Citations

Objective To provide evidence‐based recommendations and expert guidance for the management of Kawasaki disease (KD), focusing on clinical scenarios more commonly addressed by rheumatologists. Methods Sixteen clinical questions regarding diagnostic testing, treatment, and management of KD were developed in the Patient/Population, Intervention, Comparison, and Outcomes (PICO) question format. Systematic literature reviews were conducted for each PICO question. We used the Grading of Recommendations, Assessment, Development and Evaluation method to assess the quality of evidence and formulate recommendations. Each recommendation required consensus from at least 70% of the Voting Panel. Results We present 1 good practice statement, 11 recommendations, and 1 ungraded position statement to guide the management of KD and clinical scenarios of suspected KD. These recommendations for KD are focused on situations in which input from rheumatologists may be requested by other managing specialists, such as in cases of treatment‐refractory, severe, or complicated KD. The good practice statement affirms that all patients with KD should receive initial treatment with intravenous immunoglobulin (IVIG). In addition, we developed 7 strong and 4 conditional recommendations for the management of KD or suspected KD. Strong recommendations include prompt treatment of incomplete KD, treatment with aspirin, and obtaining an echocardiogram in the setting of unexplained macrophage activation syndrome or shock. Conditional recommendations include use of IVIG with other adjuvant agents for patients with KD and high‐risk features of IVIG resistance and/or coronary artery aneurysms. These recommendations endorse minimizing risk to the patient by using established therapy promptly at disease onset and identifying situations in which adjunctive therapy may be warranted. Conclusion These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and use of echocardiography in patients with suspected or confirmed KD.

Abstract Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.

AbstractBackgroundCenters discard high kidney donor profile index (KDPI) allografts, potentially related to delayed graft function and prolonged hospital use by kidney transplant recipients (KTR). We sought to determine whether high KDPI KTRs have excess health care utilization.MethodsWe conducted a retrospective cohort study from a high‐volume center analyzing KTRs from January 3, 2011 to April 12, 2015 (n = 652). We measured differences in hospital use, emergency visits, and outpatient visits within the first 90 days between low (≤85%) versus high KDPI (>85%) KTRs, as well as long‐term graft function and patient survival.ResultsHigh (n = 107) and low KDPI (n = 545) KTRs had similar length of stay (median = 3 days, P = .66), and readmission rates at 7, 30, and 90 days after surgery (all, P > .05). High KDPI kidneys were not associated with excess utilization of the hospital, emergency services, outpatient transplant clinics, or ambulatory infusion visits on univariate or multivariate analysis (all, P > .05). Low KDPI KTRs had significantly better eGFR at 2 years (Low vs. High KDPI: 60.35 vs. 41.54 ml/min, P < .001), but similar 3‐year patient and graft survival (both, P > .09).ConclusionsHigh and low KDPI KTRs demonstrated similar 90‐day risk‐adjusted health care utilization, which should encourage use of high KDPI kidneys.

Abstract Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increased by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD have historically been associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment. Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD. Here, we present an electrical stimulation approach that uses ultra-low (≤ 1Hz) frequency (ULF) spike-timing dependent plasticity (STDP) in mouse models of AUD to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors using electrical stimulation rather than approaches requiring genetic modification. This work represents a step towards fulfilling the unmet need for a reliable method of treating severe AUD through cell-type specific control with clinically available neuromodulation tools.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Although combined treatment with gemcitabine and albumin-bound paclitaxel has improved the prognosis of PDAC, both intrinsic and acquired chemoresistance cloud the outcomes. Hence, there is an urgent need to explore new therapeutic targets and formulate innovative strategies for the more effective treatment of PDAC.Methods: We transduced pancreatic cancer cells with a protein kinase library, and transfected cells were selected by puromycin treatment, followed by continuous exposure to vehicle control or gemcitabine/paclitaxel chemotherapy for 21 days. Next-generation sequencing as well as MAGeCK-VISPR analysis were performed to the identify candidate genes. Finally, we used the CRISPR-Cas9 to knockout the target gene, confirming that it is a viable target for overcoming chemoresistance in vivo and in vitro.Results: We identified several cell cycle checkpoint kinases and DNA damage-related kinases as targets for overcoming chemoresistance. Among them, cyclin-dependent kinase 7 (CDK7) ranked highly in both screenings. We demonstrated that both gene knockout and pharmacological inhibition of CDK7 by THZ1 result in cell cycle arrest, apoptosis induction. Furthermore, THZ1 synergized with gemcitabine and paclitaxel in vitro and in vivo, resulting in enhanced antitumor effects.Conclusions: Our findings support the application of CRISPR-Cas9 screening in identifying novel therapeutic targets and provide new strategies for overcoming chemoresistance in pancreatic cancer.

482 Background: Prostate radiotherapy is associated with worse oncologic outcomes in patients with bladder cancer. This is thought to be secondary to microvascular damage resulting in propagation of inflammation. There is sparse data on the effect of prior radiotherapy on the efficacy of intravesical Bacillus Calmette-Guerin (BCG) in patients with non-muscle invasive bladder cancer (NMIBC). We sought to evaluate BCG response and outcomes in NMIBC patients who have previously undergone prostate radiotherapy compared to patients with no prior history of pelvic radiotherapy. Methods: This is a retrospective cohort study that includes patients who received intravesical BCG for NMIBC at our institution from 2001 to 2019. Data were collected on patient and pathologic characteristics. Patients were stratified into three cohorts: prior radiotherapy (RT), radical prostatectomy (RP), and no prostate cancer (No PCa). Wilcoxon rank sum test and Chi-squared test were used for comparison between groups. The primary endpoints included recurrence at one-year, progression to MIBC and progression to metastatic disease. Results: In 199 total patients who underwent BCG for NMIBC, 23 had a prior history of radiotherapy treatment for prostate cancer, while 17 underwent prior radical prostatectomy. Overall, 41.2% of patients had recurrence at one year. There was no difference in recurrence at one year between the cohorts: 42.8% No PCa, 29.4% RP and 39.1% RT; p = 0.56. There was also no difference in progression to MIBC (6.9% No PCA, 0% RP, and 8.7% RT) or progression to metastatic disease (6.9% No PCA, 5.9% RP and 4.3% RT) with p = 0.50 and 0.89 respectively. Conclusions: The efficacy of intravesical BCG does not appear to be modified by prior radiation treatment for prostate cancer in patients with NMIBC.[Table: see text]

Abstract Background : Studies have proposed an inverse association between allergic diseases and cancer risk, but few studies to date have specifically investigated the risk of primary liver cancer (hepatocellular carcinoma, HCC; intrahepatic cholangiocarcinoma, ICC) in patients with or without allergic diseases. Objective : The aim of this study was to evaluate the association between allergic diseases and risk of developing liver cancer.Methods: A retrospective cohort study of the Korean National Health Insurance Service database was performed to study 405,512 South Korean adults ages 40 and above who underwent routine health screening after January 1st, 2005. All participants were followed for liver cancer diagnosis or death until December 31st, 2013. Those who died before the index date, had pre-diagnosed cancer, or did not undergo health screening were excluded. Cox proportional hazards regression was performed to determine the adjusted hazard ratios(aHRs) and 95% confidence intervals (CIs) for risk of developing liver cancer according presence or absence of atopic dermatitis, asthma and allergic rhinitis.Results: The aHR (95% CI) for overall liver cancer among allergic patients was 0.72 (0.64-0.81). Allergic patients had significantly reduced risk of HCC (aHR: 0.70, 95% CI: 0.61-0.81) but not ICC (aHR: 0.99, 95% CI: 0.71-1.08). Presence of allergic diseases was associated with significantly lower risk of liver cancer in both patients with (aHR: 0.61, 95% CI: 0.47-0.8) or without (aHR: 0.74, 95% CI: 0.65-0.85) chronic Hepatitis B/C infections. Presence of allergic diseases was associated with significantly lower risk of liver cancer in patients without cirrhosis (aHR: 0.72, 95% CI 0.63-0.82), but not in those with cirrhosis (aHR: 0.98, 95% CI 0.68-1.41). Patients with multiple allergies had even lower risk of liver cancer compared to patients with single allergy. Conclusion: Patients with allergic diseases have significantly lower risk of developing liver cancer compared to those without allergic diseases, which supports the rationale for immunotherapy as an effective treatment of liver cancer.