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]
Gallwitz B, 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, noninferiority trial.
Lancet. 2012 Jun 27. [Epub ahead of print]
2012年7月5日 8:30-8:55
８階 医局
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
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 Diagnostico Italiano, 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
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.
METHODS We performed a 19-month,
prospective, multicenter validation study involving
49 clinical sites, 3789 patients, and 4812 fineneedle 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.
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.
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.
* 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.
Figure 1. Performance of the GeneExpression Classifier (GEC), According to
the Final Histopathological Diagnoses for
Cytologically Indeterminate Samples.
NPV denotes negative predictive value and
PPV positive predictive value.
* 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.
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.
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.
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 geneexpression classifier results.
(Funded by Veracyte.)
Jameson JL.: Minimizing
Unnecessary Surgery for Thyroid
Nodules. N Engl J Med. 2012 Jun 25.
DOI: 10.1056/NEJMe1205893
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％）。
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); Boehringer Ingelheim, Ingelheim, Germany (T Rauch MD PhD, M von
Eynatten MD, K A Dugi MD, H-J Woerle MD); Boehringer Ingelheim, Biberach, Germany
(S Bhattacharya MSJ); and Boehringer Ingelheim, Bracknell, UK (S Patel MB ChB)
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).
Methods
In this 2-year, parallel-group, non-inferiority double-blind trial,
outpatients with type 2 diabetes and glycated haemoglobin
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 computergenerated 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.
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
glycated haemoglobin 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
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 noninferiority criterion of 0・35%. Fewer participants had
hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775
patients, p<0・0001) or severe hypoglycaemia (1 [<1%]
vs 12 [2%]) with linagliptin compared with glimepiride.
Linagliptin was associated with significantly fewer
cardiovascular events (12 vs 26 patients; relative risk 0・
46, 95% CI 0・23–0・91, p=0・0213).
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.
Funding Boehringer Ingelheim.
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。