2 Minute Medicine Rewind November 12, 2018

Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study

In the evaluation of thyroid nodules, fine needle aspirate (FNA) cytology can classify most thyroid nodules as benign or malignant; a minority of results, however, remain indeterminate. The Bethesda System for Reporting Thyroid Cytopathology includes 3 categories for indeterminate cytology (categories III, IV and V). Most indeterminate nodules are either sampled again or prophylactically removed. Over the last decade, molecular testing has improved the diagnostic accuracy of thyroid FNA cytology. Most recently, a new 112-gene test (ThyroSeq v3 Genomic Classifier (GC)) was developed. However, the diagnostic accuracy of this new test has not been investigated. In this prospective cohort study, 286 cytologically indeterminate thyroid nodules from 256 patients were tested using the multigene GC test to assess the diagnostic accuracy of this test in evaluating cytologically indeterminate thyroid nodules for cancer/noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Among the 286 samples evaluated, the FNA cytology diagnosis was Bethesda III in 172, Bethesda IV in 101, and Bethesda V in 13 cases. Notably, 10% of the samples failed a pre-sequencing or post-sequencing step due to low sample cellularity or low thyroid cell marker expression. Researchers found that the sensitivity of the test was high for Bethesda III and IV nodules combined at 94% (95% CI 86% to 98%). Specificity of the test was slightly lower at 82% (95% CI 75% to 87%) for Bethesda III and IV nodules combined. With a cancer/NIFTP prevalence of 28% across Bethesda III and IV nodules combined, the negative predictive value (NPV) was 97% (95% CI 93% to 99%), and the positive predictive value (PPV) was 66% (95% CI 56% to 75%). Importantly, of the 3% of samples that were found to be false-negatives, all were found to be low-risk follicular carcinoma tumors, without vascular invasion or metastasis. In summary, results from this study demonstrate the strength of the ThyroSeq GC test in ruling out thyroid cancers and NIFTP, as well as its potential role in preventing diagnostic surgeries and repeat cytology testing in patients with indeterminate thyroid nodules.

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial

Immune checkpoint inhibitors have shown significant antitumor activity in melanoma. However, previous randomized trials have excluded patients with untreated brain metastases due to concerns regarding central nervous system penetration and poor prognosis. In this phase II trial, 23 patients with stage IV melanoma and at least one 5-20 mm brain metastasis (untreated or radiographically progressing despite local therapy) were treated with pembrolizumab (a PD-1 inhibitor) every 2 weeks for up to 24 months to study the impact on brain metastasis radiographic response rate. Response to treatment was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Researchers found that 6 patients (26%) exhibited a brain metastasis response rate (95% CI 10% to 48%). Of note, 8 (35%) of patients could not be evaluated for brain metastasis response. The median progression-free and overall survival times were 2 months (95% CI 2 months to not reached) and 17 months (95% CI 10 months to not reached), respectively. At 24 months, 11 patients were alive (48%, 95% CI 31% to 73%). Interestingly, all patients who experienced disease progression had lower stromal PD-L1 expression and fewer CD8-positive tumor-infiltrating lymphocytes than those who responded to treatment. Neurologic adverse events occurred in 65% of patients, most of which were grade 1-2 in severity. Limitations of this study include the small sample size and the large number of unevaluable patients. Overall, results from this study suggest that pembrolizumab is active in small melanoma brain metastases and has an acceptable safety profile. However, larger studies are warranted to conclusively determine the antitumor effect of pembrolizumab in melanoma brain metastases.

Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants

Coronary artery disease (CAD) is the leading cause of mortality worldwide. While it has been established that CAD-related mortality rates are significantly lower in women compared to men, sex differences in various risk factors and their impact on CAD outcomes have not been well quantified. In this prospective population-based study, 471,998 patients with no history of cardiovascular disease were followed for a mean of 7 years to investigate sex differences in risk factors for fatal and non-fatal myocardial infarction (MI). At baseline, there were fewer women than men with diabetes or atrial fibrillation. Amongst women, there were also and fewer patients on lipid lowering or blood pressure lowering drugs. In addition, women had slightly lower blood pressure and were less likely to have ever smoked than men at baseline. Researchers found that, after a mean follow-up of 7 years, 5,081 MI events occurred, 28.8% of which were in women. A multivariable model revealed that the rate of MI in women was less than half that in men (HR 0.37, 95% CI 0.35 to 0.40). Interestingly, women with elevated blood pressure were at a higher risk of MI than men with elevated blood pressure (ratio of hazard ratios 1.83, 95% CI 1.33 to 2.52). A similar pattern was seen with women who had ever smoked (ratio of hazard ratios 1.55, 95% CI 1.32 to 1.83). Women with diabetes (both type 1 and type 2) were also at a higher risk of MI than men with diabetes (ratio of hazard ratios 2.91 for type 1 diabetes, 95% CI 1.56 to 5.45; ratio of HRs 1.47 for type 2 diabetes, 95% CI 1.16 to 1.87). Results from this study therefore show that women with certain risk factors have an increased risk of MI as compared to men, specifically elevated blood pressure, smoking, and diabetes. These results further underline the importance of aggressively treating and addressing cardiovascular risk factors in women.

Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial

Vitamin D has long been hypothesized to reduce the risk of cancer. However, existing data on the topic from both meta-analyses and randomized controlled trials are inconsistent. In this randomized controlled trial, 5,110 patients from 55 family practices in Auckland, New Zealand with no previous vitamin D use were assigned to either 100,000 IU of vitamin D per month or placebo and followed for a median of 3.3 years to determine the impact on time to first cancer reported and cancer incidence. Researchers found that there was no difference in the percentage of participants with cancer registrations from randomization to the primary endpoint between the vitamin D group (6.5%) and the placebo group (6.4%) (HR 1.01, 95% CI 0.81 to 1.25, p=0.95). Similarly, there was no difference in cancer outcomes between those with less than 20 ng/mL of 25(OH)D and those with 20 ng/ml or more of 25(OH)D. Observed 25(OH)D concentrations were consistently greater than 20 ng/mL higher in the vitamin D group than in the placebo group. Adherence was similar in the two groups (84.8% in the vitamin D group and 83.1% in the placebo group). No participants developed hypercalcemia. Overall, the results of this study indicate that high-dose vitamin D supplementation may not lead to an overall reduced risk of incident cancer.

Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia: A Cohort Study

Cardiac stress testing is frequently used in the diagnosis of coronary artery disease (CAD) and resulting myocardial ischemia. In the US, it is also often used in the surveillance of stable ischemic heart disease, despite current guideline recommendations against surveillance screening. Monitoring cardiac troponin levels through a recently developed high-sensitivity cardiac troponin (hs-cTn) assay has been proposed as a method to predict progression in patients with stable CAD. Specifically, the assay may be useful in identifying a low-risk subgroup without inducible myocardial ischemia. In this observational cohort study, a derivation cohort of 589 patients with stable CAD and a validation cohort of 118 patients who had survived a myocardial infarction in the past 6 months were tested with a high-sensitivity cardiac troponin (hs-cTnl) assay within one week of exercise or pharmacologic stress testing to determine the negative predictive value (NPV) of the test for inducible ischemia. Researchers found that in the derivation cohort, 10 of 101 patients with an hs-cTnl level of less than 2.5 pg/ml had inducible myocardial ischemia, producing a NPV of 90% (95% CI 83% to 95%). Three of the 101 patients had inducible ischemia involving at least 10% of the myocardium (NPV 97%, 95% CI 92% to 99%). Participants in the validation cohort were younger and less likely to be male than those in the derivation cohort. In the validation cohort, 4 of 32 patients with an hs-cTnl level of less than 2.5 pg/mL had inducible ischemia, corresponding to a NPV of 88% (95% CI 71% to 96%), while 2 of 32 patients had an inducible ischemic defect of 10% or greater (NPV 94%, 95% CI 79% to 99%). After a median follow-up of 3 years, none of the patients with an hs-cTnl level of less than 2.5 pg/mL and 7% of patients with a level of 2.5 pg/mL or greater in the derivation cohort experienced cardiovascular death or myocardial infarction. However, the specificity (23.8%) and positive predictive value (PPV) (40.2%) of the test for diagnosing inducible myocardial ischemia were low. In summary, results from this study suggest that the hs-cTnl assay may have a role in identifying patients at a low risk of inducible ischemia during cardiac stress testing. This data may not be applicable in populations without known CAD or in patients with unstable angina.

Image: PD

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