TBD Meeting (3181-17)

 

VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.

ThyroSeq v3 classifier

In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.

The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.

Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.

Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.

All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.

Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.

“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”

In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”

All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.

“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”

“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies.

“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”

According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.

“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
 

 

Afirma GSC with Hurthle classifiers

In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.

“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).

“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold.

The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.

The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.

The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.

The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).

Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.

There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).

“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”

Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
 

Afirma GSC with medullary thyroid cancer classifier

In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.

Better preoperative identification of this cancer is key for several reasons, he maintained.

“We need to know for the timing of surgery, and for the extent of both thyroidal and nodal components of surgery,” Dr. Randolph noted. “We need to know because of the aggressive nature of these lesions and the potential to be prepared for finding invasion at surgery; for the potential of bilaterality if inherited disease is present; for the potential for parathyroid disease, if familial; and finally, for the potential for intraoperative death with unrecognized pheochromocytoma and an unprepared surgeon.”

Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.

The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.

Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.

“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.

Session attendees wondered which patients are appropriate candidates and how much the test will cost.

“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”

Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”

Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.

ThyroSeq v3 classifier

In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.

The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.

Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.

Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.

All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.

Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.

“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”

In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”

All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.

“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”

“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies.

“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”

According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.

“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
 

 

Afirma GSC with Hurthle classifiers

In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.

“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).

“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold.

The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.

The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.

The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.

The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).

Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.

There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).

“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”

Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
 

Afirma GSC with medullary thyroid cancer classifier

In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.

Better preoperative identification of this cancer is key for several reasons, he maintained.

“We need to know for the timing of surgery, and for the extent of both thyroidal and nodal components of surgery,” Dr. Randolph noted. “We need to know because of the aggressive nature of these lesions and the potential to be prepared for finding invasion at surgery; for the potential of bilaterality if inherited disease is present; for the potential for parathyroid disease, if familial; and finally, for the potential for intraoperative death with unrecognized pheochromocytoma and an unprepared surgeon.”

Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.

The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.

Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.

“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.

Session attendees wondered which patients are appropriate candidates and how much the test will cost.

“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”

Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”

Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.

ThyroSeq v3 classifier

In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.

The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.

Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.

Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.

All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.

Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.

“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”

In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”

All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.

“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”

“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies.

“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”

According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.

“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
 

 

Afirma GSC with Hurthle classifiers

In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.

“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).

“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold.

The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.

The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.

The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.

The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).

Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.

There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).

“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”

Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
 

Afirma GSC with medullary thyroid cancer classifier

In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.

Better preoperative identification of this cancer is key for several reasons, he maintained.

“We need to know for the timing of surgery, and for the extent of both thyroidal and nodal components of surgery,” Dr. Randolph noted. “We need to know because of the aggressive nature of these lesions and the potential to be prepared for finding invasion at surgery; for the potential of bilaterality if inherited disease is present; for the potential for parathyroid disease, if familial; and finally, for the potential for intraoperative death with unrecognized pheochromocytoma and an unprepared surgeon.”

Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.

The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.

Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.

“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.

Session attendees wondered which patients are appropriate candidates and how much the test will cost.

“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”

Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”

Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

“These data would support closer assessment in women and during the initial 6 months of treatment with each new TKI to detect incident hypothyroidism,” commented senior author Trevor E. Angell, MD, an endocrinologist at the Brigham and Women’s Hospital, Boston, at the annual meeting of the American Thyroid Association.

Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”

“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.

Susan London, Frontline Medical News

“Further research is needed to confirm the findings,” she noted. “And I’d be interested to see subanalyses trying to look at the types of nonthyroidal cancers that were assessed, to determine if there were tendencies for patients with certain cancers to have a further increase in overall survival.”

Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”

Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.

He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.

During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.

“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.

Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.

In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.

In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).

Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.

Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.

Dr. Angell had no relevant conflicts of interest.

 

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

“These data would support closer assessment in women and during the initial 6 months of treatment with each new TKI to detect incident hypothyroidism,” commented senior author Trevor E. Angell, MD, an endocrinologist at the Brigham and Women’s Hospital, Boston, at the annual meeting of the American Thyroid Association.

Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”

“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.

Susan London, Frontline Medical News

“Further research is needed to confirm the findings,” she noted. “And I’d be interested to see subanalyses trying to look at the types of nonthyroidal cancers that were assessed, to determine if there were tendencies for patients with certain cancers to have a further increase in overall survival.”

Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”

Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.

He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.

During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.

“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.

Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.

In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.

In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).

Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.

Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.

Dr. Angell had no relevant conflicts of interest.

 

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

“These data would support closer assessment in women and during the initial 6 months of treatment with each new TKI to detect incident hypothyroidism,” commented senior author Trevor E. Angell, MD, an endocrinologist at the Brigham and Women’s Hospital, Boston, at the annual meeting of the American Thyroid Association.

Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”

“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.

Susan London, Frontline Medical News

“Further research is needed to confirm the findings,” she noted. “And I’d be interested to see subanalyses trying to look at the types of nonthyroidal cancers that were assessed, to determine if there were tendencies for patients with certain cancers to have a further increase in overall survival.”

Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”

Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.

He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.

During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.

“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.

Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.

In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.

In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).

Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.

Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.

Dr. Angell had no relevant conflicts of interest.

 

VICTORIA, B.C. – Ultrasound risk criteria for adults are no match for the training, skill, and gut instinct of an experienced radiologist when evaluating pediatric thyroid nodules, results of a retrospective cohort study reported at the annual meeting of the American Thyroid Association suggest.

“In 2015, the ATA commissioned a pediatric task force that developed valuable guidelines specific to our pediatric patients. These guidelines recommend performing an FNA [fine-needle aspiration biopsy] in any nodule with a concerning clinical history or a concerning ultrasound feature,” commented first author Ana L. Creo, MD, a pediatric endocrinology fellow at the Mayo Clinic in Rochester, Minn.

“The challenge is trying to decide what fully constitutes a concerning ultrasound feature. Most of the work has been based on relatively small pediatric sample sizes, typically 30-50 patients, or is extrapolated from adult data,” she said. “Currently, in pediatrics, we have not established any formalized, ultrasound-based scoring stratification system like the adult guidelines.”

She and her colleagues analyzed findings from diagnostic ultrasound in 112 patients aged under 21 years who had 145 thyroid nodules that were ultimately assessed histologically or cytologically.

Results showed that the radiologists’ overall impression and the ATA risk-stratification system for adults had the same high sensitivity, picking up 9 out of 10 malignant cases, she reported. But the radiologists’ overall impression had much higher specificity, correctly classifying 8 out of 10 benign cases, versus about 5 out of 10 for the risk stratification.

“These findings may have implications in trying to avoid unnecessary FNAs, particularly in our population,” Dr. Creo summarized. “Our million dollar question is trying to get in the heads of the radiologists to figure out what really goes into that overall impression. And if we can apply a specific score to that, I think that would be most clinically useful.”

“Based upon these results, further work is needed to determine the usefulness of the adult ATA ultrasound risk stratification in children, moving towards an ultrasound-based stratification system specific to our pediatric patients,” she concluded.

One session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “It seems as though we’re pretty good at picking up which nodules are malignant, but I still feel like so many of the nodules that are benign are suspicious by ultrasound. Trying to tease out what is it about those benign ones may allow us to figure out in which ones we could avoid biopsy. That’s where we see we are not that good at it.”

Nodule attributes that might help in this regard include subtypes of microcalcifications, irregular margins, and position of the nodule in the gland relative to the skin, she proposed.

The other session cochair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, stressed knowing one’s radiologist and questioned the generalizability of the findings.

“You have to know your own radiologist well and how well you can trust them. Probably, the investigators chose some of the top radiologists in their institution and maybe even in the nation, so we have to be careful as to whether this applies to places that don’t have access to such great radiologists,” he commented. “But I think even if the guidelines are not perfect, they are the best we have right now.”
 

Study details

The investigators studied pediatric patients (mean age, 15.5 years) with thyroid nodules who underwent initial ultrasound at the Mayo Clinic during 1996-2015, had at least a year of follow-up, and for whom histology or cytology results were available. Those with a known genetic tumor syndrome or a history of radiation exposure were excluded.

Two blinded radiologists assessed nodule ultrasound features using the Thyroid Imaging and Reporting Data System (TIRADS) (J Am Coll Radiol. 2015;12[12 Pt A]:1272-9) and then rendered their overall impression: malignant, indeterminate, or benign.

Next, an independent reviewer assigned each nodule an ATA adult risk category (Thyroid. 2016;26:1-133): high, intermediate, low, or very low suspicion.

Finally, both measures were compared against the reference standard of the nodule’s histology or cytology results.

Ultimately, 34% of the patients had malignant nodules, Dr. Creo reported. “This is likely quite a bit elevated from the true prevalence due to our intentional study design requiring follow-up, likely excluding some patients with benign nodules,” she commented.

Patients with benign and malignant nodules did not differ significantly on any of a variety of sociodemographic and clinical factors, such as family history and mode of detection.

For comparison of sensitivity, the investigators combined the ATA risk categories of high and intermediate suspicion and combined the overall radiologists’ impression of malignant and indeterminate. “We felt this best answered the practical clinical question of how many malignant nodules would be missed if FNA was not performed, assuming FNA would typically be performed if the ATA risk stratification was high or intermediate or if the radiologist’s overall impression was malignant or indeterminate,” Dr. Creo explained.

Results here showed that the ATA risk stratification and the radiologists’ overall impression had the same high sensitivity of 90%.

For comparison of specificity, the investigators compared the ATA risk category of high suspicion with the radiologists’ overall impression of malignant.

Results showed that the overall impression had specificity of 80%, whereas the risk category had a specificity of only about 52%. Findings were similar when analyses instead used ATA high suspicion and intermediate suspicion combined.

“The key ultrasound characteristics that drove the diagnosis included having a solid component, calcifications, irregular margins, and hypoechogenicity – all similar to those seen in pediatric studies and similar to those in adult studies as well,” Dr. Creo noted.

Compared with benign nodules, malignant nodules significantly more often had a greater than 75% solid component (84% vs. 64%; P = .01), contained calcifications (60% vs. 18%; P less than .0001), had irregular margins (70% vs. 46%; P = .0073), and were hypoechogenic (74% vs. 51%; P = .0073). Notably, size and presence of halo did not differ significantly.

“Our study adds to previous work in that it had a relatively large pediatric sample size, used strict inclusion criteria with at least a year of follow-up to increase the validity of the diagnosis, and had precise definitions of the ultrasound features,” concluded Dr. Creo, who disclosed that she had no relevant conflicts of interest.

At the same time, the study had limitations, such as its use of a referral population, likely loss to follow-up of some patients with benign nodules, and possible clustering effect. “Lastly, we had the benefit of extremely experienced pediatric radiologists, and their overall diagnostic accuracy may not universally apply across all radiologists,” she said.

 

VICTORIA, B.C. – Ultrasound risk criteria for adults are no match for the training, skill, and gut instinct of an experienced radiologist when evaluating pediatric thyroid nodules, results of a retrospective cohort study reported at the annual meeting of the American Thyroid Association suggest.

“In 2015, the ATA commissioned a pediatric task force that developed valuable guidelines specific to our pediatric patients. These guidelines recommend performing an FNA [fine-needle aspiration biopsy] in any nodule with a concerning clinical history or a concerning ultrasound feature,” commented first author Ana L. Creo, MD, a pediatric endocrinology fellow at the Mayo Clinic in Rochester, Minn.

“The challenge is trying to decide what fully constitutes a concerning ultrasound feature. Most of the work has been based on relatively small pediatric sample sizes, typically 30-50 patients, or is extrapolated from adult data,” she said. “Currently, in pediatrics, we have not established any formalized, ultrasound-based scoring stratification system like the adult guidelines.”

She and her colleagues analyzed findings from diagnostic ultrasound in 112 patients aged under 21 years who had 145 thyroid nodules that were ultimately assessed histologically or cytologically.

Results showed that the radiologists’ overall impression and the ATA risk-stratification system for adults had the same high sensitivity, picking up 9 out of 10 malignant cases, she reported. But the radiologists’ overall impression had much higher specificity, correctly classifying 8 out of 10 benign cases, versus about 5 out of 10 for the risk stratification.

“These findings may have implications in trying to avoid unnecessary FNAs, particularly in our population,” Dr. Creo summarized. “Our million dollar question is trying to get in the heads of the radiologists to figure out what really goes into that overall impression. And if we can apply a specific score to that, I think that would be most clinically useful.”

“Based upon these results, further work is needed to determine the usefulness of the adult ATA ultrasound risk stratification in children, moving towards an ultrasound-based stratification system specific to our pediatric patients,” she concluded.

One session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “It seems as though we’re pretty good at picking up which nodules are malignant, but I still feel like so many of the nodules that are benign are suspicious by ultrasound. Trying to tease out what is it about those benign ones may allow us to figure out in which ones we could avoid biopsy. That’s where we see we are not that good at it.”

Nodule attributes that might help in this regard include subtypes of microcalcifications, irregular margins, and position of the nodule in the gland relative to the skin, she proposed.

The other session cochair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, stressed knowing one’s radiologist and questioned the generalizability of the findings.

“You have to know your own radiologist well and how well you can trust them. Probably, the investigators chose some of the top radiologists in their institution and maybe even in the nation, so we have to be careful as to whether this applies to places that don’t have access to such great radiologists,” he commented. “But I think even if the guidelines are not perfect, they are the best we have right now.”
 

Study details

The investigators studied pediatric patients (mean age, 15.5 years) with thyroid nodules who underwent initial ultrasound at the Mayo Clinic during 1996-2015, had at least a year of follow-up, and for whom histology or cytology results were available. Those with a known genetic tumor syndrome or a history of radiation exposure were excluded.

Two blinded radiologists assessed nodule ultrasound features using the Thyroid Imaging and Reporting Data System (TIRADS) (J Am Coll Radiol. 2015;12[12 Pt A]:1272-9) and then rendered their overall impression: malignant, indeterminate, or benign.

Next, an independent reviewer assigned each nodule an ATA adult risk category (Thyroid. 2016;26:1-133): high, intermediate, low, or very low suspicion.

Finally, both measures were compared against the reference standard of the nodule’s histology or cytology results.

Ultimately, 34% of the patients had malignant nodules, Dr. Creo reported. “This is likely quite a bit elevated from the true prevalence due to our intentional study design requiring follow-up, likely excluding some patients with benign nodules,” she commented.

Patients with benign and malignant nodules did not differ significantly on any of a variety of sociodemographic and clinical factors, such as family history and mode of detection.

For comparison of sensitivity, the investigators combined the ATA risk categories of high and intermediate suspicion and combined the overall radiologists’ impression of malignant and indeterminate. “We felt this best answered the practical clinical question of how many malignant nodules would be missed if FNA was not performed, assuming FNA would typically be performed if the ATA risk stratification was high or intermediate or if the radiologist’s overall impression was malignant or indeterminate,” Dr. Creo explained.

Results here showed that the ATA risk stratification and the radiologists’ overall impression had the same high sensitivity of 90%.

For comparison of specificity, the investigators compared the ATA risk category of high suspicion with the radiologists’ overall impression of malignant.

Results showed that the overall impression had specificity of 80%, whereas the risk category had a specificity of only about 52%. Findings were similar when analyses instead used ATA high suspicion and intermediate suspicion combined.

“The key ultrasound characteristics that drove the diagnosis included having a solid component, calcifications, irregular margins, and hypoechogenicity – all similar to those seen in pediatric studies and similar to those in adult studies as well,” Dr. Creo noted.

Compared with benign nodules, malignant nodules significantly more often had a greater than 75% solid component (84% vs. 64%; P = .01), contained calcifications (60% vs. 18%; P less than .0001), had irregular margins (70% vs. 46%; P = .0073), and were hypoechogenic (74% vs. 51%; P = .0073). Notably, size and presence of halo did not differ significantly.

“Our study adds to previous work in that it had a relatively large pediatric sample size, used strict inclusion criteria with at least a year of follow-up to increase the validity of the diagnosis, and had precise definitions of the ultrasound features,” concluded Dr. Creo, who disclosed that she had no relevant conflicts of interest.

At the same time, the study had limitations, such as its use of a referral population, likely loss to follow-up of some patients with benign nodules, and possible clustering effect. “Lastly, we had the benefit of extremely experienced pediatric radiologists, and their overall diagnostic accuracy may not universally apply across all radiologists,” she said.

 

VICTORIA, B.C. – Ultrasound risk criteria for adults are no match for the training, skill, and gut instinct of an experienced radiologist when evaluating pediatric thyroid nodules, results of a retrospective cohort study reported at the annual meeting of the American Thyroid Association suggest.

“In 2015, the ATA commissioned a pediatric task force that developed valuable guidelines specific to our pediatric patients. These guidelines recommend performing an FNA [fine-needle aspiration biopsy] in any nodule with a concerning clinical history or a concerning ultrasound feature,” commented first author Ana L. Creo, MD, a pediatric endocrinology fellow at the Mayo Clinic in Rochester, Minn.

“The challenge is trying to decide what fully constitutes a concerning ultrasound feature. Most of the work has been based on relatively small pediatric sample sizes, typically 30-50 patients, or is extrapolated from adult data,” she said. “Currently, in pediatrics, we have not established any formalized, ultrasound-based scoring stratification system like the adult guidelines.”

She and her colleagues analyzed findings from diagnostic ultrasound in 112 patients aged under 21 years who had 145 thyroid nodules that were ultimately assessed histologically or cytologically.

Results showed that the radiologists’ overall impression and the ATA risk-stratification system for adults had the same high sensitivity, picking up 9 out of 10 malignant cases, she reported. But the radiologists’ overall impression had much higher specificity, correctly classifying 8 out of 10 benign cases, versus about 5 out of 10 for the risk stratification.

“These findings may have implications in trying to avoid unnecessary FNAs, particularly in our population,” Dr. Creo summarized. “Our million dollar question is trying to get in the heads of the radiologists to figure out what really goes into that overall impression. And if we can apply a specific score to that, I think that would be most clinically useful.”

“Based upon these results, further work is needed to determine the usefulness of the adult ATA ultrasound risk stratification in children, moving towards an ultrasound-based stratification system specific to our pediatric patients,” she concluded.

One session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “It seems as though we’re pretty good at picking up which nodules are malignant, but I still feel like so many of the nodules that are benign are suspicious by ultrasound. Trying to tease out what is it about those benign ones may allow us to figure out in which ones we could avoid biopsy. That’s where we see we are not that good at it.”

Nodule attributes that might help in this regard include subtypes of microcalcifications, irregular margins, and position of the nodule in the gland relative to the skin, she proposed.

The other session cochair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, stressed knowing one’s radiologist and questioned the generalizability of the findings.

“You have to know your own radiologist well and how well you can trust them. Probably, the investigators chose some of the top radiologists in their institution and maybe even in the nation, so we have to be careful as to whether this applies to places that don’t have access to such great radiologists,” he commented. “But I think even if the guidelines are not perfect, they are the best we have right now.”
 

Study details

The investigators studied pediatric patients (mean age, 15.5 years) with thyroid nodules who underwent initial ultrasound at the Mayo Clinic during 1996-2015, had at least a year of follow-up, and for whom histology or cytology results were available. Those with a known genetic tumor syndrome or a history of radiation exposure were excluded.

Two blinded radiologists assessed nodule ultrasound features using the Thyroid Imaging and Reporting Data System (TIRADS) (J Am Coll Radiol. 2015;12[12 Pt A]:1272-9) and then rendered their overall impression: malignant, indeterminate, or benign.

Next, an independent reviewer assigned each nodule an ATA adult risk category (Thyroid. 2016;26:1-133): high, intermediate, low, or very low suspicion.

Finally, both measures were compared against the reference standard of the nodule’s histology or cytology results.

Ultimately, 34% of the patients had malignant nodules, Dr. Creo reported. “This is likely quite a bit elevated from the true prevalence due to our intentional study design requiring follow-up, likely excluding some patients with benign nodules,” she commented.

Patients with benign and malignant nodules did not differ significantly on any of a variety of sociodemographic and clinical factors, such as family history and mode of detection.

For comparison of sensitivity, the investigators combined the ATA risk categories of high and intermediate suspicion and combined the overall radiologists’ impression of malignant and indeterminate. “We felt this best answered the practical clinical question of how many malignant nodules would be missed if FNA was not performed, assuming FNA would typically be performed if the ATA risk stratification was high or intermediate or if the radiologist’s overall impression was malignant or indeterminate,” Dr. Creo explained.

Results here showed that the ATA risk stratification and the radiologists’ overall impression had the same high sensitivity of 90%.

For comparison of specificity, the investigators compared the ATA risk category of high suspicion with the radiologists’ overall impression of malignant.

Results showed that the overall impression had specificity of 80%, whereas the risk category had a specificity of only about 52%. Findings were similar when analyses instead used ATA high suspicion and intermediate suspicion combined.

“The key ultrasound characteristics that drove the diagnosis included having a solid component, calcifications, irregular margins, and hypoechogenicity – all similar to those seen in pediatric studies and similar to those in adult studies as well,” Dr. Creo noted.

Compared with benign nodules, malignant nodules significantly more often had a greater than 75% solid component (84% vs. 64%; P = .01), contained calcifications (60% vs. 18%; P less than .0001), had irregular margins (70% vs. 46%; P = .0073), and were hypoechogenic (74% vs. 51%; P = .0073). Notably, size and presence of halo did not differ significantly.

“Our study adds to previous work in that it had a relatively large pediatric sample size, used strict inclusion criteria with at least a year of follow-up to increase the validity of the diagnosis, and had precise definitions of the ultrasound features,” concluded Dr. Creo, who disclosed that she had no relevant conflicts of interest.

At the same time, the study had limitations, such as its use of a referral population, likely loss to follow-up of some patients with benign nodules, and possible clustering effect. “Lastly, we had the benefit of extremely experienced pediatric radiologists, and their overall diagnostic accuracy may not universally apply across all radiologists,” she said.

 

VICTORIA, B.C. – Hypothyroid patients have similar cardiovascular outcomes in the shorter term whether they take generic or brand-name levothyroxine, results of a retrospective propensity-matched cohort study reported at the annual meeting of the American Thyroid Association suggest.

Investigators led by Robert Smallridge, MD, an endocrinologist at the Mayo Clinic, in Jacksonville, Fla., used a large administrative database to study nearly 88,000 treatment-naive hypothyroid patients (most having benign thyroid disease) who started levothyroxine.

Susan London/Frontline Medical News

After a median follow-up of about 1 year, those on a brand-name formula and those on a generic formula had similar risks of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, and stroke, he reported in a poster session. The findings were essentially the same among the subgroup of older adults, despite their much higher incidences of events.

However, monthly total medication costs with the brand-name medication were more than twice those with the generic.

“I don’t think we are ready yet to say everybody ought to be on generic,” Dr. Smallridge said in an interview, citing the limited treatment duration captured in the study because patients switched medications or changed insurers. “But I think, at least in the short term, it’s giving us some data that we can build upon.”

He and his coinvestigators plan additional analyses looking at longer-term users, other types of thyroid hormone preparations, and the very small group of patients who had thyroid cancer.

“I primarily take care of cancer patients, and we purposely push these patients to slightly lower [thyroid-stimulating hormone levels] in general, which presumably is going to increase your risk of atrial fibrillation and could affect these events,” he said. “The numbers are somewhat smaller, clearly, but I’d like to see that explored also, to see if there is a difference between brand and generics in that subset who are probably getting a little bit more thyroid medication.”

Both hypothyroidism and its overtreatment with thyroid hormone therapy can increase cardiovascular risk, Dr. Smallridge noted.

For the study, the investigators analyzed data from a large administrative claims database (OptumLabs Data Warehouse) for the years 2006-2014. Patients having any prior use of any thyroid hormone preparation, amiodarone, or lithium were excluded. And patients were censored if they left the insurance plan, stopped treatment, or switched medication category.

The investigators identified 201,056 hypothyroid patients who started some type of thyroid hormone therapy. The majority (70.8%) started generic levothyroxine, and 22.1% started brand-name levothyroxine (Synthroid, Levoxyl, Tirosint, Unithroid). The small remaining group started another thyroid extract, triiodothyronine (T3), or a compounded preparation.

Primary care physicians were the main identifiable prescribers (60.3%), followed by endocrinologists (10.8%). “Endocrinologists tended to prescribe brand significantly more than the primary care physicians,” Dr. Smallridge said.

The investigators used propensity matching on a variety of factors (age, sex, race, census region, Charlson comorbidity index, year of index prescription, and a dozen baseline comorbidities) to compare patients starting brand-name versus generic levothyroxine. Outcomes were assessed during a median follow-up of 1 year (range, 0-9.3 years).

Event rates per 1,000 patient-years with branded versus generic levothyroxine were similar for atrial fibrillation (2.19 vs. 1.82; hazard ratio, 1.22, P = .19), myocardial infarction (1.83 vs. 2.12; HR, 0.86, P = .35), and congestive heart failure (2.00 vs. 2.27; HR, 0.88, P = .41). There was a borderline-significant difference on hospitalization for stroke, with marginally lower risk with brand-name levothyroxine (2.38 vs. 3.10; HR, 0.77; P = .05).

Findings were essentially the same in age-stratified analyses, splitting patients into subgroups younger and older than age 65.

When average 30-day costs were compared for users of branded versus generic levothyroxine, total cost for the branded drug was more than twice as high ($18.47 vs. $8.18).

“Thyroid preparations have been the most prescribed drug in the United States for several recent years. In the neighborhood of 25 million different patients a year take thyroid medications,” Dr. Smallridge said. “In terms of the dollars spent, it’s considerably less than some of the other drugs out there. But because of sheer numbers of patients, in terms of impact on health care dollars, it’s still a significant amount of money. And this is a lifelong treatment – once you go on thyroid hormones, you’re on them for life.”

The study had several strengths. “This is a very large, diverse, real-world population across the entire country with a wide range of ages,” Dr. Smallridge explained. “We got pharmacy claims documenting that they were continuing to get the refills, although we didn’t do pill counts, so we don’t know whether they were taking the medication. And a really important thing was the propensity score matching.”

At the same time, limitations included possible variations in coding and billing, and some residual confounding. “Key issues are that we need more data on longer-term follow-up, and we didn’t have lab values,” he added.

Dr. Smallridge reported that he had no relevant conflicts of interest.

 

 

VICTORIA, B.C. – Hypothyroid patients have similar cardiovascular outcomes in the shorter term whether they take generic or brand-name levothyroxine, results of a retrospective propensity-matched cohort study reported at the annual meeting of the American Thyroid Association suggest.

Investigators led by Robert Smallridge, MD, an endocrinologist at the Mayo Clinic, in Jacksonville, Fla., used a large administrative database to study nearly 88,000 treatment-naive hypothyroid patients (most having benign thyroid disease) who started levothyroxine.

Susan London/Frontline Medical News

After a median follow-up of about 1 year, those on a brand-name formula and those on a generic formula had similar risks of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, and stroke, he reported in a poster session. The findings were essentially the same among the subgroup of older adults, despite their much higher incidences of events.

However, monthly total medication costs with the brand-name medication were more than twice those with the generic.

“I don’t think we are ready yet to say everybody ought to be on generic,” Dr. Smallridge said in an interview, citing the limited treatment duration captured in the study because patients switched medications or changed insurers. “But I think, at least in the short term, it’s giving us some data that we can build upon.”

He and his coinvestigators plan additional analyses looking at longer-term users, other types of thyroid hormone preparations, and the very small group of patients who had thyroid cancer.

“I primarily take care of cancer patients, and we purposely push these patients to slightly lower [thyroid-stimulating hormone levels] in general, which presumably is going to increase your risk of atrial fibrillation and could affect these events,” he said. “The numbers are somewhat smaller, clearly, but I’d like to see that explored also, to see if there is a difference between brand and generics in that subset who are probably getting a little bit more thyroid medication.”

Both hypothyroidism and its overtreatment with thyroid hormone therapy can increase cardiovascular risk, Dr. Smallridge noted.

For the study, the investigators analyzed data from a large administrative claims database (OptumLabs Data Warehouse) for the years 2006-2014. Patients having any prior use of any thyroid hormone preparation, amiodarone, or lithium were excluded. And patients were censored if they left the insurance plan, stopped treatment, or switched medication category.

The investigators identified 201,056 hypothyroid patients who started some type of thyroid hormone therapy. The majority (70.8%) started generic levothyroxine, and 22.1% started brand-name levothyroxine (Synthroid, Levoxyl, Tirosint, Unithroid). The small remaining group started another thyroid extract, triiodothyronine (T3), or a compounded preparation.

Primary care physicians were the main identifiable prescribers (60.3%), followed by endocrinologists (10.8%). “Endocrinologists tended to prescribe brand significantly more than the primary care physicians,” Dr. Smallridge said.

The investigators used propensity matching on a variety of factors (age, sex, race, census region, Charlson comorbidity index, year of index prescription, and a dozen baseline comorbidities) to compare patients starting brand-name versus generic levothyroxine. Outcomes were assessed during a median follow-up of 1 year (range, 0-9.3 years).

Event rates per 1,000 patient-years with branded versus generic levothyroxine were similar for atrial fibrillation (2.19 vs. 1.82; hazard ratio, 1.22, P = .19), myocardial infarction (1.83 vs. 2.12; HR, 0.86, P = .35), and congestive heart failure (2.00 vs. 2.27; HR, 0.88, P = .41). There was a borderline-significant difference on hospitalization for stroke, with marginally lower risk with brand-name levothyroxine (2.38 vs. 3.10; HR, 0.77; P = .05).

Findings were essentially the same in age-stratified analyses, splitting patients into subgroups younger and older than age 65.

When average 30-day costs were compared for users of branded versus generic levothyroxine, total cost for the branded drug was more than twice as high ($18.47 vs. $8.18).

“Thyroid preparations have been the most prescribed drug in the United States for several recent years. In the neighborhood of 25 million different patients a year take thyroid medications,” Dr. Smallridge said. “In terms of the dollars spent, it’s considerably less than some of the other drugs out there. But because of sheer numbers of patients, in terms of impact on health care dollars, it’s still a significant amount of money. And this is a lifelong treatment – once you go on thyroid hormones, you’re on them for life.”

The study had several strengths. “This is a very large, diverse, real-world population across the entire country with a wide range of ages,” Dr. Smallridge explained. “We got pharmacy claims documenting that they were continuing to get the refills, although we didn’t do pill counts, so we don’t know whether they were taking the medication. And a really important thing was the propensity score matching.”

At the same time, limitations included possible variations in coding and billing, and some residual confounding. “Key issues are that we need more data on longer-term follow-up, and we didn’t have lab values,” he added.

Dr. Smallridge reported that he had no relevant conflicts of interest.

 

 

VICTORIA, B.C. – Hypothyroid patients have similar cardiovascular outcomes in the shorter term whether they take generic or brand-name levothyroxine, results of a retrospective propensity-matched cohort study reported at the annual meeting of the American Thyroid Association suggest.

Investigators led by Robert Smallridge, MD, an endocrinologist at the Mayo Clinic, in Jacksonville, Fla., used a large administrative database to study nearly 88,000 treatment-naive hypothyroid patients (most having benign thyroid disease) who started levothyroxine.

Susan London/Frontline Medical News

After a median follow-up of about 1 year, those on a brand-name formula and those on a generic formula had similar risks of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, and stroke, he reported in a poster session. The findings were essentially the same among the subgroup of older adults, despite their much higher incidences of events.

However, monthly total medication costs with the brand-name medication were more than twice those with the generic.

“I don’t think we are ready yet to say everybody ought to be on generic,” Dr. Smallridge said in an interview, citing the limited treatment duration captured in the study because patients switched medications or changed insurers. “But I think, at least in the short term, it’s giving us some data that we can build upon.”

He and his coinvestigators plan additional analyses looking at longer-term users, other types of thyroid hormone preparations, and the very small group of patients who had thyroid cancer.

“I primarily take care of cancer patients, and we purposely push these patients to slightly lower [thyroid-stimulating hormone levels] in general, which presumably is going to increase your risk of atrial fibrillation and could affect these events,” he said. “The numbers are somewhat smaller, clearly, but I’d like to see that explored also, to see if there is a difference between brand and generics in that subset who are probably getting a little bit more thyroid medication.”

Both hypothyroidism and its overtreatment with thyroid hormone therapy can increase cardiovascular risk, Dr. Smallridge noted.

For the study, the investigators analyzed data from a large administrative claims database (OptumLabs Data Warehouse) for the years 2006-2014. Patients having any prior use of any thyroid hormone preparation, amiodarone, or lithium were excluded. And patients were censored if they left the insurance plan, stopped treatment, or switched medication category.

The investigators identified 201,056 hypothyroid patients who started some type of thyroid hormone therapy. The majority (70.8%) started generic levothyroxine, and 22.1% started brand-name levothyroxine (Synthroid, Levoxyl, Tirosint, Unithroid). The small remaining group started another thyroid extract, triiodothyronine (T3), or a compounded preparation.

Primary care physicians were the main identifiable prescribers (60.3%), followed by endocrinologists (10.8%). “Endocrinologists tended to prescribe brand significantly more than the primary care physicians,” Dr. Smallridge said.

The investigators used propensity matching on a variety of factors (age, sex, race, census region, Charlson comorbidity index, year of index prescription, and a dozen baseline comorbidities) to compare patients starting brand-name versus generic levothyroxine. Outcomes were assessed during a median follow-up of 1 year (range, 0-9.3 years).

Event rates per 1,000 patient-years with branded versus generic levothyroxine were similar for atrial fibrillation (2.19 vs. 1.82; hazard ratio, 1.22, P = .19), myocardial infarction (1.83 vs. 2.12; HR, 0.86, P = .35), and congestive heart failure (2.00 vs. 2.27; HR, 0.88, P = .41). There was a borderline-significant difference on hospitalization for stroke, with marginally lower risk with brand-name levothyroxine (2.38 vs. 3.10; HR, 0.77; P = .05).

Findings were essentially the same in age-stratified analyses, splitting patients into subgroups younger and older than age 65.

When average 30-day costs were compared for users of branded versus generic levothyroxine, total cost for the branded drug was more than twice as high ($18.47 vs. $8.18).

“Thyroid preparations have been the most prescribed drug in the United States for several recent years. In the neighborhood of 25 million different patients a year take thyroid medications,” Dr. Smallridge said. “In terms of the dollars spent, it’s considerably less than some of the other drugs out there. But because of sheer numbers of patients, in terms of impact on health care dollars, it’s still a significant amount of money. And this is a lifelong treatment – once you go on thyroid hormones, you’re on them for life.”

The study had several strengths. “This is a very large, diverse, real-world population across the entire country with a wide range of ages,” Dr. Smallridge explained. “We got pharmacy claims documenting that they were continuing to get the refills, although we didn’t do pill counts, so we don’t know whether they were taking the medication. And a really important thing was the propensity score matching.”

At the same time, limitations included possible variations in coding and billing, and some residual confounding. “Key issues are that we need more data on longer-term follow-up, and we didn’t have lab values,” he added.

Dr. Smallridge reported that he had no relevant conflicts of interest.

 

 

VICTORIA, B.C. – Even with contemporary anesthesia and surgical techniques, patients who are overtly hypothyroid at the time of major surgery have a rockier course, suggests a retrospective cohort study of 58 patients in a poster presentation at the annual meeting of the American Thyroid Association.

Actual length of stay for hypothyroid patients was twice that predicted by a commonly used risk calculator, whereas actual and predicted stays aligned well for euthyroid patients. The hypothyroid group had more cases of postoperative atrial fibrillation, ileus, reintubation, and death, although numbers were too small for statistical comparison.

“This will have an impact on how we look at patients, especially from a hospital standpoint and management. That’s quite a bit longer stay and quite a bit more cost. And the longer you stay, the more complications you have, too, so it could be riskier for the patient as well,” said first author Raquel Villavicencio, MD, a fellow at Indiana University at the time of the study, and now a clinical endocrinologist at Community Hospital in Indianapolis.

Susan London/Frontline Medical News

“Although we don’t consider hypothyroidism an absolute contraindication to surgery, especially if it’s necessary surgery, certainly anybody who is having elective surgery should have it postponed, in our opinion, until they are rendered euthyroid,” she said. “More studies are needed to look at this a little bit closer.”

Explaining the study’s rationale, Dr. Villavicencio noted, “This was a question that came up maybe three or four times a year, where we would get a hypothyroid patient and had to decide whether or not to clear them for surgery.”

Previous studies conducted at large institutions, the Mayo Clinic and Massachusetts General Hospital, had conflicting findings and were done about 30 years ago, she said. Anesthesia and surgical care have improved substantially since then, leading the investigators to hypothesize that hypothyroidism would not carry higher surgical risk today.

Dr. Villavicencio and her coinvestigator, Cary Mariash, MD, used their institutional database to identify 29 adult patients with a thyroid-stimulating hormone (TSH) level of greater than 10 mcU/mL alone or with a TSH level exceeding the upper limit of normal along with a free thyroxine (T4) level of less than 0.6 ng/dL who underwent surgery during 2010-2015. They matched each patient on age, sex, and surgical procedure with a control euthyroid patient.

The mean TSH level in the hypothyroid group was 29.2 mcU/mL. The majority of patients in each group – 59% of the hypothyroid group and 62% of the euthyroid group – had an American Surgical Association class of 3, denoting that this was a fairly sick population. The groups were generally similar on rates of comorbidity, except that the euthyroid patients had a slightly higher prevalence of obstructive sleep apnea.

In both groups, the majority of procedures were laparotomy and/or bowel resection; pharyngolaryngectomy and esophagectomy/esophagoplasty; and wound or bone debridement.

Main results showed that in the hypothyroid group, hospital length of stay predicted with the American College of Surgeons National Surgical Quality Improvement Program surgical risk calculator was 6.9 days, but actual length of stay was 14.4 days (P = .0004). In contrast, in the euthyroid group, predicted length of stay was a similar at 7.1 days, and actual length of stay was statistically indistinguishable at 9.2 days (P = .1).

“Hypothyroidism is not taken into account with this calculator,” Dr. Villavicencio noted, adding that she was unaware of any surgical calculators that do.

One patient in the hypothyroid group died, compared with none in the euthyroid group. In terms of postoperative cardiac complications, two patients in the hypothyroid group experienced atrial fibrillation, and there was one case of pulseless electrical–activity arrest in each group.

The groups did not differ on incidence of hypothermia, bradycardia, hyponatremia, time to extubation, and hypotension. However, mean arterial pressure tended to be lower in the hypothyroid group (51 mm Hg) than in the euthyroid group (56 mm Hg), and the former more often needed vasopressors. Furthermore, postoperative ileus and reintubation were more common in the hypothyroid group.

“I think that there are kind of a lot of little things that add up to explain [the longer stay],” said Dr. Villavicencio, who disclosed that she had no relevant conflicts of interest.

 

VICTORIA, B.C. – Even with contemporary anesthesia and surgical techniques, patients who are overtly hypothyroid at the time of major surgery have a rockier course, suggests a retrospective cohort study of 58 patients in a poster presentation at the annual meeting of the American Thyroid Association.

Actual length of stay for hypothyroid patients was twice that predicted by a commonly used risk calculator, whereas actual and predicted stays aligned well for euthyroid patients. The hypothyroid group had more cases of postoperative atrial fibrillation, ileus, reintubation, and death, although numbers were too small for statistical comparison.

“This will have an impact on how we look at patients, especially from a hospital standpoint and management. That’s quite a bit longer stay and quite a bit more cost. And the longer you stay, the more complications you have, too, so it could be riskier for the patient as well,” said first author Raquel Villavicencio, MD, a fellow at Indiana University at the time of the study, and now a clinical endocrinologist at Community Hospital in Indianapolis.

Susan London/Frontline Medical News

“Although we don’t consider hypothyroidism an absolute contraindication to surgery, especially if it’s necessary surgery, certainly anybody who is having elective surgery should have it postponed, in our opinion, until they are rendered euthyroid,” she said. “More studies are needed to look at this a little bit closer.”

Explaining the study’s rationale, Dr. Villavicencio noted, “This was a question that came up maybe three or four times a year, where we would get a hypothyroid patient and had to decide whether or not to clear them for surgery.”

Previous studies conducted at large institutions, the Mayo Clinic and Massachusetts General Hospital, had conflicting findings and were done about 30 years ago, she said. Anesthesia and surgical care have improved substantially since then, leading the investigators to hypothesize that hypothyroidism would not carry higher surgical risk today.

Dr. Villavicencio and her coinvestigator, Cary Mariash, MD, used their institutional database to identify 29 adult patients with a thyroid-stimulating hormone (TSH) level of greater than 10 mcU/mL alone or with a TSH level exceeding the upper limit of normal along with a free thyroxine (T4) level of less than 0.6 ng/dL who underwent surgery during 2010-2015. They matched each patient on age, sex, and surgical procedure with a control euthyroid patient.

The mean TSH level in the hypothyroid group was 29.2 mcU/mL. The majority of patients in each group – 59% of the hypothyroid group and 62% of the euthyroid group – had an American Surgical Association class of 3, denoting that this was a fairly sick population. The groups were generally similar on rates of comorbidity, except that the euthyroid patients had a slightly higher prevalence of obstructive sleep apnea.

In both groups, the majority of procedures were laparotomy and/or bowel resection; pharyngolaryngectomy and esophagectomy/esophagoplasty; and wound or bone debridement.

Main results showed that in the hypothyroid group, hospital length of stay predicted with the American College of Surgeons National Surgical Quality Improvement Program surgical risk calculator was 6.9 days, but actual length of stay was 14.4 days (P = .0004). In contrast, in the euthyroid group, predicted length of stay was a similar at 7.1 days, and actual length of stay was statistically indistinguishable at 9.2 days (P = .1).

“Hypothyroidism is not taken into account with this calculator,” Dr. Villavicencio noted, adding that she was unaware of any surgical calculators that do.

One patient in the hypothyroid group died, compared with none in the euthyroid group. In terms of postoperative cardiac complications, two patients in the hypothyroid group experienced atrial fibrillation, and there was one case of pulseless electrical–activity arrest in each group.

The groups did not differ on incidence of hypothermia, bradycardia, hyponatremia, time to extubation, and hypotension. However, mean arterial pressure tended to be lower in the hypothyroid group (51 mm Hg) than in the euthyroid group (56 mm Hg), and the former more often needed vasopressors. Furthermore, postoperative ileus and reintubation were more common in the hypothyroid group.

“I think that there are kind of a lot of little things that add up to explain [the longer stay],” said Dr. Villavicencio, who disclosed that she had no relevant conflicts of interest.

 

VICTORIA, B.C. – Even with contemporary anesthesia and surgical techniques, patients who are overtly hypothyroid at the time of major surgery have a rockier course, suggests a retrospective cohort study of 58 patients in a poster presentation at the annual meeting of the American Thyroid Association.

Actual length of stay for hypothyroid patients was twice that predicted by a commonly used risk calculator, whereas actual and predicted stays aligned well for euthyroid patients. The hypothyroid group had more cases of postoperative atrial fibrillation, ileus, reintubation, and death, although numbers were too small for statistical comparison.

“This will have an impact on how we look at patients, especially from a hospital standpoint and management. That’s quite a bit longer stay and quite a bit more cost. And the longer you stay, the more complications you have, too, so it could be riskier for the patient as well,” said first author Raquel Villavicencio, MD, a fellow at Indiana University at the time of the study, and now a clinical endocrinologist at Community Hospital in Indianapolis.

Susan London/Frontline Medical News

“Although we don’t consider hypothyroidism an absolute contraindication to surgery, especially if it’s necessary surgery, certainly anybody who is having elective surgery should have it postponed, in our opinion, until they are rendered euthyroid,” she said. “More studies are needed to look at this a little bit closer.”

Explaining the study’s rationale, Dr. Villavicencio noted, “This was a question that came up maybe three or four times a year, where we would get a hypothyroid patient and had to decide whether or not to clear them for surgery.”

Previous studies conducted at large institutions, the Mayo Clinic and Massachusetts General Hospital, had conflicting findings and were done about 30 years ago, she said. Anesthesia and surgical care have improved substantially since then, leading the investigators to hypothesize that hypothyroidism would not carry higher surgical risk today.

Dr. Villavicencio and her coinvestigator, Cary Mariash, MD, used their institutional database to identify 29 adult patients with a thyroid-stimulating hormone (TSH) level of greater than 10 mcU/mL alone or with a TSH level exceeding the upper limit of normal along with a free thyroxine (T4) level of less than 0.6 ng/dL who underwent surgery during 2010-2015. They matched each patient on age, sex, and surgical procedure with a control euthyroid patient.

The mean TSH level in the hypothyroid group was 29.2 mcU/mL. The majority of patients in each group – 59% of the hypothyroid group and 62% of the euthyroid group – had an American Surgical Association class of 3, denoting that this was a fairly sick population. The groups were generally similar on rates of comorbidity, except that the euthyroid patients had a slightly higher prevalence of obstructive sleep apnea.

In both groups, the majority of procedures were laparotomy and/or bowel resection; pharyngolaryngectomy and esophagectomy/esophagoplasty; and wound or bone debridement.

Main results showed that in the hypothyroid group, hospital length of stay predicted with the American College of Surgeons National Surgical Quality Improvement Program surgical risk calculator was 6.9 days, but actual length of stay was 14.4 days (P = .0004). In contrast, in the euthyroid group, predicted length of stay was a similar at 7.1 days, and actual length of stay was statistically indistinguishable at 9.2 days (P = .1).

“Hypothyroidism is not taken into account with this calculator,” Dr. Villavicencio noted, adding that she was unaware of any surgical calculators that do.

One patient in the hypothyroid group died, compared with none in the euthyroid group. In terms of postoperative cardiac complications, two patients in the hypothyroid group experienced atrial fibrillation, and there was one case of pulseless electrical–activity arrest in each group.

The groups did not differ on incidence of hypothermia, bradycardia, hyponatremia, time to extubation, and hypotension. However, mean arterial pressure tended to be lower in the hypothyroid group (51 mm Hg) than in the euthyroid group (56 mm Hg), and the former more often needed vasopressors. Furthermore, postoperative ileus and reintubation were more common in the hypothyroid group.

“I think that there are kind of a lot of little things that add up to explain [the longer stay],” said Dr. Villavicencio, who disclosed that she had no relevant conflicts of interest.

 

VICTORIA, B.C. – Patient perception plays a large role in subjective benefit of levothyroxine therapy for hypothyroidism, suggests a double-blind randomized controlled trial reported at the annual meeting of the American Thyroid Association.

Mood, cognition, and quality of life (QoL) did not differ whether patients’ levothyroxine dose was adjusted to achieve thyroid-stimulating hormone (TSH) levels in the low-normal, high-normal, or mildly elevated range. But despite this lack of objective benefit, the large majority of patients preferred levothyroxine doses that they perceived to be higher – whether they actually were or not.

“With these data, we believe that patients should be counseled that symptoms in these areas are not reliably related to levothyroxine doses or thyroid hormone levels,” commented first author Mary H. Samuels, MD, an endocrinologist at the Thyroid & Parathyroid Center, Oregon Health & Science University, Portland.

The study was not restricted to certain groups who might have a better response to higher levothyroxine dose, she acknowledged. Two such groups are patients with more symptoms (although volunteering for the study suggested dissatisfaction with symptom control) and patients with low tri-iodothyronine (T3) levels (although about half of patients had low baseline levels).

“We encourage further research in older subjects, men, and subjects with specific symptoms, low T3 levels, or functional polymorphisms in thyroid-relevant genes,” Dr. Samuels said. “These are really difficult, expensive studies to do, and if we are going to have any hope of getting them funded and doing them, I think that we have to be much more targeted.”

One of the session co-chairs, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “I think these are really interesting data because there’s this sense among patients that their dose really affects how they feel, and this is essentially turning that on its head. It’s not really clear, then, why are these patients still maybe not feeling well.”

“It will be interesting to see more data on this and ... more about this business of checking T3 levels. Do we need to supplement with T3? I think we really don’t know that, especially in kids, but even in adults,” she added.

The other session co-chair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, Bronx, N.Y., commented, “I think this study confirmed what a lot of us feel, that there is a lot of placebo effect when you treat in different ways to optimize the TSH or give T3.”

Other data reported in the session provide a possible explanation for the lack of benefit of adjusting pharmacologic therapy, suggesting that the volumes of various brain structures change with perturbations of thyroid function, he noted. “There might be true changes in the brain that affect how the patients feel. So these patients may truly not feel well. It’s just that we can’t fix it by adjusting the TSH level to very narrow margins or by adding T3,” he said.
 

Study details

“It is well known that overt hypothyroidism interferes with mood and a number of cognitive functions. However, neurocognitive effects of variations in thyroid function within the reference range and in mild or subclinical hypothyroidism are less clear,” Dr. Samuels noted, giving some background to the research.

“Observational studies of this question have tended to be negative but have often included less sensitive global screening tests of cognition. There are very few small-scale interventional studies,” she continued. “In the absence of conclusive data, many patients with mild hypothyroidism are started on levothyroxine to treat nonspecific quality of life, mood, or cognitive symptoms, and many additional treated patients request increased levothyroxine doses due to persistence of these symptoms.”

Dr. Samuels and her coinvestigators enrolled in the trial 138 hypothyroid but otherwise healthy patients who had been on a stable dose of levothyroxine (Synthroid and others) alone for at least 3 months and had normal TSH levels.

The patients were randomized to three groups in which clinicians adjusted levothyroxine dose every 6 weeks in blinded fashion to achieve different target TSH levels: low-normal TSH (0.34-2.50 mU/L), high-normal TSH (2.51-5.60 mU/L), or mildly elevated TSH (5.60-12.0 mU/L). Patients completed a battery of assessments at baseline and again at 6 months.

Main results confirmed that TSH targets were generally achieved, with significantly different mean TSH levels in the low-normal group (1.34 mU/L), high-normal group (3.74 mU/L), and mildly elevated group (9.74 mU/L) (P less than .05).

In crude analyses, results differed significantly across groups for only two of the dozens of measures of mood, cognition, and QoL assessed: bodily pain (26%, 11%, and 34% of patients reporting a high pain level in the low-normal, high-normal, and mildly elevated TSH groups, respectively; P = .03) and working memory on the N-Back test (86%, 58%, and 75% with a 1-back result; P = .002). However, there were no significant differences for any of the measures when analyses were repeated with statistical correction for multiple comparisons.

At the end of the study, patients were unable to say with any accuracy say whether they were receiving a dose of levothyroxine that was higher than, lower than, or unchanged from their baseline dose (P = .55 for actual vs. perceived).

However, patients preferred what they perceived to be a higher dose (P less than .001 for preferred vs. perceived). In the group perceiving their end-of-study dose was higher, the majority of patients (68%) preferred that dose, and in the group perceiving their end-of-study dose was lower, most (96%) preferred their baseline dose.

The sample size may not have been adequate to detect very small effects of changes in levothyroxine dose, acknowledged Dr. Samuels, who disclosed that she had no relevant conflicts of interest. Additionally, patients were predominantly female and younger, and heterogeneous with respect to thyroid diagnosis and length of levothyroxine therapy.

 

VICTORIA, B.C. – Patient perception plays a large role in subjective benefit of levothyroxine therapy for hypothyroidism, suggests a double-blind randomized controlled trial reported at the annual meeting of the American Thyroid Association.

Mood, cognition, and quality of life (QoL) did not differ whether patients’ levothyroxine dose was adjusted to achieve thyroid-stimulating hormone (TSH) levels in the low-normal, high-normal, or mildly elevated range. But despite this lack of objective benefit, the large majority of patients preferred levothyroxine doses that they perceived to be higher – whether they actually were or not.

“With these data, we believe that patients should be counseled that symptoms in these areas are not reliably related to levothyroxine doses or thyroid hormone levels,” commented first author Mary H. Samuels, MD, an endocrinologist at the Thyroid & Parathyroid Center, Oregon Health & Science University, Portland.

The study was not restricted to certain groups who might have a better response to higher levothyroxine dose, she acknowledged. Two such groups are patients with more symptoms (although volunteering for the study suggested dissatisfaction with symptom control) and patients with low tri-iodothyronine (T3) levels (although about half of patients had low baseline levels).

“We encourage further research in older subjects, men, and subjects with specific symptoms, low T3 levels, or functional polymorphisms in thyroid-relevant genes,” Dr. Samuels said. “These are really difficult, expensive studies to do, and if we are going to have any hope of getting them funded and doing them, I think that we have to be much more targeted.”

One of the session co-chairs, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “I think these are really interesting data because there’s this sense among patients that their dose really affects how they feel, and this is essentially turning that on its head. It’s not really clear, then, why are these patients still maybe not feeling well.”

“It will be interesting to see more data on this and ... more about this business of checking T3 levels. Do we need to supplement with T3? I think we really don’t know that, especially in kids, but even in adults,” she added.

The other session co-chair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, Bronx, N.Y., commented, “I think this study confirmed what a lot of us feel, that there is a lot of placebo effect when you treat in different ways to optimize the TSH or give T3.”

Other data reported in the session provide a possible explanation for the lack of benefit of adjusting pharmacologic therapy, suggesting that the volumes of various brain structures change with perturbations of thyroid function, he noted. “There might be true changes in the brain that affect how the patients feel. So these patients may truly not feel well. It’s just that we can’t fix it by adjusting the TSH level to very narrow margins or by adding T3,” he said.
 

Study details

“It is well known that overt hypothyroidism interferes with mood and a number of cognitive functions. However, neurocognitive effects of variations in thyroid function within the reference range and in mild or subclinical hypothyroidism are less clear,” Dr. Samuels noted, giving some background to the research.

“Observational studies of this question have tended to be negative but have often included less sensitive global screening tests of cognition. There are very few small-scale interventional studies,” she continued. “In the absence of conclusive data, many patients with mild hypothyroidism are started on levothyroxine to treat nonspecific quality of life, mood, or cognitive symptoms, and many additional treated patients request increased levothyroxine doses due to persistence of these symptoms.”

Dr. Samuels and her coinvestigators enrolled in the trial 138 hypothyroid but otherwise healthy patients who had been on a stable dose of levothyroxine (Synthroid and others) alone for at least 3 months and had normal TSH levels.

The patients were randomized to three groups in which clinicians adjusted levothyroxine dose every 6 weeks in blinded fashion to achieve different target TSH levels: low-normal TSH (0.34-2.50 mU/L), high-normal TSH (2.51-5.60 mU/L), or mildly elevated TSH (5.60-12.0 mU/L). Patients completed a battery of assessments at baseline and again at 6 months.

Main results confirmed that TSH targets were generally achieved, with significantly different mean TSH levels in the low-normal group (1.34 mU/L), high-normal group (3.74 mU/L), and mildly elevated group (9.74 mU/L) (P less than .05).

In crude analyses, results differed significantly across groups for only two of the dozens of measures of mood, cognition, and QoL assessed: bodily pain (26%, 11%, and 34% of patients reporting a high pain level in the low-normal, high-normal, and mildly elevated TSH groups, respectively; P = .03) and working memory on the N-Back test (86%, 58%, and 75% with a 1-back result; P = .002). However, there were no significant differences for any of the measures when analyses were repeated with statistical correction for multiple comparisons.

At the end of the study, patients were unable to say with any accuracy say whether they were receiving a dose of levothyroxine that was higher than, lower than, or unchanged from their baseline dose (P = .55 for actual vs. perceived).

However, patients preferred what they perceived to be a higher dose (P less than .001 for preferred vs. perceived). In the group perceiving their end-of-study dose was higher, the majority of patients (68%) preferred that dose, and in the group perceiving their end-of-study dose was lower, most (96%) preferred their baseline dose.

The sample size may not have been adequate to detect very small effects of changes in levothyroxine dose, acknowledged Dr. Samuels, who disclosed that she had no relevant conflicts of interest. Additionally, patients were predominantly female and younger, and heterogeneous with respect to thyroid diagnosis and length of levothyroxine therapy.

 

VICTORIA, B.C. – Patient perception plays a large role in subjective benefit of levothyroxine therapy for hypothyroidism, suggests a double-blind randomized controlled trial reported at the annual meeting of the American Thyroid Association.

Mood, cognition, and quality of life (QoL) did not differ whether patients’ levothyroxine dose was adjusted to achieve thyroid-stimulating hormone (TSH) levels in the low-normal, high-normal, or mildly elevated range. But despite this lack of objective benefit, the large majority of patients preferred levothyroxine doses that they perceived to be higher – whether they actually were or not.

“With these data, we believe that patients should be counseled that symptoms in these areas are not reliably related to levothyroxine doses or thyroid hormone levels,” commented first author Mary H. Samuels, MD, an endocrinologist at the Thyroid & Parathyroid Center, Oregon Health & Science University, Portland.

The study was not restricted to certain groups who might have a better response to higher levothyroxine dose, she acknowledged. Two such groups are patients with more symptoms (although volunteering for the study suggested dissatisfaction with symptom control) and patients with low tri-iodothyronine (T3) levels (although about half of patients had low baseline levels).

“We encourage further research in older subjects, men, and subjects with specific symptoms, low T3 levels, or functional polymorphisms in thyroid-relevant genes,” Dr. Samuels said. “These are really difficult, expensive studies to do, and if we are going to have any hope of getting them funded and doing them, I think that we have to be much more targeted.”

One of the session co-chairs, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “I think these are really interesting data because there’s this sense among patients that their dose really affects how they feel, and this is essentially turning that on its head. It’s not really clear, then, why are these patients still maybe not feeling well.”

“It will be interesting to see more data on this and ... more about this business of checking T3 levels. Do we need to supplement with T3? I think we really don’t know that, especially in kids, but even in adults,” she added.

The other session co-chair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, Bronx, N.Y., commented, “I think this study confirmed what a lot of us feel, that there is a lot of placebo effect when you treat in different ways to optimize the TSH or give T3.”

Other data reported in the session provide a possible explanation for the lack of benefit of adjusting pharmacologic therapy, suggesting that the volumes of various brain structures change with perturbations of thyroid function, he noted. “There might be true changes in the brain that affect how the patients feel. So these patients may truly not feel well. It’s just that we can’t fix it by adjusting the TSH level to very narrow margins or by adding T3,” he said.
 

Study details

“It is well known that overt hypothyroidism interferes with mood and a number of cognitive functions. However, neurocognitive effects of variations in thyroid function within the reference range and in mild or subclinical hypothyroidism are less clear,” Dr. Samuels noted, giving some background to the research.

“Observational studies of this question have tended to be negative but have often included less sensitive global screening tests of cognition. There are very few small-scale interventional studies,” she continued. “In the absence of conclusive data, many patients with mild hypothyroidism are started on levothyroxine to treat nonspecific quality of life, mood, or cognitive symptoms, and many additional treated patients request increased levothyroxine doses due to persistence of these symptoms.”

Dr. Samuels and her coinvestigators enrolled in the trial 138 hypothyroid but otherwise healthy patients who had been on a stable dose of levothyroxine (Synthroid and others) alone for at least 3 months and had normal TSH levels.

The patients were randomized to three groups in which clinicians adjusted levothyroxine dose every 6 weeks in blinded fashion to achieve different target TSH levels: low-normal TSH (0.34-2.50 mU/L), high-normal TSH (2.51-5.60 mU/L), or mildly elevated TSH (5.60-12.0 mU/L). Patients completed a battery of assessments at baseline and again at 6 months.

Main results confirmed that TSH targets were generally achieved, with significantly different mean TSH levels in the low-normal group (1.34 mU/L), high-normal group (3.74 mU/L), and mildly elevated group (9.74 mU/L) (P less than .05).

In crude analyses, results differed significantly across groups for only two of the dozens of measures of mood, cognition, and QoL assessed: bodily pain (26%, 11%, and 34% of patients reporting a high pain level in the low-normal, high-normal, and mildly elevated TSH groups, respectively; P = .03) and working memory on the N-Back test (86%, 58%, and 75% with a 1-back result; P = .002). However, there were no significant differences for any of the measures when analyses were repeated with statistical correction for multiple comparisons.

At the end of the study, patients were unable to say with any accuracy say whether they were receiving a dose of levothyroxine that was higher than, lower than, or unchanged from their baseline dose (P = .55 for actual vs. perceived).

However, patients preferred what they perceived to be a higher dose (P less than .001 for preferred vs. perceived). In the group perceiving their end-of-study dose was higher, the majority of patients (68%) preferred that dose, and in the group perceiving their end-of-study dose was lower, most (96%) preferred their baseline dose.

The sample size may not have been adequate to detect very small effects of changes in levothyroxine dose, acknowledged Dr. Samuels, who disclosed that she had no relevant conflicts of interest. Additionally, patients were predominantly female and younger, and heterogeneous with respect to thyroid diagnosis and length of levothyroxine therapy.

 

VICTORIA, B.C. – In the debate over the optimal duration of methimazole therapy for Graves disease, findings of a new randomized, controlled trial reported at the annual meeting of the American Thyroid Association tip the balance in favor of long-term therapy.

The relapse rate among patients who stayed on the drug long term, for a median of 96 months, was about one-third that among patients who stopped after 18 months, reported lead investigator Fereidoun Azizi, MD, of the Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran. Patients staying on the drug long term did not experience any adverse effects during that time, although only those able to tolerate the drug initially were randomized.

Susan London/Frontline Medical News

“Long-term, low-dose methimazole treatment for 60-120 months is a safe and effective treatment for Graves hyperthyroidism and is accompanied by much higher remission rates than the usual 18-24 months of methimazole treatment,” he summarized.

There may be two explanations for this benefit of long-term therapy, according to Dr. Azizi. Long-term therapy may alter immune-related molecular signaling and cell subsets in both the thymus and periphery, ultimately shifting disease course. On the other hand, establishing and maintaining euthyroidism for a prolonged period of time may quell the autoimmune response.

“We are looking at this in depth and also at some of the [molecular factors] in order to elucidate the mechanism behind our striking findings,” he said.

One of the session cochairs, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, commented, “There is a move today away from radioactive iodine – many patients do not want radioactive iodine, and we do more surgery now because of that. So this opens up a new option that we didn’t have before.”

At the same time, the potential for rare but serious toxicity of methimazole must be taken into account, especially for certain patients, such as those who travel frequently. “That’s sometimes a consideration when somebody is [on therapy] long term, because even if they don’t develop agranulocytosis, they may develop symptoms that suggest it, creating unnecessary anxiety. In those cases where this is not an issue, long-term treatment could be another new option that we didn’t have before.”

The other session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., noted that duration of therapy frequently comes up in her practice.

Susan London/Frontline Medical News

“It’s similar that there is sort of a move, if we can, to keep kids on treatment potentially longer because sometimes the kids are too young or we’d rather not do definitive therapy when they are less than 10 years of age, and we want to buy ourselves some time. So this [study] is somewhat reassuring that it’s probably safe to do that as long as they are compliant, they don’t have toxicity, those sorts of things. And there is the chance that perhaps more of them will enter remission over a long period of time,” she said. “I think it just tells us we have to be more patient, perhaps, with how long we treat these patients.”
 

Study details

Relapse of hyperthyroidism after discontinuation of antithyroid drugs remains problematic, Dr. Azizi pointed out when introducing the study.

“Many of the major papers have noted that longer antithyroid drug treatment does not really influence remission rate of Graves, and therefore most of us treat for between 12 and 24 months with antithyroid drugs, and then we stop the medication,” he said. However, recent studies and in particular a meta-analysis (Thyroid. 2017;27:1223-31) suggest there may be an advantage of long-term therapy.

Dr. Azizi and coinvestigators recruited to their trial 302 consecutive patients from a single clinic who had untreated Graves disease and were started on methimazole (Tapazole) therapy.

The 258 patients completing 18 months of therapy were randomized to stop the drug or continue on a maintenance dose long term, for 60-120 months, on a single-blind basis. (The other 44 patients withdrew mainly because of side effects, relapse, and loss to follow-up.)

Patients in the long-term therapy group stayed on the drug for a median of 96 months. The decision about specifically when to stop in this group was guided by thyroid function test results and patients’ clinical status and preferences, according to Dr. Azizi.

The rate of relapse at 48 months after stopping methimazole was 51% among patients in the short-term therapy group but just 16% among patients in the long-term therapy group (P less than or equal to .001). “Definitely, this looks like a cure of the disease if we consider this very low incidence of relapse,” he commented.

Within the group treated long term, patients who did and did not experience relapse were statistically indistinguishable with respect to temporal trends in levels of triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid-stimulating hormone receptor antibody (TRAb).

Additionally, the daily dose of methimazole therapy required to maintain TSH levels in the normal range fell similarly over time, to about half the initial dose, regardless of whether patients had a relapse or not.

“At the end of treatment, the majority of patients were taking less than 5 mg/day of methimazole,” Dr. Azizi reported. “Some patients needed only two or three pills of 5-mg methimazole per week, and this is very interesting to know, that after you continue, you have definitely more response to methimazole.”

Multivariate analyses showed that in the short-term therapy group, risk factors for relapse were age, sex, and end-of-therapy levels of T3, TSH, and TRAb. In the long-term therapy group, risk factors were end-of-therapy levels of free T4 and TSH.

“We are currently performing more in-depth analysis of genetic markers, including both SNPs [single nucleotide polymorphisms] and HLA [human leukocyte antigen] subtyping on these samples to assess any potential association between relapse rates and genetic background,” Dr. Azizi noted. “However, the problem is the low number of patients who have had a relapse long term.”

During the first 18 months of methimazole therapy, 16 patients had adverse effects in the first 2 months (14 had cutaneous reactions and 2 had elevation of liver enzymes). However, there were no serious complications, such as agranulocytosis.

“It’s very reassuring that after 18 months, in those who had long-term treatment, we did not see any minor or major complications throughout, up to the 120 months of treatment we have had in some of our patients,” Dr. Azizi commented.

Dr. Azizi disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – In the debate over the optimal duration of methimazole therapy for Graves disease, findings of a new randomized, controlled trial reported at the annual meeting of the American Thyroid Association tip the balance in favor of long-term therapy.

The relapse rate among patients who stayed on the drug long term, for a median of 96 months, was about one-third that among patients who stopped after 18 months, reported lead investigator Fereidoun Azizi, MD, of the Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran. Patients staying on the drug long term did not experience any adverse effects during that time, although only those able to tolerate the drug initially were randomized.

Susan London/Frontline Medical News

“Long-term, low-dose methimazole treatment for 60-120 months is a safe and effective treatment for Graves hyperthyroidism and is accompanied by much higher remission rates than the usual 18-24 months of methimazole treatment,” he summarized.

There may be two explanations for this benefit of long-term therapy, according to Dr. Azizi. Long-term therapy may alter immune-related molecular signaling and cell subsets in both the thymus and periphery, ultimately shifting disease course. On the other hand, establishing and maintaining euthyroidism for a prolonged period of time may quell the autoimmune response.

“We are looking at this in depth and also at some of the [molecular factors] in order to elucidate the mechanism behind our striking findings,” he said.

One of the session cochairs, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, commented, “There is a move today away from radioactive iodine – many patients do not want radioactive iodine, and we do more surgery now because of that. So this opens up a new option that we didn’t have before.”

At the same time, the potential for rare but serious toxicity of methimazole must be taken into account, especially for certain patients, such as those who travel frequently. “That’s sometimes a consideration when somebody is [on therapy] long term, because even if they don’t develop agranulocytosis, they may develop symptoms that suggest it, creating unnecessary anxiety. In those cases where this is not an issue, long-term treatment could be another new option that we didn’t have before.”

The other session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., noted that duration of therapy frequently comes up in her practice.

Susan London/Frontline Medical News

“It’s similar that there is sort of a move, if we can, to keep kids on treatment potentially longer because sometimes the kids are too young or we’d rather not do definitive therapy when they are less than 10 years of age, and we want to buy ourselves some time. So this [study] is somewhat reassuring that it’s probably safe to do that as long as they are compliant, they don’t have toxicity, those sorts of things. And there is the chance that perhaps more of them will enter remission over a long period of time,” she said. “I think it just tells us we have to be more patient, perhaps, with how long we treat these patients.”
 

Study details

Relapse of hyperthyroidism after discontinuation of antithyroid drugs remains problematic, Dr. Azizi pointed out when introducing the study.

“Many of the major papers have noted that longer antithyroid drug treatment does not really influence remission rate of Graves, and therefore most of us treat for between 12 and 24 months with antithyroid drugs, and then we stop the medication,” he said. However, recent studies and in particular a meta-analysis (Thyroid. 2017;27:1223-31) suggest there may be an advantage of long-term therapy.

Dr. Azizi and coinvestigators recruited to their trial 302 consecutive patients from a single clinic who had untreated Graves disease and were started on methimazole (Tapazole) therapy.

The 258 patients completing 18 months of therapy were randomized to stop the drug or continue on a maintenance dose long term, for 60-120 months, on a single-blind basis. (The other 44 patients withdrew mainly because of side effects, relapse, and loss to follow-up.)

Patients in the long-term therapy group stayed on the drug for a median of 96 months. The decision about specifically when to stop in this group was guided by thyroid function test results and patients’ clinical status and preferences, according to Dr. Azizi.

The rate of relapse at 48 months after stopping methimazole was 51% among patients in the short-term therapy group but just 16% among patients in the long-term therapy group (P less than or equal to .001). “Definitely, this looks like a cure of the disease if we consider this very low incidence of relapse,” he commented.

Within the group treated long term, patients who did and did not experience relapse were statistically indistinguishable with respect to temporal trends in levels of triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid-stimulating hormone receptor antibody (TRAb).

Additionally, the daily dose of methimazole therapy required to maintain TSH levels in the normal range fell similarly over time, to about half the initial dose, regardless of whether patients had a relapse or not.

“At the end of treatment, the majority of patients were taking less than 5 mg/day of methimazole,” Dr. Azizi reported. “Some patients needed only two or three pills of 5-mg methimazole per week, and this is very interesting to know, that after you continue, you have definitely more response to methimazole.”

Multivariate analyses showed that in the short-term therapy group, risk factors for relapse were age, sex, and end-of-therapy levels of T3, TSH, and TRAb. In the long-term therapy group, risk factors were end-of-therapy levels of free T4 and TSH.

“We are currently performing more in-depth analysis of genetic markers, including both SNPs [single nucleotide polymorphisms] and HLA [human leukocyte antigen] subtyping on these samples to assess any potential association between relapse rates and genetic background,” Dr. Azizi noted. “However, the problem is the low number of patients who have had a relapse long term.”

During the first 18 months of methimazole therapy, 16 patients had adverse effects in the first 2 months (14 had cutaneous reactions and 2 had elevation of liver enzymes). However, there were no serious complications, such as agranulocytosis.

“It’s very reassuring that after 18 months, in those who had long-term treatment, we did not see any minor or major complications throughout, up to the 120 months of treatment we have had in some of our patients,” Dr. Azizi commented.

Dr. Azizi disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – In the debate over the optimal duration of methimazole therapy for Graves disease, findings of a new randomized, controlled trial reported at the annual meeting of the American Thyroid Association tip the balance in favor of long-term therapy.

The relapse rate among patients who stayed on the drug long term, for a median of 96 months, was about one-third that among patients who stopped after 18 months, reported lead investigator Fereidoun Azizi, MD, of the Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran. Patients staying on the drug long term did not experience any adverse effects during that time, although only those able to tolerate the drug initially were randomized.

Susan London/Frontline Medical News

“Long-term, low-dose methimazole treatment for 60-120 months is a safe and effective treatment for Graves hyperthyroidism and is accompanied by much higher remission rates than the usual 18-24 months of methimazole treatment,” he summarized.

There may be two explanations for this benefit of long-term therapy, according to Dr. Azizi. Long-term therapy may alter immune-related molecular signaling and cell subsets in both the thymus and periphery, ultimately shifting disease course. On the other hand, establishing and maintaining euthyroidism for a prolonged period of time may quell the autoimmune response.

“We are looking at this in depth and also at some of the [molecular factors] in order to elucidate the mechanism behind our striking findings,” he said.

One of the session cochairs, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, commented, “There is a move today away from radioactive iodine – many patients do not want radioactive iodine, and we do more surgery now because of that. So this opens up a new option that we didn’t have before.”

At the same time, the potential for rare but serious toxicity of methimazole must be taken into account, especially for certain patients, such as those who travel frequently. “That’s sometimes a consideration when somebody is [on therapy] long term, because even if they don’t develop agranulocytosis, they may develop symptoms that suggest it, creating unnecessary anxiety. In those cases where this is not an issue, long-term treatment could be another new option that we didn’t have before.”

The other session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., noted that duration of therapy frequently comes up in her practice.

Susan London/Frontline Medical News

“It’s similar that there is sort of a move, if we can, to keep kids on treatment potentially longer because sometimes the kids are too young or we’d rather not do definitive therapy when they are less than 10 years of age, and we want to buy ourselves some time. So this [study] is somewhat reassuring that it’s probably safe to do that as long as they are compliant, they don’t have toxicity, those sorts of things. And there is the chance that perhaps more of them will enter remission over a long period of time,” she said. “I think it just tells us we have to be more patient, perhaps, with how long we treat these patients.”
 

Study details

Relapse of hyperthyroidism after discontinuation of antithyroid drugs remains problematic, Dr. Azizi pointed out when introducing the study.

“Many of the major papers have noted that longer antithyroid drug treatment does not really influence remission rate of Graves, and therefore most of us treat for between 12 and 24 months with antithyroid drugs, and then we stop the medication,” he said. However, recent studies and in particular a meta-analysis (Thyroid. 2017;27:1223-31) suggest there may be an advantage of long-term therapy.

Dr. Azizi and coinvestigators recruited to their trial 302 consecutive patients from a single clinic who had untreated Graves disease and were started on methimazole (Tapazole) therapy.

The 258 patients completing 18 months of therapy were randomized to stop the drug or continue on a maintenance dose long term, for 60-120 months, on a single-blind basis. (The other 44 patients withdrew mainly because of side effects, relapse, and loss to follow-up.)

Patients in the long-term therapy group stayed on the drug for a median of 96 months. The decision about specifically when to stop in this group was guided by thyroid function test results and patients’ clinical status and preferences, according to Dr. Azizi.

The rate of relapse at 48 months after stopping methimazole was 51% among patients in the short-term therapy group but just 16% among patients in the long-term therapy group (P less than or equal to .001). “Definitely, this looks like a cure of the disease if we consider this very low incidence of relapse,” he commented.

Within the group treated long term, patients who did and did not experience relapse were statistically indistinguishable with respect to temporal trends in levels of triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid-stimulating hormone receptor antibody (TRAb).

Additionally, the daily dose of methimazole therapy required to maintain TSH levels in the normal range fell similarly over time, to about half the initial dose, regardless of whether patients had a relapse or not.

“At the end of treatment, the majority of patients were taking less than 5 mg/day of methimazole,” Dr. Azizi reported. “Some patients needed only two or three pills of 5-mg methimazole per week, and this is very interesting to know, that after you continue, you have definitely more response to methimazole.”

Multivariate analyses showed that in the short-term therapy group, risk factors for relapse were age, sex, and end-of-therapy levels of T3, TSH, and TRAb. In the long-term therapy group, risk factors were end-of-therapy levels of free T4 and TSH.

“We are currently performing more in-depth analysis of genetic markers, including both SNPs [single nucleotide polymorphisms] and HLA [human leukocyte antigen] subtyping on these samples to assess any potential association between relapse rates and genetic background,” Dr. Azizi noted. “However, the problem is the low number of patients who have had a relapse long term.”

During the first 18 months of methimazole therapy, 16 patients had adverse effects in the first 2 months (14 had cutaneous reactions and 2 had elevation of liver enzymes). However, there were no serious complications, such as agranulocytosis.

“It’s very reassuring that after 18 months, in those who had long-term treatment, we did not see any minor or major complications throughout, up to the 120 months of treatment we have had in some of our patients,” Dr. Azizi commented.

Dr. Azizi disclosed that he had no relevant conflicts of interest.

VICTORIA, B.C. – Adding a nonsteroidal immunosuppressant to steroid therapy improves control of active, moderate-to-severe Graves’ orbitopathy, according to findings from a randomized controlled trial reported at the annual meeting of the American Thyroid Association.

Relative to counterparts given pulsed intravenous methylprednisolone alone, patients also given oral mycophenolate were twice as likely to achieve reduction of their ophthalmic signs and symptoms, first author George J. Kahaly, MD, PhD, reported in a session on behalf of the European Group on Graves’ Orbitopathy (EUGOGO). And the combination was generally safe and well tolerated.

Susan London/Frontline Medical News

“Since there is a clear advantage of combination treatment in response rate, in the absence of contraindication to mycophenolate, patients with active and severe orbitopathy may be considered for combination treatment,” he proposed.

A session attendee noted that a similar recent study from China suggests that mycophenolate monotherapy achieves a very high remission rate in this patient population (Clin Endocrinol (Oxf). 2017;86[2]:247-55). “Why don’t we just go for [mycophenolate] alone? Why keep pushing steroids?” he asked.

Methodology of that study was less rigorous, maintained Dr. Kahaly, who is professor of medicine and endocrinology/metabolism, chief physician of the endocrine outpatient clinic, and director of the thyroid research lab at Gutenberg University Medical Center in Mainz, Germany.

“I would say mycophenolate alone is not a powerful enough treatment to observe a response rate of 70%, 80%, 90%,” he stated. “You need more time. This is a lymphocyte-inhibiting agent, so you need the acute effect of the intravenous steroids at the beginning.”

Session cochair Angela M. Leung, MD, assistant professor of medicine at the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System, commented, “This is an intriguing study with very promising data from an active group of investigators.”

Susan London/Frontline Medical News

At the same time, benefit of add-on mycophenolate remains uncertain, in her opinion. “Clearly, more studies, perhaps longer-duration ones, are needed to assess the true effect and clinical efficacy,” she said.

Introducing the EUGOGO trial, Dr. Kahaly noted that European guidelines recommend intravenous methylprednisolone as first-line therapy for Graves’ orbitopathy that is moderate to severe or sight threatening (Eur Thyroid J. 2016;5:9-26). Some patients, however, do not achieve response on this therapy, and others who do achieve response then go on to experience relapse, underscoring the need for better therapies.

The combination the investigators selected pairs the anti-inflammatory activity of methylprednisolone with the antiproliferative activity of mycophenolate (CellCept), which is mainly used in the transplantation field.

The trial, funded in part by Novartis, was open to patients with Graves’ disease who had been euthyroid for at least 2 months but had untreated, active, moderate-to-severe orbitopathy with involvement of soft tissues and eye muscles. Those with optic neuropathy were excluded.

Patients were randomized to 12 weeks of once-weekly intravenous methylprednisolone either alone or with the addition of 24 weeks of twice-daily oral mycophenolate initiated at the same time.

Blinded observers assessed patients for orbitopathy response, defined as improvement in two or more of six outcome measures (eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and motility) in at least one eye, without deterioration in any of the same measures in either eye.

Results showed that the 24-week rate of response was 71% with methylprednisolone plus mycophenolate and 53% with methylprednisolone alone (odds ratio, 2.16; P = .026).

Dr. Kahaly acknowledged that the rate in the monotherapy group was lower than that in some in past studies and proposed this was due to both a tightening of response criteria and more conservative steroid dosing in recent years.

Benefit was similar across patient subgroups stratified by sex, smoking history, clinical activity score, duration of orbitopathy, and level of antibodies to the thyroid-stimulating hormone receptor.

The group given combination therapy also had a lower 36-week relapse rate, although this difference was not significant (4% vs. 8%; odds ratio, 0.65; P = .613). Quality-of-life scores improved in both the monotherapy group (P = .009) and the combination therapy group (P = .002).

The difference between groups in extent of proptosis was just 1 mm. “This is not enough,” he asserted, noting that teprotumumab, an investigational antibody that inhibits insulin-like growth factor I receptor, was recently found to decrease proptosis in this population by 2.7 mm (N Engl J Med. 2017;376:1748-61). “This is the only drug that has led to a significant decrease of proptosis,” he noted.

“The drugs were well tolerated, and the treatment went smoothly. We didn’t have one single dropout because of drug side effects,” Dr. Kahaly reported.

The incidence of drug-related side effects was 20% with methylprednisolone and 25% with methylprednisolone plus mycophenolate, a nonsignificant difference. In both groups, most side effects were rated as mild or moderate.

Trial limitations included the lack of a placebo control, short duration of follow-up, and missing information about subsequent surgical procedures, such as orbital decompression and squint and lid surgery, acknowledged Dr. Kahaly, who disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – Adding a nonsteroidal immunosuppressant to steroid therapy improves control of active, moderate-to-severe Graves’ orbitopathy, according to findings from a randomized controlled trial reported at the annual meeting of the American Thyroid Association.

Relative to counterparts given pulsed intravenous methylprednisolone alone, patients also given oral mycophenolate were twice as likely to achieve reduction of their ophthalmic signs and symptoms, first author George J. Kahaly, MD, PhD, reported in a session on behalf of the European Group on Graves’ Orbitopathy (EUGOGO). And the combination was generally safe and well tolerated.

Susan London/Frontline Medical News

“Since there is a clear advantage of combination treatment in response rate, in the absence of contraindication to mycophenolate, patients with active and severe orbitopathy may be considered for combination treatment,” he proposed.

A session attendee noted that a similar recent study from China suggests that mycophenolate monotherapy achieves a very high remission rate in this patient population (Clin Endocrinol (Oxf). 2017;86[2]:247-55). “Why don’t we just go for [mycophenolate] alone? Why keep pushing steroids?” he asked.

Methodology of that study was less rigorous, maintained Dr. Kahaly, who is professor of medicine and endocrinology/metabolism, chief physician of the endocrine outpatient clinic, and director of the thyroid research lab at Gutenberg University Medical Center in Mainz, Germany.

“I would say mycophenolate alone is not a powerful enough treatment to observe a response rate of 70%, 80%, 90%,” he stated. “You need more time. This is a lymphocyte-inhibiting agent, so you need the acute effect of the intravenous steroids at the beginning.”

Session cochair Angela M. Leung, MD, assistant professor of medicine at the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System, commented, “This is an intriguing study with very promising data from an active group of investigators.”

Susan London/Frontline Medical News

At the same time, benefit of add-on mycophenolate remains uncertain, in her opinion. “Clearly, more studies, perhaps longer-duration ones, are needed to assess the true effect and clinical efficacy,” she said.

Introducing the EUGOGO trial, Dr. Kahaly noted that European guidelines recommend intravenous methylprednisolone as first-line therapy for Graves’ orbitopathy that is moderate to severe or sight threatening (Eur Thyroid J. 2016;5:9-26). Some patients, however, do not achieve response on this therapy, and others who do achieve response then go on to experience relapse, underscoring the need for better therapies.

The combination the investigators selected pairs the anti-inflammatory activity of methylprednisolone with the antiproliferative activity of mycophenolate (CellCept), which is mainly used in the transplantation field.

The trial, funded in part by Novartis, was open to patients with Graves’ disease who had been euthyroid for at least 2 months but had untreated, active, moderate-to-severe orbitopathy with involvement of soft tissues and eye muscles. Those with optic neuropathy were excluded.

Patients were randomized to 12 weeks of once-weekly intravenous methylprednisolone either alone or with the addition of 24 weeks of twice-daily oral mycophenolate initiated at the same time.

Blinded observers assessed patients for orbitopathy response, defined as improvement in two or more of six outcome measures (eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and motility) in at least one eye, without deterioration in any of the same measures in either eye.

Results showed that the 24-week rate of response was 71% with methylprednisolone plus mycophenolate and 53% with methylprednisolone alone (odds ratio, 2.16; P = .026).

Dr. Kahaly acknowledged that the rate in the monotherapy group was lower than that in some in past studies and proposed this was due to both a tightening of response criteria and more conservative steroid dosing in recent years.

Benefit was similar across patient subgroups stratified by sex, smoking history, clinical activity score, duration of orbitopathy, and level of antibodies to the thyroid-stimulating hormone receptor.

The group given combination therapy also had a lower 36-week relapse rate, although this difference was not significant (4% vs. 8%; odds ratio, 0.65; P = .613). Quality-of-life scores improved in both the monotherapy group (P = .009) and the combination therapy group (P = .002).

The difference between groups in extent of proptosis was just 1 mm. “This is not enough,” he asserted, noting that teprotumumab, an investigational antibody that inhibits insulin-like growth factor I receptor, was recently found to decrease proptosis in this population by 2.7 mm (N Engl J Med. 2017;376:1748-61). “This is the only drug that has led to a significant decrease of proptosis,” he noted.

“The drugs were well tolerated, and the treatment went smoothly. We didn’t have one single dropout because of drug side effects,” Dr. Kahaly reported.

The incidence of drug-related side effects was 20% with methylprednisolone and 25% with methylprednisolone plus mycophenolate, a nonsignificant difference. In both groups, most side effects were rated as mild or moderate.

Trial limitations included the lack of a placebo control, short duration of follow-up, and missing information about subsequent surgical procedures, such as orbital decompression and squint and lid surgery, acknowledged Dr. Kahaly, who disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – Adding a nonsteroidal immunosuppressant to steroid therapy improves control of active, moderate-to-severe Graves’ orbitopathy, according to findings from a randomized controlled trial reported at the annual meeting of the American Thyroid Association.

Relative to counterparts given pulsed intravenous methylprednisolone alone, patients also given oral mycophenolate were twice as likely to achieve reduction of their ophthalmic signs and symptoms, first author George J. Kahaly, MD, PhD, reported in a session on behalf of the European Group on Graves’ Orbitopathy (EUGOGO). And the combination was generally safe and well tolerated.

Susan London/Frontline Medical News

“Since there is a clear advantage of combination treatment in response rate, in the absence of contraindication to mycophenolate, patients with active and severe orbitopathy may be considered for combination treatment,” he proposed.

A session attendee noted that a similar recent study from China suggests that mycophenolate monotherapy achieves a very high remission rate in this patient population (Clin Endocrinol (Oxf). 2017;86[2]:247-55). “Why don’t we just go for [mycophenolate] alone? Why keep pushing steroids?” he asked.

Methodology of that study was less rigorous, maintained Dr. Kahaly, who is professor of medicine and endocrinology/metabolism, chief physician of the endocrine outpatient clinic, and director of the thyroid research lab at Gutenberg University Medical Center in Mainz, Germany.

“I would say mycophenolate alone is not a powerful enough treatment to observe a response rate of 70%, 80%, 90%,” he stated. “You need more time. This is a lymphocyte-inhibiting agent, so you need the acute effect of the intravenous steroids at the beginning.”

Session cochair Angela M. Leung, MD, assistant professor of medicine at the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System, commented, “This is an intriguing study with very promising data from an active group of investigators.”

Susan London/Frontline Medical News

At the same time, benefit of add-on mycophenolate remains uncertain, in her opinion. “Clearly, more studies, perhaps longer-duration ones, are needed to assess the true effect and clinical efficacy,” she said.

Introducing the EUGOGO trial, Dr. Kahaly noted that European guidelines recommend intravenous methylprednisolone as first-line therapy for Graves’ orbitopathy that is moderate to severe or sight threatening (Eur Thyroid J. 2016;5:9-26). Some patients, however, do not achieve response on this therapy, and others who do achieve response then go on to experience relapse, underscoring the need for better therapies.

The combination the investigators selected pairs the anti-inflammatory activity of methylprednisolone with the antiproliferative activity of mycophenolate (CellCept), which is mainly used in the transplantation field.

The trial, funded in part by Novartis, was open to patients with Graves’ disease who had been euthyroid for at least 2 months but had untreated, active, moderate-to-severe orbitopathy with involvement of soft tissues and eye muscles. Those with optic neuropathy were excluded.

Patients were randomized to 12 weeks of once-weekly intravenous methylprednisolone either alone or with the addition of 24 weeks of twice-daily oral mycophenolate initiated at the same time.

Blinded observers assessed patients for orbitopathy response, defined as improvement in two or more of six outcome measures (eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and motility) in at least one eye, without deterioration in any of the same measures in either eye.

Results showed that the 24-week rate of response was 71% with methylprednisolone plus mycophenolate and 53% with methylprednisolone alone (odds ratio, 2.16; P = .026).

Dr. Kahaly acknowledged that the rate in the monotherapy group was lower than that in some in past studies and proposed this was due to both a tightening of response criteria and more conservative steroid dosing in recent years.

Benefit was similar across patient subgroups stratified by sex, smoking history, clinical activity score, duration of orbitopathy, and level of antibodies to the thyroid-stimulating hormone receptor.

The group given combination therapy also had a lower 36-week relapse rate, although this difference was not significant (4% vs. 8%; odds ratio, 0.65; P = .613). Quality-of-life scores improved in both the monotherapy group (P = .009) and the combination therapy group (P = .002).

The difference between groups in extent of proptosis was just 1 mm. “This is not enough,” he asserted, noting that teprotumumab, an investigational antibody that inhibits insulin-like growth factor I receptor, was recently found to decrease proptosis in this population by 2.7 mm (N Engl J Med. 2017;376:1748-61). “This is the only drug that has led to a significant decrease of proptosis,” he noted.

“The drugs were well tolerated, and the treatment went smoothly. We didn’t have one single dropout because of drug side effects,” Dr. Kahaly reported.

The incidence of drug-related side effects was 20% with methylprednisolone and 25% with methylprednisolone plus mycophenolate, a nonsignificant difference. In both groups, most side effects were rated as mild or moderate.

Trial limitations included the lack of a placebo control, short duration of follow-up, and missing information about subsequent surgical procedures, such as orbital decompression and squint and lid surgery, acknowledged Dr. Kahaly, who disclosed that he had no relevant conflicts of interest.

 

VICTORIA, B.C. – Thyroid hormone therapy works no better than placebo for making older adults with subclinical hypothyroidism feel better, even when they have a higher symptom burden, according to findings from a study reported at the annual meeting of the American Thyroid Association.

“In the U.S., individuals are frequently treated either for just a number – just because their thyroid-stimulating hormone (TSH) is elevated – or for nonspecific hypothyroid-type symptoms, such as weight gain, cold intolerance, and such. It’s extremely common,” lead investigator Douglas Bauer, MD, professor and internist at the University of California, San Francisco, commented in an interview.

Susan London/Frontline Medical News

“On average, this study suggests that you shouldn’t be using hypothyroid-type symptomatology to treat subclinical hypothyroidism,” he said, while also acknowledging that not writing that prescription can be challenging. “It’s hard to do nothing, I know.”

Dr. Bauer and his coinvestigators performed a subgroup analysis of the randomized controlled TRUST trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism), conducted in Switzerland, Ireland, the Netherlands, and the United Kingdom. In the trial, 737 adults aged 65 years or older with persistent subclinical hypothyroidism (TSH level, 4.60-19.99 mIU/L, with normal free thyroxine level) were given either levothyroxine or placebo on a double-blind basis.

Results for the entire trial population, previously reported, showed that at 1 year, patient-reported symptoms on a thyroid-specific quality-of-life questionnaire had improved by a similar extent in both groups, with no significant differences between them (N Engl J Med. 2017;376:2534-44).

The new analysis focused on two subgroups that might be especially expected to benefit: 132 patients with a hypothyroid symptoms score greater than 30 on a 100-point scale and 209 patients with a tiredness score greater than 30 on a 100-point scale.

Results reported in a poster session showed that at 1 year, scores had improved by about 10 points with levothyroxine and placebo alike, with no significant difference, in both the group with higher hypothyroid symptoms scores (P = .90) and the group with higher tiredness scores (P = .80).

“This provides additional evidence that it’s unlikely that the treatment of subclinical hypothyroidism, at least in this population, is going to lead to symptomatic improvement,” Dr. Bauer commented.

“I would speculate that we’ve overestimated the benefit [of thyroid hormone therapy] on symptoms based on the fact that previous studies haven’t been blinded,” he said, noting that the TRUST trial used a rigorous blinding protocol, even going so far as to change the appearance of placebo pills to convince patients in the placebo group that their dose was being titrated.

A potential criticism is that the treatment was not aggressive enough, with patients in the levothyroxine group achieving a mean TSH level of 3.6 mIU/L, according to Dr. Bauer. “I think many people treating with thyroxine would like to see this TSH fall into the 2 mIU/L to 3 mIU/L range,” he acknowledged.

Taken together, the trial’s overall and subgroup findings do not rule out potential benefit for certain patients, he cautioned. For example, patients with very high symptom burden and patients with baseline TSH levels greater than 10 mIU/L were too few for separate analysis, and younger adults were not included at all.

Additionally, treatment impact on other important clinical outcomes – cardiovascular events and fractures – could not be assessed in TRUST because of insufficient enrollment.

Dr. Bauer disclosed that he had no relevant conflicts of interest. The trial was funded by the European Union, Swiss National Science Foundation, Swiss Heart Foundation, and Velux Stiftung. Merck supplied study drug.

VICTORIA, B.C. – Thyroid hormone therapy works no better than placebo for making older adults with subclinical hypothyroidism feel better, even when they have a higher symptom burden, according to findings from a study reported at the annual meeting of the American Thyroid Association.

“In the U.S., individuals are frequently treated either for just a number – just because their thyroid-stimulating hormone (TSH) is elevated – or for nonspecific hypothyroid-type symptoms, such as weight gain, cold intolerance, and such. It’s extremely common,” lead investigator Douglas Bauer, MD, professor and internist at the University of California, San Francisco, commented in an interview.

Susan London/Frontline Medical News

“On average, this study suggests that you shouldn’t be using hypothyroid-type symptomatology to treat subclinical hypothyroidism,” he said, while also acknowledging that not writing that prescription can be challenging. “It’s hard to do nothing, I know.”

Dr. Bauer and his coinvestigators performed a subgroup analysis of the randomized controlled TRUST trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism), conducted in Switzerland, Ireland, the Netherlands, and the United Kingdom. In the trial, 737 adults aged 65 years or older with persistent subclinical hypothyroidism (TSH level, 4.60-19.99 mIU/L, with normal free thyroxine level) were given either levothyroxine or placebo on a double-blind basis.

Results for the entire trial population, previously reported, showed that at 1 year, patient-reported symptoms on a thyroid-specific quality-of-life questionnaire had improved by a similar extent in both groups, with no significant differences between them (N Engl J Med. 2017;376:2534-44).

The new analysis focused on two subgroups that might be especially expected to benefit: 132 patients with a hypothyroid symptoms score greater than 30 on a 100-point scale and 209 patients with a tiredness score greater than 30 on a 100-point scale.

Results reported in a poster session showed that at 1 year, scores had improved by about 10 points with levothyroxine and placebo alike, with no significant difference, in both the group with higher hypothyroid symptoms scores (P = .90) and the group with higher tiredness scores (P = .80).

“This provides additional evidence that it’s unlikely that the treatment of subclinical hypothyroidism, at least in this population, is going to lead to symptomatic improvement,” Dr. Bauer commented.

“I would speculate that we’ve overestimated the benefit [of thyroid hormone therapy] on symptoms based on the fact that previous studies haven’t been blinded,” he said, noting that the TRUST trial used a rigorous blinding protocol, even going so far as to change the appearance of placebo pills to convince patients in the placebo group that their dose was being titrated.

A potential criticism is that the treatment was not aggressive enough, with patients in the levothyroxine group achieving a mean TSH level of 3.6 mIU/L, according to Dr. Bauer. “I think many people treating with thyroxine would like to see this TSH fall into the 2 mIU/L to 3 mIU/L range,” he acknowledged.

Taken together, the trial’s overall and subgroup findings do not rule out potential benefit for certain patients, he cautioned. For example, patients with very high symptom burden and patients with baseline TSH levels greater than 10 mIU/L were too few for separate analysis, and younger adults were not included at all.

Additionally, treatment impact on other important clinical outcomes – cardiovascular events and fractures – could not be assessed in TRUST because of insufficient enrollment.

Dr. Bauer disclosed that he had no relevant conflicts of interest. The trial was funded by the European Union, Swiss National Science Foundation, Swiss Heart Foundation, and Velux Stiftung. Merck supplied study drug.

VICTORIA, B.C. – Thyroid hormone therapy works no better than placebo for making older adults with subclinical hypothyroidism feel better, even when they have a higher symptom burden, according to findings from a study reported at the annual meeting of the American Thyroid Association.

“In the U.S., individuals are frequently treated either for just a number – just because their thyroid-stimulating hormone (TSH) is elevated – or for nonspecific hypothyroid-type symptoms, such as weight gain, cold intolerance, and such. It’s extremely common,” lead investigator Douglas Bauer, MD, professor and internist at the University of California, San Francisco, commented in an interview.

Susan London/Frontline Medical News

“On average, this study suggests that you shouldn’t be using hypothyroid-type symptomatology to treat subclinical hypothyroidism,” he said, while also acknowledging that not writing that prescription can be challenging. “It’s hard to do nothing, I know.”

Dr. Bauer and his coinvestigators performed a subgroup analysis of the randomized controlled TRUST trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism), conducted in Switzerland, Ireland, the Netherlands, and the United Kingdom. In the trial, 737 adults aged 65 years or older with persistent subclinical hypothyroidism (TSH level, 4.60-19.99 mIU/L, with normal free thyroxine level) were given either levothyroxine or placebo on a double-blind basis.

Results for the entire trial population, previously reported, showed that at 1 year, patient-reported symptoms on a thyroid-specific quality-of-life questionnaire had improved by a similar extent in both groups, with no significant differences between them (N Engl J Med. 2017;376:2534-44).

The new analysis focused on two subgroups that might be especially expected to benefit: 132 patients with a hypothyroid symptoms score greater than 30 on a 100-point scale and 209 patients with a tiredness score greater than 30 on a 100-point scale.

Results reported in a poster session showed that at 1 year, scores had improved by about 10 points with levothyroxine and placebo alike, with no significant difference, in both the group with higher hypothyroid symptoms scores (P = .90) and the group with higher tiredness scores (P = .80).

“This provides additional evidence that it’s unlikely that the treatment of subclinical hypothyroidism, at least in this population, is going to lead to symptomatic improvement,” Dr. Bauer commented.

“I would speculate that we’ve overestimated the benefit [of thyroid hormone therapy] on symptoms based on the fact that previous studies haven’t been blinded,” he said, noting that the TRUST trial used a rigorous blinding protocol, even going so far as to change the appearance of placebo pills to convince patients in the placebo group that their dose was being titrated.

A potential criticism is that the treatment was not aggressive enough, with patients in the levothyroxine group achieving a mean TSH level of 3.6 mIU/L, according to Dr. Bauer. “I think many people treating with thyroxine would like to see this TSH fall into the 2 mIU/L to 3 mIU/L range,” he acknowledged.

Taken together, the trial’s overall and subgroup findings do not rule out potential benefit for certain patients, he cautioned. For example, patients with very high symptom burden and patients with baseline TSH levels greater than 10 mIU/L were too few for separate analysis, and younger adults were not included at all.

Additionally, treatment impact on other important clinical outcomes – cardiovascular events and fractures – could not be assessed in TRUST because of insufficient enrollment.

Dr. Bauer disclosed that he had no relevant conflicts of interest. The trial was funded by the European Union, Swiss National Science Foundation, Swiss Heart Foundation, and Velux Stiftung. Merck supplied study drug.