Pituitary, Thyroid & Adrenal Disorders

LAKE BUENA VISTA, FLA. – In contrast with at least two prior small studies, thyroid peroxidase autoantibodies were not associated with breast cancer outcomes in a large cohort of patients.

Stored serum samples from 1,974 patients with lymph node–positive or high-risk lymph node–negative breast cancer who were enrolled in the TACT (Taxotere as Adjuvant Chemotherapy for Early Breast Cancer) trial were tested, and investigators assessed the prognostic significance of thyroid peroxidase autoantibodies (TPOAb) and thyroid function for disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR).

At a median follow-up of 97.5 months, investigators found no evidence of a difference in outcomes, either on univariate or multivariable analysis, for any of those outcomes based on free thyroxine (FT4) or thyroid-stimulating hormone (TSH) levels alone or in combination as hypo- or hyperthyroidism, Dr. Ilaria Muller, of Cardiff (England) University reported at the International Thyroid Congress.

For example, the unadjusted hazard ratios for DFS, OS, and TTR based on TPOAb-positive vs. TPOAb-negative status were 0.97, 0.86, and 0.97, respectively, Dr. Muller said.

An explorative multivariable analysis of the impact of TPOab status and thyroid function on breast cancer DFS, OS, and TTR also showed no evidence of a difference (HR, 1 and 0.97 for TPOAb-negative and TPOAb-positive status; HR, 1 and 1.27 for euthyroid and hypothyroid status), Dr. Muller said.

Similarly, no evidence of a difference in outcomes was seen based on an explorative analysis of TPOAb status in clinical subgroups based on age, nodal status, tumor grade, tumor size, type of surgery, estrogen receptor (ER)-positive status, human epidermal growth factor receptor 2 (HER2)-positive status, and molecular subgroup, she noted.

Serum samples used in the study were from patients who had undergone breast cancer surgery a mean of 15.5 months prior and were mainly taken during/after adjuvant treatments for breast cancer. All had received chemotherapy: 88.4% received radiotherapy, 98.7% of ER-positive patients received hormonal therapy, and trastuzumab was given in 11.8% of HER2-positive patients.

About a fifth (20.6%) of patients were TPOAb-positive, 89.16% were euthyroid, 4.86% were hypothyroid, and 5.97% were hyperthyroid.

The TPOAb-positive and -negative patients were largely comparable, except the TPOAb-positive women were slightly older.

A sensitivity analysis performed in 123 patients with blood taken after surgery but before any adjuvant therapy for breast cancer also showed no evidence of TPOAb prognostic ability, Dr. Muller said.

Despite an ongoing debate aabout a possible association between breast cancer and thyroid autoimmunity, findings have been conflicting. Two small studies correlated TPOAb positivity with improved breast cancer outcomes, but a third did not confirm the findings.

“As a possible explanation, we hypothesized an immune response to shared thyroid/breast antigens. We recently reported that TPO is expressed in breast cancer tissue,” Dr. Muller wrote.

However, the findings of the current study – the largest retrospective study to date investigating the prognostic role of TPOAb in breast cancer – suggest that TPOAb and thyroid function are not prognostic markers in breast cancer.

“Effects of chemotherapy and/or radiotherapy for breast cancer are currently under debate. Tamoxifen exerts an antithyroid effect. However, confounding due to breast cancer adjuvant treatment is unlikely to alter significantly any results, as suggested by our sensitivity analysis performed on 123 patients,” she said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association , European Thyroid Association, and Latin American Thyroid Society.

This study was supported by a Tenovus Innovation Grant from Tenovus Cancer Care. TACT was funded by Cancer Research UK. Dr. Muller reported having no disclosures.

sworcester@frontlinemedcom.com

LAKE BUENA VISTA, FLA. – In contrast with at least two prior small studies, thyroid peroxidase autoantibodies were not associated with breast cancer outcomes in a large cohort of patients.

Stored serum samples from 1,974 patients with lymph node–positive or high-risk lymph node–negative breast cancer who were enrolled in the TACT (Taxotere as Adjuvant Chemotherapy for Early Breast Cancer) trial were tested, and investigators assessed the prognostic significance of thyroid peroxidase autoantibodies (TPOAb) and thyroid function for disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR).

At a median follow-up of 97.5 months, investigators found no evidence of a difference in outcomes, either on univariate or multivariable analysis, for any of those outcomes based on free thyroxine (FT4) or thyroid-stimulating hormone (TSH) levels alone or in combination as hypo- or hyperthyroidism, Dr. Ilaria Muller, of Cardiff (England) University reported at the International Thyroid Congress.

For example, the unadjusted hazard ratios for DFS, OS, and TTR based on TPOAb-positive vs. TPOAb-negative status were 0.97, 0.86, and 0.97, respectively, Dr. Muller said.

An explorative multivariable analysis of the impact of TPOab status and thyroid function on breast cancer DFS, OS, and TTR also showed no evidence of a difference (HR, 1 and 0.97 for TPOAb-negative and TPOAb-positive status; HR, 1 and 1.27 for euthyroid and hypothyroid status), Dr. Muller said.

Similarly, no evidence of a difference in outcomes was seen based on an explorative analysis of TPOAb status in clinical subgroups based on age, nodal status, tumor grade, tumor size, type of surgery, estrogen receptor (ER)-positive status, human epidermal growth factor receptor 2 (HER2)-positive status, and molecular subgroup, she noted.

Serum samples used in the study were from patients who had undergone breast cancer surgery a mean of 15.5 months prior and were mainly taken during/after adjuvant treatments for breast cancer. All had received chemotherapy: 88.4% received radiotherapy, 98.7% of ER-positive patients received hormonal therapy, and trastuzumab was given in 11.8% of HER2-positive patients.

About a fifth (20.6%) of patients were TPOAb-positive, 89.16% were euthyroid, 4.86% were hypothyroid, and 5.97% were hyperthyroid.

The TPOAb-positive and -negative patients were largely comparable, except the TPOAb-positive women were slightly older.

A sensitivity analysis performed in 123 patients with blood taken after surgery but before any adjuvant therapy for breast cancer also showed no evidence of TPOAb prognostic ability, Dr. Muller said.

Despite an ongoing debate aabout a possible association between breast cancer and thyroid autoimmunity, findings have been conflicting. Two small studies correlated TPOAb positivity with improved breast cancer outcomes, but a third did not confirm the findings.

“As a possible explanation, we hypothesized an immune response to shared thyroid/breast antigens. We recently reported that TPO is expressed in breast cancer tissue,” Dr. Muller wrote.

However, the findings of the current study – the largest retrospective study to date investigating the prognostic role of TPOAb in breast cancer – suggest that TPOAb and thyroid function are not prognostic markers in breast cancer.

“Effects of chemotherapy and/or radiotherapy for breast cancer are currently under debate. Tamoxifen exerts an antithyroid effect. However, confounding due to breast cancer adjuvant treatment is unlikely to alter significantly any results, as suggested by our sensitivity analysis performed on 123 patients,” she said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association , European Thyroid Association, and Latin American Thyroid Society.

This study was supported by a Tenovus Innovation Grant from Tenovus Cancer Care. TACT was funded by Cancer Research UK. Dr. Muller reported having no disclosures.

sworcester@frontlinemedcom.com

LAKE BUENA VISTA, FLA. – In contrast with at least two prior small studies, thyroid peroxidase autoantibodies were not associated with breast cancer outcomes in a large cohort of patients.

Stored serum samples from 1,974 patients with lymph node–positive or high-risk lymph node–negative breast cancer who were enrolled in the TACT (Taxotere as Adjuvant Chemotherapy for Early Breast Cancer) trial were tested, and investigators assessed the prognostic significance of thyroid peroxidase autoantibodies (TPOAb) and thyroid function for disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR).

At a median follow-up of 97.5 months, investigators found no evidence of a difference in outcomes, either on univariate or multivariable analysis, for any of those outcomes based on free thyroxine (FT4) or thyroid-stimulating hormone (TSH) levels alone or in combination as hypo- or hyperthyroidism, Dr. Ilaria Muller, of Cardiff (England) University reported at the International Thyroid Congress.

For example, the unadjusted hazard ratios for DFS, OS, and TTR based on TPOAb-positive vs. TPOAb-negative status were 0.97, 0.86, and 0.97, respectively, Dr. Muller said.

An explorative multivariable analysis of the impact of TPOab status and thyroid function on breast cancer DFS, OS, and TTR also showed no evidence of a difference (HR, 1 and 0.97 for TPOAb-negative and TPOAb-positive status; HR, 1 and 1.27 for euthyroid and hypothyroid status), Dr. Muller said.

Similarly, no evidence of a difference in outcomes was seen based on an explorative analysis of TPOAb status in clinical subgroups based on age, nodal status, tumor grade, tumor size, type of surgery, estrogen receptor (ER)-positive status, human epidermal growth factor receptor 2 (HER2)-positive status, and molecular subgroup, she noted.

Serum samples used in the study were from patients who had undergone breast cancer surgery a mean of 15.5 months prior and were mainly taken during/after adjuvant treatments for breast cancer. All had received chemotherapy: 88.4% received radiotherapy, 98.7% of ER-positive patients received hormonal therapy, and trastuzumab was given in 11.8% of HER2-positive patients.

About a fifth (20.6%) of patients were TPOAb-positive, 89.16% were euthyroid, 4.86% were hypothyroid, and 5.97% were hyperthyroid.

The TPOAb-positive and -negative patients were largely comparable, except the TPOAb-positive women were slightly older.

A sensitivity analysis performed in 123 patients with blood taken after surgery but before any adjuvant therapy for breast cancer also showed no evidence of TPOAb prognostic ability, Dr. Muller said.

Despite an ongoing debate aabout a possible association between breast cancer and thyroid autoimmunity, findings have been conflicting. Two small studies correlated TPOAb positivity with improved breast cancer outcomes, but a third did not confirm the findings.

“As a possible explanation, we hypothesized an immune response to shared thyroid/breast antigens. We recently reported that TPO is expressed in breast cancer tissue,” Dr. Muller wrote.

However, the findings of the current study – the largest retrospective study to date investigating the prognostic role of TPOAb in breast cancer – suggest that TPOAb and thyroid function are not prognostic markers in breast cancer.

“Effects of chemotherapy and/or radiotherapy for breast cancer are currently under debate. Tamoxifen exerts an antithyroid effect. However, confounding due to breast cancer adjuvant treatment is unlikely to alter significantly any results, as suggested by our sensitivity analysis performed on 123 patients,” she said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association , European Thyroid Association, and Latin American Thyroid Society.

This study was supported by a Tenovus Innovation Grant from Tenovus Cancer Care. TACT was funded by Cancer Research UK. Dr. Muller reported having no disclosures.

sworcester@frontlinemedcom.com

LAKE BUENA VISTA, FLA. – A scoring system for ultrasound evaluation of thyroid nodules is useful in predicting malignancy in cases of atypia of unknown significance but is less useful for nodules categorized as follicular lesions of undetermined significance.

Dr. Jung Hyun Soon, a radiologist at Severance Hospital, Yonsei University, Seoul, presented these findings at the International Thyroid Congress.

The atypia of unknown significance (AUS) and follicular lesion of undetermined significance (FLUS) subcategories within the Bethesda cytopathology system carry a 5%-15% risk of malignancy. The Bethesda system for assessing fine-needle aspirate (FNA) helps to identify more precisely “the different patterns of atypia associated with higher malignancy risk, and to enable adequate malignancy risk stratification of thyroid nodules,” said Dr. Yoon.

Ultrasonography also contributes to the prediction of malignancy, and the Thyroid Imaging Reporting and Data System (TIRADS) provides a framework to report and score imaging assessment of thyroid nodules. The number of suspicious features is tallied and a TIRADS score is assigned according to the sum: possible scores are 3, 4a, 4b, 4c, or 5, according to number of abnormalities. Categories of abnormalities that are scored include composition, echogenicity, margin characteristics, calcifications, and shape.

To determine whether TIRADS helps predict which patients with AUS and FLUS will have malignancy, Dr. Yoon and her colleagues enrolled 188 patients with a total 192 AUS or FLUS thyroid nodules whose diagnoses had been confirmed by surgery, sequential ultrasound, or repeat FNA. The patients’ mean age was 50.2 years, and the mean nodule size was 14.7 mm, though nodules ranged from 5 to 60 mm.

Of the 192 AUS/FLUS nodules, 82 (42.7%) were malignant and 110 (57.3%) were benign. Of the 149 nodules (77.6%) that were characterized as AUS, 45.6% were assessed as malignant, while the 43 FLUS nodules (22.4%) had a malignancy rate of 32.6%. This difference in malignancy rates was not statistically significant.

In applying TIRADS scoring to the AUS cytological subcategory, significant differences were seen in TIRADS ratings between malignant and benign nodules (P less than .001). As TIRADS scores increased, so did the likelihood of malignancy: only 15.4% of TIRADS 3 AUS nodules were malignant, while, for TIRADS 5 AUS nodules, the probability of malignancy was 80%. Intermediate values carried increasing risk. These differences were not seen, however, for FLUS nodules (P = .414).

“Suspicious ultrasound features are useful in predicting malignancy among the AUS subcategory but not in the FLUS subcategory,” Dr. Yoon said in summarizing her findings at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

She noted several study limitations, including the inherent selection bias in the study’s retrospective nature and the fact that AUS and FLUS are not universally accepted subcategories. Additionally, uniform diagnosis could not be assured since five cytopathologists made the original diagnoses from the FNA samples.

Dr. Yoon and her investigators reported no relevant disclosures.

koakes@frontlinemedcom.com

On Twitter @karioakes

LAKE BUENA VISTA, FLA. – A scoring system for ultrasound evaluation of thyroid nodules is useful in predicting malignancy in cases of atypia of unknown significance but is less useful for nodules categorized as follicular lesions of undetermined significance.

Dr. Jung Hyun Soon, a radiologist at Severance Hospital, Yonsei University, Seoul, presented these findings at the International Thyroid Congress.

The atypia of unknown significance (AUS) and follicular lesion of undetermined significance (FLUS) subcategories within the Bethesda cytopathology system carry a 5%-15% risk of malignancy. The Bethesda system for assessing fine-needle aspirate (FNA) helps to identify more precisely “the different patterns of atypia associated with higher malignancy risk, and to enable adequate malignancy risk stratification of thyroid nodules,” said Dr. Yoon.

Ultrasonography also contributes to the prediction of malignancy, and the Thyroid Imaging Reporting and Data System (TIRADS) provides a framework to report and score imaging assessment of thyroid nodules. The number of suspicious features is tallied and a TIRADS score is assigned according to the sum: possible scores are 3, 4a, 4b, 4c, or 5, according to number of abnormalities. Categories of abnormalities that are scored include composition, echogenicity, margin characteristics, calcifications, and shape.

To determine whether TIRADS helps predict which patients with AUS and FLUS will have malignancy, Dr. Yoon and her colleagues enrolled 188 patients with a total 192 AUS or FLUS thyroid nodules whose diagnoses had been confirmed by surgery, sequential ultrasound, or repeat FNA. The patients’ mean age was 50.2 years, and the mean nodule size was 14.7 mm, though nodules ranged from 5 to 60 mm.

Of the 192 AUS/FLUS nodules, 82 (42.7%) were malignant and 110 (57.3%) were benign. Of the 149 nodules (77.6%) that were characterized as AUS, 45.6% were assessed as malignant, while the 43 FLUS nodules (22.4%) had a malignancy rate of 32.6%. This difference in malignancy rates was not statistically significant.

In applying TIRADS scoring to the AUS cytological subcategory, significant differences were seen in TIRADS ratings between malignant and benign nodules (P less than .001). As TIRADS scores increased, so did the likelihood of malignancy: only 15.4% of TIRADS 3 AUS nodules were malignant, while, for TIRADS 5 AUS nodules, the probability of malignancy was 80%. Intermediate values carried increasing risk. These differences were not seen, however, for FLUS nodules (P = .414).

“Suspicious ultrasound features are useful in predicting malignancy among the AUS subcategory but not in the FLUS subcategory,” Dr. Yoon said in summarizing her findings at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

She noted several study limitations, including the inherent selection bias in the study’s retrospective nature and the fact that AUS and FLUS are not universally accepted subcategories. Additionally, uniform diagnosis could not be assured since five cytopathologists made the original diagnoses from the FNA samples.

Dr. Yoon and her investigators reported no relevant disclosures.

koakes@frontlinemedcom.com

On Twitter @karioakes

LAKE BUENA VISTA, FLA. – A scoring system for ultrasound evaluation of thyroid nodules is useful in predicting malignancy in cases of atypia of unknown significance but is less useful for nodules categorized as follicular lesions of undetermined significance.

Dr. Jung Hyun Soon, a radiologist at Severance Hospital, Yonsei University, Seoul, presented these findings at the International Thyroid Congress.

The atypia of unknown significance (AUS) and follicular lesion of undetermined significance (FLUS) subcategories within the Bethesda cytopathology system carry a 5%-15% risk of malignancy. The Bethesda system for assessing fine-needle aspirate (FNA) helps to identify more precisely “the different patterns of atypia associated with higher malignancy risk, and to enable adequate malignancy risk stratification of thyroid nodules,” said Dr. Yoon.

Ultrasonography also contributes to the prediction of malignancy, and the Thyroid Imaging Reporting and Data System (TIRADS) provides a framework to report and score imaging assessment of thyroid nodules. The number of suspicious features is tallied and a TIRADS score is assigned according to the sum: possible scores are 3, 4a, 4b, 4c, or 5, according to number of abnormalities. Categories of abnormalities that are scored include composition, echogenicity, margin characteristics, calcifications, and shape.

To determine whether TIRADS helps predict which patients with AUS and FLUS will have malignancy, Dr. Yoon and her colleagues enrolled 188 patients with a total 192 AUS or FLUS thyroid nodules whose diagnoses had been confirmed by surgery, sequential ultrasound, or repeat FNA. The patients’ mean age was 50.2 years, and the mean nodule size was 14.7 mm, though nodules ranged from 5 to 60 mm.

Of the 192 AUS/FLUS nodules, 82 (42.7%) were malignant and 110 (57.3%) were benign. Of the 149 nodules (77.6%) that were characterized as AUS, 45.6% were assessed as malignant, while the 43 FLUS nodules (22.4%) had a malignancy rate of 32.6%. This difference in malignancy rates was not statistically significant.

In applying TIRADS scoring to the AUS cytological subcategory, significant differences were seen in TIRADS ratings between malignant and benign nodules (P less than .001). As TIRADS scores increased, so did the likelihood of malignancy: only 15.4% of TIRADS 3 AUS nodules were malignant, while, for TIRADS 5 AUS nodules, the probability of malignancy was 80%. Intermediate values carried increasing risk. These differences were not seen, however, for FLUS nodules (P = .414).

“Suspicious ultrasound features are useful in predicting malignancy among the AUS subcategory but not in the FLUS subcategory,” Dr. Yoon said in summarizing her findings at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

She noted several study limitations, including the inherent selection bias in the study’s retrospective nature and the fact that AUS and FLUS are not universally accepted subcategories. Additionally, uniform diagnosis could not be assured since five cytopathologists made the original diagnoses from the FNA samples.

Dr. Yoon and her investigators reported no relevant disclosures.

koakes@frontlinemedcom.com

On Twitter @karioakes

LAKE BUENA VISTA, Fla. – The tyrosine kinase inhibitor cabozantinib significantly extended overall survival for patients with RET-M918T–positive medullary thyroid cancer.

The placebo-controlled EXAM trial did not show any significant differences in overall survival among the entire group, Dr. Steven Sherman said at the International Thyroid Congress. But in a subgroup analysis, those with RET-M918T mutations who received the drug had the best outcomes by far, with a mean overall survival 2 years longer than that of similar patients who received placebo (44 vs. 19 months; HR 0.60; P = .026).

Cabozantinib (COMETRIQ) delivers a three-way punch to thyroid tumors, said Dr. Sherman of MD Anderson Cancer Center, Houston. It inhibits tyrosine kinase, vascular endothelial growth factor receptors, and mutant RET. But EXAM does not provide any clues about the exact mechanism by which it subdued this particular class of tumors.

“We may well be targeting mutant RET as well as tyrosine kinase and VEGF-R. But the other possibility is that these RET tumors are highly dependent on VEGF for angiogenesis and that inhibiting that is the key element. The data from this study don’t allow us to speculate on which is the most important,” said Dr. Sherman.

The 2-year trial randomized 330 patients with progressive medullary thyroid cancer to cabozantinib (140 mg per day) or placebo. If patients taking placebo progressed, they were not allowed to cross over to cabozantimib. The primary endpoint was progression-free survival (PFS); results were published in 2013 in the Journal of Clinical Oncology (doi: 10.1200/JCO.2012.48.4659).

Dr. Sherman presented the final results on overall survival at the meeting, which was held by the American Thyroid Association, Asia-Oceania Thyroid Association , European Thyroid Association, and Latin American Thyroid Society.

Almost half of the cohort had received prior therapy, and 21%, a prior tyrosine kinase inhibitor. About half had RET mutations; 12% were RET negative, and genomic status was unknown in the remainder. M918T was the predominant RET mutation (74%). The main sites of metastasis were lymph nodes, liver, lung, and bone.

PFS was significantly better in those taking the study drug (11 vs. 4 months; HR 0.28; P equal to or less than .01). Significant PFS benefits were seen regardless of age, prior treatment, and RET status.

In the overall survival analysis, however, cabozantinib conferred no significant benefit over placebo across the entire cohort (26.6 vs 21 months; HR 0.85; P = .24).

RET mutation profiles were available for 65% of patients. The drug did not confer significant overall survival benefit to all those with RET mutations (31.6 vs. 24.8 months; HR 0.79; P = .24). However, those with the M918T mutation who took cabozantinib survived significantly longer than did those who took placebo.

A small number of patients (16) had RAS mutations, and those who took cabozantinib did have better overall survival than did those who took placebo, although the difference was not statistically significant.

Adverse events were more common in the cabozantinib arm and included pneumonia (4.2%), pulmonary embolism (3.3%), mucosal inflammation (2.8%), hypocalcemia (2.8%), hypertension, dysphagia, dehydration, and lung abscess (2.3% each).

The EXAM study was sponsored by Exelixis. Dr. Sherman had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

LAKE BUENA VISTA, Fla. – The tyrosine kinase inhibitor cabozantinib significantly extended overall survival for patients with RET-M918T–positive medullary thyroid cancer.

The placebo-controlled EXAM trial did not show any significant differences in overall survival among the entire group, Dr. Steven Sherman said at the International Thyroid Congress. But in a subgroup analysis, those with RET-M918T mutations who received the drug had the best outcomes by far, with a mean overall survival 2 years longer than that of similar patients who received placebo (44 vs. 19 months; HR 0.60; P = .026).

Cabozantinib (COMETRIQ) delivers a three-way punch to thyroid tumors, said Dr. Sherman of MD Anderson Cancer Center, Houston. It inhibits tyrosine kinase, vascular endothelial growth factor receptors, and mutant RET. But EXAM does not provide any clues about the exact mechanism by which it subdued this particular class of tumors.

“We may well be targeting mutant RET as well as tyrosine kinase and VEGF-R. But the other possibility is that these RET tumors are highly dependent on VEGF for angiogenesis and that inhibiting that is the key element. The data from this study don’t allow us to speculate on which is the most important,” said Dr. Sherman.

The 2-year trial randomized 330 patients with progressive medullary thyroid cancer to cabozantinib (140 mg per day) or placebo. If patients taking placebo progressed, they were not allowed to cross over to cabozantimib. The primary endpoint was progression-free survival (PFS); results were published in 2013 in the Journal of Clinical Oncology (doi: 10.1200/JCO.2012.48.4659).

Dr. Sherman presented the final results on overall survival at the meeting, which was held by the American Thyroid Association, Asia-Oceania Thyroid Association , European Thyroid Association, and Latin American Thyroid Society.

Almost half of the cohort had received prior therapy, and 21%, a prior tyrosine kinase inhibitor. About half had RET mutations; 12% were RET negative, and genomic status was unknown in the remainder. M918T was the predominant RET mutation (74%). The main sites of metastasis were lymph nodes, liver, lung, and bone.

PFS was significantly better in those taking the study drug (11 vs. 4 months; HR 0.28; P equal to or less than .01). Significant PFS benefits were seen regardless of age, prior treatment, and RET status.

In the overall survival analysis, however, cabozantinib conferred no significant benefit over placebo across the entire cohort (26.6 vs 21 months; HR 0.85; P = .24).

RET mutation profiles were available for 65% of patients. The drug did not confer significant overall survival benefit to all those with RET mutations (31.6 vs. 24.8 months; HR 0.79; P = .24). However, those with the M918T mutation who took cabozantinib survived significantly longer than did those who took placebo.

A small number of patients (16) had RAS mutations, and those who took cabozantinib did have better overall survival than did those who took placebo, although the difference was not statistically significant.

Adverse events were more common in the cabozantinib arm and included pneumonia (4.2%), pulmonary embolism (3.3%), mucosal inflammation (2.8%), hypocalcemia (2.8%), hypertension, dysphagia, dehydration, and lung abscess (2.3% each).

The EXAM study was sponsored by Exelixis. Dr. Sherman had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

LAKE BUENA VISTA, Fla. – The tyrosine kinase inhibitor cabozantinib significantly extended overall survival for patients with RET-M918T–positive medullary thyroid cancer.

The placebo-controlled EXAM trial did not show any significant differences in overall survival among the entire group, Dr. Steven Sherman said at the International Thyroid Congress. But in a subgroup analysis, those with RET-M918T mutations who received the drug had the best outcomes by far, with a mean overall survival 2 years longer than that of similar patients who received placebo (44 vs. 19 months; HR 0.60; P = .026).

Cabozantinib (COMETRIQ) delivers a three-way punch to thyroid tumors, said Dr. Sherman of MD Anderson Cancer Center, Houston. It inhibits tyrosine kinase, vascular endothelial growth factor receptors, and mutant RET. But EXAM does not provide any clues about the exact mechanism by which it subdued this particular class of tumors.

“We may well be targeting mutant RET as well as tyrosine kinase and VEGF-R. But the other possibility is that these RET tumors are highly dependent on VEGF for angiogenesis and that inhibiting that is the key element. The data from this study don’t allow us to speculate on which is the most important,” said Dr. Sherman.

The 2-year trial randomized 330 patients with progressive medullary thyroid cancer to cabozantinib (140 mg per day) or placebo. If patients taking placebo progressed, they were not allowed to cross over to cabozantimib. The primary endpoint was progression-free survival (PFS); results were published in 2013 in the Journal of Clinical Oncology (doi: 10.1200/JCO.2012.48.4659).

Dr. Sherman presented the final results on overall survival at the meeting, which was held by the American Thyroid Association, Asia-Oceania Thyroid Association , European Thyroid Association, and Latin American Thyroid Society.

Almost half of the cohort had received prior therapy, and 21%, a prior tyrosine kinase inhibitor. About half had RET mutations; 12% were RET negative, and genomic status was unknown in the remainder. M918T was the predominant RET mutation (74%). The main sites of metastasis were lymph nodes, liver, lung, and bone.

PFS was significantly better in those taking the study drug (11 vs. 4 months; HR 0.28; P equal to or less than .01). Significant PFS benefits were seen regardless of age, prior treatment, and RET status.

In the overall survival analysis, however, cabozantinib conferred no significant benefit over placebo across the entire cohort (26.6 vs 21 months; HR 0.85; P = .24).

RET mutation profiles were available for 65% of patients. The drug did not confer significant overall survival benefit to all those with RET mutations (31.6 vs. 24.8 months; HR 0.79; P = .24). However, those with the M918T mutation who took cabozantinib survived significantly longer than did those who took placebo.

A small number of patients (16) had RAS mutations, and those who took cabozantinib did have better overall survival than did those who took placebo, although the difference was not statistically significant.

Adverse events were more common in the cabozantinib arm and included pneumonia (4.2%), pulmonary embolism (3.3%), mucosal inflammation (2.8%), hypocalcemia (2.8%), hypertension, dysphagia, dehydration, and lung abscess (2.3% each).

The EXAM study was sponsored by Exelixis. Dr. Sherman had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

LAKE BUENA VISTA, FLA. – Obesity was strongly associated with more aggressive papillary thyroid carcinoma features, but not with a greater likelihood of disease recurrence in a review of nearly 7,300 patients.

Of the 7,284 consecutive surgery patients included in the study, 5,283 had normal weight (body mass index less than 25 kg/m²), 1,731 were overweight (BMI of 25 to less than 30 kg/m²), and 270 were obese (BMI of 30 kg/m² or greater). The obese patients were significantly more likely than the normal-weight and overweight patients to have a number of features associated with more aggressive disease, Dr. Eun Jeong Ban of Yonsei University Health System in Seoul, South Korea, reported at the International Thyroid Congress.

SciePro / Science Source

For example, tumors of 1 cm or greater were present in 43% of obese patients, compared with 31% of normal-weight patients and 34% of overweight patients. Multiple tumors were present in 15% of obese patients, compared with 11% of normal-weight patients and 10% of overweight patients, and bilateral tumors were present in 31% of obese patients, compared with 20% of normal-weight patients and 25% of overweight patients, Dr. Ban said.

Further, stage T3 disease was present in 62%, 51%, and 55% of obese, normal-weight and overweight patients, respectively; stage T4a disease was present in 4.4%, 1.7%, and 2.5% of the patients in the groups, respectively; stage T4b disease was present in 0.4%, 0%, and 0.1% of patients; and TNM stage IVa disease was present in 10%, 4.5%, and 7.3% of patients.

The groups did not differ with respect to regional lymph node stage or distant metastases.

They also did not differ with respect to recurrence rates, which were 1.5% in the obese patients and 1.6% and 1.7% in the normal-weight and overweight patients, respectively.

BMI was not found on multivariate analysis to predict risk for recurrence (odds ratios, 0.908 and 0.677 for BMI of 25-29 kg/m² and BMI of 30 or greater, respectively). Only tumor multiplicity (OR, 2.463) and stage N1a (OR, 3.421) and N1b disease (OR, 4.246) were found to predict recurrence.

Although epidemiologic studies have suggested that obesity increases the risk of thyroid cancer, the association between BMI and the aggressiveness of papillary thyroid carcinoma remained unclear. These findings suggest that obesity also may increase the likelihood of a more aggressive disease course, Dr. Ban said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

Dr. Ban reported having no disclosures.

sworcester@frontlinemedcom.com

LAKE BUENA VISTA, FLA. – Obesity was strongly associated with more aggressive papillary thyroid carcinoma features, but not with a greater likelihood of disease recurrence in a review of nearly 7,300 patients.

Of the 7,284 consecutive surgery patients included in the study, 5,283 had normal weight (body mass index less than 25 kg/m²), 1,731 were overweight (BMI of 25 to less than 30 kg/m²), and 270 were obese (BMI of 30 kg/m² or greater). The obese patients were significantly more likely than the normal-weight and overweight patients to have a number of features associated with more aggressive disease, Dr. Eun Jeong Ban of Yonsei University Health System in Seoul, South Korea, reported at the International Thyroid Congress.

SciePro / Science Source

For example, tumors of 1 cm or greater were present in 43% of obese patients, compared with 31% of normal-weight patients and 34% of overweight patients. Multiple tumors were present in 15% of obese patients, compared with 11% of normal-weight patients and 10% of overweight patients, and bilateral tumors were present in 31% of obese patients, compared with 20% of normal-weight patients and 25% of overweight patients, Dr. Ban said.

Further, stage T3 disease was present in 62%, 51%, and 55% of obese, normal-weight and overweight patients, respectively; stage T4a disease was present in 4.4%, 1.7%, and 2.5% of the patients in the groups, respectively; stage T4b disease was present in 0.4%, 0%, and 0.1% of patients; and TNM stage IVa disease was present in 10%, 4.5%, and 7.3% of patients.

The groups did not differ with respect to regional lymph node stage or distant metastases.

They also did not differ with respect to recurrence rates, which were 1.5% in the obese patients and 1.6% and 1.7% in the normal-weight and overweight patients, respectively.

BMI was not found on multivariate analysis to predict risk for recurrence (odds ratios, 0.908 and 0.677 for BMI of 25-29 kg/m² and BMI of 30 or greater, respectively). Only tumor multiplicity (OR, 2.463) and stage N1a (OR, 3.421) and N1b disease (OR, 4.246) were found to predict recurrence.

Although epidemiologic studies have suggested that obesity increases the risk of thyroid cancer, the association between BMI and the aggressiveness of papillary thyroid carcinoma remained unclear. These findings suggest that obesity also may increase the likelihood of a more aggressive disease course, Dr. Ban said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

Dr. Ban reported having no disclosures.

sworcester@frontlinemedcom.com

LAKE BUENA VISTA, FLA. – Obesity was strongly associated with more aggressive papillary thyroid carcinoma features, but not with a greater likelihood of disease recurrence in a review of nearly 7,300 patients.

Of the 7,284 consecutive surgery patients included in the study, 5,283 had normal weight (body mass index less than 25 kg/m²), 1,731 were overweight (BMI of 25 to less than 30 kg/m²), and 270 were obese (BMI of 30 kg/m² or greater). The obese patients were significantly more likely than the normal-weight and overweight patients to have a number of features associated with more aggressive disease, Dr. Eun Jeong Ban of Yonsei University Health System in Seoul, South Korea, reported at the International Thyroid Congress.

SciePro / Science Source

For example, tumors of 1 cm or greater were present in 43% of obese patients, compared with 31% of normal-weight patients and 34% of overweight patients. Multiple tumors were present in 15% of obese patients, compared with 11% of normal-weight patients and 10% of overweight patients, and bilateral tumors were present in 31% of obese patients, compared with 20% of normal-weight patients and 25% of overweight patients, Dr. Ban said.

Further, stage T3 disease was present in 62%, 51%, and 55% of obese, normal-weight and overweight patients, respectively; stage T4a disease was present in 4.4%, 1.7%, and 2.5% of the patients in the groups, respectively; stage T4b disease was present in 0.4%, 0%, and 0.1% of patients; and TNM stage IVa disease was present in 10%, 4.5%, and 7.3% of patients.

The groups did not differ with respect to regional lymph node stage or distant metastases.

They also did not differ with respect to recurrence rates, which were 1.5% in the obese patients and 1.6% and 1.7% in the normal-weight and overweight patients, respectively.

BMI was not found on multivariate analysis to predict risk for recurrence (odds ratios, 0.908 and 0.677 for BMI of 25-29 kg/m² and BMI of 30 or greater, respectively). Only tumor multiplicity (OR, 2.463) and stage N1a (OR, 3.421) and N1b disease (OR, 4.246) were found to predict recurrence.

Although epidemiologic studies have suggested that obesity increases the risk of thyroid cancer, the association between BMI and the aggressiveness of papillary thyroid carcinoma remained unclear. These findings suggest that obesity also may increase the likelihood of a more aggressive disease course, Dr. Ban said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

Dr. Ban reported having no disclosures.

sworcester@frontlinemedcom.com

Hypothyroidism affected almost 17% of patients with idiopathic pulmonary fibrosis and was independently associated with their mortality, according to a report in the September issue of CHEST.

“We report, to our knowledge for the first time, an association between hypothyroidism and idiopathic pulmonary fibrosis,” wrote Dr. Justin Oldham of the pulmonary and critical care section of the University of Chicago and his associates. “Hypothyroidism, a largely autoimmune process, is common among patients with IPF and may represent an additional feature of autoimmunity in this patient population.” The retrospective study could not assess causality, but raises questions about whether autoimmune abnormalities contribte to or exacerbate IPF, and whether hypothyroidism and IPF share common underlying causes, they added.

By IPFeditor (Wikimedia Commons)

Recent years have seen a “paradigm shift” away from immunologic or inflammatory causes of IPF in favor of alveolar injury and abnormal cellular repair mechanisms, but some studies point to autoimmunity in IPF, said the investigators. To further explore the question, they studied hypothyroidism – which in developed countries is most often autoimmune – among 196 patients with IPF with an equal number of age-and sex-matched controls with COPD (Chest 2015;148:692-700). Nearly 17% of IPF patients – including 13% of women and 28% of men – reported using thyroid replacement therapy with no history of thyroidectomy or radioactive iodine ablation. In contrast only 7% of COPD controls had a recorded diagnosis of hypothyroidism (odds ratio, 2.7; 95% confidence interval, 1.3 to 5.5; P = .01). Men and women with IPF and comorbid hypothyroidism had significantly shorter survival than did patients who had IPF only (P = .001). Hypothyroidism also independently predicted mortality in the multivariable analysis (hazard ratio, 2.1; 95% CI, 1.3 to 3.4), as did sequential increases in gender, age, and physiology (GAP) stage, the investigators said. “These conclusions held when transplant-free, transplant-excluded, and transplant-as-a-competing-event Cox regression models were constructed,” they reported. Furthermore, multivariable analyses of data from two IPF clinical trials (ACE-IPF and PANTHER) revealed similar associations among hypothyroidism, GAP stage, and mortality, they said.

Exactly how hypothyroidism contributes to IPF and IPF-related mortality is unclear, said Dr. Oldham and his associates. Because the study did not examine longitudinal changes in thyroid stage, they could not relate those trends to IPF progression, they noted. Although they excluded patients whose thyroid disease was known not to be autoimmune, they could not specifically confirm that all remaining patients with hypothyroidism had autoimmune thyroiditis, because most had been diagnosed years before. Future longitudinal studies should examine whether IPF and hypothyroidism share underlying causes, and should examine why hypothyroidism seems to increase IPF-related mortality, they concluded.

The National Institutes of Health funded the study. Dr. Oldham and five coauthors declared no competing interests. Senior author Dr. Imre Noth and one coauthor reported grant support and honoraria from NIH, Brystol-Myers Squibb, Gilead Sciences, Intermune, Medimmune, and several other pharmaceutical companies.

Hypothyroidism affected almost 17% of patients with idiopathic pulmonary fibrosis and was independently associated with their mortality, according to a report in the September issue of CHEST.

“We report, to our knowledge for the first time, an association between hypothyroidism and idiopathic pulmonary fibrosis,” wrote Dr. Justin Oldham of the pulmonary and critical care section of the University of Chicago and his associates. “Hypothyroidism, a largely autoimmune process, is common among patients with IPF and may represent an additional feature of autoimmunity in this patient population.” The retrospective study could not assess causality, but raises questions about whether autoimmune abnormalities contribte to or exacerbate IPF, and whether hypothyroidism and IPF share common underlying causes, they added.

By IPFeditor (Wikimedia Commons)

Recent years have seen a “paradigm shift” away from immunologic or inflammatory causes of IPF in favor of alveolar injury and abnormal cellular repair mechanisms, but some studies point to autoimmunity in IPF, said the investigators. To further explore the question, they studied hypothyroidism – which in developed countries is most often autoimmune – among 196 patients with IPF with an equal number of age-and sex-matched controls with COPD (Chest 2015;148:692-700). Nearly 17% of IPF patients – including 13% of women and 28% of men – reported using thyroid replacement therapy with no history of thyroidectomy or radioactive iodine ablation. In contrast only 7% of COPD controls had a recorded diagnosis of hypothyroidism (odds ratio, 2.7; 95% confidence interval, 1.3 to 5.5; P = .01). Men and women with IPF and comorbid hypothyroidism had significantly shorter survival than did patients who had IPF only (P = .001). Hypothyroidism also independently predicted mortality in the multivariable analysis (hazard ratio, 2.1; 95% CI, 1.3 to 3.4), as did sequential increases in gender, age, and physiology (GAP) stage, the investigators said. “These conclusions held when transplant-free, transplant-excluded, and transplant-as-a-competing-event Cox regression models were constructed,” they reported. Furthermore, multivariable analyses of data from two IPF clinical trials (ACE-IPF and PANTHER) revealed similar associations among hypothyroidism, GAP stage, and mortality, they said.

Exactly how hypothyroidism contributes to IPF and IPF-related mortality is unclear, said Dr. Oldham and his associates. Because the study did not examine longitudinal changes in thyroid stage, they could not relate those trends to IPF progression, they noted. Although they excluded patients whose thyroid disease was known not to be autoimmune, they could not specifically confirm that all remaining patients with hypothyroidism had autoimmune thyroiditis, because most had been diagnosed years before. Future longitudinal studies should examine whether IPF and hypothyroidism share underlying causes, and should examine why hypothyroidism seems to increase IPF-related mortality, they concluded.

The National Institutes of Health funded the study. Dr. Oldham and five coauthors declared no competing interests. Senior author Dr. Imre Noth and one coauthor reported grant support and honoraria from NIH, Brystol-Myers Squibb, Gilead Sciences, Intermune, Medimmune, and several other pharmaceutical companies.

Hypothyroidism affected almost 17% of patients with idiopathic pulmonary fibrosis and was independently associated with their mortality, according to a report in the September issue of CHEST.

“We report, to our knowledge for the first time, an association between hypothyroidism and idiopathic pulmonary fibrosis,” wrote Dr. Justin Oldham of the pulmonary and critical care section of the University of Chicago and his associates. “Hypothyroidism, a largely autoimmune process, is common among patients with IPF and may represent an additional feature of autoimmunity in this patient population.” The retrospective study could not assess causality, but raises questions about whether autoimmune abnormalities contribte to or exacerbate IPF, and whether hypothyroidism and IPF share common underlying causes, they added.

By IPFeditor (Wikimedia Commons)

Recent years have seen a “paradigm shift” away from immunologic or inflammatory causes of IPF in favor of alveolar injury and abnormal cellular repair mechanisms, but some studies point to autoimmunity in IPF, said the investigators. To further explore the question, they studied hypothyroidism – which in developed countries is most often autoimmune – among 196 patients with IPF with an equal number of age-and sex-matched controls with COPD (Chest 2015;148:692-700). Nearly 17% of IPF patients – including 13% of women and 28% of men – reported using thyroid replacement therapy with no history of thyroidectomy or radioactive iodine ablation. In contrast only 7% of COPD controls had a recorded diagnosis of hypothyroidism (odds ratio, 2.7; 95% confidence interval, 1.3 to 5.5; P = .01). Men and women with IPF and comorbid hypothyroidism had significantly shorter survival than did patients who had IPF only (P = .001). Hypothyroidism also independently predicted mortality in the multivariable analysis (hazard ratio, 2.1; 95% CI, 1.3 to 3.4), as did sequential increases in gender, age, and physiology (GAP) stage, the investigators said. “These conclusions held when transplant-free, transplant-excluded, and transplant-as-a-competing-event Cox regression models were constructed,” they reported. Furthermore, multivariable analyses of data from two IPF clinical trials (ACE-IPF and PANTHER) revealed similar associations among hypothyroidism, GAP stage, and mortality, they said.

Exactly how hypothyroidism contributes to IPF and IPF-related mortality is unclear, said Dr. Oldham and his associates. Because the study did not examine longitudinal changes in thyroid stage, they could not relate those trends to IPF progression, they noted. Although they excluded patients whose thyroid disease was known not to be autoimmune, they could not specifically confirm that all remaining patients with hypothyroidism had autoimmune thyroiditis, because most had been diagnosed years before. Future longitudinal studies should examine whether IPF and hypothyroidism share underlying causes, and should examine why hypothyroidism seems to increase IPF-related mortality, they concluded.

The National Institutes of Health funded the study. Dr. Oldham and five coauthors declared no competing interests. Senior author Dr. Imre Noth and one coauthor reported grant support and honoraria from NIH, Brystol-Myers Squibb, Gilead Sciences, Intermune, Medimmune, and several other pharmaceutical companies.

ESTES PARK, COLO. – Primary aldosteronism, traditionally seen as a rare, stump-the-experts-type disorder, is now accepted as the cause of 5%-10% of all cases of what has been considered essential hypertension.

Primary aldosteronism is a readily treatable disorder, either surgically or medically, depending upon the subtype. So it’s essential to know which hypertensive patients to screen and how to confirm the diagnosis and then to move forward to identify the subtype in play, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

Primary aldosteronism occurs when the adrenal gland produces excessive aldosterone without being stimulated by renin. Aldosterone causes sodium retention in the kidney in exchange for potassium and hydrogen ions. The result is the triple harms of hypertension, hypokalemia, and metabolic acidosis, explained Dr. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at University of Colorado Hospital in Aurora.

The two main subtypes of primary aldosteronism are idiopathic hyperaldosteronism (IHA), also known as bilateral adrenal hyperplasia, which accounts for two-thirds of all cases, and unilateral aldosterone-producing adenoma, which accounts for the remaining third.

Which hypertensive patients should be screened for primary aldosteronism? Anyone with resistant hypertension as defined by inadequate blood pressure control while on three or more antihypertensive drugs; those with severe hypertension, meaning readings greater than 160/100 mm Hg; patients with onset of hypertension before age 20; and any hypertensive patient with hypokalemia, which can either be provoked by diuretic therapy or in some cases occurs spontaneously, the endocrinologist continued.

Screening for primary aldosteronism entails getting a morning blood sample to measure plasma aldosterone and plasma renin activity after having the patient sit for 10 minutes. A positive screen requires both a plasma aldosterone level greater than 15 ng/dL and a plasma aldosterone/plasma renin activity ratio greater than 20.

“You can do this screening test in a patient on any medication except spironolactone. They have to stop that drug for at least 2 weeks first,” according to Dr. McDermott.

Confirmation of a positive screening test requires demonstration that the elevated aldosterone can’t be suppressed via volume expansion. This volume expansion can be accomplished in two ways: putting the patient on a high-salt diet for 3 days, which can generally be accomplished simply by eating some potato chips daily on top of a typically high-salt American diet, or by intravenous infusion of 2 L of normal saline over the course of 4 hours.

If a 24-hour urine collection on day 3 of a high-salt diet shows an aldosterone level in excess of 12 mcg, the diagnosis of primary aldosteronism is confirmed.

“If anyone in this room who doesn’t have primary aldosteronism had a high-salt diet for 3 days and we did a 24-hour urine on the third day, your aldosterone would be zero. So a level over 12 mcg is clearly abnormal,” Dr. McDermott emphasized.

Likewise, a plasma aldosterone greater than 10 ng/dL following the IV saline infusion is also confirmatory.

A good clinical clue that primary aldosteronism is due to an aldosterone-producing tumor is severe hypertension and/or severe hypokalemia in a patient under 40 years of age. A plasma aldosterone greater than 25 ng/dL or a urine aldosterone in excess of 30 mcg/24 hours is another useful clue because a tumor produces a lot more aldosterone than does bilateral adrenal hyperplasia.

If, and only if, a patient is willing to undergo surgery in the event further work-up establishes the presence of an aldosterone-producing tumor, the next step is an abdominal CT scan. If it reveals a unilateral hypodense nodule greater than 1 cm in size and the patient is less than 35 years old, referral for unilateral laparoscopic or open adrenalectomy is warranted. Preoperatively the patient should be placed on either spironolactone or eplerenone; these aldosterone antagonists block the effects of aldosterone on the kidney, with resultant normalization of hypertension and hypokalemia.

Bilateral adrenal hyperplasia is much more common than an aldosterone-producing tumor in patients older than age 35, so even when a unilateral nodule is found in such a patient it’s worthwhile to consider adrenal vein sampling. If the sampling lateralizes to one side then adrenalectomy can be offered. If there is no lateralization, however, the patient has IHA and medical management is appropriate. An aldosterone antagonist will normalize the hypokalemia but may not be sufficient to control the elevated blood pressure, in which case a calcium channel blocker, ACE inhibitor, and/or angiotensin receptor blocker can be added.

Dr. McDermott reported having no financial conflicts with regard to his presentation.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – Primary aldosteronism, traditionally seen as a rare, stump-the-experts-type disorder, is now accepted as the cause of 5%-10% of all cases of what has been considered essential hypertension.

Primary aldosteronism is a readily treatable disorder, either surgically or medically, depending upon the subtype. So it’s essential to know which hypertensive patients to screen and how to confirm the diagnosis and then to move forward to identify the subtype in play, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

Primary aldosteronism occurs when the adrenal gland produces excessive aldosterone without being stimulated by renin. Aldosterone causes sodium retention in the kidney in exchange for potassium and hydrogen ions. The result is the triple harms of hypertension, hypokalemia, and metabolic acidosis, explained Dr. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at University of Colorado Hospital in Aurora.

The two main subtypes of primary aldosteronism are idiopathic hyperaldosteronism (IHA), also known as bilateral adrenal hyperplasia, which accounts for two-thirds of all cases, and unilateral aldosterone-producing adenoma, which accounts for the remaining third.

Which hypertensive patients should be screened for primary aldosteronism? Anyone with resistant hypertension as defined by inadequate blood pressure control while on three or more antihypertensive drugs; those with severe hypertension, meaning readings greater than 160/100 mm Hg; patients with onset of hypertension before age 20; and any hypertensive patient with hypokalemia, which can either be provoked by diuretic therapy or in some cases occurs spontaneously, the endocrinologist continued.

Screening for primary aldosteronism entails getting a morning blood sample to measure plasma aldosterone and plasma renin activity after having the patient sit for 10 minutes. A positive screen requires both a plasma aldosterone level greater than 15 ng/dL and a plasma aldosterone/plasma renin activity ratio greater than 20.

“You can do this screening test in a patient on any medication except spironolactone. They have to stop that drug for at least 2 weeks first,” according to Dr. McDermott.

Confirmation of a positive screening test requires demonstration that the elevated aldosterone can’t be suppressed via volume expansion. This volume expansion can be accomplished in two ways: putting the patient on a high-salt diet for 3 days, which can generally be accomplished simply by eating some potato chips daily on top of a typically high-salt American diet, or by intravenous infusion of 2 L of normal saline over the course of 4 hours.

If a 24-hour urine collection on day 3 of a high-salt diet shows an aldosterone level in excess of 12 mcg, the diagnosis of primary aldosteronism is confirmed.

“If anyone in this room who doesn’t have primary aldosteronism had a high-salt diet for 3 days and we did a 24-hour urine on the third day, your aldosterone would be zero. So a level over 12 mcg is clearly abnormal,” Dr. McDermott emphasized.

Likewise, a plasma aldosterone greater than 10 ng/dL following the IV saline infusion is also confirmatory.

A good clinical clue that primary aldosteronism is due to an aldosterone-producing tumor is severe hypertension and/or severe hypokalemia in a patient under 40 years of age. A plasma aldosterone greater than 25 ng/dL or a urine aldosterone in excess of 30 mcg/24 hours is another useful clue because a tumor produces a lot more aldosterone than does bilateral adrenal hyperplasia.

If, and only if, a patient is willing to undergo surgery in the event further work-up establishes the presence of an aldosterone-producing tumor, the next step is an abdominal CT scan. If it reveals a unilateral hypodense nodule greater than 1 cm in size and the patient is less than 35 years old, referral for unilateral laparoscopic or open adrenalectomy is warranted. Preoperatively the patient should be placed on either spironolactone or eplerenone; these aldosterone antagonists block the effects of aldosterone on the kidney, with resultant normalization of hypertension and hypokalemia.

Bilateral adrenal hyperplasia is much more common than an aldosterone-producing tumor in patients older than age 35, so even when a unilateral nodule is found in such a patient it’s worthwhile to consider adrenal vein sampling. If the sampling lateralizes to one side then adrenalectomy can be offered. If there is no lateralization, however, the patient has IHA and medical management is appropriate. An aldosterone antagonist will normalize the hypokalemia but may not be sufficient to control the elevated blood pressure, in which case a calcium channel blocker, ACE inhibitor, and/or angiotensin receptor blocker can be added.

Dr. McDermott reported having no financial conflicts with regard to his presentation.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – Primary aldosteronism, traditionally seen as a rare, stump-the-experts-type disorder, is now accepted as the cause of 5%-10% of all cases of what has been considered essential hypertension.

Primary aldosteronism is a readily treatable disorder, either surgically or medically, depending upon the subtype. So it’s essential to know which hypertensive patients to screen and how to confirm the diagnosis and then to move forward to identify the subtype in play, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

Primary aldosteronism occurs when the adrenal gland produces excessive aldosterone without being stimulated by renin. Aldosterone causes sodium retention in the kidney in exchange for potassium and hydrogen ions. The result is the triple harms of hypertension, hypokalemia, and metabolic acidosis, explained Dr. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at University of Colorado Hospital in Aurora.

The two main subtypes of primary aldosteronism are idiopathic hyperaldosteronism (IHA), also known as bilateral adrenal hyperplasia, which accounts for two-thirds of all cases, and unilateral aldosterone-producing adenoma, which accounts for the remaining third.

Which hypertensive patients should be screened for primary aldosteronism? Anyone with resistant hypertension as defined by inadequate blood pressure control while on three or more antihypertensive drugs; those with severe hypertension, meaning readings greater than 160/100 mm Hg; patients with onset of hypertension before age 20; and any hypertensive patient with hypokalemia, which can either be provoked by diuretic therapy or in some cases occurs spontaneously, the endocrinologist continued.

Screening for primary aldosteronism entails getting a morning blood sample to measure plasma aldosterone and plasma renin activity after having the patient sit for 10 minutes. A positive screen requires both a plasma aldosterone level greater than 15 ng/dL and a plasma aldosterone/plasma renin activity ratio greater than 20.

“You can do this screening test in a patient on any medication except spironolactone. They have to stop that drug for at least 2 weeks first,” according to Dr. McDermott.

Confirmation of a positive screening test requires demonstration that the elevated aldosterone can’t be suppressed via volume expansion. This volume expansion can be accomplished in two ways: putting the patient on a high-salt diet for 3 days, which can generally be accomplished simply by eating some potato chips daily on top of a typically high-salt American diet, or by intravenous infusion of 2 L of normal saline over the course of 4 hours.

If a 24-hour urine collection on day 3 of a high-salt diet shows an aldosterone level in excess of 12 mcg, the diagnosis of primary aldosteronism is confirmed.

“If anyone in this room who doesn’t have primary aldosteronism had a high-salt diet for 3 days and we did a 24-hour urine on the third day, your aldosterone would be zero. So a level over 12 mcg is clearly abnormal,” Dr. McDermott emphasized.

Likewise, a plasma aldosterone greater than 10 ng/dL following the IV saline infusion is also confirmatory.

A good clinical clue that primary aldosteronism is due to an aldosterone-producing tumor is severe hypertension and/or severe hypokalemia in a patient under 40 years of age. A plasma aldosterone greater than 25 ng/dL or a urine aldosterone in excess of 30 mcg/24 hours is another useful clue because a tumor produces a lot more aldosterone than does bilateral adrenal hyperplasia.

If, and only if, a patient is willing to undergo surgery in the event further work-up establishes the presence of an aldosterone-producing tumor, the next step is an abdominal CT scan. If it reveals a unilateral hypodense nodule greater than 1 cm in size and the patient is less than 35 years old, referral for unilateral laparoscopic or open adrenalectomy is warranted. Preoperatively the patient should be placed on either spironolactone or eplerenone; these aldosterone antagonists block the effects of aldosterone on the kidney, with resultant normalization of hypertension and hypokalemia.

Bilateral adrenal hyperplasia is much more common than an aldosterone-producing tumor in patients older than age 35, so even when a unilateral nodule is found in such a patient it’s worthwhile to consider adrenal vein sampling. If the sampling lateralizes to one side then adrenalectomy can be offered. If there is no lateralization, however, the patient has IHA and medical management is appropriate. An aldosterone antagonist will normalize the hypokalemia but may not be sufficient to control the elevated blood pressure, in which case a calcium channel blocker, ACE inhibitor, and/or angiotensin receptor blocker can be added.

Dr. McDermott reported having no financial conflicts with regard to his presentation.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – The sweet spot for intervention in polycystic ovary syndrome occurs early: in the adolescent who doesn’t yet desire pregnancy and who is just starting to experience the classic PCOS progressive weight gain.

“The obstetricians don’t want to see these patients when they’re already 220 lb and they’re trying to induce ovulation. It’s our job to pick them up in their adolescence. You want to clamp the hormones – suppress the androgens – so that things will be better down the road,” Dr. Margaret E. Wierman urged at a conference on internal medicine sponsored by the University of Colorado.

Aggressive treatment at this stage will reduce the risk of a host of potential health problems later. In addition to infertility issues, these include increased long-term risks of diabetes, hypertension, dyslipidemia, metabolic syndrome, endometrial cancer, obstructive sleep apnea, and nonalcoholic fatty liver disease, noted Dr. Wierman, professor of medicine, ob.gyn., and physiology at the university and chief of endocrinology at the Denver VA Medical Center.

PCOS is by far the most common cause of hyperandrogenic anovulation. Indeed, 6%-8% of all women in their childbearing years have PCOS. The condition is defined by clinical and/or biochemical hyperandrogenism, oligomenorrhea or amenorrhea, and the presence of ovarian cysts or increased ovarian volume on ultrasound.

In the adolescent with PCOS who doesn’t desire pregnancy, Dr. Wierman takes a three-pronged treatment approach: regularize menses with a less androgenic oral contraceptive, such as one containing norethindrone, or by using cyclic progesterone; treat hirsutism with spironolactone at 50-100 mg once daily coupled with electrolysis for local control; and consider using short-acting metformin as an insulin-sensitizing agent.

The use of metformin in treating PCOS is controversial. It is off-label therapy. There have been no prospective, randomized, placebo-controlled, double-blind studies supporting this application of the drug. Nevertheless, Dr. Wierman is a believer.

“If you take these adolescent girls, especially as they’re beginning to start the weight gain, and you give them metformin, it will stop the weight gain, improve their androgen level and their insulin resistance, and it will help them when they’re ready to have kids later on. I use metformin, and I call it Antabuse for fat: You cheat, you pay. You have no side effects if you eat healthy. If you eat fatty foods, you will have nausea and diarrhea,” she explained.

The endocrinologist added that she finds metformin works best in the adolescent with PCOS who has a family history of diabetes, is gaining weight, but is not yet diabetic herself.

“And that’s based on clinical experience, no prospective studies,” Dr. Wierman emphasized.

She reported having no financial conflicts regarding her presentation.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – The sweet spot for intervention in polycystic ovary syndrome occurs early: in the adolescent who doesn’t yet desire pregnancy and who is just starting to experience the classic PCOS progressive weight gain.

“The obstetricians don’t want to see these patients when they’re already 220 lb and they’re trying to induce ovulation. It’s our job to pick them up in their adolescence. You want to clamp the hormones – suppress the androgens – so that things will be better down the road,” Dr. Margaret E. Wierman urged at a conference on internal medicine sponsored by the University of Colorado.

Aggressive treatment at this stage will reduce the risk of a host of potential health problems later. In addition to infertility issues, these include increased long-term risks of diabetes, hypertension, dyslipidemia, metabolic syndrome, endometrial cancer, obstructive sleep apnea, and nonalcoholic fatty liver disease, noted Dr. Wierman, professor of medicine, ob.gyn., and physiology at the university and chief of endocrinology at the Denver VA Medical Center.

PCOS is by far the most common cause of hyperandrogenic anovulation. Indeed, 6%-8% of all women in their childbearing years have PCOS. The condition is defined by clinical and/or biochemical hyperandrogenism, oligomenorrhea or amenorrhea, and the presence of ovarian cysts or increased ovarian volume on ultrasound.

In the adolescent with PCOS who doesn’t desire pregnancy, Dr. Wierman takes a three-pronged treatment approach: regularize menses with a less androgenic oral contraceptive, such as one containing norethindrone, or by using cyclic progesterone; treat hirsutism with spironolactone at 50-100 mg once daily coupled with electrolysis for local control; and consider using short-acting metformin as an insulin-sensitizing agent.

The use of metformin in treating PCOS is controversial. It is off-label therapy. There have been no prospective, randomized, placebo-controlled, double-blind studies supporting this application of the drug. Nevertheless, Dr. Wierman is a believer.

“If you take these adolescent girls, especially as they’re beginning to start the weight gain, and you give them metformin, it will stop the weight gain, improve their androgen level and their insulin resistance, and it will help them when they’re ready to have kids later on. I use metformin, and I call it Antabuse for fat: You cheat, you pay. You have no side effects if you eat healthy. If you eat fatty foods, you will have nausea and diarrhea,” she explained.

The endocrinologist added that she finds metformin works best in the adolescent with PCOS who has a family history of diabetes, is gaining weight, but is not yet diabetic herself.

“And that’s based on clinical experience, no prospective studies,” Dr. Wierman emphasized.

She reported having no financial conflicts regarding her presentation.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – The sweet spot for intervention in polycystic ovary syndrome occurs early: in the adolescent who doesn’t yet desire pregnancy and who is just starting to experience the classic PCOS progressive weight gain.

“The obstetricians don’t want to see these patients when they’re already 220 lb and they’re trying to induce ovulation. It’s our job to pick them up in their adolescence. You want to clamp the hormones – suppress the androgens – so that things will be better down the road,” Dr. Margaret E. Wierman urged at a conference on internal medicine sponsored by the University of Colorado.

Aggressive treatment at this stage will reduce the risk of a host of potential health problems later. In addition to infertility issues, these include increased long-term risks of diabetes, hypertension, dyslipidemia, metabolic syndrome, endometrial cancer, obstructive sleep apnea, and nonalcoholic fatty liver disease, noted Dr. Wierman, professor of medicine, ob.gyn., and physiology at the university and chief of endocrinology at the Denver VA Medical Center.

PCOS is by far the most common cause of hyperandrogenic anovulation. Indeed, 6%-8% of all women in their childbearing years have PCOS. The condition is defined by clinical and/or biochemical hyperandrogenism, oligomenorrhea or amenorrhea, and the presence of ovarian cysts or increased ovarian volume on ultrasound.

In the adolescent with PCOS who doesn’t desire pregnancy, Dr. Wierman takes a three-pronged treatment approach: regularize menses with a less androgenic oral contraceptive, such as one containing norethindrone, or by using cyclic progesterone; treat hirsutism with spironolactone at 50-100 mg once daily coupled with electrolysis for local control; and consider using short-acting metformin as an insulin-sensitizing agent.

The use of metformin in treating PCOS is controversial. It is off-label therapy. There have been no prospective, randomized, placebo-controlled, double-blind studies supporting this application of the drug. Nevertheless, Dr. Wierman is a believer.

“If you take these adolescent girls, especially as they’re beginning to start the weight gain, and you give them metformin, it will stop the weight gain, improve their androgen level and their insulin resistance, and it will help them when they’re ready to have kids later on. I use metformin, and I call it Antabuse for fat: You cheat, you pay. You have no side effects if you eat healthy. If you eat fatty foods, you will have nausea and diarrhea,” she explained.

The endocrinologist added that she finds metformin works best in the adolescent with PCOS who has a family history of diabetes, is gaining weight, but is not yet diabetic herself.

“And that’s based on clinical experience, no prospective studies,” Dr. Wierman emphasized.

She reported having no financial conflicts regarding her presentation.

bjancin@frontlinemedcom.com