Triple combination targeting methyltransferase, BCL-2, and PD-1 facilitates antileukemia responses in acute myeloid leukemia.

BACKGROUND: A recent breakthrough therapy combining the BCL-2 inhibitor venetoclax with hypomethylating agents (HMAs) targeting DNA methyltransferase has improved outcomes for patients with acute myeloid leukemia (AML), but the responses and long-term survival in older/unfit patients and in patients with relapsed/refractory AML remain suboptimal. Recent studies showed that inhibition of BCL-2 or DNA methyltransferase modulates AML T-cell immunity. METHODS: By using flow cytometry and time-of-flight mass cytometry, the authors examined the effects of the HMA decitabine combined with the BCL-2 inhibitor venetoclax (DAC/VEN therapy) on leukemia cells and T cells in patients with AML who received DAC/VEN therapy in a clinical trial. The authors investigated the response of programmed cell death protein 1 (PD-1) inhibition in the DAC/VEN-treated samples in vitro and investigated the triple combination of PD-1 inhibition with HMA/venetoclax in the trial patients who had AML. RESULTS: DAC/VEN therapy effectively targeted leukemia cells and upregulated the expression of the immune checkpoint-inhibitory receptor PD-1 in T cells while preserving CD4-positive and CD8-positive memory T cells in a subset of patients with AML who were tested. In vitro PD-1 inhibition potentiated the antileukemia response in DAC/VEN-treated AML samples. The combined use of azacitidine, venetoclax, and nivolumab eliminated circulating blasts and leukemia stem cells/progenitor cells and expanded the percentage of CD8-positive memory T cells in an illustrative patient with relapsed AML who responded to the regimen in an ongoing clinical trial. CONCLUSIONS: Immunomodulation by targeting PD-1 enhances the therapeutic effect of combining an HMA and venetoclax in patients with AML.

How we approach the perioperative management of patients with chronic lymphocytic leukaemia receiving continuous cancer-directed therapies.

Historically, invasive procedures and surgeries were deferred in patients with haematological malignancies including advanced stage chronic lymphocytic leukaemia (CLL) because of limited life expectancy. However, novel, and often continuous, treatments have markedly improved outcomes in CLL. Some patients may expect years of treatment response and disease control, overcoming the short life expectancy that deters interventionalists. Such patients now often undergo various invasive procedures including major surgery. To inform peri-operative management, we summarize the relevant side effects and drug interactions of continuous CLL therapies, highlight potential surgical risks, and provide recommendations on withholding specific CLL drugs around invasive procedures.

Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study.

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.

Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells.

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

Embodying cognitive ethology.

Cognitive psychology considers the environment as providing information, not affecting fundamental information processes. Thus, cognitive psychology's traditional paradigms study responses to precisely timed stimuli in controlled environments. However, new research demonstrates the environment does influence cognitive processes and offers cognitive psychology new methods. The authors examine one such proposal: cognitive ethology. Cognitive ethology improves cognitive psychology's ecological validity through first drawing inspiration from robust phenomena in the real world, then moving into the lab to test those phenomena. To support such methods, cognitive ethologists appeal to embodied cognition, or 4E cognition, for its rich relationships between agents and environments. However, the authors note while cognitive ethology focuses on new methods (epistemology) inspired by embodied cognition, it preserves most traditional assumptions about cognitive processes (ontology). But embodied cognition-particularly its radical variants-also provides strong ontological challenges to cognitive psychology, which work against cognitive ethology. The authors argue cognitive ethology should align with the ontology of less radical embodied cognition, which produces epistemological implications, offering alternative methodologies. For example, cognitive ethology can explore differences between real-world and lab studies to fully understand how cognition depends on environments.

First-in-Class Selective HDAC6 Inhibitor (ACY-1215) Has a Highly Favorable Safety Profile in Patients with Relapsed and Refractory Lymphoma.

LESSONS LEARNED: Oral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan-class inhibitors, and increased ease of use. ACY-1215 is well tolerated and led to disease stabilization in 50% of patients treated on a twice-daily dosing schedule. Rational drug combinations with ACY-1215 improve efficacy in patients with lymphoma. Biomarkers such as XBP-1 level or HDAC6-score may improve patient selection. BACKGROUND: ACY-1215, ricolinostat, is an oral, first-in-class isoform-selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY-1215 disrupted proteostasis, triggering apoptosis. METHODS: We translated these findings into a multi-institution, open-label, dose-escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma. RESULTS: Twenty-one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts [Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10)]. ACY-1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1-2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3-4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY-1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days. CONCLUSION: ACY-1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.

Generation of pralatrexate resistant T-cell lymphoma lines reveals two patterns of acquired drug resistance that is overcome with epigenetic modifiers.

While pralatrexate (PDX) has been successfully developed for the treatment of T-cell lymphoma, the mechanistic basis for its T-cell selectivity and acquired resistance remains elusive. In an effort to potentially identify synergistic combinations that might circumnavigate or delay acquired PDX resistance, we generated resistant cells lines over a broad concentration range. PDX-resistant cell lines H9-12 and H9-200 were developed, each exhibiting an IC50 of 35 and over 1000 nM, respectively. These lines were established in vitro from parental H9 cells. Expression analysis of the proteins known to be important determinants of antifolate pharmacology revealed increase expression of dihydrofolate reductase (DHFR) due to gene amplification, and reduced folate carrier1 downregulation, as the putative mechanisms of resistance in H9-12 and H9-200 cells. Cross resistance was only seen with methotrexate but not with romidepsin, azacitidine (AZA), decitabine, gemcitabine, doxorubicin, or bortezomib. Resistance to PDX was reversed by pretreatment with hypomethylating agents in a concentration-dependent fashion. Comparison of gene expression profiles of parental and resistant cell lines confirmed markedly different patterns of gene expression, and identified the dual specificity phosphatase four (DUSP4) as one of the molecular target of PDX activity. Reduced STAT5 phosphorylation following exposure to PDX was observed in the H9 but not in the H9-12 and H9-200 cells. These data suggest that combination with hypomethylating agents could be potent, and that DUSP4 and STAT5 could represent putative biomarkers of PDX activity.

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.

Survival benefit in patients with peripheral T-cell lymphomas after treatments with novel therapies and clinical trials.

The peripheral T-cell lymphomas (PTCL) are rare and heterogeneous diseases characterized by an unfavorable prognosis. Chemotherapy is standard upfront treatment in most patients, but responses are short-lived with few FDA-approved "novel" agents available. We sought to define the impact of these novel agents as single agents or in clinical trials on the outcomes of patients with PTCL. From January 1994 to May 2019, adult patients with PTCL who were managed at our institution were included in this analysis. In addition to patients with incomplete data, those diagnosed with large granular lymphocytic leukemia and cutaneous T-cell lymphoma (CTCL) except for transformed mycosis fungoides were excluded. Statistical analyses were performed using SAS version 9.4. There were 219 patients included in the analysis. The median age at diagnosis was 56 years (range, 18-90 years). First line therapies mostly consisted of combination chemotherapy (75%). There was a statistical difference among patients who received chemotherapy, novel agents alone and in chemotherapy-free combinations, other, and no treatment (P < .0001). In patients who were treated with second line chemotherapy, novel agents alone and in combination without chemotherapy, or other, there was a still a survival benefit favoring novel agents (P = .0417). In the third line, there was no statistical difference among the three groups (P = .569). All patients who received novel therapies and underwent autologous stem cell transplant (autoSCT) achieved a complete response (CR) and had a better survival compared with patients who underwent chemotherapy who had a 70% CR rate prior to autoSCT (P = .046). Exposure to FDA-approved novel agents, immunoepigenetic trials, and clinical trials in general was associated with an overall survival (OS) benefit (P = .003, P = .04, and P = .006, respectively). These data suggest that patients who receive novel agents have superior outcomes compared with patients without exposure to novel therapies who receive chemotherapy-predicated treatments.

Potentially inappropriate medication use in elderly non-Hodgkin lymphoma patients is associated with reduced survival and increased toxicities.

Survival outcomes for elderly lymphoma patients are disproportionally inferior to those of younger patients. We examined medication usage at diagnosis for 171 elderly patients (median age 70 years) with aggressive non-Hodgkin lymphoma treated between 2009 and 2014. At least one potentially inappropriate medication was used in 47% of patients according to the Beers Criteria, 59% experienced treatment delays and/or dose reduction and 65% experienced ≥ grade 3 treatment-related toxicities. We report here for the first time that potentially inappropriate medication use was associated with reduced progression-free survival and overall survival, and increased ≥ grade 3 treatment-related toxicities in multivariate analysis.

A Web-based Multimedia Program Before Colonoscopy Increased Knowledge and Decreased Anxiety, Sedation Requirement, and Procedure Time.

GOALS: Assess the impact of a web-based multimedia patient engagement program on patient anxiety, perception and knowledge about the colonoscopy in addition to procedure outcomes. BACKGROUND: The success of patients coming for a colonoscopy for colorectal cancer screening is dependent in part on patients' understanding of the preparation and of the procedure. Patients were randomized to use either our institution's standard preprocedure colonoscopy packet or a web-based multimedia patient engagement program (Emmi Solutions) before their scheduled procedure. On the day of colonoscopy, all participants completed a survey including questions to assess knowledge and perception of colonoscopy, in addition to the State Trait Anxiety Inventory. We also collected procedure data including medication doses and procedure time. STUDY RESULTS: Patients in the experimental group correctly answered knowledge questions (82%) more often than the control group (74%) (P=0.0003). More than half (58%) of patients in the experimental group felt this intervention reduced their anxiety about the procedure, and the State Trait Anxiety Inventory anxiety score was lower in the experimental group (P=0.026). Patients who viewed the program required less midazolam (3.66 vs. 4.46 mg, P=0.0035) and total procedure time was shorter (24.8 vs. 29 min, P=0.024). CONCLUSIONS: A web-based multimedia patient engagement program watched before colonoscopy decreased patient anxiety, medication requirements, and procedure time while increasing knowledge. This intervention could help patients understand and feel more comfortable about colonoscopy leading to increased screening rates while increasing efficiency and decreasing recovery time.

Comparing the Effects of Mindfulness-Based Cognitive Therapy and Sleep Psycho-Education with Exercise on Chronic Insomnia: A Randomised Controlled Trial.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) is a potential treatment for chronic insomnia. We evaluated the efficacy of MBCT for insomnia (MBCT-I) by comparing it with a sleep psycho-education with exercise control (PEEC) group. METHODS: Adults with chronic primary insomnia (n = 216) were randomly allocated to the MBCT-I or PEEC group. The MBCT-I included mindfulness and psycho-education with cognitive and behavioural components under cognitive behavioural therapy for insomnia. PEEC included psycho-education of sleep hygiene and stimulus control, and exercises. Any change in insomnia severity was measured by the Insomnia Severity Index (ISI). Secondary outcomes included sleep parameters measured by a sleep diary, health service utilisation, absence from work and mindfulness measured by the Five Facet Mindfulness Questionnaire. RESULTS: The ISI score significantly decreased in the MBCT-I group compared with the PEEC group at 2 months (i.e., post-intervention) (p = 0.023, effect size [95% CI] -0.360 [-0.675, -0.046]) but not at 5 or 8 months. Treatment response rates and remission rates based on the ISI cut-off scores were not significantly different between groups. Wake time after sleep onset (WASO) was less in the MBCT-I group at 2 and 5 months. At 8 months, both groups showed a reduced ISI score, sleep onset latency and WASO, and increased sleep efficiency and total sleep time; however, no group differences were seen. Other outcome measures did not significantly improve in either group. CONCLUSIONS: Long-term benefits were not seen in MBCT-I when compared with PEEC, although short-term benefits were seen.

T-cell lymphomas, a challenging disease: types, treatments, and future.

T-cell lymphomas are rare and aggressive malignancies associated with poor outcome, often because of the development of resistance in the lymphoma against chemotherapy as well as intolerance in patients to the established and toxic chemotherapy regimens. In this review article, we discuss the epidemiology, pathophysiology, current standard of care, and future treatments of common types of T-cell lymphomas, including adult T-cell leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, aggressive NK/T-cell lymphoma, and cutaneous T-cell lymphoma.

Mindfulness-based cognitive therapy v. group psychoeducation for people with generalised anxiety disorder: randomised controlled trial.

BACKGROUND: Research suggests that an 8-week mindfulness-based cognitive therapy (MBCT) course may be effective for generalised anxiety disorder (GAD). AIMS: To compare changes in anxiety levels among participants with GAD randomly assigned to MBCT, cognitive-behavioural therapy-based psychoeducation and usual care. METHOD: In total, 182 participants with GAD were recruited (trial registration number: CUHK_CCT00267) and assigned to the three groups and followed for 5 months after baseline assessment with the two intervention groups followed for an additional 6 months. Primary outcomes were anxiety and worry levels. RESULTS: Linear mixed models demonstrated significant group × time interaction (F(4,148) = 5.10, P = 0.001) effects for decreased anxiety for both the intervention groups relative to usual care. Significant group × time interaction effects were observed for worry and depressive symptoms and mental health-related quality of life for the psychoeducation group only. CONCLUSIONS: These results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms.

c-Abl activates janus kinase 2 in normal hematopoietic cells.

Jak2 is involved in cytokine growth factor-stimulated signal transduction, but the mechanism of its activation is largely unknown. Here, we investigated Jak2 activation in a normal hematopoietic cell line, 32D mouse myeloid cells. The bimolecular fluorescence complementation studies showed that c-Abl formed a stable complex with Jak2 in live cells. Co-immunoprecipitation results showed that c-Abl bound to the ßc chain of IL-3/IL-5/GM-CSF receptors. The kinase activities of both c-Abl and Jak2 were stimulated by IL-3 in 32D cells. Decreasing c-Abl protein expression in 32D cells by inducible shRNA decreased Jak2 activity and resulted in the failure of Jak2 activation in response to IL-3. Treatment of IL-3 and serum-starved 32D cells with 1 µM imatinib mysylate inhibited IL-3 stimulated kinase activities of both c-Abl and Jak2. In addition, the kinase-deficient Bcr-Abl mutant (p210K1172R) was defective for activation of Jak2 in 32D cells and impaired IL-3 independent growth, which was rescued by overexpression of c-Abl (+Abl). IL-3 efficiently inhibited apoptosis of 32Dp210K/R+Abl cells induced by imatinib mysylate but not Jak2 kinase inhibitor TG101209. In summary, our findings provide evidence that the kinase function of c-Abl and its C-terminal CT4 region is crucial for its interaction with Jak2 and its activation. c-Abl kinase activity induced by IL-3 is required for IL-3-stimulated Jak2 and Jak1 activation. Our findings reveal a novel regulatory role of c-Abl in Jak2 activation induced by IL-3 cytokine growth factor in 32D hematopoietic cells.

Genetic analyses of penicillin binding protein determinants in multidrug-resistant Streptococcus pneumoniae serogroup 19 CC320/271 clone with high-level resistance to third-generation cephalosporins.

We describe the dissemination of a multidrug-resistant (MDR) serogroup 19 pneumococcal clone of representative multilocus sequence type 271 (ST271) with high-level resistance to cefotaxime in Hong Kong and penicillin binding protein (pbp) genes and its relationships to Taiwan(19F)-14 and the prevalent multidrug-resistant 19A clone (MDR19A-ST320). A total of 472 nonduplicate isolates from 2006 and 2011 were analyzed. Significant increases in the rates of nonsusceptibility to penicillin (PEN) (MIC ≥ 4.0 µg/ml; 9.9 versus 23.3%; P = 0.0005), cefotaxime (CTX) (MIC ≥ 2.0 µg/ml; 12.2 versus 30.3%; P < 0.0001 [meningitis MIC ≥ 1.0 µg/ml; 30.2 versus 48.7%; P = 0.0001]), and erythromycin (ERY) (69.2 versus 84.0%; P = 0.0003) were noted when rates from 2006 and 2011 were compared. The CTX-resistant isolates with MICs of 8 µg/ml in 2011 were of serotype 19F, belonging to ST271. Analyses of the penicillin binding protein 2x (PBP2x) amino acid sequences in relation to the corresponding sequences of the R6 strain revealed M339F, E378A, M400T, and Y595F substitutions found within the ST271 clone but not present in Taiwan(19F)-14 or MDR19A. In addition, PBP2bs of ST271 strains and that of the Taiwan(19F)-14 clone were characterized by a unique amino acid substitution, E369D, while ST320 possessed the unique amino acid substitution K366N, as does that of MDR19A in the United States. We hypothesize that ST271 originated from the Taiwan(19F)-14 lineage, which had disseminated in Hong Kong in the early 2000s, and conferred higher-level ß-lactam and cefotaxime resistance through acquisitions of 19 additional amino acid substitutions in PBP2b (amino acid [aa] positions 538 to 641) and altered PBP2x via recombination events. The serogroup 19 MDR CC320/271 clone warrants close monitoring to evaluate its effect after the switch to expanded conjugate vaccines.

Treatment Patterns and Outcomes in U.S. Military Veterans Diagnosed With Chronic Lymphocytic Leukemia (CLL).

INTRODUCTION: U.S. veterans in the Veterans Affairs (VA) Healthcare System are managed in a national single-payer system with access to FDA-approved therapies. Prescribing patterns and outcomes of patients with CLL manage in the VA system are described. PATIENTS AND METHODS: This is a retrospective analysis of adult patients diagnosed with CLL managed in the VA from January 1999 through December 2020. First line treatment patterns are trended over 20 years. Factors associated with survival were analyzed in both untreated and treated patients. RESULTS: In the final analysis, 16,331 patients with CLL were included. The median overall survival (OS) for the whole cohort was 8.7 years (95% confidence interval [CI], 8.6-8.9). The median OS from diagnosis was 8.9 years (95% CI, 8.6-9.2 in untreated patients with CLL. In treated patients, the median time to first line treatment was 1.9 years (range, 0-21 years), and the median OS from initiation of treatment was 5.0 years (95% CI, 4.8-5.2). First line treatments varied over time, consistent with FDA approval of targeted therapies. Exposure to targeted therapies as either first line or in subsequent lines of therapy was associated longer survival: median OS of 8.5 years (95% CI, 8.0-9.1) compared to 3.5 years (95% CI, 3.5-3.9) in patients who never received targeted therapy (P < .0001). CONCLUSION: Patients treated in the VA have received therapies in line with current evidence-based treatment practices over the past 20 years. Treatment with targeted therapies is associated with longer median OS both in the first line and relapsed/refractory setting.

The who and the where: Attention to identities and locations in groups.

While it is widely accepted that the single gaze of another person elicits shifts of attention, there is limited work on the effects of multiple gazes on attention, despite real-world social cues often occurring in groups. Further, less is known regarding the role of unequal reliability of varying social and nonsocial information on attention. We addressed these gaps by employing a variant of the gaze cueing paradigm, simultaneously presenting participants with three faces. Block-wise, we manipulated whether one face (Identity condition) or one location (Location condition) contained a gaze cue entirely predictive of target location; all other cues were uninformative. Across trials, we manipulated the number of valid cues (number of faces gazing at target). We examined whether these two types of information (Identity vs. Location) were learned at a similar rate by statistically modelling cueing effects by trial count. Preregistered analyses returned no evidence for an interaction between condition, number of valid faces, and presence of the predictive element, indicating type of information did not affect participants' ability to employ the predictive element to alter behaviour. Exploratory analyses demonstrated (i) response times (RT) decreased faster across trials for the Identity compared with Location condition, with greater decreases when the predictive element was present versus absent, (ii) RTs decreased across trials for the Location condition only when it was completed first, and (iii) social competence altered RTs across conditions and trial number. Our work demonstrates a nuanced relationship between cue utility, condition type, and social competence on group cueing.