Clinical Review

At age 27, a woman with no family history of hypertension was diagnosed with the disease, which was left untreated. Two years later—during her first pregnancy—she was still hypertensive and was prescribed methyldopa, which was switched to lisinopril in the postpartum period. Her blood pressure (BP) remained elevated, despite titration of lisinopril and the addition of a β-blocking agent.

In the same year, the woman went to the emergency department with a severe headache and near-syncope; her BP was 180/100 mm Hg. Her medications were changed, and she was discharged with a prescription for captopril 50 mg bid and the angiotensin receptor blocker (ARB) valsartan 80 mg bid. Over the following six years, her average BP remained around 140/90 mm Hg with no further medication adjustment.

When the patient was 37, she underwent a chest x-ray (CXR), prompted by positive results on a purified protein derivative test at an employment physical; the CXR demonstrated a 3.6-cm mediastinal mass. This finding led to a chest CT exam that demonstrated a severe coarctation distal to the left subclavian artery with diffuse tubular hypoplasia, a collateral reconstitution of the descending aorta, and a true 2.7-cm aneurysm of one of the intercostal arteries.

The gradient between the ascending and descending aorta was 50 mm Hg, and the same wide pressure gradient was present between the upper and lower extremities (50 mm Hg).

Referral to pediatric cardiology was initiated. (It is not uncommon for an adult with a congenital heart lesion to be evaluated by a pediatric cardiologist in centers where adult congenital heart disease [ACHD] specialists are not available.) A cardiac MRI revealed a virtual interruption of the aortic arch in juxta-ductal position with multiple aortic collateral arteries. Subsequent cardiac catheterization demonstrated a transverse aortic arch at 1.2 cm and a narrowing to 7 mm just distal to the left subclavian artery, with a discrete coarctation of 2.5 mm.

With hypertension and a 50–mm Hg resting clinical gradient, corrective treatment was deemed necessary. Subsequently, balloon angioplasty was performed, and a drug-eluting stent was placed in the proximal distal aorta with dilation of the narrowing and a resultant decrease in BP gradient from 50 mm Hg to 7 mm Hg. Following stent placement, the aneurysm thrombosed secondary to reduced blood flow. Clinical reevaluation showed good dorsalis pedis and posterior tibial pulses with improved BP. The ARB was subsequently discontinued, and the patient continued to take captopril for mildly elevated BP (average, 130/85 mm Hg).

The patient did well until three years later, when she developed shortness of breath on exertion, claudication, and fatigue for a period of two weeks. On physical examination, her BP was noted to be elevated at 140/90 mm Hg with a clinical gradient of 20 mm between the upper and lower extremities and an increase in the gradient on echocardiogram to a peak of approximately 46 mm Hg and a mean of 21 mm Hg.

A subsequent chest CT demonstrated a narrowing of the previous stent site, and a right and left cardiac catheterization revealed neo-intimal proliferation affecting the stent with a 3–mm Hg gradient across the transverse arch and a 15–mm Hg gradient across the proximal descending aorta stent. The stent was subsequently redilated, and an additional stent was placed with no residual gradient.

The patient was discharged while taking clopidogrel 75 mg/d in addition to aspirin 325 mg/d for six months; antihypertensive medications were no longer necessary. Clinical evaluation with echocardiography was recommended every three months for the first year, and annually thereafter. At three-month and one-year follow-up, the patient was found to be symptom-free and normotensive (BP, 110/70 mm Hg).

DISCUSSION

Coarctation of the aorta (CoA) is a discrete narrowing of the thoracic aorta at the junction of the ductus arteriosus and the aortic arch, just distal to the subclavian artery. The specific anatomy, severity, and degree of hypoplasia proximal to the aortic coarctation are highly variable. For example, in some instances, coarctation presents as a long segment or a tubular hypoplasia.¹

The defect is often associated with other congenital cardiovascular abnormalities, including bicuspid aortic valve (BAV; reported incidence, up to 85%),^2,3 intracranial aneurysms (incidence, 3% to 10%),⁴ intrinsic abnormality in the aorta, aortic arch hypoplasia, ventricular septal defect, patent ductus arteriosus, aortic stenosis at different levels (valvular, subvalvular, or supravalvular), and mitral valve abnormalities.^2,5 There is evidence of increased familial risk for CoA and increased prevalence with certain disorders, including Turner syndrome, maternal phenylketonuria syndrome, and Kabuki syndrome.⁶

CoA accounts for 5% to 8% of all congenital heart disease,^2,3 and its incidence is 4 in 10,000 births.¹  (Adults presenting with CoA represent either recoarctation or a missed diagnosis of native coarctation.) The mean life expectancy of untreated patients with aortic coarctation is 35 years; 90% die before age 50.¹

Reduced life expectancy of patients with untreated CoA is due to systemic hypertension, accelerated coronary artery disease, stroke, heart failure, aortic rupture/dissection, cerebral hemorrhage, infective endarteritis/endocarditis, concomitant aortic valve disease (usually involving a BAV), and sudden cardiac death of presumed arrhythmogenic etiology.⁴ Even adults whose CoA has been detected early and managed with catheter-based and surgical interventions continue to face lifelong complications, including recoarctation, aneurysm formation, premature coronary artery disease, and cerebrovascular disease—mostly resulting from residual hypertension.³

Persistent hypertension has been reported in 68% of patients with repaired CoA at long-term follow-up. Hypertension may result in recurrence of CoA (incidence ranges from 5% to 50%), a residual CoA, or an idiopathic condition.⁷

The role of primary care providers is crucial in early detection and prompt referral to specialists in ACHD. For clinicians who manage these patients, increased morbidity and mortality from the associated cardiovascular sequelae pose an ongoing challenge.⁸

Presentation

Patients with hemodynamically stable coarctation in adolescence or adulthood are usually asymptomatic. Occasionally, a patient may be diagnosed with CoA based on its typical appearance on CXR or may come to medical attention because of an incidental murmur or management of hypertension.⁴ Symptoms vary in intensity and include headache, epistaxis, claudication, exertional fatigue, heart failure, aortic rupture, or dissection.⁷ Based on the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), and the 2008 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for adults with congenital heart disease, patients with hypertension and/or a history of CoA repair should be evaluated periodically for coarctation.⁸

Physical Examination

Physical assessment should include simultaneous palpation of the brachial and femoral pulses to assess amplitude and timing, looking for diminished arterial pulses and brachial-femoral delay. Additionally, measurement of supine bilateral arm (brachial artery) BP and right or left supine leg BP is recommended to detect differing pressures.⁸

The following physical findings may be suggestive of CoA or recoarctation:

• Systolic BP in the right arm higher than in the lower extremities, unless the origin of the right subclavian artery is anomalous and thus is not reliable; the left arm BP may not always be reliable because of the origin of the left subclavian artery, which may vary and may or may not be hypertensive

• Hyperdynamic carotid pulsations

• A pulse delay between the right arm and the femoral or popliteal arteries

• A murmur or bruit heard in the left interscapular position; a systolic ejection click of moderate intensity heard along the left sternal border

• In cases of BAV, an early diastolic decrescendo murmur of aortic regurgitation

Diagnostic Workup

The diagnosis of CoA is usually confirmed by echocardiography or radiographic imaging, including cardiac MRI or CT angiography.⁸

The initial diagnostic workup should include echocardiography, which may demonstrate left ventricular hypertrophy and secondary ST-T wave abnormalities, and a two-dimensional Doppler echocardiogram, which can establish the diagnosis and severity of the CoA, with possible associated cardiac defects.⁹ Also recommended is a CXR, which may occasionally reveal rib notching (caused by erosion of the inferior border of the posterior ribs by enlarged intercostal arteries), also known as the 3 sign. Finally, cardiac MRI is used to delineate the coarctation anatomy and to determine whether collateral arteries and/or associated vascular anomalies and flow abnormalities exist.⁹ If MRI is not possible, CT angiography can be an alternate approach. Subsequently, invasive angiography is required for better assessment of the coarctation gradient and hemodynamic measurement.⁹

Treatment

Management of CoA requires treatment of hypertension with β-blockers, ACE inhibitors, and/or ARBs as first-line medications. Aortic root size, the presence of aortic regurgitation, or both may influence the choice of antihypertensive agents.³

Intervention is recommended if the peak-to-peak coarctation gradient is ≥ 20 mm Hg, or the peak-to-peak coarctation gradient is < 20 mm Hg, with evidence of significant coarctation and collateral flow on radiologic imaging.⁸ The choice of treatment (stenting or surgery) should be decided by a team of ACHD cardiologists, interventionalists, and surgeons at an ACHD center.

Surgical intervention via a lateral left thoracotomy approach was first performed in 1944. The most common surgical repair is resection with end-to-end anastomosis, which yields a low mortality and recoarctation rate. Other techniques such as resection with replacement by a tube graft, patch aortoplasty, and bypass graft are used less frequently.^10-12 Postsurgical morbidity most commonly includes recoarctation and residual hypertension.

Thoracotomy was the only surgical treatment until 1982, when balloon angioplasty became available as an alternative.¹³ However, recoarctation, aneurysm formation, and aortic dissection are major disadvantages to balloon angioplasty.¹³

In the early 1990s, endovascular stents were introduced and have become an alternative approach to surgical repair.¹⁴ Aneurysms remain a significant complication in 4% to 7% of patients who undergo stent placement for CoA.¹⁴

Currently, there is insufficient evidence to indicate which is the best treatment for CoA: surgical or stent repair. Choice of treatment strategy will continue to depend on the operator’s skills or institutional preference until a prospective randomized controlled clinical trial is performed.¹³

Follow-Up

Based on recommendations from the ACC/AHA and the 2009 Canadian Cardiovascular Society Consensus Conference on the management of adults with congenital heart disease, lifelong follow-up is recommended for all patients with aortic coarctation (whether repaired or not), including an evaluation by a cardiologist with expertise in ACHD.^4,8

A baseline cardiac MRI or CT for complete evaluation of the thoracic aorta and intracranial vessels is required for follow-up. Patients who have previously undergone surgical or interventional CoA repair should be followed annually with echocardiography to assess for potential late complications, such as aortic dilatation and aneurysm formation. Evaluation of the coarctation repair site by MRI and/or CT at intervals of five years or less is also recommended. Moreover, patients should be monitored for recurrent resting or exercise-induced hypertension, which should be treated aggressively after recoarctation is excluded.

The guidelines recommend that every patient with systemic arterial hypertension have the brachial and femoral pulses palpated simultaneously.^4,8 This additional physical assessment will help detect significant aortic coarctation by assessing timing and amplitude of both pulses in search for a brachial-femoral delay. Moreover, measuring the differential pressure between bilateral arms (brachial artery) in a supine position and prone right or left supine leg (popliteal artery) BP should be performed.^4,8 Initial imaging and hemodynamic evaluation by transthoracic echocardiogram is recommended in suspected aortic coarctation.

CONCLUSION

This case represents a missed CoA and provides an example of recoarctation as a late complication after repair. Unfortunately, the critical need to screen for ­coarctation was not recognized by the patient’s primary care providers in a timely manner. Had the guidelines for CoA screening been applied, this defect would have been detected earlier, avoiding many years of cardiovascular system stress from the sequelae of hypertension.

 Measuring the BP gradient between the upper and lower extremities and searching for brachial-femoral timing delay are simple but crucial steps in the initial application of the clinical guidelines for early detection of CoA and recoarctation.

References

1. Jurcut R, Daraban AM, Lorber A, et al. Coarctation of the aorta in adults: what is the best treatment? Case report and literature review. J Med Life. 2011;4:189-195.

2. Teo LLS, Cannell T, Babu-Narayan SV, et al. Prevalence of associated cardiovascular abnormalities in 500 patients with aortic coarctation referred for cardiovascular magnetic resonance imaging to a tertiary center. Pediatr Cardiol. 2011;32:1120-1127.

3. Canniffe C. Hypertension after repair of aortic coarctation–a systematic review. Int J Cardiol. 2012;167:2456-2461.

4. Silversides CK, Kiess M, Beauchesne L, et al. Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: outflow tract obstruction, coarctation of the aorta, tetralogy of Fallot, Ebstein anomaly and Marfan’s syndrome. Can J Cardiol. 2010;26:e80-e97.

5. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for The Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease) Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52:e143-e263.

6. McBride KL, Pignatelli R, Lewin M, et al. Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: segregation, multiplex relative risk, and heritability. Am J Med Genet. Part A. 2005;134:
180-186.

7. Brown JW, Ruzmetov M, Hoyer MH, et al. Recurrent coarctation: is surgical repair of recurrent coarctation of the aorta safe and effective? Ann Thorac Surg. 2009;88:1923-1931.

8. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease). Circulation. 2008;118:2395-2451.

9. Darabian S, Zeb I, Rezaeian P, et al. Use of noninvasive imaging in the evaluation of coarctation of aorta. J Comput Assist Tomogr. 2013;37:75-78.

10. Backer CL, Mavroudis C, Zias EA, et al. Repair of coarctation with resection and extended end-to-end anastomosis. Ann Thorac Surg. 1998;66:1365-1370.

11. Cobanoglu A, Thyagarajan GK, Dobbs JL. Surgery for coarctation of the aorta in infants younger than 3 months: end-to-end repair versus subclavian flap angioplasty: is either operation better? Eur J Cardiothorac Surg. 1998;14:19-25.

12. Walhout RJ, Lekkerkerker JC, Oron GH, et al. Comparison of polytetrafluoroethylene patch aortoplasty and end-to-end anastomosis for coarctation of the aorta. J Thorac Cardiovasc Surg. 2003;126:521-528.

13. Pádua LM, Garcia LC, Rubira CJ, de Oliveira Carvalho PE. Stent placement versus surgery for coarctation of the thoracic aorta. Cochrane Database Syst Rev. 2012;5:CD008204.

14. Suárez de Lezo J, Pan M, Romero M, et al. Immediate and follow-up findings after stent treatment for severe coarctation of aorta. Am J Cardiol. 1999;83:400-406. 

At age 27, a woman with no family history of hypertension was diagnosed with the disease, which was left untreated. Two years later—during her first pregnancy—she was still hypertensive and was prescribed methyldopa, which was switched to lisinopril in the postpartum period. Her blood pressure (BP) remained elevated, despite titration of lisinopril and the addition of a β-blocking agent.

In the same year, the woman went to the emergency department with a severe headache and near-syncope; her BP was 180/100 mm Hg. Her medications were changed, and she was discharged with a prescription for captopril 50 mg bid and the angiotensin receptor blocker (ARB) valsartan 80 mg bid. Over the following six years, her average BP remained around 140/90 mm Hg with no further medication adjustment.

When the patient was 37, she underwent a chest x-ray (CXR), prompted by positive results on a purified protein derivative test at an employment physical; the CXR demonstrated a 3.6-cm mediastinal mass. This finding led to a chest CT exam that demonstrated a severe coarctation distal to the left subclavian artery with diffuse tubular hypoplasia, a collateral reconstitution of the descending aorta, and a true 2.7-cm aneurysm of one of the intercostal arteries.

The gradient between the ascending and descending aorta was 50 mm Hg, and the same wide pressure gradient was present between the upper and lower extremities (50 mm Hg).

Referral to pediatric cardiology was initiated. (It is not uncommon for an adult with a congenital heart lesion to be evaluated by a pediatric cardiologist in centers where adult congenital heart disease [ACHD] specialists are not available.) A cardiac MRI revealed a virtual interruption of the aortic arch in juxta-ductal position with multiple aortic collateral arteries. Subsequent cardiac catheterization demonstrated a transverse aortic arch at 1.2 cm and a narrowing to 7 mm just distal to the left subclavian artery, with a discrete coarctation of 2.5 mm.

With hypertension and a 50–mm Hg resting clinical gradient, corrective treatment was deemed necessary. Subsequently, balloon angioplasty was performed, and a drug-eluting stent was placed in the proximal distal aorta with dilation of the narrowing and a resultant decrease in BP gradient from 50 mm Hg to 7 mm Hg. Following stent placement, the aneurysm thrombosed secondary to reduced blood flow. Clinical reevaluation showed good dorsalis pedis and posterior tibial pulses with improved BP. The ARB was subsequently discontinued, and the patient continued to take captopril for mildly elevated BP (average, 130/85 mm Hg).

The patient did well until three years later, when she developed shortness of breath on exertion, claudication, and fatigue for a period of two weeks. On physical examination, her BP was noted to be elevated at 140/90 mm Hg with a clinical gradient of 20 mm between the upper and lower extremities and an increase in the gradient on echocardiogram to a peak of approximately 46 mm Hg and a mean of 21 mm Hg.

A subsequent chest CT demonstrated a narrowing of the previous stent site, and a right and left cardiac catheterization revealed neo-intimal proliferation affecting the stent with a 3–mm Hg gradient across the transverse arch and a 15–mm Hg gradient across the proximal descending aorta stent. The stent was subsequently redilated, and an additional stent was placed with no residual gradient.

The patient was discharged while taking clopidogrel 75 mg/d in addition to aspirin 325 mg/d for six months; antihypertensive medications were no longer necessary. Clinical evaluation with echocardiography was recommended every three months for the first year, and annually thereafter. At three-month and one-year follow-up, the patient was found to be symptom-free and normotensive (BP, 110/70 mm Hg).

DISCUSSION

Coarctation of the aorta (CoA) is a discrete narrowing of the thoracic aorta at the junction of the ductus arteriosus and the aortic arch, just distal to the subclavian artery. The specific anatomy, severity, and degree of hypoplasia proximal to the aortic coarctation are highly variable. For example, in some instances, coarctation presents as a long segment or a tubular hypoplasia.¹

The defect is often associated with other congenital cardiovascular abnormalities, including bicuspid aortic valve (BAV; reported incidence, up to 85%),^2,3 intracranial aneurysms (incidence, 3% to 10%),⁴ intrinsic abnormality in the aorta, aortic arch hypoplasia, ventricular septal defect, patent ductus arteriosus, aortic stenosis at different levels (valvular, subvalvular, or supravalvular), and mitral valve abnormalities.^2,5 There is evidence of increased familial risk for CoA and increased prevalence with certain disorders, including Turner syndrome, maternal phenylketonuria syndrome, and Kabuki syndrome.⁶

CoA accounts for 5% to 8% of all congenital heart disease,^2,3 and its incidence is 4 in 10,000 births.¹  (Adults presenting with CoA represent either recoarctation or a missed diagnosis of native coarctation.) The mean life expectancy of untreated patients with aortic coarctation is 35 years; 90% die before age 50.¹

Reduced life expectancy of patients with untreated CoA is due to systemic hypertension, accelerated coronary artery disease, stroke, heart failure, aortic rupture/dissection, cerebral hemorrhage, infective endarteritis/endocarditis, concomitant aortic valve disease (usually involving a BAV), and sudden cardiac death of presumed arrhythmogenic etiology.⁴ Even adults whose CoA has been detected early and managed with catheter-based and surgical interventions continue to face lifelong complications, including recoarctation, aneurysm formation, premature coronary artery disease, and cerebrovascular disease—mostly resulting from residual hypertension.³

Persistent hypertension has been reported in 68% of patients with repaired CoA at long-term follow-up. Hypertension may result in recurrence of CoA (incidence ranges from 5% to 50%), a residual CoA, or an idiopathic condition.⁷

The role of primary care providers is crucial in early detection and prompt referral to specialists in ACHD. For clinicians who manage these patients, increased morbidity and mortality from the associated cardiovascular sequelae pose an ongoing challenge.⁸

Presentation

Patients with hemodynamically stable coarctation in adolescence or adulthood are usually asymptomatic. Occasionally, a patient may be diagnosed with CoA based on its typical appearance on CXR or may come to medical attention because of an incidental murmur or management of hypertension.⁴ Symptoms vary in intensity and include headache, epistaxis, claudication, exertional fatigue, heart failure, aortic rupture, or dissection.⁷ Based on the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), and the 2008 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for adults with congenital heart disease, patients with hypertension and/or a history of CoA repair should be evaluated periodically for coarctation.⁸

Physical Examination

Physical assessment should include simultaneous palpation of the brachial and femoral pulses to assess amplitude and timing, looking for diminished arterial pulses and brachial-femoral delay. Additionally, measurement of supine bilateral arm (brachial artery) BP and right or left supine leg BP is recommended to detect differing pressures.⁸

The following physical findings may be suggestive of CoA or recoarctation:

• Systolic BP in the right arm higher than in the lower extremities, unless the origin of the right subclavian artery is anomalous and thus is not reliable; the left arm BP may not always be reliable because of the origin of the left subclavian artery, which may vary and may or may not be hypertensive

• Hyperdynamic carotid pulsations

• A pulse delay between the right arm and the femoral or popliteal arteries

• A murmur or bruit heard in the left interscapular position; a systolic ejection click of moderate intensity heard along the left sternal border

• In cases of BAV, an early diastolic decrescendo murmur of aortic regurgitation

Diagnostic Workup

The diagnosis of CoA is usually confirmed by echocardiography or radiographic imaging, including cardiac MRI or CT angiography.⁸

The initial diagnostic workup should include echocardiography, which may demonstrate left ventricular hypertrophy and secondary ST-T wave abnormalities, and a two-dimensional Doppler echocardiogram, which can establish the diagnosis and severity of the CoA, with possible associated cardiac defects.⁹ Also recommended is a CXR, which may occasionally reveal rib notching (caused by erosion of the inferior border of the posterior ribs by enlarged intercostal arteries), also known as the 3 sign. Finally, cardiac MRI is used to delineate the coarctation anatomy and to determine whether collateral arteries and/or associated vascular anomalies and flow abnormalities exist.⁹ If MRI is not possible, CT angiography can be an alternate approach. Subsequently, invasive angiography is required for better assessment of the coarctation gradient and hemodynamic measurement.⁹

Treatment

Management of CoA requires treatment of hypertension with β-blockers, ACE inhibitors, and/or ARBs as first-line medications. Aortic root size, the presence of aortic regurgitation, or both may influence the choice of antihypertensive agents.³

Intervention is recommended if the peak-to-peak coarctation gradient is ≥ 20 mm Hg, or the peak-to-peak coarctation gradient is < 20 mm Hg, with evidence of significant coarctation and collateral flow on radiologic imaging.⁸ The choice of treatment (stenting or surgery) should be decided by a team of ACHD cardiologists, interventionalists, and surgeons at an ACHD center.

Surgical intervention via a lateral left thoracotomy approach was first performed in 1944. The most common surgical repair is resection with end-to-end anastomosis, which yields a low mortality and recoarctation rate. Other techniques such as resection with replacement by a tube graft, patch aortoplasty, and bypass graft are used less frequently.^10-12 Postsurgical morbidity most commonly includes recoarctation and residual hypertension.

Thoracotomy was the only surgical treatment until 1982, when balloon angioplasty became available as an alternative.¹³ However, recoarctation, aneurysm formation, and aortic dissection are major disadvantages to balloon angioplasty.¹³

In the early 1990s, endovascular stents were introduced and have become an alternative approach to surgical repair.¹⁴ Aneurysms remain a significant complication in 4% to 7% of patients who undergo stent placement for CoA.¹⁴

Currently, there is insufficient evidence to indicate which is the best treatment for CoA: surgical or stent repair. Choice of treatment strategy will continue to depend on the operator’s skills or institutional preference until a prospective randomized controlled clinical trial is performed.¹³

Follow-Up

Based on recommendations from the ACC/AHA and the 2009 Canadian Cardiovascular Society Consensus Conference on the management of adults with congenital heart disease, lifelong follow-up is recommended for all patients with aortic coarctation (whether repaired or not), including an evaluation by a cardiologist with expertise in ACHD.^4,8

A baseline cardiac MRI or CT for complete evaluation of the thoracic aorta and intracranial vessels is required for follow-up. Patients who have previously undergone surgical or interventional CoA repair should be followed annually with echocardiography to assess for potential late complications, such as aortic dilatation and aneurysm formation. Evaluation of the coarctation repair site by MRI and/or CT at intervals of five years or less is also recommended. Moreover, patients should be monitored for recurrent resting or exercise-induced hypertension, which should be treated aggressively after recoarctation is excluded.

The guidelines recommend that every patient with systemic arterial hypertension have the brachial and femoral pulses palpated simultaneously.^4,8 This additional physical assessment will help detect significant aortic coarctation by assessing timing and amplitude of both pulses in search for a brachial-femoral delay. Moreover, measuring the differential pressure between bilateral arms (brachial artery) in a supine position and prone right or left supine leg (popliteal artery) BP should be performed.^4,8 Initial imaging and hemodynamic evaluation by transthoracic echocardiogram is recommended in suspected aortic coarctation.

CONCLUSION

This case represents a missed CoA and provides an example of recoarctation as a late complication after repair. Unfortunately, the critical need to screen for ­coarctation was not recognized by the patient’s primary care providers in a timely manner. Had the guidelines for CoA screening been applied, this defect would have been detected earlier, avoiding many years of cardiovascular system stress from the sequelae of hypertension.

 Measuring the BP gradient between the upper and lower extremities and searching for brachial-femoral timing delay are simple but crucial steps in the initial application of the clinical guidelines for early detection of CoA and recoarctation.

References

1. Jurcut R, Daraban AM, Lorber A, et al. Coarctation of the aorta in adults: what is the best treatment? Case report and literature review. J Med Life. 2011;4:189-195.

2. Teo LLS, Cannell T, Babu-Narayan SV, et al. Prevalence of associated cardiovascular abnormalities in 500 patients with aortic coarctation referred for cardiovascular magnetic resonance imaging to a tertiary center. Pediatr Cardiol. 2011;32:1120-1127.

3. Canniffe C. Hypertension after repair of aortic coarctation–a systematic review. Int J Cardiol. 2012;167:2456-2461.

4. Silversides CK, Kiess M, Beauchesne L, et al. Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: outflow tract obstruction, coarctation of the aorta, tetralogy of Fallot, Ebstein anomaly and Marfan’s syndrome. Can J Cardiol. 2010;26:e80-e97.

5. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for The Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease) Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52:e143-e263.

6. McBride KL, Pignatelli R, Lewin M, et al. Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: segregation, multiplex relative risk, and heritability. Am J Med Genet. Part A. 2005;134:
180-186.

7. Brown JW, Ruzmetov M, Hoyer MH, et al. Recurrent coarctation: is surgical repair of recurrent coarctation of the aorta safe and effective? Ann Thorac Surg. 2009;88:1923-1931.

8. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease). Circulation. 2008;118:2395-2451.

9. Darabian S, Zeb I, Rezaeian P, et al. Use of noninvasive imaging in the evaluation of coarctation of aorta. J Comput Assist Tomogr. 2013;37:75-78.

10. Backer CL, Mavroudis C, Zias EA, et al. Repair of coarctation with resection and extended end-to-end anastomosis. Ann Thorac Surg. 1998;66:1365-1370.

11. Cobanoglu A, Thyagarajan GK, Dobbs JL. Surgery for coarctation of the aorta in infants younger than 3 months: end-to-end repair versus subclavian flap angioplasty: is either operation better? Eur J Cardiothorac Surg. 1998;14:19-25.

12. Walhout RJ, Lekkerkerker JC, Oron GH, et al. Comparison of polytetrafluoroethylene patch aortoplasty and end-to-end anastomosis for coarctation of the aorta. J Thorac Cardiovasc Surg. 2003;126:521-528.

13. Pádua LM, Garcia LC, Rubira CJ, de Oliveira Carvalho PE. Stent placement versus surgery for coarctation of the thoracic aorta. Cochrane Database Syst Rev. 2012;5:CD008204.

14. Suárez de Lezo J, Pan M, Romero M, et al. Immediate and follow-up findings after stent treatment for severe coarctation of aorta. Am J Cardiol. 1999;83:400-406. 

At age 27, a woman with no family history of hypertension was diagnosed with the disease, which was left untreated. Two years later—during her first pregnancy—she was still hypertensive and was prescribed methyldopa, which was switched to lisinopril in the postpartum period. Her blood pressure (BP) remained elevated, despite titration of lisinopril and the addition of a β-blocking agent.

In the same year, the woman went to the emergency department with a severe headache and near-syncope; her BP was 180/100 mm Hg. Her medications were changed, and she was discharged with a prescription for captopril 50 mg bid and the angiotensin receptor blocker (ARB) valsartan 80 mg bid. Over the following six years, her average BP remained around 140/90 mm Hg with no further medication adjustment.

When the patient was 37, she underwent a chest x-ray (CXR), prompted by positive results on a purified protein derivative test at an employment physical; the CXR demonstrated a 3.6-cm mediastinal mass. This finding led to a chest CT exam that demonstrated a severe coarctation distal to the left subclavian artery with diffuse tubular hypoplasia, a collateral reconstitution of the descending aorta, and a true 2.7-cm aneurysm of one of the intercostal arteries.

The gradient between the ascending and descending aorta was 50 mm Hg, and the same wide pressure gradient was present between the upper and lower extremities (50 mm Hg).

Referral to pediatric cardiology was initiated. (It is not uncommon for an adult with a congenital heart lesion to be evaluated by a pediatric cardiologist in centers where adult congenital heart disease [ACHD] specialists are not available.) A cardiac MRI revealed a virtual interruption of the aortic arch in juxta-ductal position with multiple aortic collateral arteries. Subsequent cardiac catheterization demonstrated a transverse aortic arch at 1.2 cm and a narrowing to 7 mm just distal to the left subclavian artery, with a discrete coarctation of 2.5 mm.

With hypertension and a 50–mm Hg resting clinical gradient, corrective treatment was deemed necessary. Subsequently, balloon angioplasty was performed, and a drug-eluting stent was placed in the proximal distal aorta with dilation of the narrowing and a resultant decrease in BP gradient from 50 mm Hg to 7 mm Hg. Following stent placement, the aneurysm thrombosed secondary to reduced blood flow. Clinical reevaluation showed good dorsalis pedis and posterior tibial pulses with improved BP. The ARB was subsequently discontinued, and the patient continued to take captopril for mildly elevated BP (average, 130/85 mm Hg).

The patient did well until three years later, when she developed shortness of breath on exertion, claudication, and fatigue for a period of two weeks. On physical examination, her BP was noted to be elevated at 140/90 mm Hg with a clinical gradient of 20 mm between the upper and lower extremities and an increase in the gradient on echocardiogram to a peak of approximately 46 mm Hg and a mean of 21 mm Hg.

A subsequent chest CT demonstrated a narrowing of the previous stent site, and a right and left cardiac catheterization revealed neo-intimal proliferation affecting the stent with a 3–mm Hg gradient across the transverse arch and a 15–mm Hg gradient across the proximal descending aorta stent. The stent was subsequently redilated, and an additional stent was placed with no residual gradient.

The patient was discharged while taking clopidogrel 75 mg/d in addition to aspirin 325 mg/d for six months; antihypertensive medications were no longer necessary. Clinical evaluation with echocardiography was recommended every three months for the first year, and annually thereafter. At three-month and one-year follow-up, the patient was found to be symptom-free and normotensive (BP, 110/70 mm Hg).

DISCUSSION

Coarctation of the aorta (CoA) is a discrete narrowing of the thoracic aorta at the junction of the ductus arteriosus and the aortic arch, just distal to the subclavian artery. The specific anatomy, severity, and degree of hypoplasia proximal to the aortic coarctation are highly variable. For example, in some instances, coarctation presents as a long segment or a tubular hypoplasia.¹

The defect is often associated with other congenital cardiovascular abnormalities, including bicuspid aortic valve (BAV; reported incidence, up to 85%),^2,3 intracranial aneurysms (incidence, 3% to 10%),⁴ intrinsic abnormality in the aorta, aortic arch hypoplasia, ventricular septal defect, patent ductus arteriosus, aortic stenosis at different levels (valvular, subvalvular, or supravalvular), and mitral valve abnormalities.^2,5 There is evidence of increased familial risk for CoA and increased prevalence with certain disorders, including Turner syndrome, maternal phenylketonuria syndrome, and Kabuki syndrome.⁶

CoA accounts for 5% to 8% of all congenital heart disease,^2,3 and its incidence is 4 in 10,000 births.¹  (Adults presenting with CoA represent either recoarctation or a missed diagnosis of native coarctation.) The mean life expectancy of untreated patients with aortic coarctation is 35 years; 90% die before age 50.¹

Reduced life expectancy of patients with untreated CoA is due to systemic hypertension, accelerated coronary artery disease, stroke, heart failure, aortic rupture/dissection, cerebral hemorrhage, infective endarteritis/endocarditis, concomitant aortic valve disease (usually involving a BAV), and sudden cardiac death of presumed arrhythmogenic etiology.⁴ Even adults whose CoA has been detected early and managed with catheter-based and surgical interventions continue to face lifelong complications, including recoarctation, aneurysm formation, premature coronary artery disease, and cerebrovascular disease—mostly resulting from residual hypertension.³

Persistent hypertension has been reported in 68% of patients with repaired CoA at long-term follow-up. Hypertension may result in recurrence of CoA (incidence ranges from 5% to 50%), a residual CoA, or an idiopathic condition.⁷

The role of primary care providers is crucial in early detection and prompt referral to specialists in ACHD. For clinicians who manage these patients, increased morbidity and mortality from the associated cardiovascular sequelae pose an ongoing challenge.⁸

Presentation

Patients with hemodynamically stable coarctation in adolescence or adulthood are usually asymptomatic. Occasionally, a patient may be diagnosed with CoA based on its typical appearance on CXR or may come to medical attention because of an incidental murmur or management of hypertension.⁴ Symptoms vary in intensity and include headache, epistaxis, claudication, exertional fatigue, heart failure, aortic rupture, or dissection.⁷ Based on the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), and the 2008 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for adults with congenital heart disease, patients with hypertension and/or a history of CoA repair should be evaluated periodically for coarctation.⁸

Physical Examination

Physical assessment should include simultaneous palpation of the brachial and femoral pulses to assess amplitude and timing, looking for diminished arterial pulses and brachial-femoral delay. Additionally, measurement of supine bilateral arm (brachial artery) BP and right or left supine leg BP is recommended to detect differing pressures.⁸

The following physical findings may be suggestive of CoA or recoarctation:

• Systolic BP in the right arm higher than in the lower extremities, unless the origin of the right subclavian artery is anomalous and thus is not reliable; the left arm BP may not always be reliable because of the origin of the left subclavian artery, which may vary and may or may not be hypertensive

• Hyperdynamic carotid pulsations

• A pulse delay between the right arm and the femoral or popliteal arteries

• A murmur or bruit heard in the left interscapular position; a systolic ejection click of moderate intensity heard along the left sternal border

• In cases of BAV, an early diastolic decrescendo murmur of aortic regurgitation

Diagnostic Workup

The diagnosis of CoA is usually confirmed by echocardiography or radiographic imaging, including cardiac MRI or CT angiography.⁸

The initial diagnostic workup should include echocardiography, which may demonstrate left ventricular hypertrophy and secondary ST-T wave abnormalities, and a two-dimensional Doppler echocardiogram, which can establish the diagnosis and severity of the CoA, with possible associated cardiac defects.⁹ Also recommended is a CXR, which may occasionally reveal rib notching (caused by erosion of the inferior border of the posterior ribs by enlarged intercostal arteries), also known as the 3 sign. Finally, cardiac MRI is used to delineate the coarctation anatomy and to determine whether collateral arteries and/or associated vascular anomalies and flow abnormalities exist.⁹ If MRI is not possible, CT angiography can be an alternate approach. Subsequently, invasive angiography is required for better assessment of the coarctation gradient and hemodynamic measurement.⁹

Treatment

Management of CoA requires treatment of hypertension with β-blockers, ACE inhibitors, and/or ARBs as first-line medications. Aortic root size, the presence of aortic regurgitation, or both may influence the choice of antihypertensive agents.³

Intervention is recommended if the peak-to-peak coarctation gradient is ≥ 20 mm Hg, or the peak-to-peak coarctation gradient is < 20 mm Hg, with evidence of significant coarctation and collateral flow on radiologic imaging.⁸ The choice of treatment (stenting or surgery) should be decided by a team of ACHD cardiologists, interventionalists, and surgeons at an ACHD center.

Surgical intervention via a lateral left thoracotomy approach was first performed in 1944. The most common surgical repair is resection with end-to-end anastomosis, which yields a low mortality and recoarctation rate. Other techniques such as resection with replacement by a tube graft, patch aortoplasty, and bypass graft are used less frequently.^10-12 Postsurgical morbidity most commonly includes recoarctation and residual hypertension.

Thoracotomy was the only surgical treatment until 1982, when balloon angioplasty became available as an alternative.¹³ However, recoarctation, aneurysm formation, and aortic dissection are major disadvantages to balloon angioplasty.¹³

In the early 1990s, endovascular stents were introduced and have become an alternative approach to surgical repair.¹⁴ Aneurysms remain a significant complication in 4% to 7% of patients who undergo stent placement for CoA.¹⁴

Currently, there is insufficient evidence to indicate which is the best treatment for CoA: surgical or stent repair. Choice of treatment strategy will continue to depend on the operator’s skills or institutional preference until a prospective randomized controlled clinical trial is performed.¹³

Follow-Up

Based on recommendations from the ACC/AHA and the 2009 Canadian Cardiovascular Society Consensus Conference on the management of adults with congenital heart disease, lifelong follow-up is recommended for all patients with aortic coarctation (whether repaired or not), including an evaluation by a cardiologist with expertise in ACHD.^4,8

A baseline cardiac MRI or CT for complete evaluation of the thoracic aorta and intracranial vessels is required for follow-up. Patients who have previously undergone surgical or interventional CoA repair should be followed annually with echocardiography to assess for potential late complications, such as aortic dilatation and aneurysm formation. Evaluation of the coarctation repair site by MRI and/or CT at intervals of five years or less is also recommended. Moreover, patients should be monitored for recurrent resting or exercise-induced hypertension, which should be treated aggressively after recoarctation is excluded.

The guidelines recommend that every patient with systemic arterial hypertension have the brachial and femoral pulses palpated simultaneously.^4,8 This additional physical assessment will help detect significant aortic coarctation by assessing timing and amplitude of both pulses in search for a brachial-femoral delay. Moreover, measuring the differential pressure between bilateral arms (brachial artery) in a supine position and prone right or left supine leg (popliteal artery) BP should be performed.^4,8 Initial imaging and hemodynamic evaluation by transthoracic echocardiogram is recommended in suspected aortic coarctation.

CONCLUSION

This case represents a missed CoA and provides an example of recoarctation as a late complication after repair. Unfortunately, the critical need to screen for ­coarctation was not recognized by the patient’s primary care providers in a timely manner. Had the guidelines for CoA screening been applied, this defect would have been detected earlier, avoiding many years of cardiovascular system stress from the sequelae of hypertension.

 Measuring the BP gradient between the upper and lower extremities and searching for brachial-femoral timing delay are simple but crucial steps in the initial application of the clinical guidelines for early detection of CoA and recoarctation.

References

1. Jurcut R, Daraban AM, Lorber A, et al. Coarctation of the aorta in adults: what is the best treatment? Case report and literature review. J Med Life. 2011;4:189-195.

2. Teo LLS, Cannell T, Babu-Narayan SV, et al. Prevalence of associated cardiovascular abnormalities in 500 patients with aortic coarctation referred for cardiovascular magnetic resonance imaging to a tertiary center. Pediatr Cardiol. 2011;32:1120-1127.

3. Canniffe C. Hypertension after repair of aortic coarctation–a systematic review. Int J Cardiol. 2012;167:2456-2461.

4. Silversides CK, Kiess M, Beauchesne L, et al. Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: outflow tract obstruction, coarctation of the aorta, tetralogy of Fallot, Ebstein anomaly and Marfan’s syndrome. Can J Cardiol. 2010;26:e80-e97.

5. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for The Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease) Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52:e143-e263.

6. McBride KL, Pignatelli R, Lewin M, et al. Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: segregation, multiplex relative risk, and heritability. Am J Med Genet. Part A. 2005;134:
180-186.

7. Brown JW, Ruzmetov M, Hoyer MH, et al. Recurrent coarctation: is surgical repair of recurrent coarctation of the aorta safe and effective? Ann Thorac Surg. 2009;88:1923-1931.

8. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease). Circulation. 2008;118:2395-2451.

9. Darabian S, Zeb I, Rezaeian P, et al. Use of noninvasive imaging in the evaluation of coarctation of aorta. J Comput Assist Tomogr. 2013;37:75-78.

10. Backer CL, Mavroudis C, Zias EA, et al. Repair of coarctation with resection and extended end-to-end anastomosis. Ann Thorac Surg. 1998;66:1365-1370.

11. Cobanoglu A, Thyagarajan GK, Dobbs JL. Surgery for coarctation of the aorta in infants younger than 3 months: end-to-end repair versus subclavian flap angioplasty: is either operation better? Eur J Cardiothorac Surg. 1998;14:19-25.

12. Walhout RJ, Lekkerkerker JC, Oron GH, et al. Comparison of polytetrafluoroethylene patch aortoplasty and end-to-end anastomosis for coarctation of the aorta. J Thorac Cardiovasc Surg. 2003;126:521-528.

13. Pádua LM, Garcia LC, Rubira CJ, de Oliveira Carvalho PE. Stent placement versus surgery for coarctation of the thoracic aorta. Cochrane Database Syst Rev. 2012;5:CD008204.

14. Suárez de Lezo J, Pan M, Romero M, et al. Immediate and follow-up findings after stent treatment for severe coarctation of aorta. Am J Cardiol. 1999;83:400-406. 

How often does this happen to you? You walk into an exam room and ask the patient what brings him in today, and the reply is something like, “Well, doc, I have stomach cancer.” You do a double-take and scan the patient’s chart, looking for test results or notes from a referring provider. Finding nothing, you ask the patient for more information on his diagnosis. To your surprise/dismay/frustration, he says, “Naw, I Googled my symptoms and that’s what I came up with.”

While you can’t control the Web-surfing your patients do before they present, you can influence their information-seeking behavior once you’ve delivered a diagnosis and/or treatment plan. You know they (and their family/caregivers) will have questions about the patient’s condition and how it can be managed for the long term. You hope they’ll come to you for answers. But since they are likely to use the resources at their fingertips, you at least want to ensure the information they receive is accurate and trustworthy.

With that in mind, we asked several Clinician Reviews board members to share the Web sites that they recommend to their patients. Some, including Cathy St. Pierre, PhD, APRN, FNP-BC, FAANP, and Ellen Mandel, DMH, MPA, PA-C, CDE, cited behemoths such as the Mayo Clinic Web site (www.mayoclinic.com/health-information), lauding it for being up to date, easy to access, and “clear and data-driven.” Other board members, as you’ll see below, suggested specialty-specific sites.

Freddi I. Segal-Gidan, PhD, PA, may speak for many clinicians when she explains, “We offer these [resources] to patients and families as part of health education, acknowledging that learning about someone’s condition is the first step to better understanding what they are experiencing and how this may change over time—since most of what we deal with are progressive, lengthy illnesses and chronic disease management.”

If you have reliable Web-based resources that you recommend to your patients, please visit us on Facebook (www.facebook.com/ClinRev) to share them!

Alzheimer’s Disease
ADEAR—Alzheimer’s Disease Education and Referral Center
www.nia.nih.gov/alzheimers

Who recommends it: Freddi I. Segal-Gidan, PA, PhD

Why: Operated by the NIH/National Institute on Aging specifically to provide consumers with current, accurate, state-of-the-art information about Alzheimer’s disease and dementing illness

Also recommended: Alzheimer’s Association (www.alz.org); Family Caregiver Alliance (www.caregiver.org); UCSF Memory Center for information on frontotemporal dementia (www.memory.ucsf.edu/ftd); Foundation for Health in Aging (www.healthinaging.org); Kaiser Family Foundation for information about Medicare, Medicaid, and health policy related to aging (www.kff.org)

Cardiology
Cardiac Arrhythmias Research and Education Foundation, Inc (CARE)
www.longqt.org

Who recommends it: Lyle W. Larson, PhD, PA-C

Why: Provides an overview of long QT syndrome (eg, management, genetics); includes links to a study registry for persons with implantable cardioverters-defibrillators who are participating in sports and a complete list of medications to avoid in this patient population. The information is collated and disseminated by health care experts in this field and is updated continuously as new data emerges.

Also recommended: CredibleMeds™ (www.crediblemeds.org)

Dermatology
American Academy of Dermatology: For the Public
www.aad.org/for-the-public

Who recommends it: Joe R. Monroe, MPAS, PA

Why: Provides patient information about a specific topic or diagnosis that is reliable, up to date, and in understandable language.

eMedicine
http://emedicine.medscape.com

Who recommends it: Joe R. Monroe, MPAS, PA

Why: The information is current and written by authoritative dermatologists or other relevant specialists. References are copious and relevant, and links in the text guide readers to equally good information on related topics.

Caveats: The only problem with eMedicine is that it’s jargon-heavy and meant only for those who are comfortable with the terminology. I reserve this suggestion for more medically erudite patients (eg, nurses or PAs).

Diabetes
DiabetesMine
www.diabetesmine.com/

Who recommends it: Christine Kessler, RN, MN, CNS, ANP, BC-ADM

Why: This is an award-winning blog by an individual with type 1 diabetes, but it has something for every diabetic patient and his/her family. Really awesome. I recommend it to my patients, and some of them blog for it!

Also recommended: American Diabetes Association (www.diabetes.org/)

Nephrology
American Association of Kidney Patients
www.aakp.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: Their information is written for and by kidney patients. It is for all patients with kidney disease, not just dialysis patients. They offer free publications that emphasize living with kidney disease; these pubs are attractive, with realistic information.

Kidney School
www.kidneyschool.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: This site offers about 16 modules, each on a different topic ranging from dialysis options to sexuality. It is for patients and allows them to pick the topic they want and view the module as often as they wish.

National Kidney Foundation
www.kidney.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: The patient section of this site contains recipes and health information. Patients can register for the Kidney Peers Program, in which they match up either as a mentor or a mentee with another kidney patient in the US. It covers the range from moderate kidney disease to kidney failure and transplant.

Also recommended: DaVita (www.davita.com); Fresenius Medical Care (www.ultracare-dialysis.com)

Orthopedics
OrthoInfo
orthoinfo.aaos.org/

Who recommends it: Mike Rudzinski, RPh, RPA-C

Why: Endorsed by the American Academy of Orthopedic Surgeons, this site offers patients information on the most common musculoskeletal conditions. Includes patient education materials with anatomic pictures and discussion. This is my “go to” site for these conditions; it offers an incredible, comprehensive overview of the condition, options for care including potential surgery, and what the patient can do to improve the condition. It is easy to use for the patient—they just click on the anatomic body part involved and a list of conditions comes up.

Rheumatology
American College of Rheumatology
www.rheumatology.org/Practice/Clinical/Patients/Information_for_Patients/

Who recommends it: Rick Pope, MPAS, PA-C, DFAAPA, CPAAPA

Why: Vetted by the American College of Rheumatologists, whose faculty is nationwide, altruistic, and collaborative, it is chock full of resources that are the standard of thinking and care for rheumatic conditions. It includes “scary” diagnoses such as lupus and rheumatoid arthritis, with short, patient-specific resources that can take the sting out of the perceived notions of these diseases. The information is available in Spanish and English. The Spanish information sheets can be provided to our Hispanic population and European populations that speak primarily Spanish. This is an awesome service for those of us on the East Coast and likely more helpful in parts of the country where Spanish is spoken more commonly.

How often does this happen to you? You walk into an exam room and ask the patient what brings him in today, and the reply is something like, “Well, doc, I have stomach cancer.” You do a double-take and scan the patient’s chart, looking for test results or notes from a referring provider. Finding nothing, you ask the patient for more information on his diagnosis. To your surprise/dismay/frustration, he says, “Naw, I Googled my symptoms and that’s what I came up with.”

While you can’t control the Web-surfing your patients do before they present, you can influence their information-seeking behavior once you’ve delivered a diagnosis and/or treatment plan. You know they (and their family/caregivers) will have questions about the patient’s condition and how it can be managed for the long term. You hope they’ll come to you for answers. But since they are likely to use the resources at their fingertips, you at least want to ensure the information they receive is accurate and trustworthy.

With that in mind, we asked several Clinician Reviews board members to share the Web sites that they recommend to their patients. Some, including Cathy St. Pierre, PhD, APRN, FNP-BC, FAANP, and Ellen Mandel, DMH, MPA, PA-C, CDE, cited behemoths such as the Mayo Clinic Web site (www.mayoclinic.com/health-information), lauding it for being up to date, easy to access, and “clear and data-driven.” Other board members, as you’ll see below, suggested specialty-specific sites.

Freddi I. Segal-Gidan, PhD, PA, may speak for many clinicians when she explains, “We offer these [resources] to patients and families as part of health education, acknowledging that learning about someone’s condition is the first step to better understanding what they are experiencing and how this may change over time—since most of what we deal with are progressive, lengthy illnesses and chronic disease management.”

If you have reliable Web-based resources that you recommend to your patients, please visit us on Facebook (www.facebook.com/ClinRev) to share them!

Alzheimer’s Disease
ADEAR—Alzheimer’s Disease Education and Referral Center
www.nia.nih.gov/alzheimers

Who recommends it: Freddi I. Segal-Gidan, PA, PhD

Why: Operated by the NIH/National Institute on Aging specifically to provide consumers with current, accurate, state-of-the-art information about Alzheimer’s disease and dementing illness

Also recommended: Alzheimer’s Association (www.alz.org); Family Caregiver Alliance (www.caregiver.org); UCSF Memory Center for information on frontotemporal dementia (www.memory.ucsf.edu/ftd); Foundation for Health in Aging (www.healthinaging.org); Kaiser Family Foundation for information about Medicare, Medicaid, and health policy related to aging (www.kff.org)

Cardiology
Cardiac Arrhythmias Research and Education Foundation, Inc (CARE)
www.longqt.org

Who recommends it: Lyle W. Larson, PhD, PA-C

Why: Provides an overview of long QT syndrome (eg, management, genetics); includes links to a study registry for persons with implantable cardioverters-defibrillators who are participating in sports and a complete list of medications to avoid in this patient population. The information is collated and disseminated by health care experts in this field and is updated continuously as new data emerges.

Also recommended: CredibleMeds™ (www.crediblemeds.org)

Dermatology
American Academy of Dermatology: For the Public
www.aad.org/for-the-public

Who recommends it: Joe R. Monroe, MPAS, PA

Why: Provides patient information about a specific topic or diagnosis that is reliable, up to date, and in understandable language.

eMedicine
http://emedicine.medscape.com

Who recommends it: Joe R. Monroe, MPAS, PA

Why: The information is current and written by authoritative dermatologists or other relevant specialists. References are copious and relevant, and links in the text guide readers to equally good information on related topics.

Caveats: The only problem with eMedicine is that it’s jargon-heavy and meant only for those who are comfortable with the terminology. I reserve this suggestion for more medically erudite patients (eg, nurses or PAs).

Diabetes
DiabetesMine
www.diabetesmine.com/

Who recommends it: Christine Kessler, RN, MN, CNS, ANP, BC-ADM

Why: This is an award-winning blog by an individual with type 1 diabetes, but it has something for every diabetic patient and his/her family. Really awesome. I recommend it to my patients, and some of them blog for it!

Also recommended: American Diabetes Association (www.diabetes.org/)

Nephrology
American Association of Kidney Patients
www.aakp.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: Their information is written for and by kidney patients. It is for all patients with kidney disease, not just dialysis patients. They offer free publications that emphasize living with kidney disease; these pubs are attractive, with realistic information.

Kidney School
www.kidneyschool.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: This site offers about 16 modules, each on a different topic ranging from dialysis options to sexuality. It is for patients and allows them to pick the topic they want and view the module as often as they wish.

National Kidney Foundation
www.kidney.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: The patient section of this site contains recipes and health information. Patients can register for the Kidney Peers Program, in which they match up either as a mentor or a mentee with another kidney patient in the US. It covers the range from moderate kidney disease to kidney failure and transplant.

Also recommended: DaVita (www.davita.com); Fresenius Medical Care (www.ultracare-dialysis.com)

Orthopedics
OrthoInfo
orthoinfo.aaos.org/

Who recommends it: Mike Rudzinski, RPh, RPA-C

Why: Endorsed by the American Academy of Orthopedic Surgeons, this site offers patients information on the most common musculoskeletal conditions. Includes patient education materials with anatomic pictures and discussion. This is my “go to” site for these conditions; it offers an incredible, comprehensive overview of the condition, options for care including potential surgery, and what the patient can do to improve the condition. It is easy to use for the patient—they just click on the anatomic body part involved and a list of conditions comes up.

Rheumatology
American College of Rheumatology
www.rheumatology.org/Practice/Clinical/Patients/Information_for_Patients/

Who recommends it: Rick Pope, MPAS, PA-C, DFAAPA, CPAAPA

Why: Vetted by the American College of Rheumatologists, whose faculty is nationwide, altruistic, and collaborative, it is chock full of resources that are the standard of thinking and care for rheumatic conditions. It includes “scary” diagnoses such as lupus and rheumatoid arthritis, with short, patient-specific resources that can take the sting out of the perceived notions of these diseases. The information is available in Spanish and English. The Spanish information sheets can be provided to our Hispanic population and European populations that speak primarily Spanish. This is an awesome service for those of us on the East Coast and likely more helpful in parts of the country where Spanish is spoken more commonly.

How often does this happen to you? You walk into an exam room and ask the patient what brings him in today, and the reply is something like, “Well, doc, I have stomach cancer.” You do a double-take and scan the patient’s chart, looking for test results or notes from a referring provider. Finding nothing, you ask the patient for more information on his diagnosis. To your surprise/dismay/frustration, he says, “Naw, I Googled my symptoms and that’s what I came up with.”

While you can’t control the Web-surfing your patients do before they present, you can influence their information-seeking behavior once you’ve delivered a diagnosis and/or treatment plan. You know they (and their family/caregivers) will have questions about the patient’s condition and how it can be managed for the long term. You hope they’ll come to you for answers. But since they are likely to use the resources at their fingertips, you at least want to ensure the information they receive is accurate and trustworthy.

With that in mind, we asked several Clinician Reviews board members to share the Web sites that they recommend to their patients. Some, including Cathy St. Pierre, PhD, APRN, FNP-BC, FAANP, and Ellen Mandel, DMH, MPA, PA-C, CDE, cited behemoths such as the Mayo Clinic Web site (www.mayoclinic.com/health-information), lauding it for being up to date, easy to access, and “clear and data-driven.” Other board members, as you’ll see below, suggested specialty-specific sites.

Freddi I. Segal-Gidan, PhD, PA, may speak for many clinicians when she explains, “We offer these [resources] to patients and families as part of health education, acknowledging that learning about someone’s condition is the first step to better understanding what they are experiencing and how this may change over time—since most of what we deal with are progressive, lengthy illnesses and chronic disease management.”

If you have reliable Web-based resources that you recommend to your patients, please visit us on Facebook (www.facebook.com/ClinRev) to share them!

Alzheimer’s Disease
ADEAR—Alzheimer’s Disease Education and Referral Center
www.nia.nih.gov/alzheimers

Who recommends it: Freddi I. Segal-Gidan, PA, PhD

Why: Operated by the NIH/National Institute on Aging specifically to provide consumers with current, accurate, state-of-the-art information about Alzheimer’s disease and dementing illness

Also recommended: Alzheimer’s Association (www.alz.org); Family Caregiver Alliance (www.caregiver.org); UCSF Memory Center for information on frontotemporal dementia (www.memory.ucsf.edu/ftd); Foundation for Health in Aging (www.healthinaging.org); Kaiser Family Foundation for information about Medicare, Medicaid, and health policy related to aging (www.kff.org)

Cardiology
Cardiac Arrhythmias Research and Education Foundation, Inc (CARE)
www.longqt.org

Who recommends it: Lyle W. Larson, PhD, PA-C

Why: Provides an overview of long QT syndrome (eg, management, genetics); includes links to a study registry for persons with implantable cardioverters-defibrillators who are participating in sports and a complete list of medications to avoid in this patient population. The information is collated and disseminated by health care experts in this field and is updated continuously as new data emerges.

Also recommended: CredibleMeds™ (www.crediblemeds.org)

Dermatology
American Academy of Dermatology: For the Public
www.aad.org/for-the-public

Who recommends it: Joe R. Monroe, MPAS, PA

Why: Provides patient information about a specific topic or diagnosis that is reliable, up to date, and in understandable language.

eMedicine
http://emedicine.medscape.com

Who recommends it: Joe R. Monroe, MPAS, PA

Why: The information is current and written by authoritative dermatologists or other relevant specialists. References are copious and relevant, and links in the text guide readers to equally good information on related topics.

Caveats: The only problem with eMedicine is that it’s jargon-heavy and meant only for those who are comfortable with the terminology. I reserve this suggestion for more medically erudite patients (eg, nurses or PAs).

Diabetes
DiabetesMine
www.diabetesmine.com/

Who recommends it: Christine Kessler, RN, MN, CNS, ANP, BC-ADM

Why: This is an award-winning blog by an individual with type 1 diabetes, but it has something for every diabetic patient and his/her family. Really awesome. I recommend it to my patients, and some of them blog for it!

Also recommended: American Diabetes Association (www.diabetes.org/)

Nephrology
American Association of Kidney Patients
www.aakp.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: Their information is written for and by kidney patients. It is for all patients with kidney disease, not just dialysis patients. They offer free publications that emphasize living with kidney disease; these pubs are attractive, with realistic information.

Kidney School
www.kidneyschool.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: This site offers about 16 modules, each on a different topic ranging from dialysis options to sexuality. It is for patients and allows them to pick the topic they want and view the module as often as they wish.

National Kidney Foundation
www.kidney.org

Who recommends it: Jane S. Davis, DNP, CRNP

Why: The patient section of this site contains recipes and health information. Patients can register for the Kidney Peers Program, in which they match up either as a mentor or a mentee with another kidney patient in the US. It covers the range from moderate kidney disease to kidney failure and transplant.

Also recommended: DaVita (www.davita.com); Fresenius Medical Care (www.ultracare-dialysis.com)

Orthopedics
OrthoInfo
orthoinfo.aaos.org/

Who recommends it: Mike Rudzinski, RPh, RPA-C

Why: Endorsed by the American Academy of Orthopedic Surgeons, this site offers patients information on the most common musculoskeletal conditions. Includes patient education materials with anatomic pictures and discussion. This is my “go to” site for these conditions; it offers an incredible, comprehensive overview of the condition, options for care including potential surgery, and what the patient can do to improve the condition. It is easy to use for the patient—they just click on the anatomic body part involved and a list of conditions comes up.

Rheumatology
American College of Rheumatology
www.rheumatology.org/Practice/Clinical/Patients/Information_for_Patients/

Who recommends it: Rick Pope, MPAS, PA-C, DFAAPA, CPAAPA

Why: Vetted by the American College of Rheumatologists, whose faculty is nationwide, altruistic, and collaborative, it is chock full of resources that are the standard of thinking and care for rheumatic conditions. It includes “scary” diagnoses such as lupus and rheumatoid arthritis, with short, patient-specific resources that can take the sting out of the perceived notions of these diseases. The information is available in Spanish and English. The Spanish information sheets can be provided to our Hispanic population and European populations that speak primarily Spanish. This is an awesome service for those of us on the East Coast and likely more helpful in parts of the country where Spanish is spoken more commonly.

Endometrial cancer is the most common malignancy of the female reproductive tract in the United States, and its incidence continues to rise, with an estimated 49,560 new cases predicted for 2013.¹ If we are to successfully traverse the pathway from molecular cell genetics to the development of targeted therapies and personalized cancer care, we need to meet a few benchmarks:

• We need to enhance our understanding of the molecular changes that lead to endometrial cancer. Of particular interest are nonendometrioid tumors. Increased mortality from endometrial cancer appears to be related to the growing number of uterine papillary serous carcinomas and clear-cell cancers. Although these cancers constitute less than 10% of all endometrial cancers, they account for a disproportionately high number of recurrences and cancer-related deaths.^2,3 Do recent studies validate the original classification of endometrial cancers as Type I (endometrioid) or Type II (serous and clear cell), or is there more heterogeneity than was originally thought? How do recent studies affect treatment options?
• We need to establish a genomic characterization of endometrial cancer to supplement clinical research data. The identification of novel mutations specific to each histologic type has the potential to improve adjuvant therapy. How close are we to performing a comprehensive genomic analysis of endometrial cancer?
• We need to develop new adjuvant treatment options for recurrent and advanced disease. When clinical symptoms of endometrial cancer are overt, as they often are, early diagnosis is possible, with a 5-year survival rate of 80% to 90%. The prognosis declines dramatically in women with advanced-stage disease or high-risk histologies, with a 5-year survival rate of 57% and 19% for Stage III and Stage IV disease, respectively.¹ Adjuvant treatment options are limited in the setting of recurrent or advanced disease. Do any biologic agents increase survival?

In this article, we highlight the historical foundation and newest advances in the field of endometrial cancer, focusing on:

• histologic classification
• etiologic heterogeneity and molecular biology
• genome-guided clinical trials involving targeted therapy, with the ultimate goal of achieving individualized cancer care.

Should we reclassify endometrial cancers to reflect molecular characteristics of tumors?

Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013;129(2):277–284.

Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

Uterine papillary serous carcinoma (UPSC) was first established as a distinct subtype of endometrial cancer in the early 1980s, when teams led by Lauchlan4 and Hendrickson5 described it as histologically similar to serous epithelial ovarian carcinoma. Shortly thereafter, Bokhman proposed two broad categories of endometrial carcinoma characterized by distinct microscopic appearance, epidemiology, and endocrine and metabolic functioning (TABLE, page 28).6

More recently, research has focused on expanding this histologic classification system to encompass molecular differences. Brinton and colleagues conducted a study within Gynecologic Oncology Group 210, investigating the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologies. They found that risk factors for aggressive endometrial cancers, including Grade 3 endometrioid and nonendometrioid tumors, appear to differ from those of lower-grade endometrioid carcinomas.

Details of the study by Brinton and colleagues
A total of 3,434 women were included, representing endometrioid (78%) and serous (9%) carcinomas. Grade 3 endometrioid tumors resembled Type II endometrial cancers more closely than did Grade 1–2 endometrioid tumors. Patients with Grade 3 endometrioid and Type II cancers were diagnosed at a significantly older age than patients with Grades 1–2 endometrioid cancers (eg, diagnosis of serous cancers: median age, 67.4 years; Grade 3 endometrioid cancers: median age, 61.9 years; Grade 1–2 endometrioid cancers: median age, 59.6 years). They also were more likely to be nonwhite than patients with Grades 1–2 endometrioid histology. Specifically, black patients were rarely diagnosed with Grades 1–2 endometrioid cancers (5% vs 9% for Grade 3 endometrioid cancers; 20% for serous cancers, 23% for carcinosarcomas, and 12% for clear-cell cancers).

After adjustments for age, enrollment year, and race, patients with Type II tumors (serous, carcinosarcomas, or clear-cell tumors) were much more likely to be multiparous or smokers or to have a history of breast cancer treated with tamoxifen, compared with women with Grade 1–2 endometrioid cancers. An adequately powered subanalysis of serous carcinomas and Grades 1–2 endometrioid cancers revealed that associations persisted between serous carcinomas and multiparity, body mass index, and a history of breast cancer treated with tamoxifen.

Related article: The future of the Pap test: Identifying endometrial and ovarian cancers (Janelle Yates, August 2013)

Overall, this study provides some of the strongest epidemiologic support we have that endometrial cancers are heterogeneous, with evidence to suggest that we might classify Grade 3 endometrioid carcinomas as Type II cancers. These findings paved the way for molecular profiling of endometrial cancers.

Details of the study by the Cancer Genome Atlas Research Network
The Cancer Genome Atlas Research Network recently published an integrated genomic, transcriptomic, and proteomic ­characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The goal was to provide better insight into disease biology and tumor classification to help guide clinical trials and drug development, with the ultimate goal of achieving personalized cancer care.

The group classified endometrial cancers into four new categories:

• polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
• microsatellite instability (MSI) hypermutated
• somatic copy number alterations (SCNA) low
• SCNA high.

Most endometrioid tumors had few SCNA or P53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS genes. Novel mutations also were discovered in the SWI/SNF chromatin remodeling complex gene ARID5B. About 10% of endometrioid tumors had markedly increased transversion mutations and newly identified mutations in POLE, a gene involved in nuclear DNA replication and repair.

As expected, serous tumors had significantly worse progression-free survival (PFS) than endometrioid tumors (P = .003, log-rank). A subset (25%) of high-grade endometrioid tumors had SCNAs and mutation spectra similar to those of uterine serous carcinomas, suggesting that patients with such tumors might benefit from treatment options that parallel those for serous tumors.

Other overlapping treatment paradigms existed between different organ systems. For example, some molecular features were similar in uterine serous carcinomas, basal-like breast carcinomas, and high-grade serous ovarian carcinomas. All three carcinomas displayed a high frequency of P53 mutations, very low frequency of PTEN mutations, similar focal SCNA patterns, and minimal DNA methylation changes. However, investigators also found several mutations that are unique to uterine serous carcinomas (eg, PIK3CA, FBXW7, PPP2R1A, and ARID1A), providing potential opportunities for targeted pharmacotherapy.

What this evidence means for practice
These studies highlight the etiologic heterogeneity of endometrial cancer. The histologic groundwork laid by Bokhman was not only correct but provided a foundation for molecular characterization of endometrial cancers to drive translational science into targeted therapeutics.

The similar molecular phenotypes of high-grade endometrioid carcinomas and serous endometrial carcinomas strengthens existing evidence that chemotherapy may be preferable to adjuvant radiotherapy for patients with highly mutated endometrioid cancers (eg, SCNA). Current chemotherapy regimens for serous endometrial cancers remain appropriate, given the compelling similarities between these cancers and serous ovarian and basal-like breast cancers. However, the identification of unique molecular features not shared by breast or ovarian cancer may expand standard options to include more targeted therapy.

Overall, this type of research, which encompasses proper histologic classification refined by genomics, has the potential to achieve personalized cancer care.

How we are achieving individualized cancer care: 3 genome-guided clinical trials

Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285.

Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265.

Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27.

Women with locally recurrent, advanced, or metastatic endometrial cancer have limited options for treatment. Hormonal therapies have modest effects at best, with a median survival rate of 7 to 12 months.^7–9 To address this lack of options, researchers have begun to focus on targeted therapies directed at molecular pathways of cellular proliferation. These therapies include but are not limited to inhibitors of:

• mammalian target of rapamycin (mTOR)
• human epidermal growth factor receptor 2
• epidermal growth factor receptor
• vascular endothelial growth factor (VEGF).

Several studies have produced promising findings in recent years. They involve ­investigations of temsirolimus and bevacizumab as single agents in two independent clinical trials, and a study of the drugs in combination in women with recurrent or persistent endometrial carcinoma.

mTOR inhibitors elicited a greater response in chemotherapy-naïve women
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene more commonly associated with endometrioid endometrial cancers (26%–80%) than with Type II cancers.¹⁰ Loss of PTEN expression leads to deregulated signaling of the phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway. Disruption of this pathway is thought to provide cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell-cycle progression.¹⁰

Temsirolimus is an mTOR inhibitor recently explored by Oza and colleagues. They performed a multicenter, Phase II study involving 62 patients with recurrent and/or metastatic endometrial cancer as part of the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Patients were divided into two groups on the basis of their treatment history:

• chemotherapy-naïve women, with no more than one prior hormonal treatment (n = 33)
• chemotherapy-treated women (n = 27).

Temsirolimus was given weekly in 4-week cycles at an intravenous (IV) dose of 25 mg over 30 minutes.

The drug elicited a response regardless of the histologic type of cancer. That response was more pronounced in chemotherapy-naïve women and not limited to patients with PTEN loss. In the chemotherapy-naïve group, four women (14%) had a partial response, 20 (69%) had stable disease, and five (18%) had progressive disease. Median PFS was 7.33 months (95% confidence interval [CI], 3.61–9.86), compared with 3.25 months (95% CI, 1.97–3.84) in chemotherapy-treated women. Among chemotherapy-treated women, one (4%) had a partial response and 12 (48%) had stable disease.

An angiogenesis inhibitor alone was well tolerated
VEGF is the principal growth factor responsible for angiogenesis, initiating the process of neovascularization. Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A, stimulating clinical effects in multiple tumor types, including persistent or recurrent ovarian and cervical cancers.

Aghajanian and colleagues conducted a Phase II trial of single-agent bevacizumab in women with recurrent or persistent endometrial cancer to assess the drug’s activity and tolerability. Eligible patients had histologic confirmation by central pathology review, recurrent or persistent disease after one or two cytotoxic regimens, and a Gynecologic Oncology Group performance score of 2 or lower. They received IV bevacizumab 15 mg/kg every 3 weeks until the disease progressed or toxicity became prohibitive. Fifty-two women participated.

Seven women (13.5%) experienced a clinical response (one complete response and six partial responses), and 21 (40%) had PFS of at least 6 months. Median PFS and overall survival were 4.2 and 10.5 months, respectively.

Combined with temsirolimus, bevacizumab increased overall survival

Alvarez and colleagues conducted a Phase II trial of combination bevacizumab and temsirolimus in women with recurrent or persistent endometrial carcinoma. Forty-nine patients participated.

These women had undergone earlier treatment with one (82%) or two (18%) chemotherapy regimens and radiation (41%). Median PFS and overall survival were 5.6 and 16.9 months, respectively. Toxicity was significant, with 38.8% of women withdrawn from the study due to toxicity.  

What this evidence means for practice
Given the findings regarding temsirolimus and bevacizumab as single agents, their use in combination was expected to produce a robust effect. The 6-month PFS rate is similar for all three regimens, but for overall survival, combination therapy had a 6.4-month advantage over bevacizumab alone.

Given the significant toxicity associated with the combination of bevacizumab and temsirolimus, further study is needed to develop biomarkers to predict response and toxicity. Other areas meriting future research include optimal timing of angiogenesis and mTOR pathway inhibitors, different combinations of agents, and the identification, through genomic analysis, of patient populations most likely to benefit from these drugs with minimal toxicity.

The studies presented here show promise in the area of genomics and represent the beginning of our movement toward personalized cancer care.

We want to hear from you!  Tell us what you think.

Endometrial cancer is the most common malignancy of the female reproductive tract in the United States, and its incidence continues to rise, with an estimated 49,560 new cases predicted for 2013.¹ If we are to successfully traverse the pathway from molecular cell genetics to the development of targeted therapies and personalized cancer care, we need to meet a few benchmarks:

• We need to enhance our understanding of the molecular changes that lead to endometrial cancer. Of particular interest are nonendometrioid tumors. Increased mortality from endometrial cancer appears to be related to the growing number of uterine papillary serous carcinomas and clear-cell cancers. Although these cancers constitute less than 10% of all endometrial cancers, they account for a disproportionately high number of recurrences and cancer-related deaths.^2,3 Do recent studies validate the original classification of endometrial cancers as Type I (endometrioid) or Type II (serous and clear cell), or is there more heterogeneity than was originally thought? How do recent studies affect treatment options?
• We need to establish a genomic characterization of endometrial cancer to supplement clinical research data. The identification of novel mutations specific to each histologic type has the potential to improve adjuvant therapy. How close are we to performing a comprehensive genomic analysis of endometrial cancer?
• We need to develop new adjuvant treatment options for recurrent and advanced disease. When clinical symptoms of endometrial cancer are overt, as they often are, early diagnosis is possible, with a 5-year survival rate of 80% to 90%. The prognosis declines dramatically in women with advanced-stage disease or high-risk histologies, with a 5-year survival rate of 57% and 19% for Stage III and Stage IV disease, respectively.¹ Adjuvant treatment options are limited in the setting of recurrent or advanced disease. Do any biologic agents increase survival?

In this article, we highlight the historical foundation and newest advances in the field of endometrial cancer, focusing on:

• histologic classification
• etiologic heterogeneity and molecular biology
• genome-guided clinical trials involving targeted therapy, with the ultimate goal of achieving individualized cancer care.

Should we reclassify endometrial cancers to reflect molecular characteristics of tumors?

Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013;129(2):277–284.

Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

Uterine papillary serous carcinoma (UPSC) was first established as a distinct subtype of endometrial cancer in the early 1980s, when teams led by Lauchlan4 and Hendrickson5 described it as histologically similar to serous epithelial ovarian carcinoma. Shortly thereafter, Bokhman proposed two broad categories of endometrial carcinoma characterized by distinct microscopic appearance, epidemiology, and endocrine and metabolic functioning (TABLE, page 28).6

More recently, research has focused on expanding this histologic classification system to encompass molecular differences. Brinton and colleagues conducted a study within Gynecologic Oncology Group 210, investigating the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologies. They found that risk factors for aggressive endometrial cancers, including Grade 3 endometrioid and nonendometrioid tumors, appear to differ from those of lower-grade endometrioid carcinomas.

Details of the study by Brinton and colleagues
A total of 3,434 women were included, representing endometrioid (78%) and serous (9%) carcinomas. Grade 3 endometrioid tumors resembled Type II endometrial cancers more closely than did Grade 1–2 endometrioid tumors. Patients with Grade 3 endometrioid and Type II cancers were diagnosed at a significantly older age than patients with Grades 1–2 endometrioid cancers (eg, diagnosis of serous cancers: median age, 67.4 years; Grade 3 endometrioid cancers: median age, 61.9 years; Grade 1–2 endometrioid cancers: median age, 59.6 years). They also were more likely to be nonwhite than patients with Grades 1–2 endometrioid histology. Specifically, black patients were rarely diagnosed with Grades 1–2 endometrioid cancers (5% vs 9% for Grade 3 endometrioid cancers; 20% for serous cancers, 23% for carcinosarcomas, and 12% for clear-cell cancers).

After adjustments for age, enrollment year, and race, patients with Type II tumors (serous, carcinosarcomas, or clear-cell tumors) were much more likely to be multiparous or smokers or to have a history of breast cancer treated with tamoxifen, compared with women with Grade 1–2 endometrioid cancers. An adequately powered subanalysis of serous carcinomas and Grades 1–2 endometrioid cancers revealed that associations persisted between serous carcinomas and multiparity, body mass index, and a history of breast cancer treated with tamoxifen.

Related article: The future of the Pap test: Identifying endometrial and ovarian cancers (Janelle Yates, August 2013)

Overall, this study provides some of the strongest epidemiologic support we have that endometrial cancers are heterogeneous, with evidence to suggest that we might classify Grade 3 endometrioid carcinomas as Type II cancers. These findings paved the way for molecular profiling of endometrial cancers.

Details of the study by the Cancer Genome Atlas Research Network
The Cancer Genome Atlas Research Network recently published an integrated genomic, transcriptomic, and proteomic ­characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The goal was to provide better insight into disease biology and tumor classification to help guide clinical trials and drug development, with the ultimate goal of achieving personalized cancer care.

The group classified endometrial cancers into four new categories:

• polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
• microsatellite instability (MSI) hypermutated
• somatic copy number alterations (SCNA) low
• SCNA high.

Most endometrioid tumors had few SCNA or P53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS genes. Novel mutations also were discovered in the SWI/SNF chromatin remodeling complex gene ARID5B. About 10% of endometrioid tumors had markedly increased transversion mutations and newly identified mutations in POLE, a gene involved in nuclear DNA replication and repair.

As expected, serous tumors had significantly worse progression-free survival (PFS) than endometrioid tumors (P = .003, log-rank). A subset (25%) of high-grade endometrioid tumors had SCNAs and mutation spectra similar to those of uterine serous carcinomas, suggesting that patients with such tumors might benefit from treatment options that parallel those for serous tumors.

Other overlapping treatment paradigms existed between different organ systems. For example, some molecular features were similar in uterine serous carcinomas, basal-like breast carcinomas, and high-grade serous ovarian carcinomas. All three carcinomas displayed a high frequency of P53 mutations, very low frequency of PTEN mutations, similar focal SCNA patterns, and minimal DNA methylation changes. However, investigators also found several mutations that are unique to uterine serous carcinomas (eg, PIK3CA, FBXW7, PPP2R1A, and ARID1A), providing potential opportunities for targeted pharmacotherapy.

What this evidence means for practice
These studies highlight the etiologic heterogeneity of endometrial cancer. The histologic groundwork laid by Bokhman was not only correct but provided a foundation for molecular characterization of endometrial cancers to drive translational science into targeted therapeutics.

The similar molecular phenotypes of high-grade endometrioid carcinomas and serous endometrial carcinomas strengthens existing evidence that chemotherapy may be preferable to adjuvant radiotherapy for patients with highly mutated endometrioid cancers (eg, SCNA). Current chemotherapy regimens for serous endometrial cancers remain appropriate, given the compelling similarities between these cancers and serous ovarian and basal-like breast cancers. However, the identification of unique molecular features not shared by breast or ovarian cancer may expand standard options to include more targeted therapy.

Overall, this type of research, which encompasses proper histologic classification refined by genomics, has the potential to achieve personalized cancer care.

How we are achieving individualized cancer care: 3 genome-guided clinical trials

Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285.

Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265.

Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27.

Women with locally recurrent, advanced, or metastatic endometrial cancer have limited options for treatment. Hormonal therapies have modest effects at best, with a median survival rate of 7 to 12 months.^7–9 To address this lack of options, researchers have begun to focus on targeted therapies directed at molecular pathways of cellular proliferation. These therapies include but are not limited to inhibitors of:

• mammalian target of rapamycin (mTOR)
• human epidermal growth factor receptor 2
• epidermal growth factor receptor
• vascular endothelial growth factor (VEGF).

Several studies have produced promising findings in recent years. They involve ­investigations of temsirolimus and bevacizumab as single agents in two independent clinical trials, and a study of the drugs in combination in women with recurrent or persistent endometrial carcinoma.

mTOR inhibitors elicited a greater response in chemotherapy-naïve women
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene more commonly associated with endometrioid endometrial cancers (26%–80%) than with Type II cancers.¹⁰ Loss of PTEN expression leads to deregulated signaling of the phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway. Disruption of this pathway is thought to provide cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell-cycle progression.¹⁰

Temsirolimus is an mTOR inhibitor recently explored by Oza and colleagues. They performed a multicenter, Phase II study involving 62 patients with recurrent and/or metastatic endometrial cancer as part of the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Patients were divided into two groups on the basis of their treatment history:

• chemotherapy-naïve women, with no more than one prior hormonal treatment (n = 33)
• chemotherapy-treated women (n = 27).

Temsirolimus was given weekly in 4-week cycles at an intravenous (IV) dose of 25 mg over 30 minutes.

The drug elicited a response regardless of the histologic type of cancer. That response was more pronounced in chemotherapy-naïve women and not limited to patients with PTEN loss. In the chemotherapy-naïve group, four women (14%) had a partial response, 20 (69%) had stable disease, and five (18%) had progressive disease. Median PFS was 7.33 months (95% confidence interval [CI], 3.61–9.86), compared with 3.25 months (95% CI, 1.97–3.84) in chemotherapy-treated women. Among chemotherapy-treated women, one (4%) had a partial response and 12 (48%) had stable disease.

An angiogenesis inhibitor alone was well tolerated
VEGF is the principal growth factor responsible for angiogenesis, initiating the process of neovascularization. Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A, stimulating clinical effects in multiple tumor types, including persistent or recurrent ovarian and cervical cancers.

Aghajanian and colleagues conducted a Phase II trial of single-agent bevacizumab in women with recurrent or persistent endometrial cancer to assess the drug’s activity and tolerability. Eligible patients had histologic confirmation by central pathology review, recurrent or persistent disease after one or two cytotoxic regimens, and a Gynecologic Oncology Group performance score of 2 or lower. They received IV bevacizumab 15 mg/kg every 3 weeks until the disease progressed or toxicity became prohibitive. Fifty-two women participated.

Seven women (13.5%) experienced a clinical response (one complete response and six partial responses), and 21 (40%) had PFS of at least 6 months. Median PFS and overall survival were 4.2 and 10.5 months, respectively.

Combined with temsirolimus, bevacizumab increased overall survival

Alvarez and colleagues conducted a Phase II trial of combination bevacizumab and temsirolimus in women with recurrent or persistent endometrial carcinoma. Forty-nine patients participated.

These women had undergone earlier treatment with one (82%) or two (18%) chemotherapy regimens and radiation (41%). Median PFS and overall survival were 5.6 and 16.9 months, respectively. Toxicity was significant, with 38.8% of women withdrawn from the study due to toxicity.  

What this evidence means for practice
Given the findings regarding temsirolimus and bevacizumab as single agents, their use in combination was expected to produce a robust effect. The 6-month PFS rate is similar for all three regimens, but for overall survival, combination therapy had a 6.4-month advantage over bevacizumab alone.

Given the significant toxicity associated with the combination of bevacizumab and temsirolimus, further study is needed to develop biomarkers to predict response and toxicity. Other areas meriting future research include optimal timing of angiogenesis and mTOR pathway inhibitors, different combinations of agents, and the identification, through genomic analysis, of patient populations most likely to benefit from these drugs with minimal toxicity.

The studies presented here show promise in the area of genomics and represent the beginning of our movement toward personalized cancer care.

We want to hear from you!  Tell us what you think.

Endometrial cancer is the most common malignancy of the female reproductive tract in the United States, and its incidence continues to rise, with an estimated 49,560 new cases predicted for 2013.¹ If we are to successfully traverse the pathway from molecular cell genetics to the development of targeted therapies and personalized cancer care, we need to meet a few benchmarks:

• We need to enhance our understanding of the molecular changes that lead to endometrial cancer. Of particular interest are nonendometrioid tumors. Increased mortality from endometrial cancer appears to be related to the growing number of uterine papillary serous carcinomas and clear-cell cancers. Although these cancers constitute less than 10% of all endometrial cancers, they account for a disproportionately high number of recurrences and cancer-related deaths.^2,3 Do recent studies validate the original classification of endometrial cancers as Type I (endometrioid) or Type II (serous and clear cell), or is there more heterogeneity than was originally thought? How do recent studies affect treatment options?
• We need to establish a genomic characterization of endometrial cancer to supplement clinical research data. The identification of novel mutations specific to each histologic type has the potential to improve adjuvant therapy. How close are we to performing a comprehensive genomic analysis of endometrial cancer?
• We need to develop new adjuvant treatment options for recurrent and advanced disease. When clinical symptoms of endometrial cancer are overt, as they often are, early diagnosis is possible, with a 5-year survival rate of 80% to 90%. The prognosis declines dramatically in women with advanced-stage disease or high-risk histologies, with a 5-year survival rate of 57% and 19% for Stage III and Stage IV disease, respectively.¹ Adjuvant treatment options are limited in the setting of recurrent or advanced disease. Do any biologic agents increase survival?

In this article, we highlight the historical foundation and newest advances in the field of endometrial cancer, focusing on:

• histologic classification
• etiologic heterogeneity and molecular biology
• genome-guided clinical trials involving targeted therapy, with the ultimate goal of achieving individualized cancer care.

Should we reclassify endometrial cancers to reflect molecular characteristics of tumors?

Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013;129(2):277–284.

Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

Uterine papillary serous carcinoma (UPSC) was first established as a distinct subtype of endometrial cancer in the early 1980s, when teams led by Lauchlan4 and Hendrickson5 described it as histologically similar to serous epithelial ovarian carcinoma. Shortly thereafter, Bokhman proposed two broad categories of endometrial carcinoma characterized by distinct microscopic appearance, epidemiology, and endocrine and metabolic functioning (TABLE, page 28).6

More recently, research has focused on expanding this histologic classification system to encompass molecular differences. Brinton and colleagues conducted a study within Gynecologic Oncology Group 210, investigating the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologies. They found that risk factors for aggressive endometrial cancers, including Grade 3 endometrioid and nonendometrioid tumors, appear to differ from those of lower-grade endometrioid carcinomas.

Details of the study by Brinton and colleagues
A total of 3,434 women were included, representing endometrioid (78%) and serous (9%) carcinomas. Grade 3 endometrioid tumors resembled Type II endometrial cancers more closely than did Grade 1–2 endometrioid tumors. Patients with Grade 3 endometrioid and Type II cancers were diagnosed at a significantly older age than patients with Grades 1–2 endometrioid cancers (eg, diagnosis of serous cancers: median age, 67.4 years; Grade 3 endometrioid cancers: median age, 61.9 years; Grade 1–2 endometrioid cancers: median age, 59.6 years). They also were more likely to be nonwhite than patients with Grades 1–2 endometrioid histology. Specifically, black patients were rarely diagnosed with Grades 1–2 endometrioid cancers (5% vs 9% for Grade 3 endometrioid cancers; 20% for serous cancers, 23% for carcinosarcomas, and 12% for clear-cell cancers).

After adjustments for age, enrollment year, and race, patients with Type II tumors (serous, carcinosarcomas, or clear-cell tumors) were much more likely to be multiparous or smokers or to have a history of breast cancer treated with tamoxifen, compared with women with Grade 1–2 endometrioid cancers. An adequately powered subanalysis of serous carcinomas and Grades 1–2 endometrioid cancers revealed that associations persisted between serous carcinomas and multiparity, body mass index, and a history of breast cancer treated with tamoxifen.

Related article: The future of the Pap test: Identifying endometrial and ovarian cancers (Janelle Yates, August 2013)

Overall, this study provides some of the strongest epidemiologic support we have that endometrial cancers are heterogeneous, with evidence to suggest that we might classify Grade 3 endometrioid carcinomas as Type II cancers. These findings paved the way for molecular profiling of endometrial cancers.

Details of the study by the Cancer Genome Atlas Research Network
The Cancer Genome Atlas Research Network recently published an integrated genomic, transcriptomic, and proteomic ­characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. The goal was to provide better insight into disease biology and tumor classification to help guide clinical trials and drug development, with the ultimate goal of achieving personalized cancer care.

The group classified endometrial cancers into four new categories:

• polymerase (DNA-directed) epsilon catalytic subunit (POLE) ultramutated
• microsatellite instability (MSI) hypermutated
• somatic copy number alterations (SCNA) low
• SCNA high.

Most endometrioid tumors had few SCNA or P53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, and KRAS genes. Novel mutations also were discovered in the SWI/SNF chromatin remodeling complex gene ARID5B. About 10% of endometrioid tumors had markedly increased transversion mutations and newly identified mutations in POLE, a gene involved in nuclear DNA replication and repair.

As expected, serous tumors had significantly worse progression-free survival (PFS) than endometrioid tumors (P = .003, log-rank). A subset (25%) of high-grade endometrioid tumors had SCNAs and mutation spectra similar to those of uterine serous carcinomas, suggesting that patients with such tumors might benefit from treatment options that parallel those for serous tumors.

Other overlapping treatment paradigms existed between different organ systems. For example, some molecular features were similar in uterine serous carcinomas, basal-like breast carcinomas, and high-grade serous ovarian carcinomas. All three carcinomas displayed a high frequency of P53 mutations, very low frequency of PTEN mutations, similar focal SCNA patterns, and minimal DNA methylation changes. However, investigators also found several mutations that are unique to uterine serous carcinomas (eg, PIK3CA, FBXW7, PPP2R1A, and ARID1A), providing potential opportunities for targeted pharmacotherapy.

What this evidence means for practice
These studies highlight the etiologic heterogeneity of endometrial cancer. The histologic groundwork laid by Bokhman was not only correct but provided a foundation for molecular characterization of endometrial cancers to drive translational science into targeted therapeutics.

The similar molecular phenotypes of high-grade endometrioid carcinomas and serous endometrial carcinomas strengthens existing evidence that chemotherapy may be preferable to adjuvant radiotherapy for patients with highly mutated endometrioid cancers (eg, SCNA). Current chemotherapy regimens for serous endometrial cancers remain appropriate, given the compelling similarities between these cancers and serous ovarian and basal-like breast cancers. However, the identification of unique molecular features not shared by breast or ovarian cancer may expand standard options to include more targeted therapy.

Overall, this type of research, which encompasses proper histologic classification refined by genomics, has the potential to achieve personalized cancer care.

How we are achieving individualized cancer care: 3 genome-guided clinical trials

Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011;29(24):3278–3285.

Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265.

Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27.

Women with locally recurrent, advanced, or metastatic endometrial cancer have limited options for treatment. Hormonal therapies have modest effects at best, with a median survival rate of 7 to 12 months.^7–9 To address this lack of options, researchers have begun to focus on targeted therapies directed at molecular pathways of cellular proliferation. These therapies include but are not limited to inhibitors of:

• mammalian target of rapamycin (mTOR)
• human epidermal growth factor receptor 2
• epidermal growth factor receptor
• vascular endothelial growth factor (VEGF).

Several studies have produced promising findings in recent years. They involve ­investigations of temsirolimus and bevacizumab as single agents in two independent clinical trials, and a study of the drugs in combination in women with recurrent or persistent endometrial carcinoma.

mTOR inhibitors elicited a greater response in chemotherapy-naïve women
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene more commonly associated with endometrioid endometrial cancers (26%–80%) than with Type II cancers.¹⁰ Loss of PTEN expression leads to deregulated signaling of the phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway. Disruption of this pathway is thought to provide cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell-cycle progression.¹⁰

Temsirolimus is an mTOR inhibitor recently explored by Oza and colleagues. They performed a multicenter, Phase II study involving 62 patients with recurrent and/or metastatic endometrial cancer as part of the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Patients were divided into two groups on the basis of their treatment history:

• chemotherapy-naïve women, with no more than one prior hormonal treatment (n = 33)
• chemotherapy-treated women (n = 27).

Temsirolimus was given weekly in 4-week cycles at an intravenous (IV) dose of 25 mg over 30 minutes.

The drug elicited a response regardless of the histologic type of cancer. That response was more pronounced in chemotherapy-naïve women and not limited to patients with PTEN loss. In the chemotherapy-naïve group, four women (14%) had a partial response, 20 (69%) had stable disease, and five (18%) had progressive disease. Median PFS was 7.33 months (95% confidence interval [CI], 3.61–9.86), compared with 3.25 months (95% CI, 1.97–3.84) in chemotherapy-treated women. Among chemotherapy-treated women, one (4%) had a partial response and 12 (48%) had stable disease.

An angiogenesis inhibitor alone was well tolerated
VEGF is the principal growth factor responsible for angiogenesis, initiating the process of neovascularization. Bevacizumab is a humanized monoclonal antibody that binds to circulating VEGF-A, stimulating clinical effects in multiple tumor types, including persistent or recurrent ovarian and cervical cancers.

Aghajanian and colleagues conducted a Phase II trial of single-agent bevacizumab in women with recurrent or persistent endometrial cancer to assess the drug’s activity and tolerability. Eligible patients had histologic confirmation by central pathology review, recurrent or persistent disease after one or two cytotoxic regimens, and a Gynecologic Oncology Group performance score of 2 or lower. They received IV bevacizumab 15 mg/kg every 3 weeks until the disease progressed or toxicity became prohibitive. Fifty-two women participated.

Seven women (13.5%) experienced a clinical response (one complete response and six partial responses), and 21 (40%) had PFS of at least 6 months. Median PFS and overall survival were 4.2 and 10.5 months, respectively.

Combined with temsirolimus, bevacizumab increased overall survival

Alvarez and colleagues conducted a Phase II trial of combination bevacizumab and temsirolimus in women with recurrent or persistent endometrial carcinoma. Forty-nine patients participated.

These women had undergone earlier treatment with one (82%) or two (18%) chemotherapy regimens and radiation (41%). Median PFS and overall survival were 5.6 and 16.9 months, respectively. Toxicity was significant, with 38.8% of women withdrawn from the study due to toxicity.  

What this evidence means for practice
Given the findings regarding temsirolimus and bevacizumab as single agents, their use in combination was expected to produce a robust effect. The 6-month PFS rate is similar for all three regimens, but for overall survival, combination therapy had a 6.4-month advantage over bevacizumab alone.

Given the significant toxicity associated with the combination of bevacizumab and temsirolimus, further study is needed to develop biomarkers to predict response and toxicity. Other areas meriting future research include optimal timing of angiogenesis and mTOR pathway inhibitors, different combinations of agents, and the identification, through genomic analysis, of patient populations most likely to benefit from these drugs with minimal toxicity.

The studies presented here show promise in the area of genomics and represent the beginning of our movement toward personalized cancer care.

We want to hear from you!  Tell us what you think.

Despite the long-term survivorship and clinical effectiveness of total knee arthroplasty (TKA), the percentage of patients who indicate dissatisfaction with their procedures (little improvement in pain and function) can be as high as 15% to 30%.^1-3 Although early reports on survivorship of unicompartmental knee arthroplasty (UKA) were discouraging, recent studies assessing modern implant designs and surgical techniques have found 10-year survival rates of 90% to 98%.4 The number of UKAs performed over the past decade has increased by 30%, as numerous studies have demonstrated shorter hospital stays, decreased perioperative morbidity, faster functional recovery, increased range of motion (ROM), and improved knee kinematics compared with TKA.⁴

[Introductory paragraph provided in lieu of abstract]

Despite the long-term survivorship and clinical effectiveness of total knee arthroplasty (TKA), the percentage of patients who indicate dissatisfaction with their procedures (little improvement in pain and function) can be as high as 15% to 30%.^1-3 Although early reports on survivorship of unicompartmental knee arthroplasty (UKA) were discouraging, recent studies assessing modern implant designs and surgical techniques have found 10-year survival rates of 90% to 98%.4 The number of UKAs performed over the past decade has increased by 30%, as numerous studies have demonstrated shorter hospital stays, decreased perioperative morbidity, faster functional recovery, increased range of motion (ROM), and improved knee kinematics compared with TKA.⁴

[Introductory paragraph provided in lieu of abstract]

Despite the long-term survivorship and clinical effectiveness of total knee arthroplasty (TKA), the percentage of patients who indicate dissatisfaction with their procedures (little improvement in pain and function) can be as high as 15% to 30%.^1-3 Although early reports on survivorship of unicompartmental knee arthroplasty (UKA) were discouraging, recent studies assessing modern implant designs and surgical techniques have found 10-year survival rates of 90% to 98%.4 The number of UKAs performed over the past decade has increased by 30%, as numerous studies have demonstrated shorter hospital stays, decreased perioperative morbidity, faster functional recovery, increased range of motion (ROM), and improved knee kinematics compared with TKA.⁴

[Introductory paragraph provided in lieu of abstract]

SAN DIEGO – If you’re skeptical about the impact that you as a primary care provider can make on patients who seek assistance from you with weight loss, think again, advised Dr. Lindsay Botsford.

"You can really make a big difference in your office," Dr. Botsford, a family physician who practices in Sugar Land, Tex., said at the annual meeting of the American Academy of Family Physicians.

During her presentation, she spotlighted the success of Practice-Based Opportunities for Weight Reduction (POWER-UP), a 2-year randomized controlled trial of obesity treatment in the primary care setting. For the trial, 390 patients at six primary care practices were randomized to one of three interventions: usual care, which consisted of quarterly visits that included education about weight management; brief lifestyle counseling, which consisted of quarterly primary care visits combined with short monthly sessions with lifestyle coaches who instructed patients about behavioral control; and enhanced brief lifestyle counseling, which consisted of quarterly primary care visits combined with short monthly sessions with lifestyle coaches who instructed patients about behavioral control, plus meal replacements or orlistat or sibutramine to potentially increase weight loss (N. Engl. J. Med. 2011;365[2]:1969-79).

At the end of the second year, patients in the enhanced lifestyle counseling group lost an average of 4.6 kg, which exceeded the average weight loss experienced by patients in the brief lifestyle counseling and usual care groups (an average of 2.9 kg and 1.7 kg, respectively). The proportion of patients who achieved a weight loss of more than 5% at the end of the second year was also greatest in the enhanced lifestyle group (34.9% vs. 26% and 21.5% in the other two groups, respectively).

Some patients harbor sensitivity about their weight, so if they want to talk about the issue, Dr. Botsford recommended avoiding the term "obesity" and instead using terms such as "weight," "excess weight," "unhealthy body weight," and "BMI." She also recommended involving other members of the staff. For example, front desk staff can ask patients to fill out a fitness inventory and medical assistants can check BMI, measure waist circumference, and provide basic counseling advice about weight loss strategies such as keeping a food journal and portion control.

Regarding how patients perceive overweight physicians, Dr. Botsford noted, "In general, patients find overweight physicians less credible. I find that a little sad, but your view on the subject can influence patients. If you are not at your healthy weight, try to overcome this by sharing personal stories with them."

In counseling patients who express interest in losing weight, she said she begins with a 24-hour dietary recall and then reviews the U.S. Preventive Services Task Force’s "5 A’s" framework to create goals. The five A’s include assess (ask about or assess behavioral health risk[s] and factors affecting choice of behavior change goals); advise (give clear, specific, and personalized behavior change advice, including information about harms and benefits); agree (collaboratively select treatment goals and methods based on interest and willingness to change); assist (using behavior change techniques, help patient to acquire the skills, confidence, and social or environmental supports for behavior change, supplemented with medical treatments when needed); and arrange (schedule follow-up to provide ongoing assistance or support and to adjust the treatment plan as needed).

Other evidence-based counseling tips include recommending that patients avoid artificial sweetener, eating out of a bag, eating in front of the television, eating bread when dining out, and being mindful of liquid calorie intake. She also said she advises patients to stay hydrated, leave one-third of the portion on the plate when dining out, order "small" sizes when possible, and use small plates and bowls at home.

"Study after study has shown that low-calorie diets – 1,000-1,200 kcal/day for women and 1,200-1,600 kcal/day for men are the most successful for maintaining weight loss in the long term," Dr. Botsford said. "Adherence is a big thing when it comes to diets. The most common thing is that people stop. They can’t stick with it. Low glycemic load may help adherence. That’s still within the context of a low-calorie diet. There is certain evidence that having more fiber and more protein will make you feel fuller along the way, but in the end, a low-calorie diet is best."

Tools that can help patients keep a handle on food intake include the AAFP\'s initiative Americans in Motion Healthy Interventions and smartphone apps such as Lose It!, Calorie Counter and Diet Tracker by MyFitnessPal.com, healthfinder.gov, and Weight Watchers Mobile. "Exercise alone is better than nothing, but it only translates into a small weight loss," Dr. Botsford said. "However, exercise reduces blood pressure, triglycerides, and fasting glucose, and it decreases abdominal adipose tissue. To make the real difference you need exercise and diet. You also improve your strength, balance, and peak oxygen consumption. The more intense your exercise, [the more] you will increase your weight loss."

Medicare will reimburse for obesity counseling, but the patient’s BMI has to be greater than 30 kg/m²; the patient has to be competent and alert, and the counseling has to be done in a primary care setting or by the primary care provider. "Medicare will cover up to 22 visits in 12 months in a staged way," Dr. Botsford said, noting that the ICD-9 code for a BMI of 30 or more is G0447. "For the first month they’ll cover once a week. The only caveat is that you cannot bill for any other services on the same day as the visit for obesity counseling."

Dr. Botsford said she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – If you’re skeptical about the impact that you as a primary care provider can make on patients who seek assistance from you with weight loss, think again, advised Dr. Lindsay Botsford.

"You can really make a big difference in your office," Dr. Botsford, a family physician who practices in Sugar Land, Tex., said at the annual meeting of the American Academy of Family Physicians.

During her presentation, she spotlighted the success of Practice-Based Opportunities for Weight Reduction (POWER-UP), a 2-year randomized controlled trial of obesity treatment in the primary care setting. For the trial, 390 patients at six primary care practices were randomized to one of three interventions: usual care, which consisted of quarterly visits that included education about weight management; brief lifestyle counseling, which consisted of quarterly primary care visits combined with short monthly sessions with lifestyle coaches who instructed patients about behavioral control; and enhanced brief lifestyle counseling, which consisted of quarterly primary care visits combined with short monthly sessions with lifestyle coaches who instructed patients about behavioral control, plus meal replacements or orlistat or sibutramine to potentially increase weight loss (N. Engl. J. Med. 2011;365[2]:1969-79).

At the end of the second year, patients in the enhanced lifestyle counseling group lost an average of 4.6 kg, which exceeded the average weight loss experienced by patients in the brief lifestyle counseling and usual care groups (an average of 2.9 kg and 1.7 kg, respectively). The proportion of patients who achieved a weight loss of more than 5% at the end of the second year was also greatest in the enhanced lifestyle group (34.9% vs. 26% and 21.5% in the other two groups, respectively).

Some patients harbor sensitivity about their weight, so if they want to talk about the issue, Dr. Botsford recommended avoiding the term "obesity" and instead using terms such as "weight," "excess weight," "unhealthy body weight," and "BMI." She also recommended involving other members of the staff. For example, front desk staff can ask patients to fill out a fitness inventory and medical assistants can check BMI, measure waist circumference, and provide basic counseling advice about weight loss strategies such as keeping a food journal and portion control.

Regarding how patients perceive overweight physicians, Dr. Botsford noted, "In general, patients find overweight physicians less credible. I find that a little sad, but your view on the subject can influence patients. If you are not at your healthy weight, try to overcome this by sharing personal stories with them."

In counseling patients who express interest in losing weight, she said she begins with a 24-hour dietary recall and then reviews the U.S. Preventive Services Task Force’s "5 A’s" framework to create goals. The five A’s include assess (ask about or assess behavioral health risk[s] and factors affecting choice of behavior change goals); advise (give clear, specific, and personalized behavior change advice, including information about harms and benefits); agree (collaboratively select treatment goals and methods based on interest and willingness to change); assist (using behavior change techniques, help patient to acquire the skills, confidence, and social or environmental supports for behavior change, supplemented with medical treatments when needed); and arrange (schedule follow-up to provide ongoing assistance or support and to adjust the treatment plan as needed).

Other evidence-based counseling tips include recommending that patients avoid artificial sweetener, eating out of a bag, eating in front of the television, eating bread when dining out, and being mindful of liquid calorie intake. She also said she advises patients to stay hydrated, leave one-third of the portion on the plate when dining out, order "small" sizes when possible, and use small plates and bowls at home.

"Study after study has shown that low-calorie diets – 1,000-1,200 kcal/day for women and 1,200-1,600 kcal/day for men are the most successful for maintaining weight loss in the long term," Dr. Botsford said. "Adherence is a big thing when it comes to diets. The most common thing is that people stop. They can’t stick with it. Low glycemic load may help adherence. That’s still within the context of a low-calorie diet. There is certain evidence that having more fiber and more protein will make you feel fuller along the way, but in the end, a low-calorie diet is best."

Tools that can help patients keep a handle on food intake include the AAFP\'s initiative Americans in Motion Healthy Interventions and smartphone apps such as Lose It!, Calorie Counter and Diet Tracker by MyFitnessPal.com, healthfinder.gov, and Weight Watchers Mobile. "Exercise alone is better than nothing, but it only translates into a small weight loss," Dr. Botsford said. "However, exercise reduces blood pressure, triglycerides, and fasting glucose, and it decreases abdominal adipose tissue. To make the real difference you need exercise and diet. You also improve your strength, balance, and peak oxygen consumption. The more intense your exercise, [the more] you will increase your weight loss."

Medicare will reimburse for obesity counseling, but the patient’s BMI has to be greater than 30 kg/m²; the patient has to be competent and alert, and the counseling has to be done in a primary care setting or by the primary care provider. "Medicare will cover up to 22 visits in 12 months in a staged way," Dr. Botsford said, noting that the ICD-9 code for a BMI of 30 or more is G0447. "For the first month they’ll cover once a week. The only caveat is that you cannot bill for any other services on the same day as the visit for obesity counseling."

Dr. Botsford said she had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – If you’re skeptical about the impact that you as a primary care provider can make on patients who seek assistance from you with weight loss, think again, advised Dr. Lindsay Botsford.

"You can really make a big difference in your office," Dr. Botsford, a family physician who practices in Sugar Land, Tex., said at the annual meeting of the American Academy of Family Physicians.

During her presentation, she spotlighted the success of Practice-Based Opportunities for Weight Reduction (POWER-UP), a 2-year randomized controlled trial of obesity treatment in the primary care setting. For the trial, 390 patients at six primary care practices were randomized to one of three interventions: usual care, which consisted of quarterly visits that included education about weight management; brief lifestyle counseling, which consisted of quarterly primary care visits combined with short monthly sessions with lifestyle coaches who instructed patients about behavioral control; and enhanced brief lifestyle counseling, which consisted of quarterly primary care visits combined with short monthly sessions with lifestyle coaches who instructed patients about behavioral control, plus meal replacements or orlistat or sibutramine to potentially increase weight loss (N. Engl. J. Med. 2011;365[2]:1969-79).

At the end of the second year, patients in the enhanced lifestyle counseling group lost an average of 4.6 kg, which exceeded the average weight loss experienced by patients in the brief lifestyle counseling and usual care groups (an average of 2.9 kg and 1.7 kg, respectively). The proportion of patients who achieved a weight loss of more than 5% at the end of the second year was also greatest in the enhanced lifestyle group (34.9% vs. 26% and 21.5% in the other two groups, respectively).

Some patients harbor sensitivity about their weight, so if they want to talk about the issue, Dr. Botsford recommended avoiding the term "obesity" and instead using terms such as "weight," "excess weight," "unhealthy body weight," and "BMI." She also recommended involving other members of the staff. For example, front desk staff can ask patients to fill out a fitness inventory and medical assistants can check BMI, measure waist circumference, and provide basic counseling advice about weight loss strategies such as keeping a food journal and portion control.

Regarding how patients perceive overweight physicians, Dr. Botsford noted, "In general, patients find overweight physicians less credible. I find that a little sad, but your view on the subject can influence patients. If you are not at your healthy weight, try to overcome this by sharing personal stories with them."

In counseling patients who express interest in losing weight, she said she begins with a 24-hour dietary recall and then reviews the U.S. Preventive Services Task Force’s "5 A’s" framework to create goals. The five A’s include assess (ask about or assess behavioral health risk[s] and factors affecting choice of behavior change goals); advise (give clear, specific, and personalized behavior change advice, including information about harms and benefits); agree (collaboratively select treatment goals and methods based on interest and willingness to change); assist (using behavior change techniques, help patient to acquire the skills, confidence, and social or environmental supports for behavior change, supplemented with medical treatments when needed); and arrange (schedule follow-up to provide ongoing assistance or support and to adjust the treatment plan as needed).

Other evidence-based counseling tips include recommending that patients avoid artificial sweetener, eating out of a bag, eating in front of the television, eating bread when dining out, and being mindful of liquid calorie intake. She also said she advises patients to stay hydrated, leave one-third of the portion on the plate when dining out, order "small" sizes when possible, and use small plates and bowls at home.

"Study after study has shown that low-calorie diets – 1,000-1,200 kcal/day for women and 1,200-1,600 kcal/day for men are the most successful for maintaining weight loss in the long term," Dr. Botsford said. "Adherence is a big thing when it comes to diets. The most common thing is that people stop. They can’t stick with it. Low glycemic load may help adherence. That’s still within the context of a low-calorie diet. There is certain evidence that having more fiber and more protein will make you feel fuller along the way, but in the end, a low-calorie diet is best."

Tools that can help patients keep a handle on food intake include the AAFP\'s initiative Americans in Motion Healthy Interventions and smartphone apps such as Lose It!, Calorie Counter and Diet Tracker by MyFitnessPal.com, healthfinder.gov, and Weight Watchers Mobile. "Exercise alone is better than nothing, but it only translates into a small weight loss," Dr. Botsford said. "However, exercise reduces blood pressure, triglycerides, and fasting glucose, and it decreases abdominal adipose tissue. To make the real difference you need exercise and diet. You also improve your strength, balance, and peak oxygen consumption. The more intense your exercise, [the more] you will increase your weight loss."

Medicare will reimburse for obesity counseling, but the patient’s BMI has to be greater than 30 kg/m²; the patient has to be competent and alert, and the counseling has to be done in a primary care setting or by the primary care provider. "Medicare will cover up to 22 visits in 12 months in a staged way," Dr. Botsford said, noting that the ICD-9 code for a BMI of 30 or more is G0447. "For the first month they’ll cover once a week. The only caveat is that you cannot bill for any other services on the same day as the visit for obesity counseling."

Dr. Botsford said she had no relevant financial conflicts to disclose.

[email protected]