Well-differentiated neuroendocrine tumors (WDNETs) of the pancreas are graded on the basis of mitotic count or Ki67 index. Mitotic count has a narrow cutoff; its assessment is time consuming and carries poor interobserver reproducibility. Phosphohistone H3 (PHH3) is a mitosis-specific marker whose value has been validated in several tumor types. We sought to assess the utility of PHH3 in histologic grading of pancreatic WDNETs. Sixty-three cases of surgically resected primary pancreatic WDNETs were retrieved, and immunohistochemical analysis for PHH3 and Ki67 was performed. Mitotic rate was independently assessed by 4 pathologists on hematoxylin and eosin (HE; in 50 high-power fields [HPFs], expressed as mitoses/10 HPF) and PHH3 stains (in 50 HPFs, one 10×, and one 20× hotspot). PHH3 and Ki67 labeling indices were determined on a single 20× hotspot and expressed as the percentage of positive cells to total cells. We found that mitotic counts by various methods significantly correlated with each other and also with PHH3 and Ki67 indices, with the best correlation seen within the 3 different PHH3 counts (in 50 HPFs, one 10× and one 20× hotspot). Moreover, mitotic count on PHH3 was less time consuming than that on HE (1.68 vs. 3.67 min for 50 HPFs, P<0.0001). Histologic grade determined by PHH3 significantly correlated with disease-specific and disease-free survivals, with the best cutoffs of ≥4 mitoses/10 HPF (2 mm), ≥7 mitoses/10× hotspot, ≥5 mitoses/20× hotspot (log rank test, P<0.0001), and ≥0.16% for PHH3 labeling index (log rank test, P<0.0006). Tumor grades based on PHH3 stain also showed significant correlation with patient survivals in multivariate Cox proportional hazards models (P<0.05). Histologic grades by mitotic counts on PHH3 demonstrated high concordance and κ agreement with grades determined by mitotic count on HE. PHH3 stain also showed improved interobserver agreement in both original mitotic count (intraclass correlation 0.98 vs. 0.79) and final grade assignment (Fleiss κ 0.69 vs. 0.46) as compared with HE. Thus, our data confirmed that histologic grading by PHH3 stain has practical and prognostic values and offers reduced time and improved interobserver reproducibility in mitotic rate assessment and grade assignment. Although larger series are needed for validation, mitotic rate can potentially be determined by counting 1 hotspot, which will greatly facilitate the assessment of histologic grade in pancreatic WDNETs.
BACKGROUND Contemporary population‐based data on characteristics associated with blood donation in the United States (U.S.) are limited. STUDY DESIGN AND METHODS A cross‐sectional analysis was performed among 28,739 persons aged 18 years and older who participated in the 2016 National Health Interview Survey, a household survey of the noninstitutionalized U.S. civilian population. Analyses were weighted and accounted for the complex survey design. Adjusted prevalence ratios (aPR) were estimated by multivariable log‐binomial regression. RESULTS The percentage of individuals reporting a past‐year history of blood donation was 5.7% (95% confidence interval [CI], 5.3%‐6.1%) and was highest in the youngest age group (18‐24 years, 8.4%). A past‐year history of blood donation was more common in males compared to females (6.3% vs. 5.1%; aPR, 1.12 [95% CI, 0.99‐1.27]) and those born in the U.S. compared to individuals born outside the U.S. (6.4% vs. 2.4%; aPR, 1.92 [95% CI, 1.49‐2.47]). The percentage of individuals with a past‐year history of blood donation was significantly lower in blacks (3.9%; aPR, 0.60 [95% CI, 0.47‐0.75]) and Hispanics (3.0%; aPR, 0.63 [95% CI, 0.48‐0.83]) in comparison to whites (6.9%). Being a college graduate, being employed, being physically active, and never being a cigarette smoker were factors positively associated with blood donation. The percentage of individuals with a past‐year history of blood donation varied by geographic census region, with prevalence being higher in the Midwest (7.3%) and South (6.0%) compared to the Northeast (4.7%) and West (4.4%). CONCLUSION Continued differences in the blood donor population with reference to the U.S. population underscore the need to understand barriers or deterrents to blood donation. Evidence‐based donor recruitment and related policies remain imperative to ensure that there is a sustainable blood supply.
Background Analysis of melanomas for actionable mutations has become the standard of care. Recently, a classification scheme has been proposed that categorizes BRAF mutations based on their mechanisms for activation of the MAPK pathway. Methods In this analysis BRAF , KIT , NRAS , and PIK3CA mutations were examined by next generation sequencing (NGS) in 446 melanomas in a clinical diagnostic setting. KRAS and HRAS were also analyzed to elucidate coexisting BRAF and RAS mutations. BRAF mutations were categorized into class-1 (kinase-activated, codon 600), class-2 (kinase-activated, non-codon 600) and class-3 (kinase-impaired), based on the newly proposed classification scheme. Results NGS demonstrated high analytic sensitivity. Among 355 mutations detected, variant allele frequencies were 2–5% in 21 (5.9%) mutations and 2–10% in 47 (13%) mutations. Mutations were detected in BRAF (42%), NRAS (25%), KIT (4.9%) and PIK3CA (2.7%). The incidence of class-1, class-2 and class-3 mutations were 33% (26% p.V600E and 6.1% p.V600K), 3.1 and 4.9% respectively. With a broader reportable range of NGS, class-1, class-2 and class-3 mutations accounted for 77, 7.4 and 12% of all BRAF mutations. Class-3 mutations, commonly affecting codons 594, 466 and 467, showed a higher incidence of coexisting RAS mutations, consistent with their RAS-dependent signaling. Significant association with old age and primary tumors of head/neck/upper back suggest chronic solar damage as a contributing factor for melanomas harboring BRAF p.V600K or class-3 mutations. Conclusion This study categorizes the range, frequency, coexisting driver mutations and clinical characteristics of the three classes of BRAF mutations in a large cohort of melanomas in a clinical diagnostic setting. Further prospective studies are warranted to elucidate the clinical outcomes and benefits of newly developed targeted therapy in melanoma patients carrying each class of BRAF mutation. Electronic supplementary material The online version of this article (10.1186/s12885-019-5864-1) contains supplementary material, which is available to authorized users.
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