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Published:August 12, 2014DOI:https://doi.org/10.1016/j.cgh.2014.08.006

      Tall Individuals Have a Lower Risk of Barrett’s Esophagus and Esophageal Adenocarcinoma (Than Short Ones!)

      Greater height is associated with increased risk of cancer in general. The relationship between height and risk of developing esophageal adenocarcinoma (EAC) or its precursor, Barrett's esophagus (BE), is unclear. In this issue of CGH, Thrift et al used epidemiologic and genome-wide data from individuals of European ancestry in the Barrett's and Esophageal Adenocarcinoma Consortium: 999 EAC cases, 2061 BE cases, and 2168 population controls. They reported that height was inversely associated with EAC (per 10 cm increase in height: odds ratio [OR], 0.70; 95% confidence interval [CI], 0.62–0.79 for males, and OR, 0.57; 95% CI, 0.40–0.80 for females) and BE (per 10 cm increase in height: OR, 0.69; 95% CI, 0.62–0.77 for males, and OR, 0.61; 95% CI, 0.48–0.77 for females). The relationship between height and risk of BE and EAC in men is shown in Figure 1. They found the same results in an additional analysis using Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable. The paper concludes that height was inversely associated with risks of EAC and BE. To know more about the possible mechanistic studies of the effect of height on EAC and BE and the utility of these findings in clinical risk stratification, read the accompanying editorial entitled “The Taller They Come: Height and Esophageal Adenocarcinoma” by Dr Joel H. Rubenstein and Dr Elena M. Stoffel on page 1677.
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      Figure 1Restricted cubic spline models of the relationship between height and EAC in males. Plots are restricted to heights of 155 to 195 cm in males for clarity and consistency.

      Familial Barrett’s Esophagus Affects up to 7% of Patients With BE or EAC

      Studying familial clustering of BE and EAC may improve the knowledge regarding processes involved in BE and EAC development, both for familial and sporadic cases. The study by Verbeek et al identified first- and second-degree relatives of patients with BE and EAC to determine the extent of familial clustering of these conditions, as well as reflux symptoms, in a European cohort and studied differences between familial and nonfamilial cases. The investigators sent questionnaires to 838 patients diagnosed with BE or EAC, from 2000 through 2011, at 3 hospitals in the Netherlands; 603 patients (71%) responded and were included in the analysis. Familial statuses of BE defined as definitive (>1 first- or second-degree relative with BE or EAC), possible (>1 reported relative with BE or esophageal cancer, without histologic confirmation), unlikely (no family history), or unknown. Diagnoses of affected relatives were confirmed using the Dutch Pathology Registry. Familial BE was definitive for 7% of cases, possible for 6%, unlikely for 49%, and unknown for 38% (n = 231). Definitive cases of familial BE were younger at onset of heartburn and EAC diagnosis; their first-degree relatives more frequently had reflux symptoms and a prior upper endoscopy, compared with unlikely cases of familial BE. Total number of positive relatives with BE or EAC within a family (a total number of 39 families) in addition to the index patient in definitive familial BE is shown in Figure 2. These findings indicate that genetic factors may contribute to BE susceptibility. This study is placed in the context of the history and future of familial and genetic risk of BE and EAC in the editorial entitled “What We Know and What We Need to Know About Familial Gastroesophageal Reflux Disease and Barrett's Esophagus” by Dr Xiangquing Sun and colleagues on page 1664.
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      Figure 2Number of affected relatives per family. Total number of positive relatives with BE or EAC within a family in addition to the index patient in definitive familial BE subdivided into first- and second-degree relatives. Total number of families = 39.

      A MicroRNA-Based Test Improves Endoscopic Ultrasound–Guided Cytologic Diagnosis of Pancreatic Cancer

      The clinical utility of endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) in combination with cytopathology for diagnosis and staging of pancreatic ductal adenocarcinoma is limited by high rates of indeterminate or false-negative results. MicroRNAs (miRNAs) have unique features, which have made a promising class of candidate biomarkers for many human cancers. miRNAs are stable and easily recovered from formalin-fixed, paraffin-embedded (FFPE) tissues as well as from clinical specimens with limited tissue yield. Several specific miRNAs were previously found up- as well as down-regulated in pancreatic cancer. In a multicenter study, Brand et al report the findings of developing and prospective double-blinded validating an miRNA-based test to improve preoperative detection of pancreatic ductal adenocarcinoma. Levels of miRNAs were analyzed in a central clinical laboratory by relative quantitative polymerase chain reaction in 95 FFPE specimens and 228 samples collected by EUS-FNA of patients with solid pancreatic masses. The investigators developed a 5-miRNA expression classifier consisting of MIR24, MIR130B, MIR135B, MIR148A, and MIR196 that could identify pancreatic ductal adenocarcinoma in FFPE specimens. During validation of this classifier, detection of pancreatic ductal adenocarcinoma in EUS-FNA samples increased from 78.8% by cytology analysis alone (95% CI, 72.2%–84.5%) to 90.8% when combined with miRNA analysis (95% CI, 85.6%–94.5%); other results highlights are shown in Table 1. The miRNA classifier correctly identified 22 additional true pancreatic ductal adenocarcinoma cases among 39 samples initially classified as benign, indeterminate, or nondiagnostic by cytology. This test might aid in the diagnosis of pancreatic cancer by reducing the number of FNAs without a definitive adenocarcinoma diagnosis, thereby reducing the number of repeat EUS-FNA procedures. Further validation of this novel molecular diagnostic tool warrants additional studies to determine whether miRNAs may also be used clinically for the prediction of a patient’s prognosis or for guiding the choice of therapy.
      Table 1Performance of Cytology and/or Molecular Testing in EUS-FNA Specimens
      Diagnostic modalitySpecimen, nMalignant detection rate (95% CI), %Benign detection rate (95% CI), %
      Cytology alone210
      Includes all specimens with a final clinical diagnosis of pancreatic ductal adenocarcinoma (n = 184) or benign (n = 26), independent of initial cytology diagnosis.
      78.8 (72.2–84.5)69.2 (48.2–85.7)
      Molecular alone210
      Includes all specimens with a final clinical diagnosis of pancreatic ductal adenocarcinoma (n = 184) or benign (n = 26), independent of initial cytology diagnosis.
      82.6 (76.3–87.8)96.1 (80.4–99.9)
      Combined molecular cytology210
      Includes all specimens with a final clinical diagnosis of pancreatic ductal adenocarcinoma (n = 184) or benign (n = 26), independent of initial cytology diagnosis.
      90.8 (85.6–94.5)96.1 (80.4–99.9)
      Cytology alone213
      Includes all specimens with adenocarcinoma, benign, indeterminate, or nondiagnostic cytology (n = 210 plus 1 ampullary carcinoma, 1 cholangiocarcinoma, and 1 neuroendocrine tumor).
      78.1 (71.5–83.8)69.2 (48.2–85.7)
      Molecular alone213
      Includes all specimens with adenocarcinoma, benign, indeterminate, or nondiagnostic cytology (n = 210 plus 1 ampullary carcinoma, 1 cholangiocarcinoma, and 1 neuroendocrine tumor).
      81.8 (75.5–87.1)96.1 (80.4–99.9)
      Combined molecular cytology213
      Includes all specimens with adenocarcinoma, benign, indeterminate, or nondiagnostic cytology (n = 210 plus 1 ampullary carcinoma, 1 cholangiocarcinoma, and 1 neuroendocrine tumor).
      90.4 (85.2–94.2)96.1 (80.4–99.9)
      Combined molecular cytology228
      Includes all specimens eligible for this study (n = 213 plus 15 non–pancreatic ductal adenocarcinoma malignancies identified by cytology).
      91.1 (86.3–94.6)96.1 (80.4–99.9)
      CI, confidence interval.
      a Includes all specimens with a final clinical diagnosis of pancreatic ductal adenocarcinoma (n = 184) or benign (n = 26), independent of initial cytology diagnosis.
      b Includes all specimens with adenocarcinoma, benign, indeterminate, or nondiagnostic cytology (n = 210 plus 1 ampullary carcinoma, 1 cholangiocarcinoma, and 1 neuroendocrine tumor).
      c Includes all specimens eligible for this study (n = 213 plus 15 non–pancreatic ductal adenocarcinoma malignancies identified by cytology).

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