Citations

Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

Abstract Context Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a new entity replacing the diagnosis of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC). Significant variability in the incidence of NIFTP diagnosed in different world regions has been reported. Objective To investigate the rate of adoption of NIFTP, change in practice patterns, and uniformity in applying diagnostic criteria among pathologists practicing in different regions. Methods Two surveys distributed to pathologists of the International Endocrine Pathology Discussion Group with multiple-choice questions on NIFTP adoption into pathology practice and whole slide images of 5 tumors to collect information on nuclear score and diagnosis. Forty-eight endocrine pathologists, including 24 from North America, 8 from Europe, and 16 from Asia/Oceania completed the first survey and 38 the second survey. Results A 94% adoption rate of NIFTP by the pathologists was found. Yet, the frequency of rendering NIFTP diagnosis was significantly higher in North America than in other regions (P = .009). While the highest concordance was found in diagnosing lesions with mildly or well-developed PTC-like nuclei, there was significant variability in nuclear scoring and diagnosing NIFTP for tumors with moderate nuclear changes (nuclear score 2) (case 2, P < .05). Pathologists practicing in North America and Europe showed a tendency for lower thresholds for PTC-like nuclei and NIFTP than those practicing in Asia/Oceania. Conclusion Despite a high adoption rate of NIFTP across geographic regions, NIFTP is diagnosed more often by pathologists in North America. Significant differences remain in diagnosing intermediate PTC-like nuclei and respectively NIFTP, with more conservative nuclear scoring in Asia/Oceania, which may explain the geographic differences in NIFTP incidence.

Abstract Rationale Ground-glass opacities (GGOs) in the absence of interstitial lung disease are understudied. Objectives To assess the association of GGOs with white blood cells (WBCs) and progression of quantified chest computed tomography emphysema. Methods We analyzed data of participants in the SPIROMICS study (Subpopulations and Intermediate Outcome Measures in COPD Study). Chest radiologists and pulmonologists labeled regions of the lung as GGOs, and the adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGOs (%GGOAMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGOAMFM with WBCs, changes in percentage emphysema, and clinical outcomes. Measurements and Main Results Among 2,714 participants, 1,680 had chronic obstructive pulmonary disease (COPD) and 1,034 had normal spirometry. Among participants with COPD, on the basis of multivariable analysis, current smoking and chronic productive cough were associated with higher %GGOAMFM. Higher %GGOAMFM was cross-sectionally associated with higher WBC and neutrophil concentrations. Higher %GGOAMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at 1-year follow-up visit by 11.7% (relative increase; 95% confidence interval, 7.5–16.1%; P < 0.001). We found no association between %GGOAMFM and 1-year FEV1 decline, but %GGOAMFM was associated with exacerbations and all-cause mortality during a median follow-up of 1,544 days (interquartile interval, 1,118–2,059). Among normal spirometry participants, we found similar results, except that %GGOAMFM was associated with progression to COPD at 1-year follow-up. Conclusions Our findings suggest that GGOAMFM is associated with increased systemic inflammation and emphysema progression.

2001 Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided >89% power to detect RR >20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .

OBJECTIVE Deficiency in patient education has been correlated with increased disease-related morbidity and decreased access to care. However, the associations between educational level, preoperative disease severity, and postoperative outcomes in patients with lumbar spondylolisthesis have yet to be explored. METHODS The spondylolisthesis dataset of the Quality Outcomes Database (QOD)—a cohort with prospectively collected data by the SpineCORe study team of the 12 highest enrolling sites with an 81% follow-up at 5 years —was utilized and stratified for educational level. Patients were classified into three categories (high school or less, graduate, or postgraduate). Patient-reported outcome measures (PROMs) documented at baseline and follow-up included Oswestry Disability Index (ODI) score, EQ-5D in quality-adjusted life years, and numeric rating scale (NRS) scores for back and leg pain. Disease severity was measured with PROMs. Postoperatively, patients also completed the North American Spine Society assessment to measure their satisfaction with surgery. Multivariable regression analysis was used to compare education level with disease severity and postoperative outcomes. RESULTS A total of 608 patients underwent analysis, with 260 individuals (42.8%) at an educational level of high school or less. On univariate analysis, baseline disease severity was worse among patients with lower levels of education. On multivariable regression analysis, patients with postgraduate level of education had significantly lower ODI scores (β = −3.75, 95% CI −7.31 to −0.2, p = 0.039) compared to graduates, while the other PROMs were not associated with significant differences at baseline. Five years postoperatively, patients from various educational backgrounds exhibited similar rates of minimal clinically important differences in PROMs. Nevertheless, patients with the lowest educational level had higher ODI scores (27.1, p < 0.01), lower EQ-5D scores (0.701, p < 0.01), and higher NRS leg pain (3.0, p < 0.01) and back pain (4.0, p < 0.01) scores compared to those with graduate or postgraduate levels of education. The odds for postoperative satisfaction were also comparable between cohorts at 5 years (reference, graduate level; high school or less, OR 0.87, 95% CI 0.46–1.64, p = 0.659; postgraduate, OR 1.6, 95% CI 0.7–3.65, p = 0.262). CONCLUSIONS Lower patient education level was associated with a greater baseline disease severity in patients with lumbar spondylolisthesis. Surgery demonstrated similar benefits irrespective of educational background; however, individuals with lower educational level reported lower outcomes overall. This emphasizes the need for enhanced health literacy to mitigate disparities for reported outcomes.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Abstract Background The extravascular implantable cardioverter defibrillator (EV ICD) has recently emerged as a new option for guideline indicated ICD patients. Previous study results from the EV ICD Pilot and Pivotal studies have demonstrated that the device can provide safe and effective therapy through chronic follow up. However, less has been reported regarding EV ICD lead removal. Purpose To report on the experience of lead removal in the EV ICD Pivotal Study. Methods The EV ICD Pivotal study was an international, prospective, single-arm, premarket clinical study. Patients with a class I or IIa indication for a single-chamber ICD per ESC or ACC/AHA/HRS guidelines were enrolled. Lead removal summary data was reported. Results Of 316 patients with an implant attempt, (74.7% male, age 53.8±13.1 years, 82% primary prevention, LVEF of 38.9%±15.4%, and NYHA Class I [23.7%] or II/III [65.5%]) 299 were fully implanted; 17 (5.7%) of which had a lead removal procedure (14–752 days post-implant, at 13 sites) with 3 of them having been implanted for more than 1 year. Reasons for lead removal were lead dislodgement (n=7), infection (n=5), high impedance alert due to lead fracture (n=2), pacing indication (n=1), cardiac transplant (n=1), or scheduled sternotomy (n=1). New EV ICD leads were placed in 7/17 (41.2%) patients. No serious adverse events were adjudicated as related to the explant procedures. There was a single observation of incision site haemorrhage, that was resolved with wound care. Additional details on lead removal will be included at the time of presentation. Conclusions The EV ICD lead was successfully removed 14-752 days post implant. Nine patients were re-implanted with either extravascular or transvenous systems. Longer term extraction data collection is ongoing through the EV ICD Pivotal study and through the EV ICD post-approval study and will continue to provide additional insights.Lead removed 24 months post-implant.

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade, increasing evidence from preclinical models suggests that mesenchymal stromal cells, which are not normally resident in the lung, can be used to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathological remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of “omics” technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference.

Abstract Background Precision medicine, sometimes referred to as personalized medicine, is rapidly changing the possibilities for how people will engage health care in the near future. As technology to support precision medicine exponentially develops, there is an urgent need to proactively improve our understanding of precision medicine and pose important research questions (RQs) related to its inclusion in the education and training of future emergency physicians. Methods A seven‐step process was employed to develop a research agenda exploring the intersection of precision and emergency medicine education/training. A literature search of articles about precision medicine was conducted first, which informed the creation of future four scenarios in which trainees and practicing physicians regularly discuss and incorporate precision medicine tools into their discussions and work. Based on these futurist narratives, potential education RQs were generated by an expert panel. A total of 59 initial questions were subsequently categorized and refined to a priority list through a nominal group voting method. The top/priority questions were presented at the 2023 SAEM Consensus Conference on Precision Medicine, Austin, Texas, for further input. Results Eight high‐value education RQs were developed, reflecting a holistic view of the challenges and opportunities for precision medicine education in the knowledge, skills, and attitudes relevant to emergency medicine. These questions contend with topics such as most effective pedagogical methods; intended resulting outcomes and behaviors; the generational differences between practicing emergency physicians, educators, and future trainees; and the desires and expectations of patients. Conclusions Emergency medicine and emergency physicians must be prepared to understand precision medicine and incorporate this information into their “toolbox” of thinking, problem solving, and communication with patients and colleagues. This research agenda on how best to educate future emergency physicians in the use of personalized data to provide optimal health care is the focus of this article.