Citations

BACKGROUND There is a paucity of literature describing risk factors for canalicular injury (CI) during periocular Mohs micrographic surgery (Mohs). OBJECTIVE This study aimed to determine factors associated with CI after Mohs. This information may inform patient counseling and surgical planning. MATERIALS AND METHODS This case–control study compared subjects with canalicular injury after Mohs with subjects requiring ophthalmologic Mohs repair without canalicular injury. All subjects who had CI after Mohs were included in the control group. CI from other causes were excluded. RESULTS Basal cell carcinoma was the most common etiologic tumor (p < .00001). Canalicular injury was associated with infiltrative, morpheaform, and/or micronodular-type basal cell carcinoma. Initial tumor location involving the medial canthus was not statistically different between cases and controls (32% vs 17%, p = .22). Having a final defect involving the medial canthus region was more likely in cases versus controls (55% vs 26%, p = .01952). CONCLUSION Although most final defects involved the medial canthal region, a substantial number of tumors resulting in CI did not initially seem to involve the medial canthus. Surgeons cannot rely simply on anatomical location when assessing risk for CI, and anticipation of need for canalicular reconstruction is challenging.

Suicidality is increased in autism spectrum disorder (ASD), yet effective interventions are lacking. Developing biologically based approaches for preventing and treating suicidality in ASD hinges on the identification of biomarkers of suicidal ideation (SI). Here, we assessed magnetic resonance spectroscopy (MRS) markers of glutamatergic neurotransmission in ASD youth and young adults. Twenty-eight ASD participants (16–33 years) underwent 1H-MRS, and metabolites were quantified using LCModel. N-acetylaspartate (NAA), glutamate (Glu), and the NAA/Glu ratio from the left dorsolateral prefrontal cortex were compared between ASD SI+ (n = 13) and ASD SI− (n = 15) participants. We found that ASD SI+ participants had a higher NAA/Glu ratio compared ASD SI- participants. The NAA/Glu ratio also predicted SI and significantly discriminated between ASD SI+/SI− participants. All analyses including NAA and Glu alone were non-significant. Here, we provide preliminary evidence for the importance of NAA/Glu in ASD with SI, with implications for biomarker discovery. Further mechanistic research into risk and interventional approaches to address SI in ASD are needed.

Abstract Background: Previous studies have demonstrated poorer survival of Black women with breast cancer. We assessed whether race/ethnicity was associated with disease-free (DFS) and overall survival (OS) among women with breast cancer enrolled in clinical trials for early-stage breast cancer according to tumor subtype, age, and body mass index (BMI). Methods: 10,011 women enrolled in one of four adjuvant chemotherapy trials: CALGB 9741, CALGB 49907, CALGB 40101, or NCCTG N9831. 9918 participants had available DFS and/or OS data and were included in the analysis. Cox models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between race/ethnicity and DFS and OS. We compared Non-Hispanic (NH) Black (n=871), Hispanic (n=436), and other race participants (n=283) to NH Whites (n=7889). We assessed associations within strata of age group (&lt;50, 50-&lt;65, or ≥65), tumor subtype (hormone receptor (HR)+/HER2-, HR-/HER2+, or HR-/HER2-), and BMI (&lt;25, 25-&lt;30, or ≥30). Results: In multivariable-adjusted models, NH Black patients under 50 years of age had worse DFS compared to NH White patients (HR: 1.34, 95% CI: 1.10-1.62) and worse OS (HR: 1.64, 95% CI: 1.30-2.07). The differences in DFS and OS persisted in patients ages 50 to &lt;65, though there were no significant differences in DFS or OS between NH Black and NH White patients ages ≥65. Among Hispanic and NH White participants, younger age at diagnosis was associated with greater DFS compared with older age overall while this was not true for NH Black patients. Among patients with HR+/HER2- tumors, NH Black patients when compared to NH White patients had worse DFS (HR 1.33, 95% CI: 1.04-1.70) but there was not a significant difference in OS (HR 1.35, 95% CI: 1.00-1.83). DFS and OS for other tumor subtypes did not significantly differ by race. Among patients with BMI &lt;25, NH Black patients had significantly worse DFS (HR: 1.70, 95% CI: 1.25-2.30) and OS (HR:1.76, 95% CI:1.20-2.58) compared to NH White patients. There was no difference in survival between different race/ethnicity groups among individuals with BMI ≥25. Conclusions: Our results identified subgroups that may contribute to the observed disparities in survival between NH Black and NH White women with early-stage breast cancer. The greatest disparities are among individuals &lt;50 years of age, those with HR+/HER2-, and those with BMI &lt;25. These differences exist even within clinical trial populations with similar initial therapy, suggesting that disparities may be influenced by inequities in survivorship care and long-term treatment, such as endocrine therapy adherence and persistence, and/or differences in tumor or host biology. Support: U10CA180821 and U10CA180882; ClinicalTrials.gov Identifiers: NCT00003088, NCT00005970, NCT00024102, NCT00041119; https://acknowledgments.alliancefound.org Citation Format: Marla Lipsyc-Sharf, Karla V. Ballman, Jordan D. Campbell, Hyman B. Muss, Edith A. Perez, Lawrence N. Shulman, Lisa A. Carey, Ann H. Partridge, Erica T. Warner. Role of age, BMI, and tumor subtype in racial/ethnic disparities in breast cancer survival: A pooled analysis of four Alliance adjuvant clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 494.

Background TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01742117.

e19514 Background: Zanubrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), demonstrated superior overall response rate and a trend toward improved progression-free survival (PFS) as compared to ibrutinib in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) in the phase 3 ALPINE trial (NCT03734016) based on interim analysis. However, its comparative efficacy with other treatments is not known. The goal of this study was to estimate the relative efficacy of zanubrutinib compared with standard treatments for R/R CLL through a network meta-analysis (NMA). Methods: The efficacy of zanubrutinib from ALPINE (study of zanubrutinib and ibrutinib in patients with R/R CLL was compared to ibrutinib, acalabrutinib, bendamustine and rituximab (BR), and venetoclax + rituximab (V+R) using data from 4 RCTs. Relevant RCTs were identified using a systematic literature review. A network was constructed that composed RCTs (ALPINE, ELEVATE-RR [NCT02477696], ASCEND [NCT02970318], and MURANO [NCT02005471]). Bayesian network meta-analysis (NMA) models were used to simultaneously synthesize hazard ratios (HRs) and 95% credible intervals (CrIs) for investigator-assessed PFS and overall survival (OS) to estimate the relative efficacy of zanubrutinib versus comparators of interest. An assumption of constant hazard ratio was applied in the NMA analysis. Analyses were performed using well-established codes published by the National Institute for Health and Care Excellence (NICE) Decision Support Unit and were implemented with OpenBUGS (version 3.2.3). Results: The NMA suggested a significant improvement in PFS for zanubrutinib over acalabrutinib (HR=0.52, 95% CrI [0.30, 0.90]), ibrutinib (0.47, [0.29, 0.76]), and BR (0.13, [0.06, 0.26]). Zanubrutinib had a numerically better PFS than V+R (0.69, [0.32, 1.46]) while not reaching statistical significance. For OS, NMA results showed a trend favoring zanubrutinib over acalabrutinib (0.75, [0.35, 1.59]), ibrutinib (0.62, [0.31, 1.22]), and BR (0.52, [0.21, 1.24]). The difference was not statistically significant with wide CrIs, suggesting a high uncertainty as inherent limitation of the analysis. Conclusions: This NMA reports the first summary of comparative PFS of available treatments for R/R CLL. Indirect treatment comparisons suggest PFS on zanubrutinib may be superior to other BTKis and immunochemotherapies in R/R CLL patients.[Table: see text]

505 Background: We investigated the clinical utility of SET2,3, a novel biomarker designed to measure to endocrine sensitivity. SET2,3 measures nonproliferative hormone receptor-related transcription (SETER/PR) adjusted for a baseline prognosis index derived from tumor size, nodes involved and a 4-gene molecular subtype (RNA4). CALGB 9471 is a seminal phase III study that showed improved DFS and OS from 2-weekly dose-dense (DD) vs 3-weekly chemotherapy in ER-negative cancers. Risk of recurrence (ROR-PT) score (intrinsic subtype, proliferation score and tumor size) measured by Nanostring assay was reported to be prognostic in CALGB 9741, but did not predict benefit from DD chemotherapy. Methods: SET2,3 was performed using an aliquot of 200-300 ng RNA (residual from prior ROR-PT testing) from 682 ER+ tumor samples and tested using the QuantiGene Plex bead-based hybridization assay (ThermoFisher, Luminex). We report results for the primary and two secondary objectives of the NCI/CTEP-approved correlative science proposal CSC0154) to evaluate SET2,3 in CALGB 9741 for prognosis (primary endpoint: 95%CI for 5-year (yr) DFS > 75% for High SET2,3 using the predefined prognostic cutpoint 2.10), SET2,3 prognostic independence from ROR-PT, and prediction of outcome according to chemotherapy regimen. We used Cox models to estimate hazard ratios (HR) for prognosis and comparison with ROR-PT results (using c-indices) and for prediction according to chemotherapy schedule using an interaction term (prespecified significance level for interaction: p < 0.10). Results: The study met its primary endpoint with a 5-yr DFS of 85.6% (95%CI 81.3-90.2) in the High-SET subset (244/613, 40%). High-SET vs Low-SET was significantly associated with favorable outcomes at 5 yr (DFS 85.6% vs 69%, p <.0001; OS 95.3% vs 84.6%, p <.0001) and 10 yr (DFS 77.7% vs 58.2%, p <.0001; OS 86.9% vs 65.9%, p <.0001). PAM50 ROR-PT and SET classification were available for 596 tumors. In multivariate models for DFS and OS, SET2,3 remained an independent prognostic variable for DFS (SET high vs low HR = 0.46, 95% CI, 0.34 – 0.63, p < 0.0001; PAM50 ROR-PT high vs low HR = 1.22, 95% CI, 0.91 – 1.64, p = 0.18) and for OS (SET high vs low HR = 0.36, 95% CI, 0.25 – 0.53, p < 0.0001; PAM50 ROR-PT high vs low HR = 1.26, 95% CI, 0.91 – 1.75, p = 0.16). Similar observations were seen in models including SET and PAM50 ROR-PT as continuous variables. Lower SET2,3 values predicted improved outcomes from DD vs 3-weekly chemotherapy (interaction p=0.0998 for DFS, 0.042 for RFS and 0.027 for OS). This was unrelated to menopausal status and lower SET2,3 values favored DD concurrent treatments. Conclusions: SET2,3 index was strongly prognostic, independent of ROR-PT, and predicted survival benefit from DD chemotherapy in pre- and postmenopausal women with ER+ cancer. Clinical trial information: NCT00003088.

AbstractBackgroundUropathogen resistance, fluoroquinolone‐resistance (FQR), and extended spectrum beta‐lactamase (ESBL), has been observed to be emerging worldwide with prevalences above recommended thresholds for routine empirical treatment. The primary aim of our study was to determine the prevalence of FQR from a geographically diverse sample of United States emergency departments (EDs).MethodsWe conducted a multi‐center, observational cohort study using a network of 15 geographically diverse US EDs. All patients ≥18 years of age with the primary or secondary diagnosis of urinary tract infection (UTI) in the ED identified using International Classification of Diseases (ICD‐10) diagnosis code of cystitis, pyelonephritis, or UTI from 2018 to 2020 were included. We calculated descriptive statistics for uropathogens and susceptibilities. Logistic regression analysis was used to identify antimicrobial resistance risk factors associated with FQR Escherichia coli.ResultsAmong 3779 patients who met inclusion criteria, median age was 62.9 years (interquartile range [IQR]: 41–77.6) and 76.3% were female. The most common diagnoses were complicated (41.2%) and uncomplicated cystitis (40.3%). E. coli was the most common pathogen (63.2%), followed by Klebsiella pneumoniae (13.2%) and Enterococcus species (5.8%). Across all sites, overall E. coli FQ‐resistance prevalence was 22.1%, ranging from 10.5 to 29.7% by site. The prevalence of ESBL‐producing uropathogen was 7.4%, ranging from 3.6% to 11.6% by site. Previous IV or oral antimicrobial use in the past 90‐days and history of a multi‐drug resistant pathogen were associated with FQ‐resistant E. coli (odds ratio [OR] 2.68, 95% confidence interval [CI]: 2.04–3.51, and OR 6.93, 95% CI: 4.95–9.70, respectively). Of the patients who had FQ‐resistant E. coli or an ESBL‐producing uropathogen isolated, 116 (37.1%) and 61 (36.7%) did not have any documented risk factors for resistance.ConclusionFQ‐resistant E. coli is widely prevalent across US sites highlighting the need for ongoing monitoring of antimicrobial resistance and, at some locations, modification of empirical treatments.

Background Infective endocarditis is a heart infection with a first-year mortality rate of ≈ 30%. It has long been thought that infective endocarditis is causally associated with bloodstream seeding with oral bacteria in ≈ 40–45% of cases. This theorem led guideline committees to recommend that individuals at increased risk of infective endocarditis should receive antibiotic prophylaxis before undergoing invasive dental procedures. However, to the best of our knowledge, there has never been a clinical trial to prove the efficacy of antibiotic prophylaxis and there is no good-quality evidence to link invasive dental procedures with infective endocarditis. Many contend that oral bacteria-related infective endocarditis is more likely to result from daily activities (e.g. tooth brushing, flossing and chewing), particularly in those with poor oral hygiene. Objective The aim of this study was to determine if there is a temporal association between invasive dental procedures and subsequent infective endocarditis, particularly in those at high risk of infective endocarditis. Design This was a self-controlled, case-crossover design study comparing the number of invasive dental procedures in the 3 months immediately before an infective endocarditis-related hospital admission with that in the preceding 12-month control period. Setting The study took place in the English NHS. Participants All individuals admitted to hospital with infective endocarditis between 1 April 2010 and 31 March 2016 were eligible to participate. Interventions This was an observational study; therefore, there was no intervention. Main outcome measure The outcome measure was the number of invasive and non-invasive dental procedures in the months before infective endocarditis-related hospital admission. Data sources NHS Digital provided infective endocarditis-related hospital admissions data and dental procedure data were obtained from the NHS Business Services Authority. Results The incidence rate of invasive dental procedures decreased in the 3 months before infective endocarditis-related hospital admission (incidence rate ratio 1.34, 95% confidence interval 1.13 to 1.58). Further analysis showed that this was due to loss of dental procedure data in the 2–3 weeks before any infective endocarditis-related hospital admission. Limitations We found that urgent hospital admissions were a common cause of incomplete courses of dental treatment and, because there is no requirement to record dental procedure data for incomplete courses, this resulted in a significant loss of dental procedure data in the 2–3 weeks before infective endocarditis-related hospital admissions. The data set was also reduced because of the NHS Business Services Authority’s 10-year data destruction policy, reducing the power of the study. The main consequence was a loss of dental procedure data in the critical 3-month case period of the case-crossover analysis (immediately before infective endocarditis-related hospital admission), which did not occur in earlier control periods. Part of the decline in the rate of invasive dental procedures may also be the result of the onset of illness prior to infective endocarditis-related hospital admission, and part may be due to other undefined causes. Conclusions The loss of dental procedure data in the critical case period immediately before infective endocarditis-related hospital admission makes interpretation of the data difficult and raises uncertainty over any conclusions that can be drawn from this study. Future work We suggest repeating this study elsewhere using data that are unafflicted by loss of dental procedure data in the critical case period. Trial registration This trial is registered as ISRCTN11684416. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 28. See the NIHR Journals Library website for further project information.