Esophageal cancer: Does inaccuracy in clinical staging affect our ability to reach optimal outcomes?

BACKGROUND: Pretreatment clinical staging is used to decide the course of treatment in early-stage esophageal cancer. Few studies assess the effect of inaccurate clinical staging on oncologic outcomes. METHODS: We queried the National Cancer Database to identify patients undergoing esophagectomy for clinical stage cT1bN0 esophageal carcinoma between 2010 and 2019. Patients were categorized as being upstaged if, on final pathology, they had histopathologic disease that would have warranted treatment with neoadjuvant therapy. The textbook oncologic outcome was defined as margin-negative resection, 15 lymph nodes examined, a hospital stay of <21 days, no unplanned 30-day readmission or mortality, and stage-appropriate use of neoadjuvant therapy. RESULTS: In total, 916 patients met inclusion criteria; 378 (41.2%) had a pathologic stage that differed from their pretreatment clinical stage. By multivariable regression, factors associated upstaging included: presentation between 2015 and 2019 (odds ratio 1.92 95% confidence interval [1.19, 3.13]), delay to esophagectomy of >30 days (odds ratio 2.38 95% confidence interval [1.13, 5.57]), larger tumor size (>2 cm relative to <2 cm, odds ratio 2.73 95% confidence interval [1.72, 4.39]), and poorly differentiated histology (odds ratio 2.79 95% confidence interval [1.75, 4.49]). The rate of textbook oncologic outcome assuming reliable clinical staging was 43.8%; accounting for upstaging, the rate of textbook oncologic outcome was 22.5% (P < .001). CONCLUSION: In patients with cT1bN0 esophageal cancer, tumor size and histology are associated with the risk of inaccurate pretreatment clinical staging. Inaccuracies in clinical staging impact the rate at which providers achieve optimal oncologic outcomes.

Prognosis of Unresected vs Resected Small Pulmonary Carcinoid Tumors.

BACKGROUND: Previous studies have shown that overall survival after lung resection for pulmonary carcinoid tumors is favorable. It is unclear what the prognosis is for observation rather than resection for small carcinoid tumors. METHODS: We queried the National Cancer Database to identify patients presenting with primary pulmonary carcinoid tumors between 2004 and 2017. We included patients with small (<3 cm) primary pulmonary carcinoids, who were observed or underwent a lung resection. To minimize confounding by indication, we used propensity score matching, while accounting for age, sex, race, insurance type, Charlson-Deyo comorbidity score, typical and atypical histology, tumor size, and year of diagnosis. We used Kaplan-Meier survival analyses to compare 5-year overall survival in the matched cohorts. RESULTS: Of 8435 patients with small pulmonary carcinoids, 783 (9.3%) underwent observation and 7652 (91%) underwent surgical resection. After propensity score matching, surgical resection was associated with improved 5-year overall survival (66% vs 81%, P < .001). No significant difference in overall survival was found between wedge and anatomic resection (88% vs 88%, P = .83). In patients undergoing resection, lymph node sampling at the time of wedge and anatomic resection increased 5-year overall survival (90% vs 86%, P = .0042; 88% vs 82%, P = .04, respectively). CONCLUSIONS: Surgical resection of small pulmonary carcinoids is associated with improved survival compared with observation. When surgical resection is performed, wedge and anatomic resection result in similar survival, and lymph node sampling improves survival.

Is local excision an appropriate treatment modality in patients presenting with early-stage (cT1 N0 M0) rectal adenocarcinoma?

BACKGROUND: Prior studies evaluating the safety and efficacy of local excision relative to surgical resection in early-stage rectal adenocarcinoma have primarily included low rectal cancers treated with abdominoperineal resection as control comparison cohorts. The role of local excision in early-stage rectal adenocarcinoma is incompletely defined. METHODS: We queried the National Cancer Database to identify patients with cT1 N0 M0 rectal adenocarcinoma between 2004 and 2019. Patients undergoing abdominoperineal resection were excluded. Multivariable regression was used to identify factors associated with use of local excision instead of low anterior resection. Patients undergoing local excision were propensity score matched for age, sex, demographic characteristics, Charlson-Deyo comorbidity class score, and tumor grade and size to those undergoing low anterior resection. Short-term clinical outcomes and 5-year overall survival for matched cohorts were compared by standard methods. RESULTS: A total of 5,693 patients met inclusion criteria; 1,973 patients underwent local excision and 3,720 low anterior resection. Age (adjusted odds ratio 1.26; 95% confidence interval, 1.17-1.37), tumor histology (poorly differentiated histology: adjusted odds ratio 0.66; 95% confidence interval, 0.51-0.86), and size (>4 cm: adjusted odds ratio 0.20; 95% confidence interval, 0.16-0.25) were associated with choice of intervention. On comparison of matched cohorts, patients undergoing LE demonstrated shorter hospital stay (2.4 ±9.8 vs 5.6 ±8.1 days; P < .001) and lower readmission rate (4% vs 7%; P = .002) but higher margin-positive resection rates (8% vs 2%; P < .001). Overall survival profiles for patients undergoing local excision were comparable with those for low anterior resection. CONCLUSION: In patients with cT1 N0 M0 rectal adenocarcinoma, local excision is associated with a higher margin-positive resection rate than low anterior resection but affords accelerated postprocedure recovery and comparable rates of overall survival.

Effects of LDL Cholesterol and Statin Use on Verbal Learning and Memory in Older Adults at Genetic Risk for Alzheimer's Disease.

BACKGROUND: The apolipoprotein epsilon 4 (APOE4) allele is a well-established genetic risk factor for Alzheimer's disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning. OBJECTIVE: This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD. METHODS: Neuropsychological, LDL, statin use, and APOE4 data were extracted from an ongoing longitudinal study at the Banner Alzheimer's Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47-75, with a family history of probable AD in at least one first-degree relative. RESULTS: In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers. CONCLUSION: LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status.

Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression.

Early life adversity and insecure attachment style are known risk factors for perinatal depression. The biological pathways linking these experiences, however, have not yet been elucidated. We hypothesized that overlap in patterns of DNA methylation in association with each of these phenomena could identify genes and pathways of importance. Specifically, we wished to distinguish between allostatic-load and role-transition hypotheses of perinatal depression. We conducted a large-scale analysis of methylation patterns across 5 × 106 individual CG dinucleotides in 54 women participating in a longitudinal prospective study of perinatal depression, using clustering-based criteria for significance to control for multiple comparisons. We identified 1580 regions in which methylation density was associated with childhood adversity, 3 in which methylation density was associated with insecure attachment style, and 6 in which methylation density was associated with perinatal depression. Shorter telomeres were observed in association with childhood trauma but not with perinatal depression or attachment insecurity. A detailed analysis of methylation density in the oxytocin receptor gene revealed similar patterns of DNA methylation in association with perinatal depression and with insecure attachment style, while childhood trauma was associated with a distinct methylation pattern in this gene. Clinically, attachment style was strongly associated with depression only in pregnancy and the early postpartum, whereas the association of childhood adversity with depression was time-invariant. We concluded that the broad DNA methylation signature and reduced telomere length associated with childhood adversity could indicate increased allostatic load across multiple body systems, whereas perinatal depression and attachment insecurity may be narrower phenotypes with more limited DNA methylation signatures outside the CNS, and no apparent association with telomere length or, by extension, allostatic load. In contrast, the finding of matching DNA methylation patterns within the oxytocin receptor gene for perinatal depression and attachment insecurity is consistent with the theory that the perinatal period is a time of activation of existing attachment schemas for the purpose of structuring the mother-child relationship, and that such activation may occur in part through specific patterns of methylation of the oxytocin receptor gene.

Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease.

Insulin resistance (IR) is a metabolic state preceding development of type 2 diabetes (DM2), cardiovascular disease, and neurodegenerative disorders, including Alzheimer's Disease (AD). Liraglutide, a glucagon-like peptide-1 (GLP) agonist, is an insulin-sensitizing agent with neuroprotective properties, as shown in animal studies. The purpose of this double-blinded, placebo-controlled study was to examine the neural effects of administration of liraglutide in cognitively normal late middle-aged individuals with subjective cognitive complaints (half of subjects had family history of AD). Seed-based resting state connectivity using functional magnetic resonance imaging (fMRI) was conducted before and after 12 weeks of liraglutide treatment or placebo. Neuropsychological testing was conducted before and after treatment to determine whether there were any potential behavioral correlates to neural changes. RESULTS: At baseline (time point 1), higher fasting plasma glucose (FPG) was associated with decreased connectivity between bilateral hippocampal and anterior medial frontal structures. At time point 2, we observed significant improvement in intrinsic connectivity within the default mode network (DMN) in the active group relative to placebo. There were no detectable cognitive differences between study groups after this duration of treatment. To our knowledge, this is the first placebo-controlled study to report neural effects of liraglutide in a middle-aged population with subjective cognitive complaints. Larger and longer duration studies are warranted to determine whether liraglutide has neuroprotective benefits in individuals at risk for AD.