Journal Club

1. Journal Club Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, Livolsi VA, Mandel SJ, Raab SS, Rosai J, Steward DL, Walsh PS, Wilde JI, Zeiger MA, Lanman RB, Haugen BR. Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology. N Engl J Med. 2012 Jun 25. [Epub ahead of print] GallwitzB, Rosenstock J, Rauch T, Bhattacharya S, Patel S, von Eynatten M, Dugi KA, Woerle HJ. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 2012 Jun 27. [Epub ahead of print] 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文 Matsuda, Masafumi 2012年7月5日8:30-8:55 ８階　医局

2. the Departments of Medicine (E.K.A.) and Pathology (E.S.C.), Brigham and Women’s Hospital and Harvard Medical School, Boston; Veracyte, South San Francisco, CA (G.C.K., D.C., J.D., L.F., P.S.W., J.I.W., R.B.L.); the Departments of Pathology (Z.W.B., V.A.L.) and Medicine (S.J.M.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Medicine, Ohio State University College of Medicine, Columbus (R.T.K.); the Department of Pathology, University of Washington School of Medicine, Seattle (S.S.R.); Centro DiagnosticoItaliano, Milan ( J.R.); the Department of Surgery, University of Cincinnati College of Medicine, Cincinnati (D.L.S.); the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore (M.A.Z.); and the Department of Medicine, University of Colorado School of Medicine, Aurora (B.R.H.). N Engl J Med 2012.DOI: 10.1056/NEJMoa1203208

3. BACKGROUND Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment.

4. METHODS We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed.

5. Study Population accrued from 49 different clinical sites over a 2 year period. Color highlighting: blue, samples with gene expression classifier (GEC) results; purple, samples with gene expression classifier results and available “gold” reference standard (RS); green, samples included and analyzed in the study. *Out of 414 indeterminate samples at time of sample selection, one was subsequently determined to be benign by cytology.

6. Sample collection and Pathology Diagnoses Prospective FNA samples from VERA001 for molecular analysis were aspirated in vivo, using either one or two passes, at outpatient clinical sites and directly placed into FNAprotect preservative solution (Qiagen, Valencia, CA). Samples were shipped either chilled or frozen. Temperature stability studies indicate that RNA quality and quantity are preserved with both shipping methods (Walsh et al. manuscript in preparation). Samples were stored at -80℃upon receipt at Veracyte, Inc.

9. * P<0.05 for the comparison of results for patients who underwent surgery for indeterminate nodules versus patients who did not. † P<0.05 for the comparison of results for patients who underwent surgery for indeterminate nodules and were included in the final validation set versus those who were not included.

10. Figure 1. Performance of the Gene-Expression Classifier (GEC), According to the Final Histopathological Diagnoses for Cytologically Indeterminate Samples. NPV denotes negative predictive value and PPV positive predictive value.

11. * One benign follicular nodule was a colloid nodule. † One papillary thyroid carcinoma was the tall-cell variant. ‡ Among the Hürthle-cell carcinomas, eight showed capsular invasion and two showed vascular invasion. § Among the follicular carcinomas, four showed capsular invasion, one showed vascular invasion, four were well-differentiated carcinomas not otherwise specified, and one was a poorly differentiated carcinoma.

13. Figure 2 Molecular Signal Intensities in Samples of Papillary Thyroid Carcinoma (Including the Follicular Variant and Tall-Cell Variant). The box plots indicate the interquartile range and median value; the box plot whiskers indicate the most extreme data points still within 1.5 times the interquartile range from each edge of the box plot. Signal intensity was stratified according to both the cytologic (indeterminate [Cyto-I] or malignant [Cyto-M]) category and the result (or “call”) of gene-expression classification (benign or suspicious). In each panel, the box plot on the left shows false negative results (Cyto-I, benign; 6 samples), the box in the center shows true positive results (Cyto-I, suspicious; 54 samples), and the box on the right shows true positive results (Cyto-M, suspicious; 53 samples). Panels A and B show the signal intensity of markers of thyroid cancer (cytokeratin 19 and CITED1, respectively). Panels C through F show the signal intensity of follicular-cell markers (cytokeratin 7, thyrotropin receptor, thyroglobulin, and thyroid transcription factor 1 [TTF-1], respectively). Dashed horizontal lines indicate the 10th, 20th, and 30th percentiles of intensity for the marker in the entire cohort of cytologically indeterminate samples. P values are for the difference in signal intensity between Cyto-I samples classified as benign and those classified as suspicious on the basis of gene-expression classification.

14. RESULTS Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for “atypia (or follicular lesion) of undetermined clinical significance,” “follicular neoplasm or lesion suspicious for follicular neoplasm,” or “suspicious cytologic findings” were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule.

15. CONCLUSIONS These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.)

16. Jameson JL.: Minimizing Unnecessary Surgery for Thyroid Nodules. N Engl J Med. 2012 Jun 25. DOI: 10.1056/NEJMe1205893

17. Message 甲状腺結節の微細針吸引生検を受けた患者3789人から得られた鑑別困難な265個の結節を対象に、165遺伝子の発現による新しい診断テストの診断的手術前のリスク評価改善効果を前向き試験で検証。悪性と鑑別された結節85個のうち、遺伝子発現による分類では75個が特異度52％で悪性疑いと同定された（感度92％）。

19. Department of Medicine IV, Universitatsklinikum Tubingen, Tubingen, Germany (Prof B Gallwitz MD); Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA (J Rosenstock MD); BoehringerIngelheim, Ingelheim, Germany (T Rauch MD PhD, M von Eynatten MD, K A Dugi MD, H-J Woerle MD); BoehringerIngelheim, Biberach, Germany (S Bhattacharya MSJ); and BoehringerIngelheim, Bracknell, UK (S Patel MB ChB)

20. Background Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride).

21. Methods In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycatedhaemoglobin A1c (HbA1c) 6・5–10・0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1–4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA1c from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA1c measurement, and had at least one on-treatment HbA1c measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284.

22. Figure 1: Trial profi le *One patient might have had more than one inclusion or exclusion criterion. †Treated set included randomised patients who received at least one dose of treatment. ‡Recorded by the investigators on the discontinuation page. §Full analysis set (FAS) included randomised patients who received at least one dose of treatment, had a baseline glycatedhaemoglobin A1c (HbA1c) measurement, and had at least one on-treatment HbA1c measurement. ¶Per-protocol set (PPS) completers included patients in FAS who did not have important protocol violations, completed at least 684 days of treatment, and had HbA1c measured at week 104. ||Completers cohort included PPS completers who met specifi c glycaemic targets (from week 4 to week 12, fasting plasma glucose [FPG] ≤13・3 mmol/L; after week 12 through week 16, FPG ≤12・2 mmol/L; after week 16 to week 28, FPG ≤11・1 mmol/L; after week 28 to week 52, HbA1c ≤8%; and after week 52 to week 104, HbA1c ≤7・5%). **Meal tolerance test (MTT) set included patients in the FAS who had a valid MTT done at baseline and once on treatment.

31. Findings 777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA1c (baseline 7・69% [SE 0・03] in both groups) were similar in the linagliptin (−0・16% [SE 0・03]) and glimepiride groups (−0・36% [0・03]; difference 0・20%, 97・5% CI 0・09–0・30), meeting the predefined non-inferiority criterion of 0・35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs280 [36%] of 775 patients, p<0・0001) or severe hypoglycaemia (1 [<1%] vs12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs26 patients; relative risk 0・46, 95% CI 0・23–0・91, p=0・0213).

32. Interpretation The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative effectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The findings could improve decision making for clinical treatment when metformin alone is insufficient. FundingBoehringerIngelheim.

33. Message メトホルミンでコントロール不良の2型糖尿病患者1519人を対象に、グリメピリドに対するリナグリプチンの非劣性を無作為化二重盲検試験で検証。104週後、ベースラインからのHbA1c値の調整後平均低下率はリナグリプチン群0.16％、グリメピリド群0.36％で、差は0.2％であり、非劣性基準の0.35％を満たした。