response rate (ORR) during the ixazomib monotherapy window. Correlations included gene expression profiling and response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Thirty-three patients with follicular lymphoma (FL) (n = 20), marginal zone lymphoma (n = 7), and other iNHL were treated with a median follow-up of 30.3 months. During the 6-month ixazomib window, the ORR was 24%, including 35% in FL. The best ORR over the entire study period was 52% overall and 65% in FL; complete response was achieved in 33% and 45%, respectively. The median duration of response was 25.8 months (range, 0-49.7), and the 24-month progression-free and overall survival rates were 51% (95% confidence interval [CI], 32-67) and 91% (95% CI, 74-97), respectively. Ixazomib was well tolerated. Baseline downregulation of proteasome genes, PSMB9 (P = .03) and PSMB8 (P = .007), were associated with response. All evaluated patients generated anti-S antibodies to SARS-CoV-2 vaccination, with a median of 254.9 binding arbitrary unit per mL. Ixazomib demonstrated efficacy alone and with short-course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of the B-cell immune response. This trial is registered at www.clinicaltrials.gov as NCT02339922.

Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas.

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877.

Geo-temporal patterns to design cost-effective interventions for zoonotic diseases -the case of brucellosis in the country of Georgia.

Introduction: Control of zoonosis can benefit from geo-referenced procedures. Focusing on brucellosis, here the ability of two methods to distinguish disease dissemination patterns and promote cost-effective interventions was compared. Method: Geographical data on bovine, ovine and human brucellosis reported in the country of Georgia between 2014 and 2019 were investigated with (i) the Hot Spot (HS) analysis and (ii) a bio-geographical (BG) alternative. Results: More than one fourth of all sites reported cases affecting two or more species. While ruminant cases displayed different patterns over time, most human cases described similar geo-temporal features, which were associated with the route used by migrant shepherds. Other human cases showed heterogeneous patterns. The BG approach identified small areas with a case density twice as high as the HS method. The BG method also identified, in 2018, a 2.6-2.99 higher case density in zoonotic (human and non-human) sites than in non-zoonotic sites (which only reported cases affecting a single species) -a finding that, if corroborated, could support cost-effective policy-making. Discussion: Three dissemination hypotheses were supported by the data: (i) human cases induced by sheep-related contacts; (ii) human cases probably mediated by contaminated milk or meat; and (iii) cattle and sheep that infected one another. This proof-of-concept provided a preliminary validation for a method that may support cost-effective interventions oriented to control zoonoses. To expand these findings, additional studies on zoonosis-related decision-making are recommended.

Predictors of response to axicabtagene-ciloleucel CAR T cells in aggressive B cell lymphomas: A real-world study.

Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH).

The impact of histological grade on outcomes in follicular lymphoma: An analysis of patients in the SEER database in the context of evolving disease classification and treatment.

Currently, there is no convincing evidence that the grade of follicular lymphoma (FL) impacts patient outcome. We correlated grades in 33 925 patients with nodal FL during 1992-2018 in the SEER database with disease-specific survival (DSS) and overall survival (OS). Patients with FL grade 3 had lower DSS and OS as compared to FL grades 1-2. During 1992-2005, the 10-year DSS for patients with FL grades 3 and grades 1-2 were 68.6%, and 71.4%, respectively, and in 2006-2018, they were 77.7% and 82.6%, respectively. The 10-year OS estimates in 1992-2005 were 49.9% and 54.2% for grade 3 and grades 1-2 respectively, and in 2006-2018, they were 59.1% and 63.5% for grade 3 and grades 1-2, respectively. After adjustment for stage and age, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 during 1992-2005 were 1.09 (1.02-1.16) and 1.07 (1.02-1.12), respectively, compared to FL grades 1-2; and during 2006-2018, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 were 1.34 (1.22-1.45) and 1.16 (1.10-1.23), respectively compared to FL grades 1-2. The grade of FL is an important determinant of disease biology.

Predictors of cytopenias after treatment with axicabtagene ciloleucel in patients with large B-cell lymphoma.

Cytopenias are important but less studied adverse events following chimeric antigen receptor-engineered T cell (CAR-T) therapy. In our analysis of patients with large cell lymphoma who received axicabtagene ciloleucel (axi-cel), we sought to determine the rate and risk factors of clinically significant short term cytopenias defined as grade ≥3 neutropenia, anemia, or thrombocytopenia, or treatment with growth factors or blood product transfusions between days 20-30 after axi-cel. Fifty-three pts received axi-cel during the study period and severe cytopenias were observed in 32 (60%) pts. Significant cytopenias were more common in non-responders (stable or progressive disease) vs. responders (partial or complete response) (100% vs. 70%; p = .01). In the multivariable model, platelet transfusion within a month before leukapheresis, number of red blood cell and platelet transfusions between leukapheresis to lymphodepletion, pre-lymphodepletion absolute neurophil count, pre-lymphodepletion lactate dehydrogenase, and number of dexamethasone treatments after CAR-T were significantly associated with severe cytopenias after axi-cel.