Citations

Abstract Background Limited data are available on the development of skin cancer and the associated risk factors for non‐White liver transplant (LT) recipients. The aim of this study is to determine the incidence of newly diagnosed skin cancer postoperatively and to identify the risk factors for the development of skin cancer in non‐White LT recipients. Methods We conducted an initial retrospective chart review of non‐White LT patients who received a transplant at our center between January 1, 2011, and December 31, 2013. Results Of the 96 patients in the study cohort, 32% were Black, 17% were Asian, 15% were White Hispanic, and 10% were Black Hispanic. One patient had a history of nonmelanoma skin cancer before transplant. No skin cancers were diagnosed during follow‐up (median, 1.3 years; range, 17 days to 8.6 years). Conclusion Our center’s experience is consistent with the literature and suggests that the incidence of newly diagnosed skin cancer in non‐White liver transplant recipients is low. Longer follow‐up may provide additional insights into the specific risk factors for the posttransplant development of skin cancer.

Abstract In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0.

Abstract Background Community-acquired pneumonia (CAP) in children is usually treated with 10 days of antibiotics. Shorter antibiotic courses may be beneficial if proven effective, with potentially fewer antibiotic adverse effects and decreased antibiotic exposure. Methods This randomized, double-blind, placebo-controlled superiority trial (NCT02891915) compared a strategy of short vs standard course ß-lactam therapy for outpatient CAP in children ages 6–71 months. Children demonstrating clinical improvement by day 3–5 of initial therapy were considered for enrollment. Enrolled children were randomized 1:1 to receive either 5 additional days of the originally prescribed antibiotic (standard) or matching placebo (short). The Desirability of Outcome Ranking (DOOR; PMID: 26113652) was the primary outcome, and was defined by classifying the global experience of children into an ordinal clinical response (OCR) that combined the response to CAP treatment and antibiotic adverse effects 11–15 days after the start of therapy. For those subjects with equivalent OCR, documented days of antibiotic administration was used to further rank the desirability of the outcome with the a priori assumption that shorter antibiotic exposure was more desirable. The OCR was a secondary outcome. The intention to treat population was used to estimate the probability of a more desirable outcome for the strategy of short vs. standard course therapy for both outcomes. Results 385 children were enrolled; 380 had complete data for analysis. Baseline characteristics were similar between the two strategies. In both strategies, > 90% of children had an adequate response to CAP treatment and most antibiotic adverse effects were minor (Table). In the OCR analysis, short course therapy had a 48% probability (95% CI: 42%-53%) of a more desirable outcome. In the DOOR analysis, short course therapy was superior to standard therapy with a 69% probability (95% CI: 63%-72%; p< 0.001) of a more desirable outcome. Conclusion Among children with CAP demonstrating initial clinical improvement with outpatient therapy, both strategies had a similar response to CAP treatment and antibiotic adverse effects, but short course therapy was superior in our a priori defined outcome that incorporated decreased antibiotic exposure. Disclosures Emmanuel B. Walter, MD, MPH, Moderna (Grant/Research Support)Pfizer (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) W. Charles Huskins, MD, MSc, ADMA Biologics (Consultant)Pfizer, Inc (Consultant)

AbstractBackgroundHearing impairment is associated with cognitive decline but whether it is a cause or marker is unknown. We investigated the association of hearing impairment with brain volumes and 8‐year cognitive decline. Because the superior temporal gyrus (STG) is the location of the primary auditory cortex, we stratified results by STG volume to investigate if the association of hearing and cognition differed among participants with and without evidence of possible hearing‐related brain atrophy.MethodWe used data from 1195 community‐dwelling adults (72‐94 years, 61% female, 36% black) from the Atherosclerosis Risk in Communities Study. A composite cognitive score was created from 10 neuropsychological tests administered at 3 study visits spanning 8 years (2011‐13 to 2018‐19). Brain volumes were calculated from structural magnetic resonance imaging scans for 6 regions of interest. Pure tone air conduction hearing thresholds (frequencies 0.5‐4 kHz) were obtained in 2016‐17 and averaged, with better‐ear hearing impairment defined as an average >25 dB. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes, adjusting for intracranial volume, demographic and clinical covariates. We estimated differences in annual rates of cognitive change by hearing impairment status adjusting for demographic and clinical covariates using linear mixed models; results were stratified by intracranial volume‐adjusted STG volume (below vs. equal to or greater than the median value).ResultThe mean STG volume difference comparing hearing impairment to normal hearing was ‐0.121 standard deviations (SD) (95% CI: ‐0.213, ‐0.028). Overall, the difference in the rate of cognitive decline associated with hearing impairment was ‐0.014 SD (‐0.023, ‐0.005). Hearing was more strongly associated with cognitive decline among participants with smaller STG volumes; rate difference, ‐0.014 SD (‐0.027, ‐0.002) compared to ‐0.008 (‐0.022, 0.006) for participants with larger STG volumes.ConclusionHearing impairment was associated with smaller brain volumes in the primary auditory region, but not with other regions. Our stratified analysis suggests that hearing treatment might be an important possible strategy to delay cognitive decline, even among participants with hearing‐related brain atrophy. Furthermore, the adverse cognitive effects of hearing impairment could potentially be mitigated if early hearing treatment can prevent STG atrophy.

AbstractBackgroundRecently, hearing loss has been identified as a promising modifiable risk factor for dementia. Several hypotheses explaining a potential underlying pathway have been proposed, including the sensory deprivation hypothesis, describing a direct causal relationship in which hearing loss leads to neuroplastic changes in the brain. Indeed, hearing loss has been associated with smaller macrostructural brain volumes, which is believed to at least partly explain the association between hearing loss and neurodegenerative disease. However, microstructural changes precede macrostructural changes. Therefore, we aimed to assess the association between hearing loss and microstructural integrity of the brain.Methods1,086 dementia‐free older adults from the Atherosclerosis Risk in Communities (ARIC) study (mean age = 75.2 [SD: 4.9], 61.4% female) underwent hearing assessment (2016‐2017) and magnetic resonance imaging (MRI) of the brain (2011‐2013). Hearing was assessed with pure‐tone audiometry. Microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD)) of multiple brain regions was determined with diffusion tensor imaging (DTI). Multivariable linear regression models were used to investigate the association between hearing loss and microstructural integrity of the lobes, temporal lobe gyri, medial temporal lobe structures and white matter (WM) tracts, adjusting for relevant confounders.ResultHearing loss was associated with lower WM microstructural integrity in the temporal lobe (difference in SD FA for moderate/severe hearing loss as compared to normal hearing: ‐0.19 [95% CI: ‐0.35, ‐0.03]; and difference in SD MD for moderate/severe hearing loss as compared to normal hearing: 0.15 [95% CI: 0.01, 0.28]). Hearing loss was associated with lower gray matter (GM) microstructure of the hippocampus, but not the amygdala. Moreover, hearing loss was associated with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus (Figure 1).ConclusionOur results demonstrate that age‐related hearing loss is associated with lower WM microstructural integrity in the temporal lobe, the limbic tracts and the uncinate fasciculus and lower GM microstructure in the hippocampus. These associations suggest that poorer hearing may affect brain regions that are important for different cognitive processes. However, the results should be interpreted with caution as this study is of a cross‐sectional design.

Abstract Purpose: Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting. Patients and Methods: Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose. Results: Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal (n = 12), mild (n = 8), moderate (n = 5), and severe (n = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m2) and severe (5 mg/m2) impairment cohort were 114% and 116% of the normal cohort (14 mg/m2). Conclusions: Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.

AbstractIntroductionAs hearing loss has been identified as an important risk factor for dementia, we aimed to assess the association between hearing loss and microstructural integrity of the brain.MethodsA total of 1086 dementia‐free participants (mean age = 75.2 [standard deviation: 4.9], 61.4% female) of the population‐based Atherosclerosis Risk in Communities (ARIC) study underwent hearing assessment (2016–2017) and magnetic resonance imaging of the brain (2011–2013). Microstructural integrity was determined with diffusion tensor imaging. Multivariable linear regression was used to investigate associations between hearing loss and microstructural integrity of different brain regions and white matter (WM) tracts.ResultsHearing loss was associated with lower WM microstructural integrity in the temporal lobe, lower gray matter integrity of the hippocampus, and with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus.ConclusionOur results demonstrate that hearing loss is indepedently associated with lower microstructural integrity in brain regions that are important for different cognitive processes.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

7008 Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) is recommended for diagnosis and staging of known or suspected NSCLC. Meta-analyses examining the accuracy of FDG-PET to diagnose lung cancer demonstrated high sensitivity 94% and specificity 83% but were performed in select centers. The purpose of this study is to evaluate the accuracy of FDG-PET to diagnose NSCLC and examine enrolling site differences in the national prospective ACOSOG Z4031 trial. Methods: 1,074 patients with clinical stage I (cT1-2N0M0) known or suspected NSCLC were enrolled between 2004 and 2006 in the Z4031 study and underwent surgical resection. The final diagnosis was determined by pathological examination. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: not avid and not cancerous (SUV=0), low avidity and likely not cancerous (SUV>0 and <2.5), avid and probably cancerous (SUV>2.5 and <5) and highly avid and likely cancerous (SUV>5). Sensitivity analysis of FDG-PET diagnostic accuracy was performed for varying levels of avidity and by preoperative lesion size. Differences in accuracy by enrolling site were examined. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 682 participants. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% CI: 79-85), and specificity was 31% (95% CI: 23-40). Positive and negative predictive values were 85% and 26%, respectively and accuracy improved with lesion size. There were 80 false positive scans and 69% were granulomas. False negative scans occurred in 101 patients (11were ≤10mm) with adenocarcinoma, squamous, bronchoalveolar cell and neuroendocrine tumors responsible for 64%, 12%, 10% and 8% of false negative results, respectively. Specificity did not differ between the 8 sites with >25 patients (p=0.74). Conclusions: In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared to published studies. Reasons for poor test performance should be explored.

Background Changes in white matter microstructural integrity are detectable before appearance of white matter lesions on magnetic resonance imaging as a manifestation of cerebral small‐vessel disease. The information relating poor white matter microstructural integrity to aortic stiffness, a hallmark of aging, is limited. We aimed to examine the association between aortic stiffness and white matter microstructural integrity among older adults. Methods and Results We conducted a cross‐sectional study to examine the association between aortic stiffness and white matter microstructural integrity among 1484 men and women (mean age, 76 years) at the 2011 to 2013 examination of the ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study). Aortic stiffness was measured as carotid‐femoral pulse wave velocity. Cerebral white matter microstructural integrity was measured as fractional anisotropy and mean diffusivity using diffusion tensor imaging. Multivariable linear regression was used to examine the associations of carotid‐femoral pulse wave velocity with fractional anisotropy and mean diffusivity of the overall cerebrum and at regions of interest. Each 1‐m/s higher carotid‐femoral pulse wave velocity was associated with lower overall fractional anisotropy (β=−0.03; 95% CI , −0.05 to −0.02) and higher overall mean diffusivity (β=0.03; 95% CI , 0.02–0.04). High carotid‐femoral pulse wave velocity (upper 25th percentile) was associated with lower fractional anisotropy (β=−0.40; 95% CI , −0.61 to −0.20) and higher overall mean diffusivity (β=0.27; 95% CI , 0.10–0.43). Similar associations were observed at individual regions of interest. Conclusions High aortic stiffness is associated with low cerebral white matter microstructural integrity among older adults. Aortic stiffness may serve as a target for the prevention of poor cerebral white matter microstructural integrity.