Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study.

This global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor-positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio [HR] = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.

Autologous stem cell transplant in fit patients with refractory or early relapsed diffuse large B-cell lymphoma that responded to salvage chemotherapy.

Chimeric antigen receptor T-cell therapy is the new standard of care in fit patients with refractory or early relapsed diffuse large B-cell lymphoma (DLBCL). However, there may still be a role for salvage chemotherapy (ST) and autologous stem cell transplant (ASCT) in certain circumstances (e.g., lack of resources for chimeric antigen receptor T-cell therapy, chemosensitive relapses). We retrospectively studied 230 patients with refractory or early relapsed DLBCL who underwent ST and ASCT. The median line of ST was one (range, 1-3). Best response before ASCT was complete response in 106 (46%) and partial response in 124 (54%) patients. The median follow-up after ASCT was 89.4 months. The median progression-free (PFS) and overall survival (OS) were 16.1 and 43.3 months, respectively. Patients relapsing between 6 to 12 months after frontline therapy had a numerically better median PFS (29.6 months) and OS (88.5 months). Patients who required one line of ST, compared to those requiring more than one line, had a better median PFS (37.9 vs. 3.9 months; P=0.0005) and OS (68.3 vs. 12.0 months; P=0.0005). Patients who achieved complete response had a better median PFS (71.1 vs. 6.3 months; P<0.0001) and OS (110.3 vs. 18.9 months; P<0.0001) than those in partial response. Patients who achieved complete response after one line of ST had the most favorable median PFS (88.5 months) and OS (117.2 months). Post-ASCT survival outcomes of patients with refractory or early relapsed DLBCL appeared reasonable and were particularly favorable in those who required only one line of ST to achieve complete response before ASCT, highlighting the role of this procedure in select patients with chemosensitive disease.

Anti-CD19 chimeric antigen receptor T-cell therapy in older patients with relapsed or refractory large B-cell lymphoma: A multicenter study.

Chimeric antigen receptor T-cell (CAR-T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B-cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR-T therapy in older patients with RR LBCL in the real-world setting. Patients aged ≥65 years with RR LBCL, treated with anti-CD19 CAR-T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65-89). Best objective and complete response rates were 86% and 62%, respectively. Median follow-up after infusion was 18.3 months. The median progression-free survival (PFS) was 6.9 months, with 6- and 12-month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR-T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR-T in older patients, including those aged ≥80 years. The age at CAR-T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR-T therapy solely based on their chronological age.

Day 100 Natural Killer Cell/CD14+HLA-DRDIM ratio and survival in lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.

INTRODUCTION: The infusion of autograft Natural Killer Cells (NKC)/CD14+ HLA-DRDIM ratio is a predictor of survival in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). This study evaluated if the Day 100 NKC/CD14+ HLA-DRDIM ratio still functions as a prognostic immune-biomarker. METHODS: This was a retrospective, single-institution, cohort analysis including 107 patients in this study that had clinical assessment at Day 100 post-APBHSCT from our prior phase III trial. We evaluated the prognostic ability of the Day 100 NKC/CD14+ HLA-DRDIM ratio to predict overall survival (OS) and progression-free survival (PFS) using Cox regression model for outcome analysis and survival by Kaplan-Meier method. RESULTS: The median follow-up from day 100 was 94.7 months (range 4.83-158.1 months) for the entire cohort. Patients with a Day 100 NKC/CD14+ HLA-DRDIM ratio ≥1.67 experienced better OS and PFS versus those with a Day 100 NKC/CD14+ HLA-DRDIM ratio <1.67: median OS was not reached versus 49.7 months, the 5-year OS rates were 91% (95% CI, 81%-96%) versus 40% (95% CI, 27%-55%), p < .0001, respectively; and median PFS was not reached versus 23.5 months, the 5-year PFS rates were 66% (95% CI, 55%-81%) versus 21% (95% CI, 15%-40%), p < .0001, respectively. Day 100 NKC/CD14+ HLA-DRDIM ratio was an independent predictor for OS and PFS in the multivariate analysis. CONCLUSIONS: Day 100 NKC/CD14+ HLA-DRDIM ratio is a prognostic immune-biomarker in lymphoma patients post- APBHSCT.

Measuring synovial thickness on knee MRI in pediatric patients with arthritis: is contrast necessary?

BACKGROUND: The use of contrast-enhanced imaging has long been standard for magnetic resonance imaging (MRI) assessments of synovitis in juvenile idiopathic arthritis (JIA). However, advancements in MRI technology have allowed for reliable identification of synovium without contrast. OBJECTIVE: To assess the equivalence of unenhanced MRI with contrast-enhanced MRI in evaluating synovial thickness. MATERIALS AND METHODS: This is an institutional review board approved, retrospective study performed in a tertiary children's hospital. Pediatric JIA patients under 21 years old were included who underwent knee MRI scans (1.5 T or 3 T) without and with contrast between January 2012 and January 2022. Two radiologists independently measured synovial thickness at 6 knee sites on contrast-enhanced and unenhanced sequences. Numerical measurements and ordinal scores based on juvenile idiopathic arthritis magnetic resonance imaging scoring (JAMRIS) system were recorded, and tests of equivalence were conducted, as well as between-reader and within-reader reliability by concordance correlation coefficient (CCC). All tests were considered significant at the 5% level. RESULTS: A total of 38 studies from 35 patients (25 females, median age 14 years; interquartile range 7 to 15.7) were included. Equivalence was demonstrated at each of the 6 sites for both continuous measurements (P-values < 0.05) and ordinal scores (P-values < 0.05) based on the average over readers. Within-reader reliability was moderate to high (CCC 0.50-0.89), except for the cruciate ligaments site. Averaged over the 6 sites, reliability between readers was low for unenhanced (CCC 0.47, with 95% CI: [0.41, 0.53]) and moderate for contrast-enhanced (CCC 0.64, with 95% CI: [0.59, 0.69]) sequences. CONCLUSION: Unenhanced knee MRI is equivalent to contrast-enhanced MRI in assessment of synovial thickness using conventional MRI sequences. Contrast material helped improve inter-reader reliability.

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial.

BACKGROUND: Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. METHODS: TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18-75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET-positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously-R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)-followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. FINDINGS: Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4-11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1-not reached]) compared with the standard-of-care group (2·3 months [2·2-4·3]; stratified hazard ratio 0·35; 95% CI 0·23-0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group. INTERPRETATION: These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. FUNDING: Celgene, a Bristol-Myers Squibb Company.

Consolidative radiotherapy for residual fluorodeoxyglucose activity on day +30 post CAR T-cell therapy in non-Hodgkin lymphoma.

Majority of non-Hodgkin lymphoma (NHL) patients who achieve partial response (PR) or stable disease (SD) to CAR T-cell therapy (CAR T) on day +30 progress and only 30% achieve spontaneous complete response (CR). This study is the first to evaluate the role of consolidative radiotherapy (cRT) for residual fluorodeoxyglucose (FDG) activity on day +30 post- CAR T in NHL. We retrospectively reviewed 61 patients with NHL who received CAR T and achieved PR or SD on day +30. Progression-free survival (PFS), overall survival (OS), and local relapse-free survival (LRFS) were assessed from CAR T infusion. cRT was defined as comprehensive - treated all FDG-avid sites - or focal. Following day +30 positron emission tomography scan, 45 patients were observed and 16 received cRT. Fifteen (33%) observed patients achieved spontaneous CR, and 27 (60%) progressed with all relapses involving initial sites of residual FDG activity. Ten (63%) cRT patients achieved CR, and four (25%) progressed with no relapses in the irradiated sites. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (P<0.001). The 2-year PFS was 73% and 37% (P=0.025) and the 2-year OS was 78% and 43% (P=0.12) in the cRT and observation groups, respectively. Patients receiving comprehensive cRT (n=13) had superior 2- year PFS (83% vs. 37%; P=0.008) and 2-year OS (86% vs. 43%; P=0.047) compared to observed or focal cRT patients (n=48). NHL patients with residual FDG activity following CAR T are at high risk of local progression. cRT for residual FDG activity on day +30 post-CAR T appears to alter the pattern of relapse and improve LRFS and PFS.

Event-Related Potentials Index Prediction Error Signalling During Perceptual Processing of Emotional Facial Expressions.

Humans use socially relevant stimuli to guide perceptual processing of the surrounding environment, with emotional stimuli receiving preferential attention due to their social importance. Predictive coding theory asserts this cognitive process occurs efficiently by combining predictions about what is to be perceived with incoming sensory information, generating prediction errors that are then used to update future predictions. Recent evidence has identified differing neural activity that demonstrates how spatial and feature-based attention may interact with prediction, yet how emotion-guided attention may influence this relationship remains unknown. In the present study, participants viewed a display of two faces in which attention, prediction, and emotion were manipulated, and responded to a face expressing a specific emotion (anger or happiness). The N170 was found to be enhanced by unpredictable as opposed to predictable stimuli, indicating that it indexes general prediction error signalling processes. The N300 amplitudes were also enhanced by unpredictable stimuli, but they were also affected by the attentional status of angry but not happy faces, suggesting that there are differences in prediction error processes indexed by the N170 and N300. Overall, the findings suggest that the N170 and N300 both index violations of expectation for spatial manipulations of stimuli in accordance with prediction error responding processes.

The pseudo-caspase FLIP(L) regulates cell fate following p53 activation.

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

A Quantum Model of Trust Calibration in Human-AI Interactions.

This exploratory study investigates a human agent's evolving judgements of reliability when interacting with an AI system. Two aims drove this investigation: (1) compare the predictive performance of quantum vs. Markov random walk models regarding human reliability judgements of an AI system and (2) identify a neural correlate of the perturbation of a human agent's judgement of the AI's reliability. As AI becomes more prevalent, it is important to understand how humans trust these technologies and how trust evolves when interacting with them. A mixed-methods experiment was developed for exploring reliability calibration in human-AI interactions. The behavioural data collected were used as a baseline to assess the predictive performance of the quantum and Markov models. We found the quantum model to better predict the evolving reliability ratings than the Markov model. This may be due to the quantum model being more amenable to represent the sometimes pronounced within-subject variability of reliability ratings. Additionally, a clear event-related potential response was found in the electroencephalographic (EEG) data, which is attributed to the expectations of reliability being perturbed. The identification of a trust-related EEG-based measure opens the door to explore how it could be used to adapt the parameters of the quantum model in real time.

Person identity-specific adaptation effects in the ventral occipito-temporal cortex.

Identifying the faces of familiar persons requires the ability to assign several different images of a face to a common identity. Previous research showed that the occipito-temporal cortex, including the fusiform and the occipital face areas, is sensitive to personal identity. Still, the viewpoint, facial expression and image-independence of this information are currently under heavy debate. Here we adapted a rapid serial visual stimulation paradigm Johnston et al. (2016, https://doi.org/10.1016/j.cortex.2016.10.002) and presented highly variable ambient-face images of famous persons to measure functional magnetic resonance imaging (fMRI) adaptation. fMRI adaptation is considered as the neuroimaging manifestation of repetition suppression, a neural phenomenon currently explained as a correlate of reduced predictive error responses for expected stimuli. We revisited the question of image-invariant identity-specific encoding mechanisms of the occipito-temporal cortex, using fMRI adaptation with a particular interest in predictive mechanisms. Participants were presented with trials containing eight different images of a famous person, images of eight different famous persons or seven different images of a particular famous person followed by an identity change to violate potential expectation effects about person identity. We found an image-independent adaptation effect of identity for famous faces in the fusiform face area. However, in contrast to previous electrophysiological studies, using similar paradigms, no release of the adaptation effect was observed when identity-specific expectations were violated. Our results support recent multivariate pattern analysis studies, showing image-independent identity encoding in the core face-processing areas of the occipito-temporal cortex. These results are discussed in the frame of recent identity-processing models and predictive mechanisms.

Zanubrutinib for treatment-naïve and relapsed/refractory chronic lymphocytic leukaemia: long-term follow-up of the phase I/II AU-003 study.

The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Clinical characteristics, prognostic indicators, and survival outcomes in intravascular lymphoma: Mayo Clinic experience (2003-2018).

Intravascular lymphoma (IVL) is a rare extranodal non-Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003-2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS-IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non-CNS-IVL patients with abnormal FDG-PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS-IVL and 63.5% (35/55) had non-CNS-IVL. CNS-IVL group consists of clinically isolated CNS involvement (CNS-only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M-IVL) (14.5%; 8/55). Non-CNS-IVL group consists of clinically isolated skin involvement (skin-only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P-IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B-cell IVL. Rituximab + high-dose methotrexate-based regimen were used in 75% (12/16) of CNS-IVL patients and RCHOP in 60% (17/28) of non-CNS-IVL patients. Estimated 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin-only IVL was associated with excellent survival. Platelet count <150x109 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

Advanced imaging of disease unrelated to the coronavirus disease 2019 (COVID-19) during the pandemic: effect of patient demographics in a pediatric emergency department.

BACKGROUND: Coronavirus disease 2019 (COVID-19) disproportionately affected children from underrepresented minorities and marginalized populations, but little is understood regarding the pandemic's effect on non-COVID-19-related illnesses. OBJECTIVE: To examine the effect of the COVID-19 pandemic and related stay-at-home orders on pediatric emergency department (ED) imaging of non-COVID-19-related diseases across patient demographic groups. MATERIALS AND METHODS: We retrospectively reviewed radiology reports from advanced imaging (US, CT, MRI and fluoroscopy) on children in the ED during the month of April for the years 2017, 2018, 2019 and 2020, excluding imaging for respiratory illness and trauma. We used imaging results and the electronic medical record to identify children with positive diagnoses on advanced imaging, and whether these children were admitted to the hospital. Demographic variables included age, gender, race/ethnicity and insurance type. We used multivariable Poisson regression models to report rate ratio (RR) and binomial logistic regression models to report odds ratio (OR) with 95% confidence interval (CI). RESULTS: We included 1,418 ED encounters for analysis. Compared to pre-2020, fewer children underwent ED imaging in April 2020 (RR 0.63, 95% CI 0.52, 0.76). The odds of positive imaging results increased (OR 2.18, 95% CI 1.59, 3.00) overall, and for all racial/ethnic groups except Hispanic patients (OR 0.83, 95% CI 0.34, 2.03). No differences occurred in admission rates for positive imaging results in 2020 compared to pre-2020. CONCLUSION: In April 2020 compared to pre-2020, there were decreased imaging and increased positivity rates for imaging for non-respiratory and non-trauma ED visits. COVID-19 stay-at-home advisories might have resulted in triaging for urgent health care by families or referring clinicians during this month of the pandemic.

Emergency pediatric radiology imaging trends for non-COVID-19-related illnesses through different stages of the pandemic.

PURPOSE: To evaluate how the COVID-19 pandemic affected the imaging utilization patterns for non-COVID-19-related illness in a pediatric emergency department (ED). METHODS: We retrospectively reviewed radiology reports for ultrasound, CT, MRI, and fluoroscopy studies performed at a pediatric ED in April from 2017 to 2021, excluding studies for respiratory symptoms and trauma. Radiology reports and medical records were reviewed to determine if patients had a positive radiology diagnosis, the type of diagnosis, and whether it required hospital admission. Results from during the pandemic were compared to predicted rates based on pre-pandemic years. RESULTS: A total of 2198 imaging studies were included. During the COVID-19 pandemic, fewer ED imaging studies were performed compared to predicted. The decrease was greater in April 2020 (RR = 0.56, p < 0.001) than in April 2021 (RR = 0.80, p = 0.038). The odds of positive diagnosis was higher during the pandemic than before, and higher in 2020 (OR 2.53, p < 0.001) than in 2021 (OR 1.38, p = 0.008). The expected numbers of positive diagnoses and hospital admittances remained within the predicted range during the pandemic (p = 0.505-0.873). CONCLUSIONS: Although imaging volumes decreased during the studied months of the pandemic, the number of positive findings was unchanged compared to prior years. No differences were demonstrated in the percentage of patients admitted to the hospital with positive imaging findings. This suggests that, at our institution, the pandemic did not lead to a substantial number of missed diagnoses or severely delay the diagnosis of non-COVID-related conditions. While still lower than expected, imaging volumes increased in April 2021 suggesting a return towards baseline patient behavior as the pandemic conditions improved.

Turning the Face Inversion Effect on Its Head: Violated Expectations of Orientation, Lighting, and Gravity Enhance N170 Amplitudes.

Face inversion effects occur for both behavioral and electrophysiological responses when people view faces. In EEG, inverted faces are often reported to evoke an enhanced amplitude and delayed latency of the N170 ERP. This response has been attributed to the indexing of specialized face processing mechanisms within the brain. However, inspection of the literature revealed that, although N170 is consistently delayed to a variety of face representations, only photographed faces invoke enhanced N170 amplitudes upon inversion. This suggests that the increased N170 amplitudes to inverted faces may have other origins than the inversion of the face's structure. We hypothesize that the unique N170 amplitude response to inverted photographed faces stems from multiple expectation violations, over and above structural inversion. For instance, rotating an image of a face upside-down not only violates the expectation that faces appear upright but also lifelong priors about illumination and gravity. We recorded EEG while participants viewed face stimuli (upright vs. inverted), where the faces were illuminated from above versus below, and where the models were photographed upright versus hanging upside-down. The N170 amplitudes were found to be modulated by a complex interaction between orientation, lighting, and gravity factors, with the amplitudes largest when faces consistently violated all three expectations. These results confirm our hypothesis that face inversion effects on N170 amplitudes are driven by a violation of the viewer's expectations across several parameters that characterize faces, rather than a disruption in the configurational disposition of its features.

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL.

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Outcomes in primary cutaneous diffuse large B-cell lymphoma, leg type.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. Immunochemotherapy with or without involved-site radiation therapy (ISRT) is considered standard front-line therapy. Over-expression of PD-L1/PD-L2 is seen in a high proportion of PCDLBCL, LT cases, but efficacy of immune checkpoint inhibitors (ICI) in relapsed/refractory, PCDLBCL, LT has not been thoroughly studied. We conducted a retrospective cohort study of patients diagnosed with PCDLBCL, LT seen at Mayo Clinic from 1 January 2000 to 31 December 2020. Using the Kaplan-Meier method, we calculated progression-free survival, duration of response, and overall survival in patients who received front-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with and without ISRT, and salvage ICI therapy for relapsed/refractory disease. A total of 28 patients with PCDLBCL, LT were identified. The median PFS in patients treated with R-CHOP plus ISRT was 58 months (95% CI: 18-112) compared to 14 months (95% CI: 5-not reached; p = 0.04) in those treated with R-CHOP without ISRT. The median PFS from salvage ICI therapy was 10 months (95% CI: 4-not reached), and median DOR from salvage ICI therapy was 23 months [95% CI: 4-26]. R-CHOP with ISRT had a significantly longer median PFS compared to R-CHOP without ISRT as front-line therapy for PCDLBCL, LT. ICIs may have a role in treating relapsed/refractory disease as reasonable activity in heavily pre-treated patients was observed in this study.

Impact of hypoalbuminemia on the prognosis of relapsed/refractory B-cell lymphoma treated with axicabtagene ciloleucel.

INTRODUCTION: Hypoalbuminemia is a known adverse prognostic factor in lymphomas. Yet, it is unknown if axicabtagene ciloleucel (axi-cel) overcomes the adverse prognostic impact of hypoalbuminemia in relapsed/refractory large B-cell lymphoma. METHODS: We conducted a retrospective analysis across three Mayo Clinic centers to assess the relationship of hypoalbuminemia (defined as a serum albumin (SA) levels ≤ 3.5 g/dL) on outcomes of patients treated with axi-cel. RESULTS: This analysis included 81 patients. Two patients had no available SA levels preceding axi-cel infusion. Eighteen patients (22.8%) had hypoalbuminemia with a median SA of 3.3 g/dL. Patients with normal SA had a statistically higher ORR than those without hypoalbuminemia (P = .018). There was no difference in 1-year PFS and OS between the group with hypoalbuminemia and the group with normal SA levels (48% vs 49%, P = .81) and (74% vs 73%, P = .97), respectively. There was no difference in the severity or median duration of cytokine release syndrome or neurotoxicity between the two groups. CONCLUSION: Notwithstanding the limitations related to the relatively small sample size, axi-cel therapy appears to overcome the adverse effect of hypoalbuminemia on OS and PFS. Large multicenter clinical studies are certainly needed to validate these findings.