Citations

1592 Background: While ongoing efforts to decrease opioid use have dramatically altered the prescribing landscape, the impact on patients with cancer is not well understood. We examined trends in new and persistent opioid use in opioid-naïve older patients with and without cancer in the United States. Methods: This retrospective cohort study used SEER-Medicare linked data for patients with solid tumors malignancies diagnosed from 2012 through 2017, and a random sample of patients without cancer. We included patients who did not receive opioids for 3 months prior to the diagnosis or randomly assigned index date. We identified new opioid use (claim in 0-90 days after diagnosis/index date), early persistent opioid use (claims in days 0-90 and 91-180), and long-term persistent opioid use (claims in days 0-90 and 91-180 and months 13-15). Further analysis focused on 4 clinical strata: non-cancer, metastatic cancer, cancer treated with surgery alone, and cancer treated with surgery plus chemotherapy and/or radiotherapy ("surgery+"). We calculated relative changes in the predicted probability of opioid use from 2012 to 2017 based on a logit model adjusted for patient demographics. Results: We identified 238,470 eligible patients with cancer (mean age 76.3 years). Among patients with cancer, 46.4% had new opioid use; use was higher among those receiving surgery+ (70.6%), those treated with surgery alone (58.8%) and those with metastatic cancer (50.0%), compared to patients without cancer (6.9%). From 2012 to 2017, the predicted probability of new opioid use declined in all groups, with lower relative decline in the cancer subgroups (6.8% surgery+; 9.5% surgery alone; 10.2% metastatic cancer) compared to the non-cancer comparator (24.7%). For instance, in patients with metastatic cancer, predicted probability of new use decreased from 52.4 to 47.1% (10.2%) vs. 8.0 to 6.0% (24.7%) in patients without cancer. Relative decline in predicted probability of long-term persistent opioid use was lower in the surgical cancer strata (44.2% surgery+; 46.1% surgery alone) vs. the non-cancer comparator (54.0%). Conclusions: While opioid use remains common in patients with cancer, new and persistent opioid use declined over time in all patients, though with steeper relative declines in non-cancer compared to cancer populations. Our study suggests important but tempered effects of the changing opioid climate on patients with cancer.[Table: see text]

Background: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. Methods: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow–derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. Results: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow–derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)–induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. Conclusions: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Abstract A false pituitary tumor describes pituitary enlargement due to intracranial hypotension. Reported previously primarily in the neurological literature, we present this case referred to endocrinology for evaluation of a pituitary mass. A 24-year-old male was referred to endocrinology for evaluation of pituitary enlargement without a hypo-enhancing lesion on magnetic resonance imaging (MRI). The main symptom reported was headache that was worse in the standing position and in the afternoon. He had no symptoms or signs of pituitary mass-effect, or hormone excess or deficiencies. Past medical history was relevant for a history of nerve schwannoma status post resection with subsequent spinal fusion. Biochemical evaluation of pituitary hormones was normal. Upon review of his pituitary MRI, other abnormalities seen were suggestive of intracranial hypotension. Based on his history and imaging findings, he was diagnosed with intracranial hypotension causing a “false pituitary tumor” rather than pituitary enlargement or abnormality. Further evaluation revealed multiple spinal leaks that were patched. His symptoms subsided within a few days of repair. Endocrinologists should be aware of the possible misdiagnosis of a pituitary mass due to intracranial hypotension.

Abstract Introduction People with heart failure (HF) have frequent hospitalizations, and emergency department (ED) visits. We examined the effects of insomnia and rest-activity rhythms (RARs) on time to hospitalizations and ED visits after controlling for other known risk factors among participants in a randomized controlled trial of cognitive behavioral therapy for insomnia compared to heart failure self-management education (attention control). Methods The analysis included 168 HF patients who had available medical records for dates of hospitalization, ED visit, transplant, and death from a randomized clinical trial for insomnia of people with HF and insomnia. The known risk factors included age, sex, New York Heart Association (NYHA) Class, ejection fraction, and comorbid conditions. We used the insomnia severity index (ISI) and evaluated the strength of RAR using the ratio of the amplitude to the MESOR estimated with cosinor analysis with activity counts from a wrist-actigraph worn for at least five consecutive days. Cox proportional hazard models were used to examine ­insomnia and the RAR metrics with the known risk factors on time to first hospitalization, ED visit, transplant, and death. Results Eighty-five (50.1%) had at least one hospitalization, and ninety-one (54.2%) participants had an ED visit. Approximately 42% of the participants were admitted to the hospital due to cardiac events. Older age, male sex, higher NYHA, and greater comorbidity were associated with earlier hospitalization or ED visits. After controlling for those risk factors, stronger RAR was associated with later time to hospitalization, and ED visit with hazard ratios (HRs) of 0.26 (95% CI=[0.07, 0.91]) and 0.25 (95% CI=[0.07, 0.89]); higher insomnia severity (ISI ≥22) was associated with shorter time to ED visits, with an HR of 2.28 (95% CI=[1.19, 4.38]). Conclusion In addition to known demographic and clinical risk factors, insomnia severity and RAR predict hospitalizations and ED visits in people with HF. Further research is necessary to assess the biological mechanism of the associations and examine whether the effects of the risk factors could be modified by improving insomnia severity and RAR in people with HF. Support (if any) This study was financially supported by grants R01NR016191 and P20NR014126 from NIH/NINR.

Abstract Introduction Penile prosthesis placement in men on active anti-coagulation (AC) is controversial. The bleeding risk of continued blood thinners must be weighed against the increased thrombotic risk for patients when stopping them. Previously utilized techniques to decrease complication rates from AC include the use of a malleable implant only, leaving the IPP partially inflated for hemostasis, and placement of a drain. Objective We sought to assess outcomes of penile implant placement in men on clopidogrel, warfarin, apixaban, enoxaparin, and rivaroxaban in a multi-institutional study. Methods Data from 3 high volume implant centers were retrospectively obtained. Demographic characteristics, comorbidities, case information including secondary procedures, placement of drain, drain output, and complications were recorded. Data on patients with aspirin any dose alone were not included as all 3 centers do not routinely discontinue ASA at time of penile implant. One center never placed drains and used a penoscrotal approach, one center left a drain at least one day and removed when output was < 50 ml/8 hours and used a penoscrotal approach, and the last center placed a drain for 3 days and utilized an infra-pubic approach. Results 202 patients were continued on AC throughout surgery. 112 patients were on clopidogrel, 35 warfarin, 38 apixaban, 1 enoxaparin, 15 rivaroxaban, and 1 on combination therapy with clopidogrel and enoxaparin. AC requirement included peripheral vascular disease (55%), CHF (11%), cardiac stents (11.6%), DVT/PE/history of thrombosis (7%), atrial fibrillation (11%), cardiac valves (2.2%), stroke (1.3%), and preventive (0.9%). Nine patients on AC (3.98%) experienced complications including 4 significant events (1.9%): 1 major retropubic bleed requiring transfusion, 3 IPP infections and 5 minor events: 3 minor hematomas, 1 minor wound dehiscence and 1 CT negative stroke event. Drain outputs for the 3 day center averaged 113 ml, 81 ml and 30 ml of output per day respectively with a total average output average of 223 ml and experienced no hematomas nor infections. Drain output for the center with removal when < 50 ml/8 hours averaged 121 ml with the majority or patients having the drain for only one day. Drain output was significantly higher than historical non AC controls (121 vs. 72 ml p=.001) but there was no difference in hematoma rate. Three hematomas and 1 infection occurred in this group. AC type, revision surgery, scrotoplasty, or reservoir technique did not affect outcomes nor drainage (P>.05). Complication rate (IPP infection and hematoma rate) where not different when compared to large cohorts from respective institutions. Conclusions Our data shows a 1.9% rate of major complications in patients undergoing IPP placement on anticoagulation in high volume implant centers. Although this approach appears feasible and similar in complication rates in men not on AC, careful consideration of the risk benefit ratio should be undertaken. Our data indicate closed suction draining for 3 days may be warranted. Additionally, the retropubic bleed case argues for only submuscular reservoirs placed under direct vision which minimizes occult bleeding risk. In the majority of cases, elective IPP surgery should be delayed until it is safe to discontinue anticoagulation therapy. Disclosure No

Abstract Introduction Perception of penile curvature (PC) varies widely, and correction of PC is in the eye of the beholder. Objective We sought to investigate if patients with Peyronie’s Disease (PD) had differing opinions on correction of PC compared to general andrology (AD) patients without PD and general urology (URO) patients. Methods A cross-sectional survey was administered to adult patients in andrology and general urology clinics at 3 geographically separate institutions. Patients were grouped with having PD vs AD vs URO conditions. The survey consisted of unlabeled images of penis models with varying degrees of PC (range 10-90°). Respondents were asked to select the images they would want surgically corrected. Univariable and multivariable analyses were performed to identify demographic variables associated with willingness to consider correction. Results Ninety-four PD, 106 AD, and 302 URO patients were recruited. When comparing the 3 groups, besides obvious gender differences with PD patients, PD patients were less in 25-34 age range and more in 55-64 age range (p=0.01 and p=0.007). PD was less represented in Mid-Atlantic (p<0.001). 8% of PD, 12% of AD, and 20% of URO patients chose not to surgically correct any degree of PC (p=0.001). Among those who endorsed willingness to surgically correct PC, the average threshold for correction was 52.5° (SD 13) for PD, 37.2° (SD 29.5) for AD, and 51.0° (SD 19.9) for URO patients. When comparing PD patients with AD patients, no difference in the decision to surgically correct was found (p=0.42). This was also found to be the case when comparing PD with URO (p=0.46) and PD+AD patients vs URO (p=0.67). On univariable analysis, among AD patients, those ages 55-64 were more willing to undergo PC correction at lower degrees of PC (p=0.03) but did not hold up on multivariable analysis (p=0.40). No other demographic factors among PD and AD groups were found to have an impact on willingness to undergo PC correction (Table 1). Conclusions No significant differences were seen in the decision to surgically correct PC when comparing the perspectives of patients with PD, AD, and URO. Roughly 10% of all of these patients would defer on surgical management of any degree of PC. Despite having PC, no demographic differences were seen among PD patients’ willingness to correct PC. Disclosure No

ObjectiveTo compare improvement in patient‐reported outcomes (PROM) in persons undergoing endoscopic and open surgical management of Zenker diverticula (ZD).MethodologyProspective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative who underwent surgery for ZD. Patient survey, radiography reports, and the 10‐item Eating Assessment Tool (EAT‐10) pre‐ and post‐procedure were abstracted from a REDCap database, which summarized means, medians, percentages, and frequencies of. Outcome based on operative intervention (endoscopic vs. open) was compared using t‐test, Wilcoxon rank sum test or chi‐square test, as appropriate.ResultsOne hundred and forty‐seven persons were prospectively followed. The mean age (SD) of the cohort was 68.7 (11.0). Overall, 66% of patients reported 100% improvement in EAT‐10; 81% of patients had greater than 75% improvement; and 88% had greater than 50% improvement. Endoscopic was used for n = 109 patients, and open surgical intervention was used for n = 38. The median [interquartile range, IQR] EAT‐10 percent improvement for endoscopic treatment was 93.3% [72, 100], and open was 100% [92.3, 100] (p = 0.05). The incidence of intraoperative complications was 3.7% for endoscopic and 7.9% for open surgical management. The median [IQR] in follow‐up was 86 and 97.5 days, respectively.ConclusionBoth endoscopic and open surgical management of ZD provide significant improvement in patient‐reported outcomes. The data suggest that open diverticulectomy may provide a modest advantage in symptomatic improvement compared to endoscopic management. The data suggest that the postoperative complication rate is higher in the open surgical group.Level of Evidence3 Laryngoscope, 134:97–102, 2024

Abstract Background Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP-Ec isolates obtained from a prospective cohort. Methods Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-β-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture. Results Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non–MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non–MBL-Ec was 62% (95% CI: 48.2–74.3%). Among infected patients, non–MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec. Conclusions Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non–MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations.