Citations

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments. Methods: To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci. Results: We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production. Conclusions: We identified 38 candidates of protein biomarkers for PDAC risk. Impact: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.

Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

Abstract Background Close associations between insomnia with other clinical factors have been identified in migraine, but there have been few studies investigating associations between insomnia and clinical factors in patients with persistent post-traumatic headache (PPTH). The study objective was to contrast the severity of insomnia symptoms in PPTH, migraine, and healthy controls, and to identify factors associated with insomnia in patients with PPTH vs. migraine. Methods In this cross-sectional cohort study, 57 individuals with PPTH attributed to mild traumatic brain injury, 39 with migraine, and 39 healthy controls were included. Participants completed a detailed headache characteristics questionnaire, the Migraine Disability Assessment Scale (MIDAS), Insomnia Severity Index (ISI), Hyperacusis Questionnaire (HQ), Allodynia Symptom Checklist, Photosensitivity Assessment Questionnaire, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory, Post-Traumatic Stress Disorder (PTSD) checklist, Ray Auditory Verbal Learning Test, and the Trail Making Test A and B to assess headache characteristics, disability, insomnia symptoms, sensory hypersensitivities, and neuropsychological factors. Fisher’s test and one-way ANOVA or Tukey’s Honest Significant Difference were used to assess group differences of categorical and continuous data. Stepwise linear regression analyses were conducted to identify clinical variables associated with insomnia symptoms. Results Those with PPTH had significantly higher ISI scores (16.7 ± 6.6) compared to migraine patients (11.3 ± 6.4) and healthy controls (4.1 ± 4.8) ( p < 0.001). For those with PPTH, insomnia severity was most strongly correlated with the BDI (Spearman's rho ( Common.EditSubmissionSteps.Transform.EquationText ) = 0.634, p < 0.01), followed by Trait Anxiety ( Common.EditSubmissionSteps.Transform.EquationText = 0.522, p < 0.01), PTSD ( Common.EditSubmissionSteps.Transform.EquationText = 0.505, p < 0.01), HQ ( Common.EditSubmissionSteps.Transform.EquationText = 0.469, p < 0.01), State Anxiety ( Common.EditSubmissionSteps.Transform.EquationText = 0.437, p < 0.01), and MIDAS scores ( Common.EditSubmissionSteps.Transform.EquationText = 0.364, p < 0.01). According to linear regression models, BDI, headache intensity, and hyperacusis scores were significantly positively associated with insomnia severity in those with PPTH, while only delayed memory recall was negatively associated with insomnia severity in those with migraine. Conclusions Insomnia symptoms were more severe in those with PPTH compared to migraine and healthy control cohorts. Depression, headache intensity, and hyperacusis were associated with insomnia in individuals with PPTH. Future studies should determine the bidirectional impact of treating insomnia and its associated symptoms.

LncRNAs play an indispensable role in the process of M1 macrophage via regulating the development of macrophages and their responses to bacterial pathogens and viral infections. However, there are few studies on the lncRNA-mediated functions and regulatory mechanisms of M2 macrophage polarization. In this study, we found a number of differentially expressed lncRNAs between human monocyte derived M0 and M2 macrophages according to array analysis and qRT-PCR validation. The lncRNA RP11-389C8.2 (we named lnc-M2 in this study) was observed to be highly expressed in M2 macrophages. In Situ Localization and Quantification Analysis showed that lnc-M2 was expressed in the nucleus and cytosolic compartments of M2 macrophages. Notably, lnc-M2 knockdown enhanced the phagocytic ability of M2 macrophages. Ulteriorly, the results of RNA-Protein interaction experiments indicated that protein kinase A (PKA) was a lnc-M2 associated RNA-binding protein (RBP). Western blot showed that p-CREB, a well-known key downstream transcription factor of PKA, was lowly phosphorylated in lnc-M2-silencing M2 macrophages. Furthermore, we found that transcriptional factor STAT3 promoted lnc-M2 transcription along with the up-regulation of epigenetic histone modification markers at the lnc-M2 promoter locus, indicating that STAT3 activated lnc-M2 and eventually facilitated the process of M2 macrophage differentiation via the PKA/CREB pathway. Collectively, our date provide evidence that the transcription factor STAT3 can promote the transcription of lnc-M2 and facilitated the process of M2 macrophage differentiation via the PKA/CREB pathway. This study highlights a novel mechanism underlying the M2 macrophage differentiation.

Abstract Background: Breast cancer incidence and mortality rates are increased in patients’ older than 65 years. However, there are limited reports on age-specific efficacy, safety, and drug tolerability, particularly in elderly patients older than 75 years old. Abemaciclib demonstrated clinically meaningful progression-free survival (PFS) improvement in combination with endocrine therapy (ET) in HR+, HER2- advanced breast cancer patients in the Phase 3 studies, MONARCH 2 and 3. Here we report exploratory subgroup analyses of MONARCH 2 and 3 to provide age-specific outcomes. Methods: In MONARCH 2 (NCT02107703), patients progressing while on prior ET received abemaciclib (or placebo) plus fulvestrant; in MONARCH 3 (NCT02246621), postmenopausal women with no prior systemic therapy for recurrent or metastatic breast cancer received abemaciclib (or placebo) plus letrozole or anastrozole. Exploratory outcome analyses of MONARCH 2 and 3 studies were performed for three age groups (women aged &lt;65, 65-74, and ≥75 years). Using pooled safety data, we performed age-specific subgroup analyses of the most common treatment-emergent adverse events (TEAEs) associated with either ET or ET plus abemaciclib. To assess the impact of age on efficacy, a subgroup analysis of PFS was performed using a Cox model for each trial independently. Results: Pooled safety data were available for 1152 patients treated in MONARCH 2 and 3 trials, including 59.7% pts &lt;65 years, 28.7% pts between 65 and 74 years, and 11.5% pts ≥ 75 years. Of those, 768 women received abemaciclib plus ET and 384 women received placebo plus ET. The most frequent TEAE was diarrhea and the most common Grade ≥3 TEAE was neutropenia. While diarrhea (any grade) occurred with similar incidence in abemaciclib-treated patients across age groups, clinically relevant diarrhea (Grade 2/3) was higher in the elderly (&lt;65, 39.5%; 65-74, 45.2%; ≥75, 55.4%); however, in the ≥75 group, diarrhea (Grade 2/3) incidence was also higher for placebo plus ET (&lt;65, 6.8%; 65-74, 4.5%; ≥75, 16.0%). Similarly, nausea and decreased appetite were moderately higher (by 10-20%) in the 2 abemaciclib-treated elderly subgroups. Fatigue (any grade) was higher in the 2 abemaciclib-treated elderly subgroups (&lt;65, 34.8%; 65-74, 48.4%; ≥75, 51.8%), while no differences were found across the 3 placebo subgroups. In contrast, the rates of Grade 3/4 neutropenia did not differ as a function of age in either the abemaciclib plus ET arm (&lt;65, 25.8%; 65-74, 27.4%; ≥75, 18.1%) or placebo plus ET arm. For efficacy, a consistent PFS benefit was observed with abemaciclib plus ET versus placebo plus ET across all three age-specified subgroups in both studies (Table). Conclusion: Abemaciclib in combination with ET demonstrates a tolerable safety profile and consistent efficacy benefit across all age subgroups examined, supporting the use of this combination in elderly patient populations. Despite the limited number of patients in the ≥75 group with potentially confounding comorbidities, the safety data suggest that patient education and appropriate management of toxicities, including dose adjustments and use of supportive medication for gastrointestinal toxicities, could maximize the benefit of abemaciclib. Table: Age-specified PFS outcomes from MONARCH 2 and 3MONARCH 2MONARCH 3Age GroupAbemaciclib + ETPlacebo + ETHR (95% CI)P-value *Abemaciclib + ETPlacebo + ETHR (95% CI)P-value *Events/NEvents/NEvents/NEvents/N&lt;65140/29192/1330.52 (0.40, 0.68)0.69581/18065/910.48 (0.35, 0.67)0.63465-7461/11442/600.63 (0.43, 0.94)40/10631/540.64 (0.40, 1.02)≥7521/4123/300.62 (0.34, 1.11)17/4212/200.54 (0.26, 1.13)Abbreviations: CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; PFS, progression-free survival.*P-value corresponds to the interaction test between age and treatment. Citation Format: Matthew P. Goetz, Meena Okera, Hans Wildiers, Mario Campone, Eva-Maria Grischke, Luis Manso, Valerie Anne Marie Andre, Amy Lee Chong, Belen San Antonio, Masakazu Toi, George W Sledge Jr. Safety and efficacy of abemaciclib plus endocrine therapy (ET) in elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+, HER2-) advanced breast cancer: An age-specific subgroup analysis of MONARCH 2 and 3 trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-10.

Abstract Background: Close associations between insomnia with other clinical factors have been identified in migraine, but there have been few studies investigating associations between insomnia and clinical factors in patients with persistent post-traumatic headache (PPTH). The study objective was to contrast the severity of insomnia symptoms in PPTH, migraine, and healthy controls, and to identify factors associated with insomnia in patients with PPTH vs. migraine. Methods: In this cross-sectional cohort study, 57 individuals with PPTH attributed to mild traumatic brain injury, 39 with migraine, and 39 healthy controls were included. Participants completed a detailed headache characteristics questionnaire, the Migraine Disability Assessment Scale (MIDAS), Insomnia Severity Index (ISI), Hyperacusis Questionnaire (HQ), Allodynia Symptom Checklist, Photosensitivity Assessment Questionnaire, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory, Post-Traumatic Stress Disorder (PTSD) checklist, Ray Auditory Verbal Learning Test, and the Trail Making Test A and B to assess headache characteristics, disability, insomnia symptoms, sensory hypersensitivities, and neuropsychological factors. Fisher’s test and one-way ANOVA were used to assess group differences of categorical and continuous data. Stepwise logistic regression analyses were conducted to identify clinical variables associated with insomnia symptoms. Results: Those with PPTH had significantly higher ISI scores (16.72 ± 6.58) compared to migraine patients (11.28 ± 6.42) and healthy controls (4.05 ± 4.80) (p < 0.001). For those with PPTH, insomnia severity was most strongly correlated with the BDI (Spearman's rho (ρ) = 0.634, p < 0.01), followed by Trait Anxiety (ρ = 0.522, p < 0.01), PTSD (ρ = 0.505, p < 0.01), HQ (ρ = 0.469, p < 0.01), State Anxiety (ρ = 0.437, p < 0.01), and MIDAS scores (ρ = 0.364, p < 0.01). According to linear regression models, BDI, headache intensity, and hyperacusis scores were significantly positively associated with insomnia severity in those with PPTH, while only delayed memory recall was negatively associated with insomnia severity in those with migraine. Conclusions: Insomnia symptoms were more severe in those with PPTH compared to migraine and healthy control cohorts. Depression, headache intensity, and hyperacusis were associated with insomnia in individuals with PPTH. Future studies should determine the bidirectional impact of treating insomnia and its associated symptoms.

Objectives The hypothalamus plays a key role in both migraine and cluster headache (CH). As brain region‐to‐region structural correlations are believed to reflect structural and functional brain connectivity patterns, we assessed the structural covariance patterns between the volume of the hypothalamic region and vertex‐by‐vertex measurements of cortical thickness in patients with migraine and in those with CH relative to healthy controls (HC). Methods T1‐weighted images were acquired on a 3T MRI scanner for a total of 59 subjects including 18 patients with CH (age: mean = 43.8, SD = 12.4), 19 with migraine (age: mean = 40.1, SD = 12.2), and 22 HCs (age: mean = 39.1, SD = 8.2). Imaging was collected between attacks (migraineurs) and during out‐of‐bout phases (CH). Data were post‐processed using FreeSurfer version 6.0 and within‐group correlations between hypothalamic region volume with cortical thickness were explored using a whole‐brain vertex‐wise linear model approach. Between‐group differences in correlation slopes between hypothalamic region volume and vertex‐by‐vertex measurements of cortical thickness were interrogated using post‐hoc comparisons. Results There were no significant between‐group differences (migraine vs CH; migraine vs HC; or CH vs HC) for age, sex, total brain volume or volume of the left or right hypothalamic region. For each group, there were significant positive correlations ( P < .01) between right and left hypothalamic region volumes with cortical thickness measurements. HC had significant positive correlations between hypothalamic region volume and cortical thickness over large portions of the superior and rostral medial frontal, orbitofrontal cortex and rostral anterior cingulate, and smaller clusters in the superior and middle temporal, posterior cingulate, fusiform, and precentral cortex. Post‐hoc analysis showed significant differences in covariance patterns in those with migraine and CH relative to HC, with both migraine patients and CH having weaker structural covariance of hypothalamic region volume with frontal and temporal cortical thickness. Conclusion Recent evidence suggests hypothalamic region connectivity to frontal and temporal areas to be relevant for regulating pain perception. Thus, the diminished structural covariance in migraineurs and CH might suggest abnormal functioning of the pain control circuitry and contribute to mechanisms underlying central sensitization and chronification of pain.

Background and Objectives Migraine with aura (MwA) is associated with increased brain hyper‐responsiveness to visual stimuli and increased visual network connectivity relative to migraine without aura (MwoA). Despite this, prior studies have provided conflicting results regarding whether MwA is associated with higher photophobia symptom scores compared to MwoA. The relationships between MwA and other types of sensory hypersensitivity, such as phonophobia and cutaneous allodynia (CA), have not been previously investigated. The purpose of this cross‐sectional observational study was to investigate whether MwA is associated with greater symptoms of photophobia, phonophobia, and CA compared to MwoA. Methods This analysis included 321 migraine patients (146 MwA; 175 MwoA) who had been enrolled into the American Registry for Migraine Research. The diagnosis of either MwoA or MwA was determined by headache specialists using ICHD diagnostic criteria. Patients completed the Photosensitivity Assessment Questionnaire, the Hyperacusis Questionnaire, and the Allodynia Symptom Checklist. Mean or median values were compared between groups. Regression models were created to analyze the relationship between MwA with photophobia scores, hyperacusis scores, and the presence of interictal CA. Results Those with MwA had higher mean photophobia scores than those with MwoA (4.1 vs 3.0, P = .0003). MwA was positively associated with photophobia symptom severity ( B = 0.50 [SE = 0.14], P = .0003), after controlling for age, patient sex, and headache frequency. Aura was not associated with hyperacusis symptom severity ( B = 0.07 [SE = 0.08], P = .346) or the presence of interictal CA (OR 1.33 [95% CI 0.70‐2.53], P = .381). Conclusion MwA is associated with higher photophobia symptom scores compared to MwoA. Aura is not associated with greater hyperacusis or interictal allodynia scores. These findings complement prior imaging and neurophysiologic studies that demonstrated MwA to be associated with hyper‐responsiveness of brain visual processing regions. The findings suggest that MwA is associated specifically with visual hypersensitivity, as opposed to being associated with a general hypersensitivity to multiple types of sensory stimuli.

Background: Gastric cancer is one of the leading causes of cancer-related mortality worldwide, accounting for 8.2% of cancer-related deaths. The purpose of this study was to investigate the geographic and sociodemographic disparities in gastric adenocarcinoma patients. Methods: We conducted a retrospective study in gastric adenocarcinoma patients between 2004 and 2013. Data were obtained from the National Cancer Data Base (NCDB). Univariate and multivariable analyses were performed to evaluate overall survival (OS). Socio-demographic factors, including the location of residence [metro area (MA) or rural area (RA)], gender, race, insurance status, and marital status, were analyzed. Results: A total of 88,246 [RA, N = 12,365; MA, N = 75,881] patients were included. Univariate and multivariable analysis showed that RA had worse OS (univariate HR = 1.08, p < 0.01; multivariate HR = 1.04; p < 0.01) compared to MA. When comparing different racial backgrounds, Native American and African American populations had poorer OS when compared to the white population; however, Asian patients had a better OS (multivariable HR = 0.68, p < 0.01). From a quality of care standpoint, MA patients had fewer median days to surgery (28 vs. 33; p < 0.01) with fewer positive margins (6.3% vs. 6.9%; p < 0.01) when compared to RA patients. When comparing the extent of lymph node dissection, 19.6% of MA patients underwent an extensive dissection (more than or equal to 15 lymph nodes) in comparison to 18.7% patients in RA (p = 0.03). Discussion: This study identifies socio-demographic disparities in gastric adenocarcinoma. Future health policy initiatives should focus on equitable allocation of resources to improve the outcomes.