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Aims It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL). Methods and results Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL. Conclusions EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.

Stable oxygen isotope (δ18O) compositions from vertebrate tooth enamel are widely used as biogeochemical proxies for paleoclimate. However, the utility of enamel oxygen isotope values for environmental reconstruction varies among species. Herein, we evaluate the use of stable oxygen isotope compositions from pronghorn (Antilocapra americana Gray, 1866) enamel for reconstructing paleoclimate seasonality, an elusive but important parameter for understanding past ecosystems. We serially sampled the lower third molars of recent adult pronghorn from Wyoming for δ18O in phosphate (δ18OPO4) and compared patterns to interpolated and measured yearly variation in environmental waters as well as from sagebrush leaves, lakes, and rivers (δ18Ow). As expected, the oxygen isotope compositions of phosphate from pronghorn enamel are enriched in 18O relative to environmental waters. For a more direct comparison, we converted δ18Ow values into expected δ18OPO4* values (δ18OW‐PO4*). Pronghorn δ18OPO4 values from tooth enamel record nearly the full amplitude of seasonal variation from Wyoming δ18OW‐PO4* values. Furthermore, pronghorn enamel δ18OPO4 values are more similar to modeled δ18OW‐PO4* values from plant leaf waters than meteoric waters, suggesting that they obtain much of their water from evaporated plant waters. Collectively, our findings establish that seasonality in source water is reliably reflected in pronghorn enamel, providing the basis for exploring changes in the amplitude of seasonality of ancient climates. As a preliminary test, we sampled historical pronghorn specimens (1720 ± 100 AD), which show a mean decrease (a shift to lower values) of 1–2‰ in δ18OPO4 compared to the modern specimens. They also exhibit an increase in the δ18O amplitude, representing an increase in seasonality. We suggest that the cooler mean annual and summer temperatures typical of the 18th century, as well as enhanced periods of drought, drove differences among the modern and historical pronghorn, further establishing pronghorn enamel as excellent sources of paleoclimate proxy data.

PURPOSE Subtypes of depression have been under studied in women during the peripartum period and the year after childbirth and delivery. Due to heterogeneity of depression, researchers have attempted to identify phenotypes of maternal and postpartum depression based on key symptoms that may represent underlying genes and biological etiology (Leuchter et al. Dialog Clinic Neurosci 16(4):525, 2014). METHODS The current study collected self-report data from 587 women and utilized exploratory and confirmatory factor analyses (CFA) to identify subtypes of depression symptoms across two measures. RESULTS Findings of the study showed that: (1) using the Beck Depression Inventory (BDI-II) and the Postpartum Depression Screening Scale (PDSS), a five-factor solution best fit the data in our sample of mothers with infants aged 4-14 months. The factors included: anxiety/thought disorder; cognitive depression; suicide; somatic/neurovegetative; and sleep [χ2 (454, N = 587) = 1102.61, p

Purpose of review Glioma represents of variety of brain malignancies, the majority of which confer a poor prognosis despite treatment. With the widespread use of next-generation sequencing, gene fusions are being found in greater numbers. Gene fusions in glioma represent an opportunity to deliver targeted therapies to those with limited options for treatment. Recent findings Extensive studies on these gene fusions have shown that they can exhibit distinct phenotypes, such as PTPRZ1-MET fusions in secondary glioblastoma or FGFR3-TACC3 fusions in IDH wildtype gliomas. Responses have been observed with the use of targeted therapies but some have been short lived because of the development of treatment resistance. Summary Increasing detection of gene fusions in glioma along with basket trials have helped define different fusion phenotypes and paved the way for targeted kinase inhibitor-based therapies. Targeting NTRK fusions has been the most successful fusion-guided therapy to date and evaluating all patients for these fusions may be warranted.

Background The pathophysiology of rigidity in Parkinson's disease (PD) is poorly understood. Multi-sequence functional and structural brain MRI may further clarify the origin of this clinical characteristic. Purpose To examine both joint and unique relationships of MRI-based functional and structural imaging modalities to rigidity and other clinical features of PD. Study type Retrospective cross-sectional study. Population 31 PD subjects (aged 68.0 ± 5.9 years, 21 males) with average disease duration 9.3 ± 5.4 years. Field strength/sequence Multi-echo GRASE, diffusion-weighted echo planar imaging (EPI), and blood oxygen level dependent contrast EPI T2*-weighted sequences on a 3T scanner. Assessment Myelin water fraction (MWF) and fractional anisotropy (FA) of 20 white-matter regions of interest (ROIs), and functional connectivity derived from resting-state fMRI among 56 ROIs were assessed. The Unified Parkinson's Disease Rating Scale-Part III, Montreal Cognitive Assessment, Beck Depression Index, and Apathy Rating Scales were used to assess motor and non-motor symptoms. Statistical tests Multiset canonical correlation analysis (MCCA) and canonical correlation analysis (CCA) were utilized to examine the joint and unique relationships of multiple imaging measures with clinical symptoms of PD. A permutation test was used to determine statistical significance (P Results MCCA revealed a single significant component jointly linking MWF, FA, and functional connectivity to age, bradykinesia, and leg agility, non-motor symptoms of cognition, depression, and apathy, but not rigidity (P = 0.77), tremor (P = 0.50 and 0.67 on the left and right side), or sex (P = 0.54). After controlling for this joint component, CCA found a unique significant association between MWF and rigidity, but no other associations were detected, including with FA (P = 0.87). Data conclusion MWF, FA, and functional connectivity can serve as multi-sequence imaging markers to characterize many PD symptoms. However, rigidity in PD is additionally associated with widespread myelin changes. Evidence level 4 TECHNICAL EFFICACY: Stage 3.

Irritability is a common reason why children and adolescents are brought for psychiatric care. Although research is advancing what is known about the underlying brain and behavior mechanisms of irritability, clinicians often are shut out of that research. This article explains some of these research methods, providing brief summaries of what is known about brain/behavior mechanisms in disorders involving irritability, including bipolar disorder, disruptive mood dysregulation disorder, attention-deficit/hyperactivity disorder, and autism spectrum disorder. Greater access to these methods may help clinicians now and in the future, with such mechanisms translated into improved care, as occurs in the treatment of childhood leukemia.

t(6;9)(p22;q34.1)/DEK-NUP214 is a recurrent genetic abnormality that occurs in 1-2% of patients with acute myeloid leukemia (AML), and rarely in myelodysplastic syndrome (MDS). It has been suggested by others that all myeloid neoplasms with t(6;9)/DEK-NUP214 may be considered as AML, even when blast count is

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

Chronic myeloid leukemia (CML) is an age-dependent blood malignancy. Like many other age-dependent human diseases, laboratory animal research of CML uses young mice that do not factor in the influence of aging. To understand how aging may impact animal modeling of human age-dependent diseases, we established the first aging mouse model of human CML in BALB/c mice in the advanced age defined by 75% survival. This model was developed by noncytotoxic depletion of bone marrow lineage-positive cells followed by BCR-ABL retroviral transduction and transplantation. CML developed in aging mice shared many similarities to that in young mice, but had increased incidence of anemia that is often seen in human CML. Importantly, we showed that aging of both donor hematopoietic stem cells and recipient bone marrow niche impacted BCR-ABL mediated leukemogenesis and leukemia spectrum. Optimal CML induction relied on age-matching for donors and recipients, and cross-transplantation between young and old mice produced a mixture of different leukemia. Therefore, our model provides initial evidence of the feasibility and merit of CML modeling in aging mice and offers a new tool for future studies of CML stem cell drug resistance and therapeutic intervention in which aging would be taken into consideration as an influencing factor.

DNA-damage repair (DDR) pathway mutations can sensitize cancer cells to a class of cancer therapeutics known as PARP inhibitors. Given that DDR alterations can be found in up to one-third of advanced prostate cancers, PARP inhibitors have recently been established in treatment-refractory settings. We provide an updated review of the clinical data supporting the 4 PARP inhibitors that have undergone the most investigation thus far in metastatic castrate-resistant prostate cancer (mCRPC). Two of these agents are currently approved for the treatment of DDR-altered mCRPC. We end with a discussion on integration of approved PARP inhibitors into advanced prostate cancer clinical practice.

Multiparametric MRI is highly sensitive for detection of clinically significant prostate cancer, but has a 10–20% false negative rate. It is unknown if there are clinical factors that predict MRI invisibility. We sought to identify predictors of MRI-invisible (MRI(−)) disease. Men undergoing MRI/US-fusion targeted + systematic biopsy by two surgeons at our institution from 2015 to 2018 were reviewed. Patient demographics, clinical data, MRI metrics, and biopsy pathology results were obtained by chart review. An MRI(−) tumor was defined as a positive systematic biopsy in a zone without an MRI lesion. Factors associated with presence of MRI(−) tumors were identified using stepwise multivariable logistic regression. Of 194 men included in the analysis, 79 (41%) and 25 (13%) men had GG1+ and GG2+ MRI(−) tumors, respectively. On multivariable analysis, only Black race was associated with presence of GG1+ MRI(−) tumors (OR 2.2, 95% CI 1.02–4.96). Black race (OR 3.5, 95% CI 1.24–9.87) and higher PSA density (OR 2.0, 95% CI 1.34–3.20) were associated with presence of GG2+ MRI(−) tumors. In non-Black and Black men, detection of MRI(−) tumors on systematic biopsy upgraded patients from no disease to GG2+ disease 1% and 11% of the time, respectively, and from GG1 to GG2+ disease 42% and 60% of the time, respectively. Black race and PSA density were associated with presence of MRI(−) prostate cancer. Further study on racial differences is warranted based on these results. Surgeons should consider pre-biopsy risk factors before deciding to omit systematic prostate biopsy regardless of mpMRI results.

Upper tract urothelial carcinoma is a rare malignancy for which surgery provides definitive management. Open radical nephroureterectomy was the gold standard treatment, but laparoscopic and robot-assisted approaches are alternative options. Kidney-sparing approaches are feasible for carefully selected patients with ureteral cancer. This article discusses the evaluation of patients with upper tract urothelial carcinoma and definitive management using robot-assisted surgical approaches. Patients with urothelial carcinoma of the upper tract can be treated with robot-assisted nephroureterectomy, distal ureterectomy, and segmental ureterectomy.

VGX-3100 is an investigational DNA-based immunotherapy being developed as an alternative to surgery and ablation for cervical High-Grade Squamous Intraepithelial Lesion (HSIL) with the aim of preserving reproductive health while treating precancerous disease. Response durability up to 1.5 y following dosing is now reported. Histologic regression and HPV16 and/or HPV 18 (HPV16/18) clearance were previously demonstrated in a randomized, placebo-controlled, double-blind trial and reported for 6 months after the last dose of VGX-3100 or placebo. The presence of HPV16/18, Pap smear diagnoses, and immunogenicity longer-term responses were assessed at 18 months after the last dose. 91% (32/35) VGX-3100-treated women, whose cervical HSIL regressed and avoided excision at 6 months following study treatment completion, had no detectable HPV16/18 at 18 months following treatment completion. These results were comparable to those for women who received placebo and then later underwent surgery. For VGX-3100 recipients who regressed at 6 months following study treatment completion and avoided excision during the trial, Pap testing showed no HSIL recurrence at 18 months following VGX-3100 treatment. VGX-3100-induced cellular immune responses specific for HPV 16/18 E6/E7 remained higher than for placebo control recipients at 18 months. In women with cervical HSIL who responded to VGX-3100 and were able to avoid surgery, clinical outcomes were comparable to the placebo control group which underwent conventional surgical treatment. These findings extend the understanding of the durability of the treatment effect of VGX-3100 up to 1.5 y and support that VGX-3100 could be used as an alternative to surgery.

PURPOSE Pretreatment estimates of seminal vesicle invasion (SVI) are challenging and significantly influence the management of prostate cancer. We sought to improve current models to predict SVI through the development of an SVI prediction genomic signature. PATIENTS AND METHODS A total of 15,889 patients who underwent radical prostatectomy (RP) with available baseline clinical, pathology, and transcriptome data were retrieved from the GRID registry (ClinicalTrials.gov identifier: NCT02609269 ) and other retrospective cohorts. These data were divided into a training (n = 6,766), test (n = 3,363), and two validation (n = 5,062 and 698) cohorts. Multivariable logistic regression was performed to assess the predictive effect of the genomic SVI (gSVI) classifier in the presence of established nomograms (Partin Tables and Memorial Sloan Kettering Cancer Center [MSKCC]). RESULTS In the training cohort, univariable filtering identified 2,132 genes that were differentially expressed between RP tumors with and without SVI. Model parameters were tuned to maximize the area under the curve (AUC) in the testing cohort, resulting in a logistic generalized linear model with 581 genes. The gSVI model scores range from 0 to 1. In the first validation set, gSVI showed superior discrimination of patients with and without SVI at RP compared with other prognostic signatures trained to predict distant metastasis or clinical recurrence. Of the 698 patients in the second validation set, gSVI combined with the MSKCC nomogram had a superior AUC (0.86) compared with either nomogram individually (0.81). CONCLUSION The gSVI represents a novel and validated expression signature to predict the presence of SVI before treatment with surgery. This genomic tool adds discriminatory power to existing clinical predictive nomograms and may help with pretreatment counseling and decision making.

Evaluate the effect of intravenous golimumab on health-related quality of life (HRQoL) in patients with ankylosing spondylitis (AS) through week 28 of the phase III, multicenter, randomized, double-blind, placebo-controlled GO-ALIVE study.Adult patients (n = 208) were randomized to IV golimumab 2 mg/kg (n = 105) at weeks 0, 4, and 12 and every 8 weeks or placebo (n = 103) at weeks 0, 4, and 12, with crossover to golimumab 2mg/kg at weeks 16, 20, and every 8 weeks. General HRQoL was evaluated using the Short Form Health Survey (SF-36) Physical Component Summary/Mental Component Summary (PCS/MCS), and the EQ VAS, and AS disease-specific HRQoL was assessed using the Ankylosing Spondylitis Quality of Life (ASQoL) instrument.Mean improvements from baseline in SF-36 PCS were greater in the golimumab group versus the placebo group at weeks 8 and 16 (6.8 vs 2.1 and 8.5 vs 2.9, respectively; P.001); similar results were observed for SF-36 MCS (5.6 vs 1.7 and 6.5 vs 0.8, respectively; P.001). Mean improvement in each of 8 subscale scores of the SF-36 were also greater for golimumab-treated patients versus placebo at weeks 8 and 16. Mean improvements in EQ VAS and ASQoL were greater in the golimumab group versus placebo at week 8 and week 16. Greater proportions of golimumab-treated patients had clinically meaningful improvement in SF-36 PCS, SF-36 MCS, EQ VAS, and ASQoL at weeks 8 and 16; improvements in SF-36 PCS/MCS, EQ VAS, and ASQoL were maintained through week 28.Golimumab-treated patients had greater mean improvements in HRQoL measures compared with placebo through week 16. Clinically meaningful improvements were observed as early as week 8 and continued through week 28.

The effect of intravenous (IV) golimumab on health-related quality of life (HRQoL) and productivity in patients with ankylosing spondylitis (AS) was evaluated. Patients were randomized to IV golimumab 2 mg/kg (n = 105) at weeks 0, 4, then every 8 weeks (q8w) through week 52 or placebo (n = 103) at weeks 0, 4, 12, with crossover to golimumab 2 mg/kg at weeks 16, 20, then q8w through week 52. Changes from baseline in EuroQol-5 dimension-5 level (EQ-5D-5L) index and visual analog scale (EQ-VAS), daily productivity VAS, Work Limitations Questionnaire (WLQ), and Ankylosing Spondylitis Quality of Life (ASQoL) were assessed. Correlations between these outcomes and disease activity and patient functioning outcomes were evaluated post hoc. At week 16, changes from baseline (mean ± standard deviation) in EQ-5D-5L index (0.17 ± 0.16 vs 0.05 ± 0.14), EQ-VAS (20.3 ± 24.6 vs 4.8 ± 23.5), daily productivity VAS (− 2.9 ± − 2.9 vs − 1.1 ± − 2.5), WLQ productivity loss score (− 3.5 ± − 5.3 vs − 1.9 ± − 4.0), and ASQoL (− 5.4 ± − 5.0 vs − 1.8 ± − 4.5) were greater in the IV golimumab versus placebo group, respectively. At week 28, changes from baseline were similar between the IV golimumab and placebo-crossover groups (EQ-5D-5L index: 0.18 ± 0.17 and 0.16 ± 0.16, EQ-VAS: 20.5 ± 27.9 and 22.5 ± 23.1, daily productivity VAS: − 3.1 ± − 3.0 and − 3.1 ± − 2.8, WLQ productivity loss: − 3.9 ± − 5.5 and − 4.5 ± − 4.5, and ASQoL: − 5.3 ± − 5.2 and − 5.3 ± − 4.8, respectively); improvements were maintained through week 52. HRQoL and productivity outcomes were generally moderately correlated with disease activity and functioning outcomes. In patients with AS, IV golimumab produced sustained improvements in HRQoL and productivity through 1 year, which correlated with improvements in disease activity and functioning. ClinicalTrials.gov registry number is NCT02186873.

BackgroundCentral line-associated bloodstream infections (CLABSIs) are major contributors to preventable harm in the inpatient paediatric setting. Despite multiple guidelines to reduce CLABSI, sustaining reliable central line maintenance bundle compliance remains elusive. We identified frontline and family engagement as key drivers for this initiative. The baseline CLABSI rate for all our paediatric inpatient units (January 2016–January 2017) was 1.71/1000 central line days with maintenance bundle compliance at 87.9% (monthly range 44%–100%).ObjectiveTo reduce CLABSI by increasing central line maintenance bundle compliance to greater than 90% using kamishibai card (K-card) audits and family ‘key card’ education.MethodsWe transitioned our central line maintenance bundle audits from checklists to directly observed K-card audits. K-cards list the central line maintenance bundle elements to be reviewed with frontline staff. Key cards are cue cards developed using a plain-language summary of CLABSI K-cards and used by frontline staff to educate families. Key cards were distributed to families of children with central lines to simultaneously engage patients, families and frontline staff after a successful implementation of the K-card audit process. A survey was used to obtain feedback from families.ResultsIn the postintervention period (February 2017–December 2019), our CLABSI rate was 0.63/1000 central line days, and maintenance bundle compliance improved to 97.1% (monthly range 86%–100%, pConclusionCombining the key card programme with K-card audits was associated with improved maintenance bundle compliance and a reduction in CLABSI. This programme has the potential for use in multiple healthcare improvement initiatives.

Context Multiparametric magnetic resonance imaging (mpMRI) detects most, but not all, clinically significant prostate cancer. The genetic basis of prostate cancer visibility and invisibility on mpMRI remains uncertain. Objective To systematically review the literature on differential gene expression between mpMRI-visible and mpMRI-invisible prostate cancer, and to use bioinformatic analysis to identify enriched processes or cellular components in genes validated in more than one study. Evidence acquisition We performed a systematic literature search of the Medline, EMBASE, PubMed, and Cochrane databases up to January 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The primary endpoint was differential genetic features between mpMRI-visible and mpMRI-invisible tumours. Secondary endpoints were explanatory links between gene function and mpMRI conspicuity, and the prognostic value of differential gene enrichment. Evidence synthesis We retrieved 445 articles, of which 32 met the criteria for inclusion. Thematic synthesis from the included studies showed that mpMRI-visible cancer tended towards enrichment of molecular features associated with increased disease aggressivity, including phosphatase and tensin homologue (PTEN) loss and higher genomic classifier scores, such as Oncotype and Decipher. Three of the included studies had accompanying publicly available data suitable for further bioinformatic analysis. An over-representation analysis of these datasets revealed increased expression of genes associated with extracellular matrix components in mpMRI-visible tumours. Conclusions Prostate cancer that is visible on mpMRI is generally enriched with molecular features of tumour development and aggressivity, including activation of proliferative signalling, DNA damage, and inflammatory processes. Additionally, there appears to be concordant cellular components and biological processes associated with mpMRI conspicuity, as highlighted by bioinformatic analysis of large genetic datasets. Patient summary Prostate cancer that is detected by magnetic resonance imaging (MRI) tends to have genetic features that are associated with more aggressive disease. This suggests that MRI can be used to assess the likelihood of aggressive prostate cancer, based on tumour visibility., Take Home Message The genomic evidence surrounding multiparametric magnetic resonance imaging (mpMRI) visibility is varied and often discordant; however, the literature suggests that tumour mpMRI visibility correlates with aggressive genomic features.

Objective The present study was undertaken to evaluate the safety and efficacy of intravenous (IV) golimumab in patients with active psoriatic arthritis (PsA) through 1 year. Methods GO-VIBRANT was a phase III, randomized, placebo-controlled trial of 480 adults with active PsA. Patients were randomized to receive IV placebo (n = 239) or golimumab 2 mg/kg (n = 241) at weeks 0, 4, and every 8 weeks, with placebo crossover to golimumab at weeks 24, 28, and every 8 weeks thereafter. Efficacy through week 52 was assessed using the American College of Rheumatology (ACR) ≥20%, 50%, or 70% improvement criteria (ACR20/50/70), and the Psoriasis Area and Severity Index ≥75% improvement criteria (PASI75). Radiographic progression was measured using the PsA-modified Sharp/van der Heijde score (SHS). Adverse events (AEs) were monitored through week 60. Results The primary and major secondary end points through week 24 were achieved. At week 52, 76.8% of patients in the golimumab group and 77.0% in the placebo-crossover group achieved an ACR20 response, 58.1% and 53.6%, respectively, achieved an ACR50 response, and 38.6% and 33.9%, respectively, achieved an ACR70 response. Among patients with ≥3% body surface area affected, 71.9% in the golimumab group and 60.6% in the placebo-crossover group achieved a PASI75 response at week 52. Mean change from baseline in total SHS at week 52 was -0.5 in the golimumab group and 0.8 in the placebo-crossover group. Through week 60, 50.9% of all golimumab-treated patients had ≥1 AE, and 5.2% had ≥1 serious AE. There were no opportunistic infections, 2 malignancies, and 1 death in patients treated with golimumab. Conclusion Sustained improvements in joint and skin disease in patients with PsA were maintained through 1 year in the GO-VIBRANT study. No new safety signals for IV golimumab were identified.

Diamond dust particles were identified within patients’ eyes both during vitrectomy procedures using diamond-dusted membrane scrapers and in postoperative clinical examinations. The particles had no impact on the patients’ vision and caused no apparent sequelae. Scanning electron microscopy analysis showed the average particle size to be 23.4 μm and an unequal surface area for particle adhesion onto the soft tip. It was determined that diamond dust particles can dislodge from the silicone tip of the Tano diamond-dusted membrane scrapers during the insertion into valve trocars throughout vitrectomy operations and deposit on the retinal surface or within macular holes. Ophthalmologists should be aware of residual diamond particles during procedures and consider diamond dust retinopathy in the differential diagnosis of crystalline retinopathies. Understanding the appearance of residual particles on the retina allows for future studies revealing the long-term impact on patient’s visual performance.

Background: ER- HER2+ BC is comprised of a heterogeneous mix of intrinsic BC subtypes which have differential responsiveness to preop HER2-directed therapies combined with chemotherapy. Patients (pts) with ER- HER2+ BC whose disease progressed while on or who had no response to preop HER2-directed therapy are uncommon and the mechanisms of resistance within this primary-refractory disease are unknown. We utilized RPPA-based protein pathway activation mapping to map the drug target signaling architecture in pts’ primary-refractory ER- HER2+ BCs to begin to assess mechanisms of resistance. Methods: Eight primary-refractory ER- HER2+ FFPE BC tissues obtained from 5 pts (preop biopsies n=4 and/or post-treatment surgical resection n=4) underwent laser capture microdissection to isolate pure tumor epithelium followed by RPPA-based analysis of the levels and/or activation/phosphorylation of approximately 130 key signaling proteins known to be involved in tumorigenesis and metastatic progression. Results: Pts were all treated with preop trastuzumab, pertuzumab, docetaxel, and carboplatin (TCHP) with no response and/or with progression of disease. Three pts also received preop doxorubicin/cyclophosphamide without response. RPPA-based analysis revealed that post-TCHP surgical samples had higher activation of a number of drug targets including receptor tyrosine kinases (RTK) such as MET and ALK, as well as HER family signaling proteins phospho-HER3 and phospho-EGFR compared to the matched pre-TCHP samples. Conclusions: In these ER- HER2+ BCs that were primary-refractory to preop TCHP, in those pts with patient-matched pre/post treatment samples, activation of several potential resistance pathways such as alternative RKT signaling as well as EGFR and HER3 signaling was observed. These data are hypothesis-generating and require exploration in additional ER- HER2+ primary-refractory tissues. Citation Format: Mariaelena Pierobon, Maren K Levin, Elisa Baldelli, Leslie SL Kim, Lance Liotta, Emanuel F Petricoin, Joyce O'Shaughnessy. Patterns of protein expression and signaling assessed by reverse phase protein array (RPPA) in estrogen-receptor negative (ER-), HER2-amplified breast cancer (BC) that was primary-refractory to preoperative (preop) HER2-directed therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-31.

Suicide is currently the second leading cause of death for 10–34 year-olds. Moreover, up to 20% of adolescents report engaging in non-suicidal self-injury (NSSI) at some point in their lifetime. Despite the urgent need, the literature on effective treatment options for children and adolescents struggling with suicide, NSSI, and other self-injurious behaviors (SIBs) is relatively limited. This article reviews the efficacy of current treatments for youth suicidality and SIBs. Most of the existing literature on treatment for suicidality and NSSI in children and adolescents is focused on psychotherapy, specifically cognitive behavioral therapy (CBT), dialectical behavioral therapy (DBT), psychoeducation, family therapy, and school-based interventions. In contrast, psychopharmacology studies have focused on addressing disorders related to suicidality and NSSI such as major depressive disorder, rather than on the behaviors themselves. Currently, there is no single treatment that is considered the gold standard for child and adolescents struggling with suicidality and NSSI. While individual psychotherapies, including CBT and DBT, and psychopharmacological agents, such as selective serotonin reuptake inhibitors (SSRIs), show promise in addressing suicide and related psychopathology, there is considerable need for novel approaches to address the underlying mechanisms leading to youth suicidality and NSSI.

Background Prostate cancer (PC) is the most commonly diagnosed solid tumor in men. A major challenge in PC immunotherapy is the lack of an animal model that resembles human adenocarcinoma and allows for manipulation or monitoring of the immune response. Mouse models are needed for preclinical testing of new immunotherapies, whether used alone or in combination with established drugs, and to develop companion biomarkers that can be validated in clinical trials. Methods To develop a syngeneic prostate adenocarcinoma model with a well-defined tumor antigen, murine RM1 PC cells were transfected with the endogenous mouse melanoma protein, gp100 (RM1-gp100). Gp100 was attractive because it is a self-protein and it instantly allowed us to use the large trove of immune research tools developed for melanoma research. A dendritic cell (DC) vaccine was used as model immunotherapy to demonstrate that adoptive immunotherapy against gp100 decreases the growth of RM1-gp100 but not RM1. Results Expressing gp100 did not change the growth of RM1 cell in vitro or in vivo. The DCs pulsed with RM1-gp100 could be used to stimulate Pmel-1 lymphocyte proliferation and activation. Pmel-1 lymphocytes could be adoptively transferred into C57Bl/6 mice that were treated with DCs pulsed with RM1-gp100. The resulting Pmel-1 lymphocytes were monitored to assess the primary cellular immune response and memory response. Conclusion We describe a murine model for prostate adenocarcinoma with a well-characterized antigen that can be used in an immunologically intact mice to monitor the temporal CD8+ lymphocyte-mediated antitumor immunity.

Fusion partners of KMT2A affect disease phenotype and influence the current World Health Organization classification of hematologic neoplasms. The t(11;16)(q23;p13)/KMT2A-CREBBP is considered presumptive evidence of a myelodysplastic syndrome (MDS) and a MDS-related cytogenetic abnormality in the classification of acute myeloid leukemia (AML). Here, we report 18 cases of hematologic neoplasms with t(11;16). There were 8 males and 10 females with a median age of 51.9 years at time of detection of t(11;16). Of 17 patients with enough clinical information and pathological materials for review, 16 had a history of cytotoxic therapies for various malignancies including 12/15 patients who received topoisomerase II inhibitors, and 15 were classified as having therapy-related neoplasms. The median interval from the diagnosis of primary malignancy to the detection of t(11;16) was 23.2 months. Dysplasia, usually mild, was observed in 7/17 patients. Blasts demonstrated monocytic differentiation in 8/8 patients who developed AML at the time or following detection of t(11;16). t(11;16) was observed as the sole chromosomal abnormality in 10/18 patients. KMT2A rearrangement was confirmed in 11/11 patients. The median survival from the detection of t(11;16) was 15.4 months. In summary, t(11;16)(q23;p13) is rare and overwhelmingly associated with prior exposure of cytotoxic therapy. Instead of being considered presumptive evidence of myelodysplasia, we suggest that the detection of t(11;16) should automatically prompt a search for a history of malignancy and cytotoxic therapy so that proper risk stratification and clinical management are made accordingly. The dismal outcome of patients with t(11;16) is in keeping with that of therapy-related neoplasms.

Neurocognitive deficits, such as cognitive flexibility impairments, are common in bipolar disorder (BD) and predict poor academic, occupational, and functional outcomes. However, the association between neurocognition and illness trajectory is not well understood, especially across developmental transitions. This study examined cognitive flexibility and subsequent mood symptom and suicidal ideation (SI) course in young adults with childhood-onset BD-I (with distinct mood episodes) vs. BD-not otherwise specified (BD-NOS) vs. typically-developing controls (TDCs). Sample included 93 young adults (ages 18-30) with prospectively verified childhood-onset DSM-IV BD-I (n = 34) or BD-NOS (n = 15) and TDCs (n = 44). Participants completed cross-sectional neuropsychological tasks and clinical measures. Then participants with BD completed longitudinal assessments of mood symptoms and SI at 6-month intervals (M = 39.18 ± 16.57months of follow-up data). Analyses included ANOVAs, independent-samples t tests, chi-square analyses, and multiple linear regressions. Participants with BD-I had significant deficits in cognitive flexibility and executive functioning vs. BD-NOS and TDCs, and impaired spatial working memory vs. TDCs only. Two significant BD subtype-by-cognitive flexibility interactions revealed that cognitive flexibility deficits were associated with subsequent percentage of time depressed and with SI in BD-I but not BD-NOS, regardless of other neurocognitive factors (full-scale IQ, executive functioning, spatial working memory) and clinical factors (current and prior mood and SI symptoms, age of BD onset, global functioning, psychiatric medications, comorbidity). Thus, cognitive flexibility may be an important etiological brain/behavior mechanism, prognostic indicator, and intervention target for childhood-onset BD-I, as this deficit appears to endure into young adulthood and is associated with worse prognosis for subsequent depression and SI.

Purpose: There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering. Experimental Design: Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy. Results: Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas. Conclusions: Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.

Purpose and Background Clopidogrel is a commonly used antiplatelet for the prevention of thromboembolic complications following several types of neuroendovascular procedures. Its widespread use stems from its relatively low cost, good efficacy, and safety profile. However, concern has emerged for the possibility that clopidogrel may induce severe, intolerable fatigue in a small subset of patients. Thus, the purpose of this study is to systematically investigate this phenomenon and to better characterize the demographic at risk. Methods We performed a dual-institution, 9-year, retrospective study of patients undergoing dual antiplatelet therapy with clopidogrel and aspirin for neuroendovascular procedures. Patients were included only if their response to clopidogrel was assessed by a VerifyNow P2Y12 (VNP) assay, which measures platelet inhibition using P2Y12 reactivity units (PRU). A hyper-response to clopidogrel is defined by a PRU ≤ 60. Patients were considered to have had clopidogrel-induced severe fatigue if 1) the onset of severe, intolerable fatigue followed the initiation of clopidogrel, 2) fatigue resolved or improved following a reduction in the dose of clopidogrel, 3) no hemorrhagic event occurred while on clopidogrel, and 4) fatigue could not be attributed to any other medical explanation. Results Clinical and demographic data were collected on 348 patients across 2 separate institutions. Five patients (1.4%) were identified as having met criteria for clopidogrel-induced severe fatigue. All 5 patients were female, ages 39-68. In addition to severe fatigue, they suffered from headache, nausea, vertigo, and dyspnea. Each patient had been taking clopidogrel for at least one week prior to the onset of symptoms, and VNP assays obtained while the patients were experiencing their symptoms revealed hyper-responses to clopidogrel, with PRU between 0-22. Four of these patients initially had an appropriate response to clopidogrel, with a PRU > 60 immediately prior to the intervention, and they did not report fatigue until later. In response to the severe, intolerable fatigue, clopidogrel was reduced by half, resulting in resolution or improvement of symptoms in all 5 patients. However, VNP assays returned persistently low values (0-16 PRU). One patient developed anemia after her symptoms had already resolved, but no additional complications were reported during the course of their therapy. Notably, 30% of patients (n = 103) demonstrated a hyper-response to clopidogrel on at least one VNP assay, but the vast majority of these patients did not suffer from severe fatigue. The rate of hyper-responses was similar across institutions and across genders. Conclusions Severe, intolerable fatigue is a rare but clinically significant side effect of clopidogrel. It is associated with a hyper-response to therapy as determined by a PRU value ≤ 60 on a VNP assay, but it appears that inhibition of platelet aggregation is merely epiphenomenal. Symptoms develop after an initial loading period and respond well to decreasing the dosage of clopidogrel. Only women were affected in our study, but this gender effect may reflect a sample bias as most of our patients were women. Disclosures D. Bass: None. C. Young: None. M. Park: None. D. Bass: None. K. Carroll: None. K. Vanet: None. C. Lee: None. R. Sen: None. S. Levy: None. C. Kelly: None. L. Kim: None. M. Levitt: None.

PURPOSE Multiparametric magnetic resonance imaging (mpMRI) is used widely for prostate cancer (PCa) evaluation. Approximately 35% of aggressive tumors, however, are not visible on mpMRI. We sought to identify the molecular alterations associated with mpMRI-invisible tumors and determine whether mpMRI visibility is associated with PCa prognosis. METHODS Discovery and validation cohorts included patients who underwent mpMRI before radical prostatectomy and were found to harbor both mpMRI-visible (Prostate Imaging and Reporting Data System 3 to 5) and -invisible (Prostate Imaging and Reporting Data System 1 or 2) foci on surgical pathology. Next-generation sequencing was performed to determine differential gene expression between mpMRI-visible and -invisible foci. A genetic signature for tumor mpMRI visibility was derived in the discovery cohort and assessed in an independent validation cohort. Its association with long-term oncologic outcomes was evaluated in a separate testing cohort. RESULTS The discovery cohort included 10 patients with 26 distinct PCa foci on surgical pathology, of which 12 (46%) were visible and 14 (54%) were invisible on preoperative mpMRI. Next-generation sequencing detected prioritized genetic mutations in 14 (54%) tumor foci (n = 8 mpMRI visible, n = 6 mpMRI invisible). A nine-gene signature (composed largely of cell organization/structure genes) associated with mpMRI visibility was derived (area under the curve = 0.89), and the signature predicted MRI visibility with 75% sensitivity and 100% specificity (area under the curve = 0.88) in the validation cohort. In the testing cohort (n = 375, median follow-up 8 years) there was no significant difference in biochemical recurrence, distant metastasis, or cancer-specific mortality in patients with predicted mpMRI-visible versus -invisible tumors (all P > .05). CONCLUSION Compared with mpMRI-invisible disease, mpMRI-visible tumors are associated with underexpression of cellular organization genes. mpMRI visibility does not seem to be predictive of long-term cancer outcomes, highlighting the need for biopsy strategies that detect mpMRI-invisible tumors.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confirmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is a potent and selective inhibitor of FGFR4 and demonstrates clinical benefit and tumor regression in patients with HCC with aberrant FGF19 expression. Mutations were identified in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients treated with fisogatinib, which were confirmed to mediate resistance in vitro and in vivo. A gatekeeper-agnostic, pan-FGFR inhibitor decreased HCC xenograft growth in the presence of these mutations, demonstrating continued FGF19–FGFR4 pathway dependence. These results validate FGFR4 as an oncogenic driver and warrant further therapeutic targeting of this kinase in the clinic. Significance: Our study is the first to demonstrate on-target FGFR4 kinase domain mutations as a mechanism of acquired clinical resistance to targeted therapy. This further establishes FGF19–FGFR4 pathway activation as an oncogenic driver. These findings support further investigation of fisogatinib in HCC and inform the profile of potential next-generation inhibitors. See related commentary by Subbiah and Pal, p. 1646. This article is highlighted in the In This Issue feature, p. 1631

Background Sepsis risk stratification tools typically predict mortality, although stays in the intensive care unit (ICU) of 24 hours or longer may be more clinically relevant for emergency department disposition. Objective To explore predictors of ICU stay of 24 hours or longer among infected, hypotensive emergency department patients. Methods A secondary analysis of 2 prospective, observational studies of adult patients with severe sepsis or an infection with a systolic blood pressure less than 90 mm Hg in 3 urban, academic emergency departments was performed. Patients with hypotension and infection were included. Patients with emergency department intubation, vasopressor administration, and/or death were excluded. The primary outcome was ICU stay of 24 hours or longer or death in less than 24 hours. Multivariable logistic regression was used to predict ICU stay of 24 hours or longer. Results Of 233 patients, 108 (46.4%) had ICU stays of 24 hours or longer. History of heart failure (odds ratio, 3.6; 95% CI, 1.5-8.3), bicarbonate level less than 20 mEq/L (odds ratio, 2.0; 95% CI, 1.1-3.8), respiratory rate greater than 20/min (odds ratio, 2.0; 95% CI, 1.1-3.7), and creatinine level greater than 2.0 mg/dL (odds ratio, 3.6; 95% CI, 1.9-6.7) were independent predictors of ICU stay of 24 hours or longer (area under curve, 0.74). The presence of 1 of these factors predicted ICU stay of 24 hours or longer (area under curve, 0.74) with 82.4% sensitivity and 49.6% specificity. Conclusions These exploratory results show that heart failure, bicarbonate level of less than 20 mEq/L, tachypnea, or creatinine level greater than 2.0 mg/dL increases the likelihood of an ICU stay of 24 hours or longer among infected, hypotensive emergency department patients.

Background We aimed to validate Decipher to predict adverse pathology (AP) at radical prostatectomy (RP) in men with National Comprehensive Cancer Network (NCCN) favorable-intermediate risk (F-IR) prostate cancer (PCa), and to better select F-IR candidates for active surveillance (AS). Methods In all, 647 patients diagnosed with NCCN very low/low risk (VL/LR) or F-IR prostate cancer were identified from a multi-institutional PCa biopsy database; all underwent RP with complete postoperative clinicopathological information and Decipher genomic risk scores. The performance of all risk assessment tools was evaluated using logistic regression model for the endpoint of AP, defined as grade group 3−5, pT3b or higher, or lymph node invasion. Results The median age was 61 years (interquartile range 56–66) for 220 patients with NCCN F-IR disease, 53% classified as low-risk by Cancer of the Prostate Risk Assessment (CAPRA 0−2) and 47% as intermediate-risk (CAPRA 3−5). Decipher classified 79%, 13% and 8% of men as low-, intermediate- and high-risk with 13%, 10%, and 41% rate of AP, respectively. Decipher was an independent predictor of AP with an odds ratio of 1.34 per 0.1 unit increased (p value = 0.002) and remained significant when adjusting by CAPRA. Notably, F-IR with Decipher low or intermediate score did not associate with significantly higher odds of AP compared to VL/LR. Conclusions NCCN risk groups, including F-IR, are highly heterogeneous and should be replaced with multivariable risk-stratification. In particular, incorporating Decipher may be useful for safely expanding the use of AS in this patient population.

Objective To measure effects of ED crowding on lung-protective ventilation (LPV) utilization in critically ill ED patients. Methods This is a retrospective cohort study of adult mechanically ventilated ED patients admitted to the medical intensive care unit (MICU), over a 3.5-year period at a single academic tertiary care hospital. Clinical data, including reason for intubation, severity of illness (MPM0-III), acute respiratory distress syndrome (ARDS) risk score (EDLIPS), and ventilator settings were extracted via electronic query of electronic health record and standardized chart abstraction. Crowding metrics were obtained at 5-min intervals and averaged over the ED stay, stratified by acuity and disposition. Multivariate logistic regression was used to predict likelihood of LPV prior to ED departure. Results Mechanical ventilation was used in 446 patients for a median ED duration of 3.7 h (interquartile ratio, IQR, 2.3, 5.6). Mean MPM0-III score was 32.5 ± 22.7, with high risk for ARDS (EDLIPS ≥5) seen in 373 (82%) patients. Initial and final ED ventilator settings differed in 134 (30.0%) patients, of which only 47 (35.1%) involved tidal volume changes. Higher percentages of active ED patients (workup in-progress) and those requiring eventual admission were associated with lower odds of LPV utilization by ED departure (OR 0.97, 95%CI 0.94–1.00; OR 0.97, 95%CI 0.94–1.00, respectively). In periods of high volume, ventilator adjustments to settings other than the tidal volume were associated with higher odds of LPV utilization. Reason for intubation, MPM0-III, and EDLIPS were not associated with LPV utilization, with no interactions detected in times of crowding. Conclusions ED patients remain on suboptimal tidal volume settings with infrequent ventilator adjustments during the ED stay. Hospitals should focus on both systemic factors and bedside physician and/or respiratory therapist interventions to increase LPV utilization in times of ED boarding and crowding for all patients.

Few data are available on the gender-related differences in the prognostic impact of diabetes in people with heart failure. This study was performed to investigate whether there is a gender difference in the association between diabetes and long-term clinical outcomes in people hospitalized for heart failure.A total of 3162 people hospitalized with heart failure (aged 67.4 ± 14.1 years, 50.4% females) from the data set of the nationwide registry were analysed. The primary endpoint was a composite of all-cause mortality and heart failure readmission.People with diabetes (30.5% for males vs. 31.1% for females, P = 0.740) were older and had more unfavourable risk factors and laboratory findings than those without diabetes in both genders. During a median follow-up period of 549 days, there were 1418 cases of composite events (44.8%). In univariable analysis, the coexistence of diabetes was significantly associated with a higher incidence of composite events in both genders (P 0.05 each for males and females). In multivariable analysis, the prognostic impact of diabetes on the development of composite events remained significant in females even after controlling for potential confounders (hazard ratio 1.43, 95% confidence intervals 1.12-1.84; P = 0.004). However, an independent association between diabetes and composite events was not seen in males in the same multivariable analysis (P 0.05).In people with heart failure, the impact of diabetes on long-term mortality and heart failure readmission seems to be stronger in females than in males. More careful and intensive management is needed especially in females with heart failure and diabetes.

Background Suicide is the second leading cause of death among adolescents. The purpose of this study was to test a family-focused outpatient cognitive behavioral treatment (F-CBT) protocol for depressed adolescents following psychiatric hospitalization for a suicide attempt or suicidal ideation, and who had a co-occurring risk factor (suicidal behavior prior to the index admission, nonsuicidal self-injury, and/or a substance use disorder), in a randomized Phase 2 efficacy trial. Method One hundred forty-seven adolescents (mean age = 14.91 years; 76.2% female, 85.5% White) and their families, recruited primarily from an inpatient psychiatric hospitalization program, were randomly assigned to F-CBT or enhanced treatment-as-usual (E-TAU). A suicide attempt was the primary outcome variable. Depression, suicidal ideation, and nonsuicidal self-injury are also reported here. Assessments were completed at pretreatment as well as 6, 12, and 18-months postrandomization (Trial Registration ClinicalTrials.gov Identifier: NCT01732601). Results In the sample as a whole, rates of attempts decreased from 20% at 6 months to 9% at 12 months to 7% at 18 months. There was no evidence of a significant difference between treatment arms in rates of suicide attempts, major depressive disorder, suicidal ideation, or nonsuicidal self-injury at any of the postrandomization assessment points. Conclusions Though F-CBT was associated with reductions in suicidality, depression, and nonsuicidal self-injury, E-TAU showed an equally strong effect. Greater frequency of F-CBT treatment sessions, particularly at the start of care, and alternative approaches to transitioning to care at 12 months, may be necessary when using F-CBT with this population.

Background: Prognostication is an essential component of palliative care for patients with advanced cancer but also poses challenges. Little is known about physicians’ perspectives on prognostication and prognostic tools used in palliative care practice in Eastern countries. Objectives: To explore Korean physicians’ perspectives and experiences with prognostication in their palliative care practices. Methods: Semi-structured interviews were conducted in Korea in 11 palliative care physicians. A constant comparative and grounded theory approach was used to derive themes from interview transcripts. Results: Participants on average had 6.4 (SD = 4.5, range 0.5-15) years of hospice and palliative care experience. We identified 4 main themes about prognostication: (1) the importance of prognostication (to help patients and their families prepare for death, to determine the appropriate time of transition to hospice care, to facilitate appropriate decision making, and to facilitate communication with patients and their families); (2) difficulties of prognostication (discomfort estimating the exact date of death); (3) basis of prognostication (clinical prediction of survival as well as prognostic scores); and (4) areas for further research (need for a simpler scoring system or parameters to predict survival with greater certainty). Conclusion: Palliative care physicians in Korea reported similar perceptions about the role and challenges inherent in prognostication compared to clinicians in Western cultures. However, they emphasize the need to predict final days to keep families with dying patients, reflecting family-centered aspects of Asian culture. They reported frustrations with inaccurate prognostication schemas and called for the development of simpler, more accurate predictors as a focus of future research.

Background: In ST-segment–elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. Methods: In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. Results: All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P =0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P =0.53). Conclusions: We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270.

Community resource referral systems have been implemented into care settings that serve persons with dementia but with little input from caregivers. Focus groups were conducted with African American, Hispanic, and Asian caregivers to describe their preferences for community resource referral information. Caregivers discussed the significance of a community resource list for dementia caregiving and self-care and articulated strategies for effective information delivery during a medical visit. Most caregivers acknowledged that resource needs change with progression of dementia, but no patterns emerged with regard to preference for information delivered incrementally based on disease stage or all at once. Hispanic and Asian caregivers felt that resource information should specify service providers’ language and cultural capabilities. All caregivers agreed that delivery by a member of the care team with knowledge of dementia-specific resources would be most effective. Optimal delivery of community resource referrals is caregiver-centered and customizable to individual and subgroup preferences.

Current treatments for chronic pain have limited benefit. We describe a resilience intervention for individuals with chronic pain which is based on a model of viewing chronic pain as dysregulated homeostasis and which seeks to restore homeostatic self-regulation using strategies exemplified by survivors of extreme environments. The intervention is expected to have broad effects on well-being and positive emotional health, to improve cognitive functions, and to reduce pain symptoms thus helping to transform the suffering of pain into self-growth. A total of 88 Veterans completed the pre-assessment and were randomly assigned to either the treatment intervention (n = 38) or control (n = 37). Fifty-eight Veterans completed pre- and post-testing (intervention n = 31, control = 27). The intervention covered resilience strengths organized into four modules: (1) engagement, (2) social relatedness, (3) transformation of pain and (4) building a good life. A broad set of standardized, well validated measures were used to assess three domains of functioning: health and well-being, symptoms, and cognitive functions. Two-way Analysis of Variance was used to detect group and time differences. Broadly, results indicated significant intervention and time effects across multiple domains: (1) Pain decreased in present severity [F(1, 56) = 5.02, p < 0.05, η2p = 0.08], total pain over six domains [F(1, 56) = 14.52, p < 0.01, η2p = 0.21], and pain interference [F(1, 56) = 6.82, p < 0.05, η2p = 0.11]; (2) Affect improved in pain-related negative affect [F(1, 56) = 7.44, p < 0.01, η2p = 0.12], fear [F(1, 56) = 7.70, p < 0.01, η2p = 0.12], and distress [F(1, 56) = 10.87, p < 0.01, η2p = 0.16]; (3) Well-being increased in pain mobility [F(1, 56) = 5.45, p < 0.05, η2p = 0.09], vitality [F(1, 56) = 4.54, p < 0.05, η2p = 0.07], and emotional well-being [F(1, 56) = 5.53, p < 0.05, η2p = 0.09] Mental health symptoms and the cognitive functioning domain did not reveal significant effects. This resilience intervention based on homeostatic self-regulation and survival strategies of survivors of extreme external environments may provide additional sociopsychobiological tools for treating individuals with chronic pain that may extend beyond treating pain symptoms to improving emotional well-being and self-growth.Clinical Trial Registration: Registered with ClinicalTrials.gov (NCT04693728).

In developing countries, anemia is a major public health problem; anemia affects 24.8% of the global population, corresponding to 1.62 billion people. As anemia is defined as a low hemoglobin level in the blood, it is important to measure exact hemoglobin content in grams per deciliter of the blood. Recent advances in mobile health (mHealth) technologies for blood hemoglobin levels are promising, but often rely on additional complex components to the smartphone and require blood sampling. As a result, noninvasive quantification of hemoglobin content in the blood is still limited. We have recently developed intravital mHealth spectroscopy to extract spectrally encoded microvascular and blood information from peripheral tissue. Spectral learning virtually transforms the built-in camera of a smartphone into a hyperspectral imager for spectroscopic analyses. Owing to the easy accessibility and relatively uniform microvasculature, the inner eyelid is used as a sensing site. Spectroscopic analyses of spectra acquired from the inner eyelid further result in key parameters about the blood and the microvasculature that are used for predicting blood hemoglobin levels in a noninvasive and real-time manner. Our clinical study conducted in sub-Saharan Africa supports reliable performance of blood hemoglobin quantification and anemia prediction. As our mHealth technology requires no additional attachment (our data-centric approach minimizes hardware complexity), the key features include mobility, simplicity, and affordability for rapid and scalable adaptation. Successful implementation with local governments and community healthcare workers can potentially provide unreached and underserved remote populations with accessible and affordable healthcare services in low-resource settings.

Introduction/objectives To evaluate changes in health-related quality of life (HRQoL) and productivity following treatment with intravenous (IV) golimumab in patients with psoriatic arthritis (PsA). Methods Patients were randomized to IV golimumab 2 mg/kg (n=241) at Weeks 0, 4, then every 8 weeks (q8w) through Week 52 or placebo (n=239) at Weeks 0, 4, then q8w, with crossover to IV golimumab 2 mg/kg at Weeks 24, 28, then q8w through Week 52. Change from baseline in EuroQol-5 dimension-5 level (EQ-5D-5L) index and visual analog scale (EQ-VAS), daily productivity VAS, and the Work Limitations Questionnaire (WLQ) was assessed. Relationships between these outcomes and disease activity and patient functional capability were evaluated post hoc. Results At Week 8, change from baseline in EQ-5D-5L index (0.14 vs 0.04), EQ-VAS (17.16 vs 3.69), daily productivity VAS (−2.91 vs −0.71), and WLQ productivity loss score (−2.92 vs −0.78) was greater in the golimumab group versus the placebo group, respectively. At Week 52, change from baseline was similar in the golimumab and placebo-crossover groups (EQ-5D-5L index: 0.17 and 0.15; EQ-VAS: 21.61 and 20.84; daily productivity VAS: −2.89 and −3.31; WLQ productivity loss: −4.49 and −3.28, respectively). HRQoL and productivity were generally associated with disease activity and functional capability, with continued association from Week 8 through Week 52. Conclusion IV golimumab resulted in early and sustained improvements in HRQoL and productivity from Week 8 through 1 year in patients with PsA. HRQoL and productivity improvements were associated with improvements in disease activity and patient functional capability. Key Points• In patients with active psoriatic arthritis (PsA), intravenous (IV) golimumab improved health-related quality of life (HRQoL) and productivity as early as 8 weeks and maintained improvement through 1 year• Improvements in HRQoL and productivity outcomes in patients with PsA treated with IV golimumab were associated with improvements in disease activity and patient functional capability outcomes• IV golimumab is an effective treatment option for PsA that can mitigate the negative effects of the disease on HRQoL and productivity

PURPOSE Caregivers of cancer patients experience distress that can manifest as caregiving burden, burnout, depression, and fatigue. Caregiving distress affects physical health in various ways such as causing the dysregulation of inflammatory functions. We examined the relationships between psychological distress experienced by and inflammatory cytokine levels of family caregivers of cancer patients. METHODS A descriptive, cross-sectional study involving 93 family caregivers of cancer patients was conducted. Self-report questionnaires were used to measure the distress variables, which included the caregiving burden, burnout, depression, and fatigue, and peripheral blood samples were collected to measure the IL-6, IL-10, and TNF-α levels. Multiple linear regression analyses were conducted to evaluate the impact of caregivers' distress on their inflammatory cytokine levels. RESULTS Inflammatory cytokine levels were negatively correlated with caregiving distress. High fatigue levels (B = - 0.047, p = 0.026) and additional days of care provided per week (B = - 0.048, p = 0.009) was associated with low IL-6 levels. High depression levels (B = - 0.250, p = 0.007), high fatigue levels (B = - 0.054, p = 0.027), and more days of care provided per week (B = - 0.048, p = 0.033) were associated with low TNF-α levels. The age of the caregiver (B = - 0.011, p = 0.020) and days of care provided per week (B = - 0.138, p = 0.031) were associated factors for IL-10 levels. CONCLUSION The inflammatory responses were associated with the distress in family caregiving for cancer patients. Thus, interventions are needed to support caregivers and manage their caregiving distress.

Background. Activating vestibular afferents via galvanic vestibular stimulation (GVS) has been recently shown to have a number of complex motor effects in Parkinson’s disease (PD), but the basis of these improvements is unclear. The evaluation of network-level connectivity changes may provide us with greater insights into the mechanisms of GVS efficacy. Objective. To test the effects of different GVS stimuli on brain subnetwork interactions in both health control (HC) and PD groups using fMRI. Methods. FMRI data were collected for all participants at baseline (resting state) and under noisy, 1 Hz sinusoidal, and 70-200 Hz multisine GVS. All stimuli were given below sensory threshold, blinding subjects to stimulation. The subnetworks of 15 healthy controls and 27 PD subjects (on medication) were identified in their native space, and their subnetwork interactions were estimated by nonnegative canonical correlation analysis. We then determined if the inferred subnetwork interaction changes were affected by disease and stimulus type and if the stimulus-dependent GVS effects were influenced by demographic features. Results. At baseline, interactions with the visual-cerebellar network were significantly decreased in the PD group. Sinusoidal and multisine GVS improved (i.e., made values approaching those seen in HC) subnetwork interactions more effectively than noisy GVS stimuli overall. Worsening disease severity, apathy, depression, impaired cognitive function, and increasing age all limited the beneficial effects of GVS. Conclusions. Vestibular stimulation has widespread system-level brain influences and can improve subnetwork interactions in PD in a stimulus-dependent manner, with the magnitude of such effects associating with demographics and disease status.

Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders is severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons are significantly perturbed (e.g., reduced membrane capacitance, lower action potential thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter Purkinje neuron neural activity, including a progressive reduction in spontaneous action potential firing frequency that correlates with both cerebellar atrophy and ataxia over the animal’s first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Lastly, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

With recurring carcinogen exposures, individual tumors develop in a field of genetic mutations through a stepwise process of clonal expansion and evolution. Once established, this “cancer field” persists in the absence of continued carcinogen exposures, resulting in a sustained risk for cancer development. Using a bioimaging approach, we previously demonstrated that a dermal premalignant field characterized by inflammatory angiogenesis persists following the cessation of ultraviolet light exposures and accurately predicts future overlying epidermal tumor formation. Following ultraviolet light treatments, others have observed that patches of p53 immunopositive cells persist stochastically throughout the epidermal stem cell population. However, these studies were done by random biopsies, introducing sampling bias. We now show that, rather than being randomly distributed, p53+ epidermal cells are enriched only in areas overlying this multi-focal dermal field. Moreover, we also show that the dermal field is characterized by a senescent phenotype. We propose that persistence of the overlying epithelial cancerization field in the absence of exogenous carcinogens or promoters requires a two-field composite consisting of a dermal senescent field driving the persistence of the overlying epidermal cancer field. These observations challenge current models that suggest that persistence of cancer risk in the absence of continued carcinogen exposures is simply a function of stochastically arranged, long-lived but dormant epithelial clonal stem cells mutants. The model proposed here could provide new insights into how cancer risk persists following cessation of carcinogenic exposures.

Background: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor–positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i. Patients and Methods: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers. Results: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib. Conclusions: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.

Facial emotion recognition deficits are common in bipolar disorder (BD) and associated with impairment. However, the relationship between facial emotion recognition and mood course is not well understood. This study examined facial emotion recognition and subsequent mood symptoms in young adults with childhood-onset BD versus typically developing controls (TDCs). The sample included 116 young adults (ages 18–30, 58% male, 78% White) with prospectively verified childhood-onset BD (n = 52) and TDCs (n = 64). At baseline, participants completed a facial emotion recognition task (Diagnostic Analysis of Non-Verbal Accuracy-2) and clinical measures. Then, participants with BD completed mood symptom assessments every 6 months (M = 8.7 ± 5.2 months) over two years. Analyses included independent-samples t tests and mixed-effects regression models. Participants with BD made significantly more recognition errors for child expressions than TDCs. There were no significant between-group differences for recognition errors for adult expressions, or errors for specific child or adult emotional expressions. Participants had moderate baseline mood symptoms. Significant time-by-facial emotion recognition interactions revealed more recognition errors for child emotional expressions predicted lower baseline mania and stable/consistent trajectory; fewer recognition errors for child expressions predicted higher baseline mania and decreasing trajectory. In addition, more recognition errors for adult sad expressions predicted stable/consistent depression trajectory and decreasing mania; fewer recognition errors for adult sad expressions predicted decreasing depression trajectory and stable/consistent mania. Effects remained when controlling for baseline demographics and clinical variables. Facial emotion recognition may be an important brain/behavior mechanism, prognostic indicator, and intervention target for childhood-onset BD, which endures into young adulthood and is associated with mood trajectory.

INTRODUCTION AND OBJECTIVE:Prognosis for metastatic RCC (mRCC) is variable. Aberrant HIF signaling is associated with progression of RCC. Using primary tumor tissue from Cancer and Leukemia Group B...