Letters

ment to prevent HUS in patients with EHEC and should be further studied.

Clinical Decision Making in Patients With Thyroid Nodules

Stefan Lüth, MD Thorben W. Fründt, MD Thomas Rösch, MD Christoph Schlee, MS Ansgar W. Lohse, MD Author Affiliations: Department of Medicine I, University Hospital Hamburg-Eppendorf, Hamburg, Germany (Lüth, Fründt, Schlee, Lohse); Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany (Rösch). Corresponding Author: Stefan Lüth, MD, Department of Medicine I, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany ([email protected]). Published Online: April 28, 2014. doi:10.1001/jamainternmed.2014.1175. Author Contributions: Drs Lüth and Fründt had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lüth and Fründt contributed equally to the manuscript. Study concept and design: Lüth, Fründt, Lohse. Acquisition, analysis, or interpretation of data: Lüth, Fründt, Rösch, Schlee, Lohse. Drafting of the manuscript: Lüth, Fründt, Rösch, Schlee. Critical revision of the manuscript for important intellectual content: Lüth, Rösch, Lohse. Statistical analysis: Lüth, Fründt, Schlee, Lohse. Obtained funding: Lüth. Administrative, technical, or material support: Lüth, Lohse. Study supervision: Lüth, Rösch, Lohse. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by the Deutsche Forschungsgemeinschaft (grant LU B62/2-1) and the Federal Ministry of Health (grant 1501/544 01). Role of the Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Moritz Tacke, MD (Department of Pediatrics, Ludwig-Maximilians University, Munich, Germany), Johannes Kluwe, MD, and Katharina Freadrich-Zimmermann, MD (Department of Medicine I, University Hospital Hamburg-Eppendorf), and Marina Nesselrode, MD (Department of Medicine III, University Hospital Hamburg-Eppendorf), collaborated on the study. Ulf Panzer, MD (Department of Medicine III, University Hospital Hamburg-Eppendorf), and Karl Wegscheider, PhD (Department of Medical Biometry and Epidemiology, University Hospital Hamburg-Eppendorf), provided administrative assistance in preparing the manuscript. No compensation was received by any of the persons listed. 1. Karmali MA, Steele BT, Petric M, Lim C. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools. Lancet. 1983;1(8325):619-620. 2. Robert Koch-Institut. Bericht: Abschließende Darstellung und Bewertung der epidemiologischen Erkenntnisse im: EHEC O104:H4 Ausbruch, Deutschland 2011. Berlin, Germany 2011. http://edoc.rki.de/documents/rki_ab /reeFNxULvsdZo/PDF/262b4Pk2TGGs.pdf. Accessed September 6, 2013. 3. Frank C, Werber D, Cramer JP, et al; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med. 2011;365(19):1771-1780. 4. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365(9464):1073-1086. 5. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342(26):1930-1936.

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COMMENT & RESPONSE

To the Editor In a recent issue of JAMA Internal Medicine, SmithBindman et al1 addressed the question of which ultrasound imaging characteristics are useful in identifying patients with thyroid nodules who are more likely to have thyroid cancer. This study adds important information for the proper clinical decision making in patients with thyroid nodules; however, some aspects need further clarification. First and foremost is the definition of noncancerous nodules, which was already addressed in the Invited Commentary.2 The definition adopted for benign nodules was based on the assumption that no cancer was identified, when in fact it is unknown how many of these patients underwent fine-needle aspiration or surgery. Indeed, the degree of uncertainty regarding this aspect is crucial and somewhat worrying because all analyses presented were based on this assumption. Second, the size of the nodule is another aspect that deserves further discussion. In this context, a receiver operating characteristic curve analysis of the size of nodules would have added value to identify possible thresholds of size associated with increased risk of harboring a thyroid cancer. This is clinically relevant because recent reports observed that approximately 19% to 30% of patients with thyroid microcarcinoma may present a more aggressive tumor behavior with regional and distant metastasis.3,4 Finally, it would be interesting to present the posttest probability of each ultrasound imaging characteristic by using the Fagan nomogram.5 By doing so, the unusual low pretest probability of thyroid cancer (1.6%) in this sample of patients with thyroid nodules would have been taken into consideration, providing better estimates of the clinical applicability of the studied ultrasonographic parameters. Jorge Luiz Gross, MD, PhD Caroline K. Kramer, MD, PhD Luciana Reck Remonti, MD Author Affiliations: Serviço de Endocrinologia do Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre-RS, Brazil (Gross, Remonti); Division of Endocrinology, University of Toronto and Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada (Kramer). Corresponding Author: Jorge Luiz Gross, MD, PhD, Serviço de Endocrinologia do Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Predio 12, 4 Andar, 90035-003 Porto Alegre-RS, Brazil ([email protected]). Conflict of Interest Disclosures: None reported. 1. Smith-Bindman R, Lebda P, Feldstein VA, et al. Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: results of a population-based study. JAMA Intern Med. 2013;173(19):1788-1796. 2. Alexander EK, Cooper D. The importance, and important limitations, of ultrasound imaging for evaluating thyroid nodules. JAMA Intern Med. 2013;173 (19):1796-1797. 3. Ardito G, Revelli L, Giustozzi E, et al. Aggressive papillary thyroid microcarcinoma: prognostic factors and therapeutic strategy. Clin Nucl Med. 2013;38(1):25-28. 4. Kuo EJ, Roman SA, Sosa JA. Patients with follicular and Hurthle cell microcarcinomas have compromised survival: a population level study of 22,738 patients. Surgery. 2013;154(6):1246-1254. 5. Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. BMJ. 2004;329 (7458):168-169. JAMA Internal Medicine June 2014 Volume 174, Number 6

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1005

Letters

In Reply My colleagues and I thank Gross and colleagues for giving us the opportunity to clarify our study.1 To determine whether a nodule was benign or malignant, we included the results of all biopsies conducted at the University of California, San Francisco, and linked the entire cohort of more than 8000 patients with the California Cancer Registry (CCR) that collects cancer incidence data on all patients who received a diagnosis in California and 22 additional states with whom the CCR shares data. By linking with the CCR, we learned about cancers that occurred as long as 6 years after ultrasonography and confirmed that nodules were benign as long as 11 years after ultrasonography. Thus, we know with a high degree of certainty which nodules were malignant or benign. In contrast, all previous of thyroid ultrasonography studies limited their analysis to patients who underwent immediate biopsy, where the decision to perform a biopsy was influenced by the ultrasonography result. This will miss cancers that would not have been considered suspicious on the ultrasonogram, and this ascertainment bias will overestimate the accuracy of ultrasonography. This is why we found a lower risk of cancer and lower predictive values associated with specific findings compared with prior reports: this reflects our complete follow-up of patients many years after ultrasonography to determine the true cancer status in the entire cohort. The completeness of cancer information makes our cohort the most representative and accurate way to estimate the risk of cancer among patients in whom incidental thyroid nodules are identified. We found that thyroid tumors occur at every size; in our sample, approximately a third were smaller than 10 mm, a third were between 10 and 20 mm, and a third were larger than 20 mm. However, it is only in nodules larger than 20 mm that there is a statistically significant increased risk of cancer. For the other size categories, most of the nodules identified are benign, and size cannot be used to identify nodules with a greater-thanaverage likelihood of cancer. We found that thyroid nodules 5 mm or larger were present in 56% of patients. In contrast, clinically apparent thyroid cancer is rare, affecting 1 in 10 000 people annually. Because of the high prevalence of nodules and the rarity of symptomatic cancer, only a minority of thyroid nodules is malignant. There are no imaging criteria that can be used (other than the 3 we report in our results: entirely solid, size >2 cm, or microcalcifications) that can distinguish nodules that are likely benign from those with an increased risk of malignancy. If it is deemed important to identify every microcarcinoma, then the only way to do this would be to biopsy every nodule seen on thyroid ultrasonography. This would require performing a biopsy in over half of the population who undergoes thyroid ultrasonography and performing multiple biopsies in the 34% of patients who have multiple thyroid nodules. The likelihood ratios presented in Table 6 of our article1 can be used to estimate a patient’s posttest risk of cancer, if you know from another source their pretest risk of harboring cancer. Rebecca Smith-Bindman, MD 1006

Author Affiliations: Department of Radiology and Biomedical Imaging, University of California, San Francisco; Department of Epidemiology and Biostatistics, University of California, San Francisco ; Department of Health Policy and Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco; Radiology Outcomes Research Lab, University of California, San Francisco. Corresponding Author: Rebecca Smith-Bindman, MD, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 350 Parnassus Ave, Ste 307, San Francisco, CA 94143-0336 (rebecca.smith-bindman @ucsf.edu). Conflict of Interest Disclosures: None reported. 1. Smith-Bindman R, Lebda P, Feldstein VA, et al. Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: results of a population-based study. JAMA Intern Med. 2013;173(19):1788-1796.

Coronary Artery Bypass Grafting vs Percutaneous Coronary Intervention in Multivessel Disease To the Editor We read with great interest the meta-analysis by Sipahi et al1 in which 6 randomized clinical trials (RCTs) of percutaneous coronary intervention (PCI) vs coronary artery bypass grafting (CABG) in multivessel disease (MVD) were included. There was a significant reduction in 1-year-orgreater all-cause mortality with CABG compared with PCI (risk ratio [RR], 0.73; 95% CI, 0.62-0.86; P < .001). The design of included RCTs, however, is heterogeneous: ie, using exclusively bare-metal stents (BMS) in 3 trials, drug-eluting stents (DES) in 2 trials (SYNTAX [Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery] multivessel and FREEDOM [Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease] [references 12 and 16, respectively, in the original article1]), and both BMS and DES in 1 trial (CARDia [Coronary Artery Revascularization in Diabetes] [reference 7 in the original article 1 ]). The authors stated that their aim was to “overcome the power limitation” of the existing data sets.1(p224) Pooling heterogeneous-design RCTs just merely to overcome the power limitation (thereby, probably expecting statistically significant results), however, would be inappropriate. Regarding PCI with exclusive BMS vs CABG in MVD, previous meta-analyses2,3 of 4 RCTs demonstrated no statistically significant differences in all-cause mortality. Thus, cardiac interventionalists and surgeons are now interested in the evidence of PCI with exclusive DES vs CABG in MVD.4,5 To our knowledge, however, the results of only 2 RCTs (SYNTAX multivessel and FREEDOM) of PCI with DES vs CABG in MVD have been reported to date. Yan et al4 demonstrated, in their meta-analysis of unadjusted data, that all-cause mortality at 12 months (1 RCT and 11 observational studies enrolling a total of 7754 patients [RR, 0.98; 95% CI, 0.61-1.56; P = .92]) and 24 months (5 observational studies enrolling a total of 1374 patients [RR, 0.81; 95% CI, 0.55-1.18; P = .27]) were similar between PCI with DES and CABG in MVD. On the other hand, in our meta-analysis5 we pooled 2 crude hazard ratios from 2 RCTs and 19 adjusted HRs from 11 observational studies and suggested that PCI with DES may increase 1-year-or-greater all-cause mortality by 24% over CABG in MVD (hazard ratio, 1.24; 95% CI, 1.02-1.50; P = .03). To determine whether PCI with DES increases all-cause mortality

JAMA Internal Medicine June 2014 Volume 174, Number 6

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Clinical decision making in patients with thyroid nodules--reply.

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