Diagnosis: Lichen sclerosus et atrophicus with morphea

Lichen sclerosus et atrophicus (LSetA) is a chronic inflammatory condition mediated primarily by lymphocytic infiltration. It is up to 10 times more likely to occur in women than men. There is a genetic component, as approximately 12% of affected patients also have relatives with the condition. Human leukocyte antigen subtypes DQ7, DQ8, and DQ9 have been associated with LSetA, which is thought to be primarily autoimmune in nature. There is also a strong association with other autoimmune diseases, predominantly thyroid disease, vitiligo, alopecia areata, and pernicious anemia.

LSetA is most commonly seen in the vulvar region, but can also present extragenitally. Vulvar LSetA has a bimodal distribution, peaking in prepubertal and postmenopausal women. The most common symptoms are pruritus and pain. On physical examination, LSetA appears as thick white plaques with a thin epidermis resembling “cigarette paper.” Chronic inflammation can also lead to permanent scarring. Pruritus or pain can result, which can significantly affect quality of life.

Morphea is characterized by thickened skin as a result of deep dermal fibrosis. Also known as localized scleroderma, morphea presents with the cutaneous findings of scleroderma without the systemic complications. Like LSetA, morphea is more common in females than males, although the ratio is not as high. Plaque morphea is the most prevalent type and presents as circumscribed, edematous plaques on the trunk or extremities. Morphea has been reported as a consequence of localized injury or infection, but is also commonly associated with various autoimmune conditions.

Histologic changes of LSetA include epidermal atrophy and homogenization of collagen limited to the superficial dermis. In contrast, morphea histologically consists of deep dermal fibrosis with associated epidermal hyperkeratosis. While LSetA and morphea are usually distinct entities, they can rarely occur together. The diagnosis of LSetA with morphea can be confirmed when the deep and superficial histologic findings are consistent with both entities.

Treatment options for LSetA include short-term, high-potency topical corticosteroids followed by maintenance therapy with emollients. Reducing exposure to irritants is also crucial for a sustained response. Other modalities such as topical calcineurin inhibitors, photodynamic therapy, surgery, and methotrexate are potential alternatives in recalcitrant cases. Morphea can be treated with methotrexate and systemic glucocorticoids, which are usually given in combination. Systemic glucocorticoids can be tapered to avoid long-term side effects, while tapering the methotrexate based on clinical response. In general, the evidence supports the use of systemic therapy for extensive plaquetype morphea over topical treatments; however, there is some evidence to support the use of topical calcineurin inhibitors in resistant cases.

This patient was started on a prednisone taper in addition to weekly methotrexate. Gabapentin was prescribed for pain control. The patient returned to the clinic during the next several months with improvement in her symptoms and reduction in the size and induration of the lesions.

This case and photo were submitted by Adam Aldahan, Dr. Alyx Rosen, and Dr. Anne Burdick of the University of Miami department of dermatology.

Diagnosis: Lichen sclerosus et atrophicus with morphea

Lichen sclerosus et atrophicus (LSetA) is a chronic inflammatory condition mediated primarily by lymphocytic infiltration. It is up to 10 times more likely to occur in women than men. There is a genetic component, as approximately 12% of affected patients also have relatives with the condition. Human leukocyte antigen subtypes DQ7, DQ8, and DQ9 have been associated with LSetA, which is thought to be primarily autoimmune in nature. There is also a strong association with other autoimmune diseases, predominantly thyroid disease, vitiligo, alopecia areata, and pernicious anemia.

LSetA is most commonly seen in the vulvar region, but can also present extragenitally. Vulvar LSetA has a bimodal distribution, peaking in prepubertal and postmenopausal women. The most common symptoms are pruritus and pain. On physical examination, LSetA appears as thick white plaques with a thin epidermis resembling “cigarette paper.” Chronic inflammation can also lead to permanent scarring. Pruritus or pain can result, which can significantly affect quality of life.

Morphea is characterized by thickened skin as a result of deep dermal fibrosis. Also known as localized scleroderma, morphea presents with the cutaneous findings of scleroderma without the systemic complications. Like LSetA, morphea is more common in females than males, although the ratio is not as high. Plaque morphea is the most prevalent type and presents as circumscribed, edematous plaques on the trunk or extremities. Morphea has been reported as a consequence of localized injury or infection, but is also commonly associated with various autoimmune conditions.

Histologic changes of LSetA include epidermal atrophy and homogenization of collagen limited to the superficial dermis. In contrast, morphea histologically consists of deep dermal fibrosis with associated epidermal hyperkeratosis. While LSetA and morphea are usually distinct entities, they can rarely occur together. The diagnosis of LSetA with morphea can be confirmed when the deep and superficial histologic findings are consistent with both entities.

Treatment options for LSetA include short-term, high-potency topical corticosteroids followed by maintenance therapy with emollients. Reducing exposure to irritants is also crucial for a sustained response. Other modalities such as topical calcineurin inhibitors, photodynamic therapy, surgery, and methotrexate are potential alternatives in recalcitrant cases. Morphea can be treated with methotrexate and systemic glucocorticoids, which are usually given in combination. Systemic glucocorticoids can be tapered to avoid long-term side effects, while tapering the methotrexate based on clinical response. In general, the evidence supports the use of systemic therapy for extensive plaquetype morphea over topical treatments; however, there is some evidence to support the use of topical calcineurin inhibitors in resistant cases.

This patient was started on a prednisone taper in addition to weekly methotrexate. Gabapentin was prescribed for pain control. The patient returned to the clinic during the next several months with improvement in her symptoms and reduction in the size and induration of the lesions.

This case and photo were submitted by Adam Aldahan, Dr. Alyx Rosen, and Dr. Anne Burdick of the University of Miami department of dermatology.

Diagnosis: Lichen sclerosus et atrophicus with morphea

Lichen sclerosus et atrophicus (LSetA) is a chronic inflammatory condition mediated primarily by lymphocytic infiltration. It is up to 10 times more likely to occur in women than men. There is a genetic component, as approximately 12% of affected patients also have relatives with the condition. Human leukocyte antigen subtypes DQ7, DQ8, and DQ9 have been associated with LSetA, which is thought to be primarily autoimmune in nature. There is also a strong association with other autoimmune diseases, predominantly thyroid disease, vitiligo, alopecia areata, and pernicious anemia.

LSetA is most commonly seen in the vulvar region, but can also present extragenitally. Vulvar LSetA has a bimodal distribution, peaking in prepubertal and postmenopausal women. The most common symptoms are pruritus and pain. On physical examination, LSetA appears as thick white plaques with a thin epidermis resembling “cigarette paper.” Chronic inflammation can also lead to permanent scarring. Pruritus or pain can result, which can significantly affect quality of life.

Morphea is characterized by thickened skin as a result of deep dermal fibrosis. Also known as localized scleroderma, morphea presents with the cutaneous findings of scleroderma without the systemic complications. Like LSetA, morphea is more common in females than males, although the ratio is not as high. Plaque morphea is the most prevalent type and presents as circumscribed, edematous plaques on the trunk or extremities. Morphea has been reported as a consequence of localized injury or infection, but is also commonly associated with various autoimmune conditions.

Histologic changes of LSetA include epidermal atrophy and homogenization of collagen limited to the superficial dermis. In contrast, morphea histologically consists of deep dermal fibrosis with associated epidermal hyperkeratosis. While LSetA and morphea are usually distinct entities, they can rarely occur together. The diagnosis of LSetA with morphea can be confirmed when the deep and superficial histologic findings are consistent with both entities.

Treatment options for LSetA include short-term, high-potency topical corticosteroids followed by maintenance therapy with emollients. Reducing exposure to irritants is also crucial for a sustained response. Other modalities such as topical calcineurin inhibitors, photodynamic therapy, surgery, and methotrexate are potential alternatives in recalcitrant cases. Morphea can be treated with methotrexate and systemic glucocorticoids, which are usually given in combination. Systemic glucocorticoids can be tapered to avoid long-term side effects, while tapering the methotrexate based on clinical response. In general, the evidence supports the use of systemic therapy for extensive plaquetype morphea over topical treatments; however, there is some evidence to support the use of topical calcineurin inhibitors in resistant cases.

This patient was started on a prednisone taper in addition to weekly methotrexate. Gabapentin was prescribed for pain control. The patient returned to the clinic during the next several months with improvement in her symptoms and reduction in the size and induration of the lesions.

This case and photo were submitted by Adam Aldahan, Dr. Alyx Rosen, and Dr. Anne Burdick of the University of Miami department of dermatology.

As young physicians, we are taught to be as objective as possible when evaluating a patient; however, cognitive biases are regularly encountered in day-to-day patient experiences and can unfortunately influence our clinical decision-making skills to be subpar.

Consider the following case: An overweight 74-year-old man with diabetes mellitus and a nonhealing ulceration on the left lower extremity presented to the emergency department for repeat evaluation. He previously had been treated by an outside dermatologist for stasis dermatitis and was being managed with compression, elevation, and lubrication of both lower extremities. Often, the initial reaction is to conclude that the patient does in fact have an ulceration associated with stasis dermatitis and changing the management strategy or performing a biopsy would not change the outcome. However, this response limits the potential to provide the patient with a thorough examination. If the patient is treated with the same management strategies that previously failed rather than delving into all the causes for nonhealing ulceration on the left lower extremity, a vital diagnosis could be missed. In this scenario, when the patient was ultimately biopsied, the diagnosis was an ulcerative squamous cell carcinoma.

These subconscious predetermined decisions regarding difficult patient encounters come from the physician’s heuristics, a process of decision-making wherein a snap judgment about a patient occurs because it is similar to prior patient encounters or a set of views from prior knowledge of the disease.^1,2

A recent article by Cohen and Burgin³ elucidated a set of cognitive biases that often are encountered in dermatology practices, including affective, anchoring, availability, and confirmation biases; zebra retreat; and Sutton’s slip.

Affective Bias

Affective bias is a process in which emotions regarding a patient interaction alter the objective prospective and reasoning of a patient. For example, consider the case of a pemphigus vulgaris patient who does not want to be on prednisone due to weight gain and persistently presents to the dermatology clinic insisting that the physician taper the dosage. To avoid the constant frustration and upsetting the patient further, the dermatologist tapers the dosage of prednisone prematurely and the patient has a flare.

Anchoring Bias

Anchoring bias occurs when initial information regarding a patient causes one to jump to a conclusion rather than developing a thorough history. An example may be if an infant presents with a mole on the nasal dorsum that the patient’s father reports has only been present for a short while. Without performing imaging studies or asking for further history, the physician decides to biopsy the lesion. The biopsy results show a neural mass, such that a nasal glioma cannot be ruled out. In this bias, magnetic resonance imaging would have been prudent prior to biopsy and premature action.

Availability Bias

Availability bias refers to a diagnosis that immediately comes to mind, as it is common or recently encountered, such as in the example presented at the beginning of this column about the patient with squamous cell carcinoma.

Confirmation Bias

Confirmation bias caters to elucidating information that confirms your own clinical suspicion as opposed to determining the true cause of the disease etiology. Consider the following example: An obese patient presents with a history of painful sores on the bilateral lower extremities. The physician asks specifically about diabetes mellitus and mobility. When the patient answers yes to poor mobility and diabetes mellitus, the physician asks questions confirming an initial suspected diagnosis of stasis dermatitis. Unfortunately, as the patient continues to get worse, it is revealed that his medication history indicates he has been taking sulfasalazine for several years, and it is eventually determined that the patient has cutaneous Crohn disease.

Zebra Retreat

This bias describes a physician’s unwillingness to consider a diagnosis because it is very obscure, even if it is correct. For example, the case of the patient described in the previous example with a diagnosis of cutaneous Crohn disease also can be considered as an example of zebra retreat. Because the clinician may rarely think of this diagnosis due to its infrequent presentation, he/she may not consider doing a biopsy or investigate further.

Sutton’s Slip

This bias describes a situation in which a physician disregards a problem because a thorough examination is not performed, which is classically noted when physicians treat their family and friends. If asked about a mole or lesion regarding its questionable nature, a dermatologist may either disregard it or not evaluate it carefully, as the person is in a casual setting.

Final Thoughts

Although there are several other types of cognitive biases, those described here show that on several occasions, dermatologists can be swayed toward an incorrect diagnosis simply because of a subconscious thought process. Often times, such as in multiple-choice examinations, initial guesses are usually the best answers, but care has to be taken when in a clinical setting. Our patients rarely are good historians and do not present in well-written question stems. The biases emphasize that dermatologists in training should keep their minds open, focus on getting a clear and concise history, and use their knowledge as a tool to derive a well thought-out answer.

As young physicians, we are taught to be as objective as possible when evaluating a patient; however, cognitive biases are regularly encountered in day-to-day patient experiences and can unfortunately influence our clinical decision-making skills to be subpar.

Consider the following case: An overweight 74-year-old man with diabetes mellitus and a nonhealing ulceration on the left lower extremity presented to the emergency department for repeat evaluation. He previously had been treated by an outside dermatologist for stasis dermatitis and was being managed with compression, elevation, and lubrication of both lower extremities. Often, the initial reaction is to conclude that the patient does in fact have an ulceration associated with stasis dermatitis and changing the management strategy or performing a biopsy would not change the outcome. However, this response limits the potential to provide the patient with a thorough examination. If the patient is treated with the same management strategies that previously failed rather than delving into all the causes for nonhealing ulceration on the left lower extremity, a vital diagnosis could be missed. In this scenario, when the patient was ultimately biopsied, the diagnosis was an ulcerative squamous cell carcinoma.

These subconscious predetermined decisions regarding difficult patient encounters come from the physician’s heuristics, a process of decision-making wherein a snap judgment about a patient occurs because it is similar to prior patient encounters or a set of views from prior knowledge of the disease.^1,2

A recent article by Cohen and Burgin³ elucidated a set of cognitive biases that often are encountered in dermatology practices, including affective, anchoring, availability, and confirmation biases; zebra retreat; and Sutton’s slip.

Affective Bias

Affective bias is a process in which emotions regarding a patient interaction alter the objective prospective and reasoning of a patient. For example, consider the case of a pemphigus vulgaris patient who does not want to be on prednisone due to weight gain and persistently presents to the dermatology clinic insisting that the physician taper the dosage. To avoid the constant frustration and upsetting the patient further, the dermatologist tapers the dosage of prednisone prematurely and the patient has a flare.

Anchoring Bias

Anchoring bias occurs when initial information regarding a patient causes one to jump to a conclusion rather than developing a thorough history. An example may be if an infant presents with a mole on the nasal dorsum that the patient’s father reports has only been present for a short while. Without performing imaging studies or asking for further history, the physician decides to biopsy the lesion. The biopsy results show a neural mass, such that a nasal glioma cannot be ruled out. In this bias, magnetic resonance imaging would have been prudent prior to biopsy and premature action.

Availability Bias

Availability bias refers to a diagnosis that immediately comes to mind, as it is common or recently encountered, such as in the example presented at the beginning of this column about the patient with squamous cell carcinoma.

Confirmation Bias

Confirmation bias caters to elucidating information that confirms your own clinical suspicion as opposed to determining the true cause of the disease etiology. Consider the following example: An obese patient presents with a history of painful sores on the bilateral lower extremities. The physician asks specifically about diabetes mellitus and mobility. When the patient answers yes to poor mobility and diabetes mellitus, the physician asks questions confirming an initial suspected diagnosis of stasis dermatitis. Unfortunately, as the patient continues to get worse, it is revealed that his medication history indicates he has been taking sulfasalazine for several years, and it is eventually determined that the patient has cutaneous Crohn disease.

Zebra Retreat

This bias describes a physician’s unwillingness to consider a diagnosis because it is very obscure, even if it is correct. For example, the case of the patient described in the previous example with a diagnosis of cutaneous Crohn disease also can be considered as an example of zebra retreat. Because the clinician may rarely think of this diagnosis due to its infrequent presentation, he/she may not consider doing a biopsy or investigate further.

Sutton’s Slip

This bias describes a situation in which a physician disregards a problem because a thorough examination is not performed, which is classically noted when physicians treat their family and friends. If asked about a mole or lesion regarding its questionable nature, a dermatologist may either disregard it or not evaluate it carefully, as the person is in a casual setting.

Final Thoughts

Although there are several other types of cognitive biases, those described here show that on several occasions, dermatologists can be swayed toward an incorrect diagnosis simply because of a subconscious thought process. Often times, such as in multiple-choice examinations, initial guesses are usually the best answers, but care has to be taken when in a clinical setting. Our patients rarely are good historians and do not present in well-written question stems. The biases emphasize that dermatologists in training should keep their minds open, focus on getting a clear and concise history, and use their knowledge as a tool to derive a well thought-out answer.

As young physicians, we are taught to be as objective as possible when evaluating a patient; however, cognitive biases are regularly encountered in day-to-day patient experiences and can unfortunately influence our clinical decision-making skills to be subpar.

Consider the following case: An overweight 74-year-old man with diabetes mellitus and a nonhealing ulceration on the left lower extremity presented to the emergency department for repeat evaluation. He previously had been treated by an outside dermatologist for stasis dermatitis and was being managed with compression, elevation, and lubrication of both lower extremities. Often, the initial reaction is to conclude that the patient does in fact have an ulceration associated with stasis dermatitis and changing the management strategy or performing a biopsy would not change the outcome. However, this response limits the potential to provide the patient with a thorough examination. If the patient is treated with the same management strategies that previously failed rather than delving into all the causes for nonhealing ulceration on the left lower extremity, a vital diagnosis could be missed. In this scenario, when the patient was ultimately biopsied, the diagnosis was an ulcerative squamous cell carcinoma.

These subconscious predetermined decisions regarding difficult patient encounters come from the physician’s heuristics, a process of decision-making wherein a snap judgment about a patient occurs because it is similar to prior patient encounters or a set of views from prior knowledge of the disease.^1,2

A recent article by Cohen and Burgin³ elucidated a set of cognitive biases that often are encountered in dermatology practices, including affective, anchoring, availability, and confirmation biases; zebra retreat; and Sutton’s slip.

Affective Bias

Affective bias is a process in which emotions regarding a patient interaction alter the objective prospective and reasoning of a patient. For example, consider the case of a pemphigus vulgaris patient who does not want to be on prednisone due to weight gain and persistently presents to the dermatology clinic insisting that the physician taper the dosage. To avoid the constant frustration and upsetting the patient further, the dermatologist tapers the dosage of prednisone prematurely and the patient has a flare.

Anchoring Bias

Anchoring bias occurs when initial information regarding a patient causes one to jump to a conclusion rather than developing a thorough history. An example may be if an infant presents with a mole on the nasal dorsum that the patient’s father reports has only been present for a short while. Without performing imaging studies or asking for further history, the physician decides to biopsy the lesion. The biopsy results show a neural mass, such that a nasal glioma cannot be ruled out. In this bias, magnetic resonance imaging would have been prudent prior to biopsy and premature action.

Availability Bias

Availability bias refers to a diagnosis that immediately comes to mind, as it is common or recently encountered, such as in the example presented at the beginning of this column about the patient with squamous cell carcinoma.

Confirmation Bias

Confirmation bias caters to elucidating information that confirms your own clinical suspicion as opposed to determining the true cause of the disease etiology. Consider the following example: An obese patient presents with a history of painful sores on the bilateral lower extremities. The physician asks specifically about diabetes mellitus and mobility. When the patient answers yes to poor mobility and diabetes mellitus, the physician asks questions confirming an initial suspected diagnosis of stasis dermatitis. Unfortunately, as the patient continues to get worse, it is revealed that his medication history indicates he has been taking sulfasalazine for several years, and it is eventually determined that the patient has cutaneous Crohn disease.

Zebra Retreat

This bias describes a physician’s unwillingness to consider a diagnosis because it is very obscure, even if it is correct. For example, the case of the patient described in the previous example with a diagnosis of cutaneous Crohn disease also can be considered as an example of zebra retreat. Because the clinician may rarely think of this diagnosis due to its infrequent presentation, he/she may not consider doing a biopsy or investigate further.

Sutton’s Slip

This bias describes a situation in which a physician disregards a problem because a thorough examination is not performed, which is classically noted when physicians treat their family and friends. If asked about a mole or lesion regarding its questionable nature, a dermatologist may either disregard it or not evaluate it carefully, as the person is in a casual setting.

Final Thoughts

Although there are several other types of cognitive biases, those described here show that on several occasions, dermatologists can be swayed toward an incorrect diagnosis simply because of a subconscious thought process. Often times, such as in multiple-choice examinations, initial guesses are usually the best answers, but care has to be taken when in a clinical setting. Our patients rarely are good historians and do not present in well-written question stems. The biases emphasize that dermatologists in training should keep their minds open, focus on getting a clear and concise history, and use their knowledge as a tool to derive a well thought-out answer.

Registration is open for the Coding and Reimbursement Workshop, to be held Oct. 21-22, 2016, at the Millennium Knickerbocker Hotel in Chicago.

The workshop addresses the 2016 updates, including changes to endovascular stent placement outside the lower extremity and PQRS as well as coding for intravascular embolization and retrograde intrathoracic carotid stenting.

The course also will focus on reporting standards for interventional and open surgical procedures, plus includes information about the global surgical package and how it impacts billing and reimbursement, along with the application of modifiers for streamlined reimbursement.

Learn more and register here.

Registration is open for the Coding and Reimbursement Workshop, to be held Oct. 21-22, 2016, at the Millennium Knickerbocker Hotel in Chicago.

The workshop addresses the 2016 updates, including changes to endovascular stent placement outside the lower extremity and PQRS as well as coding for intravascular embolization and retrograde intrathoracic carotid stenting.

The course also will focus on reporting standards for interventional and open surgical procedures, plus includes information about the global surgical package and how it impacts billing and reimbursement, along with the application of modifiers for streamlined reimbursement.

Learn more and register here.

Registration is open for the Coding and Reimbursement Workshop, to be held Oct. 21-22, 2016, at the Millennium Knickerbocker Hotel in Chicago.

The workshop addresses the 2016 updates, including changes to endovascular stent placement outside the lower extremity and PQRS as well as coding for intravascular embolization and retrograde intrathoracic carotid stenting.

The course also will focus on reporting standards for interventional and open surgical procedures, plus includes information about the global surgical package and how it impacts billing and reimbursement, along with the application of modifiers for streamlined reimbursement.

Learn more and register here.

Endovascular treatments are the focus

The Society for Vascular Surgery has released new reporting standards focused on endovascular treatment of chronic lower extremity peripheral artery disease.

Recommended reporting standards for lower extremity ischemia were last published by the SVS in 1997.

The variety of endovascular devices and techniques to treat occlusive disease has exploded over the past 10 years and critical evaluation of the reported results may be problematic.

This document clarifies and updates the 1997 standards, specifically for reports on endovascular treatment. The document is divided into sections: Claudication Reporting, Critical Limb Ischemia Reporting, Preintervention Assessment and Nonanatomic Treatment, Intervention, Outcome Measures – Procedural, Outcome Measures – Disease Specific and Complications.

The linked document provides a summary for reporting endovascular revascularization techniques in the setting of chronic disease, with much of it based on prior publications and SVS-proposed standards.

The document also should:

• Serve as a guide for the design of clinical trials

• Be a reference for journal editors and reviewers when considering scientific work pertaining to endovascular therapy for chronic lower extremity arterial disease.

Endovascular treatments are the focus

The Society for Vascular Surgery has released new reporting standards focused on endovascular treatment of chronic lower extremity peripheral artery disease.

Recommended reporting standards for lower extremity ischemia were last published by the SVS in 1997.

The variety of endovascular devices and techniques to treat occlusive disease has exploded over the past 10 years and critical evaluation of the reported results may be problematic.

This document clarifies and updates the 1997 standards, specifically for reports on endovascular treatment. The document is divided into sections: Claudication Reporting, Critical Limb Ischemia Reporting, Preintervention Assessment and Nonanatomic Treatment, Intervention, Outcome Measures – Procedural, Outcome Measures – Disease Specific and Complications.

The linked document provides a summary for reporting endovascular revascularization techniques in the setting of chronic disease, with much of it based on prior publications and SVS-proposed standards.

The document also should:

• Serve as a guide for the design of clinical trials

• Be a reference for journal editors and reviewers when considering scientific work pertaining to endovascular therapy for chronic lower extremity arterial disease.

Endovascular treatments are the focus

The Society for Vascular Surgery has released new reporting standards focused on endovascular treatment of chronic lower extremity peripheral artery disease.

Recommended reporting standards for lower extremity ischemia were last published by the SVS in 1997.

The variety of endovascular devices and techniques to treat occlusive disease has exploded over the past 10 years and critical evaluation of the reported results may be problematic.

This document clarifies and updates the 1997 standards, specifically for reports on endovascular treatment. The document is divided into sections: Claudication Reporting, Critical Limb Ischemia Reporting, Preintervention Assessment and Nonanatomic Treatment, Intervention, Outcome Measures – Procedural, Outcome Measures – Disease Specific and Complications.

The linked document provides a summary for reporting endovascular revascularization techniques in the setting of chronic disease, with much of it based on prior publications and SVS-proposed standards.

The document also should:

• Serve as a guide for the design of clinical trials

• Be a reference for journal editors and reviewers when considering scientific work pertaining to endovascular therapy for chronic lower extremity arterial disease.

Antihemophilic factor

The European Medicines Agency (EMA) has started a review of medicines containing factor VIII (FVIII) to assess the risk of inhibitor development among patients starting treatment for hemophilia A.

The agency is conducting this review because results of the SIPPET study suggested that patients are more likely to develop inhibitors if they receive FVIII products made by DNA recombinant technology rather than FVIII products derived from blood.

The EMA is evaluating data from the SIPPET study as well as all other relevant data on blood-derived and recombinant FVIII products.

The agency said it will consider the implications of these data for previously untreated patients with hemophilia A and whether there is a need for risk minimization measures or other changes to the marketing authorizations of these products.

The review will cover all medicines containing FVIII that are authorized for use within the European Union. For details on the products to be reviewed, including the different product names used in each country, visit the EMA website (Factor VIII Article-31 referral - Annex I).

The EMA’s review has been initiated at the request of the Paul-Ehrlich-Institute, under Article 31 of Directive 2001/83/EC.

The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.

Those recommendations will then be sent to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt the EMA’s opinion.

Finally, the European Commission will adopt a legally binding decision applicable in all member states of the European Union.

Antihemophilic factor

The European Medicines Agency (EMA) has started a review of medicines containing factor VIII (FVIII) to assess the risk of inhibitor development among patients starting treatment for hemophilia A.

The agency is conducting this review because results of the SIPPET study suggested that patients are more likely to develop inhibitors if they receive FVIII products made by DNA recombinant technology rather than FVIII products derived from blood.

The EMA is evaluating data from the SIPPET study as well as all other relevant data on blood-derived and recombinant FVIII products.

The agency said it will consider the implications of these data for previously untreated patients with hemophilia A and whether there is a need for risk minimization measures or other changes to the marketing authorizations of these products.

The review will cover all medicines containing FVIII that are authorized for use within the European Union. For details on the products to be reviewed, including the different product names used in each country, visit the EMA website (Factor VIII Article-31 referral - Annex I).

The EMA’s review has been initiated at the request of the Paul-Ehrlich-Institute, under Article 31 of Directive 2001/83/EC.

The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.

Those recommendations will then be sent to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt the EMA’s opinion.

Finally, the European Commission will adopt a legally binding decision applicable in all member states of the European Union.

Antihemophilic factor

The European Medicines Agency (EMA) has started a review of medicines containing factor VIII (FVIII) to assess the risk of inhibitor development among patients starting treatment for hemophilia A.

The agency is conducting this review because results of the SIPPET study suggested that patients are more likely to develop inhibitors if they receive FVIII products made by DNA recombinant technology rather than FVIII products derived from blood.

The EMA is evaluating data from the SIPPET study as well as all other relevant data on blood-derived and recombinant FVIII products.

The agency said it will consider the implications of these data for previously untreated patients with hemophilia A and whether there is a need for risk minimization measures or other changes to the marketing authorizations of these products.

The review will cover all medicines containing FVIII that are authorized for use within the European Union. For details on the products to be reviewed, including the different product names used in each country, visit the EMA website (Factor VIII Article-31 referral - Annex I).

The EMA’s review has been initiated at the request of the Paul-Ehrlich-Institute, under Article 31 of Directive 2001/83/EC.

The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.

Those recommendations will then be sent to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt the EMA’s opinion.

Finally, the European Commission will adopt a legally binding decision applicable in all member states of the European Union.

Mouse embryo

Photo by Matthias Zepper

Researchers may have identified the cells responsible for MLL-AF4+ infant B-cell acute lymphoblastic leukemia, according to a paper published in Cell Reports.

The team analyzed mouse embryos and discovered a “window of opportunity” during which a pre-leukemic state can take hold.

They also found evidence to suggest this pre-leukemic state is driven by lymphoid-primed multipotent progenitor cells.

“One of the most common and aggressive types of infant blood cancer is associated with the MLL-AF4 fusion gene, which arises during pregnancy,” said study author Katrin Ottersbach, PhD, of the University of Edinburgh in the UK.

“One of the main impediments to improving the survival rates in infants is the lack of knowledge on where and when during development this mutation arises and how it affects the developing blood system of the baby.”

To gain some insight, Dr Ottersbach and her colleagues bred mice where one parent carries an inactive form of the MLL-AF4 fusion gene and the other parent expresses a gene for an enzyme that activates the fusion gene.

The embryos from this pairing entered a pre-leukemic state between days 12 and 14. The researchers found that MLL-AF4 imparted enhanced B lymphoid potential and increased repopulation and self-renewal capacity during this time.

Further investigation suggested that lymphoid-primed multipotent progenitor cells were the major contributors to the enhanced B lymphoid output and may therefore be the cells of origin.

The researchers noted that the mice did not actually develop infant leukemia, so more research is needed to identify the events required for progression to MLL-AF4+ infant B-cell acute lymphoblastic leukemia.

“Our findings reveal the first changes that take place in blood development caused by the MLL-AF4 mutation during a pre-cancerous state,” Dr Ottersbach said. “This has increased our knowledge on how this aggressive disease develops and will help identify early signs of disease and points for therapeutic intervention.”

Mouse embryo

Photo by Matthias Zepper

Researchers may have identified the cells responsible for MLL-AF4+ infant B-cell acute lymphoblastic leukemia, according to a paper published in Cell Reports.

The team analyzed mouse embryos and discovered a “window of opportunity” during which a pre-leukemic state can take hold.

They also found evidence to suggest this pre-leukemic state is driven by lymphoid-primed multipotent progenitor cells.

“One of the most common and aggressive types of infant blood cancer is associated with the MLL-AF4 fusion gene, which arises during pregnancy,” said study author Katrin Ottersbach, PhD, of the University of Edinburgh in the UK.

“One of the main impediments to improving the survival rates in infants is the lack of knowledge on where and when during development this mutation arises and how it affects the developing blood system of the baby.”

To gain some insight, Dr Ottersbach and her colleagues bred mice where one parent carries an inactive form of the MLL-AF4 fusion gene and the other parent expresses a gene for an enzyme that activates the fusion gene.

The embryos from this pairing entered a pre-leukemic state between days 12 and 14. The researchers found that MLL-AF4 imparted enhanced B lymphoid potential and increased repopulation and self-renewal capacity during this time.

Further investigation suggested that lymphoid-primed multipotent progenitor cells were the major contributors to the enhanced B lymphoid output and may therefore be the cells of origin.

The researchers noted that the mice did not actually develop infant leukemia, so more research is needed to identify the events required for progression to MLL-AF4+ infant B-cell acute lymphoblastic leukemia.

“Our findings reveal the first changes that take place in blood development caused by the MLL-AF4 mutation during a pre-cancerous state,” Dr Ottersbach said. “This has increased our knowledge on how this aggressive disease develops and will help identify early signs of disease and points for therapeutic intervention.”

Mouse embryo

Photo by Matthias Zepper

Researchers may have identified the cells responsible for MLL-AF4+ infant B-cell acute lymphoblastic leukemia, according to a paper published in Cell Reports.

The team analyzed mouse embryos and discovered a “window of opportunity” during which a pre-leukemic state can take hold.

They also found evidence to suggest this pre-leukemic state is driven by lymphoid-primed multipotent progenitor cells.

“One of the most common and aggressive types of infant blood cancer is associated with the MLL-AF4 fusion gene, which arises during pregnancy,” said study author Katrin Ottersbach, PhD, of the University of Edinburgh in the UK.

“One of the main impediments to improving the survival rates in infants is the lack of knowledge on where and when during development this mutation arises and how it affects the developing blood system of the baby.”

To gain some insight, Dr Ottersbach and her colleagues bred mice where one parent carries an inactive form of the MLL-AF4 fusion gene and the other parent expresses a gene for an enzyme that activates the fusion gene.

The embryos from this pairing entered a pre-leukemic state between days 12 and 14. The researchers found that MLL-AF4 imparted enhanced B lymphoid potential and increased repopulation and self-renewal capacity during this time.

Further investigation suggested that lymphoid-primed multipotent progenitor cells were the major contributors to the enhanced B lymphoid output and may therefore be the cells of origin.

The researchers noted that the mice did not actually develop infant leukemia, so more research is needed to identify the events required for progression to MLL-AF4+ infant B-cell acute lymphoblastic leukemia.

“Our findings reveal the first changes that take place in blood development caused by the MLL-AF4 mutation during a pre-cancerous state,” Dr Ottersbach said. “This has increased our knowledge on how this aggressive disease develops and will help identify early signs of disease and points for therapeutic intervention.”

An implanted vagus nerve stimulator like that used for epilepsy treatment reduced inflammatory markers and significantly improved symptoms and function in a small cohort of patients with rheumatoid arthritis.

After 42 days, almost 30% of patients had achieved disease remission, Frieda A. Koopman, MD, and her colleagues reported in the July issue of the Proceedings of the National Academy of Science (doi: 10.1073/pnas.1605635113). The improvements disappeared rapidly when the devices were turned off, but were quickly reestablished after stimulation resumed.

“This first-in-class study supports a conceptual framework for further studies of electronic medical devices in diseases currently treated with drugs, an approach termed ‘bioelectronic medicine,’” wrote Dr. Koopman of the University of Amsterdam, and her coauthors.

The team built on evidence of what they termed a “reflex neural circuit” in the vagus that strongly influences the production of inflammatory cytokines. Animal studies showed that electrical stimulation of the vagus nerve encouraged choline acetyltransferase–positive T cells to secrete acetylcholine in the spleen and other tissues. Acetylcholine binds to a class of nicotinic receptors on monocytes, macrophages, and stromal cells, and inhibits their inflammatory response.

“Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in experimental models of endotoxemia, sepsis, colitis, and other preclinical animal models of inflammatory syndromes,” the team noted.

The group reported on two human studies, totaling 25 patients. The first comprised seven patients with epilepsy who received the implanted vagus nerve stimulator for medically refractory seizures. None of these patients had a history of RA or any other inflammatory disease. The second group was all patients with active RA.

Each epilepsy patient contributed peripheral blood for study, which was collected before, during and after the implantation surgery. The team studied inflammatory markers by adding endotoxin to the samples. Those collected after the patient had been exposed to a single 30-second stimulation at 20 Hertz showed significantly inhibited production of TNF-alpha, compared with that seen in unexposed blood. Interleukin (IL)-6 and IL-1beta was also inhibited significantly by vagus nerve stimulation.

The next study involved 17 patients who had active RA, but not epilepsy. Of these, seven had failed methotrexate but were naïve to biologics; the rest had failed methotrexate and at least two biologics from different classes. Their average disease duration was 11 years.

The 86-day study gradually titrated the stimulation dose, but even at its highest, stimulation was far less than what is typically employed in epilepsy, “in which current is delivered at 60-second intervals, followed by an off interval of 5-180 minutes, repeated continuously,” the investigators wrote. “Thus, epilepsy patients may receive electrical current delivery for up to 240 minutes daily. Preclinical studies have established that stimulation of the inflammatory reflex for as little as 60 seconds confers significant inhibition of cytokine production for up to 24 hours.”

There was a 14-day post-implantation washout period with no stimulation, followed by 28 days of treatment titration. During that time, stimulation was ramped up from single 60-second stimulation with electric pulses of 250-microseconds duration at 10 Hertz and an output current between 0.25-2.0 milliamps, to the highest amperage tolerated (up to 2.0 milliamps).

That dose was the treatment target, and delivered once daily for 60 seconds in 250-microsecond pulse widths at 10 Hertz. At day 28, patients who had not had good clinical response according to EULAR response criteria, had their stimulation increased to four times daily.

In the group of seven methotrexate-resistant patients, two received electric current pulses four times daily. In the group of 10 methotrexate- and biologic-resistant patients, 6 received the four-dose stimulation.

On day 42, TNF-alpha levels in cultured peripheral blood were significantly reduced from baseline.

At that time, the vagus nerve stimulator was turned off for 14 days. By the end of the silent period, TNF-alpha levels had risen significantly from the day 42 levels. The stimulator was restarted on day 56. By day 84, after 28 more days of stimulation, TNF-alpha levels had again decreased significantly.

Symptoms and function as measured by the Disease Activity Score 28 followed a similar trajectory, improving during the initial treatment, worsening during the period of no stimulation, and improving again when stimulation was restarted. Symptom and function scores correlated positively with change in TNF levels.

The investigators also assessed the response rates according to American College of Rheumatology criteria. At day 42, 71% of those in the methotrexate-resistant group had achieved a 20% response; 57% a 50% response; and 28.6% a 70% response. Response was not as dramatic in the group resistant to both drug classes: rates were 70%, 30%, and 0%.

By day 42, nearly 30% of patients overall achieved remission, which was defined as a DAS28 score of less than 2.6. This constituted improvement in all the score components, including tender joint count, swollen joint count, patient’s assessment of pain, patient’s global assessment, physician’s global assessment, and C-reactive protein.

Finally, the investigators noted decreased levels of most serum cytokines. Most, including serum TNF, IL-10, IL-12p70, IL-13, IL-1alpha, IL-1beta, IL-2, IL-4, IL-5, and TNF-a-beta, were below 1 pg/ml.

Adverse events were common (16 patients) but reported as mild-moderate. The included hoarseness (5), hypoesthesia (4), parasthesia (2), dyspnea (2), and bradycardia (1), among others. There were no implantation-related infections. One patient reported postimplantation pain.

SetPoint Medical, of Valencia, Calif., makes the device and conducted the study. Dr. Koopman made no financial disclosures. However, several of the other authors are employees of Set Point, and of GlaxoSmithKline, which holds equity interest in the company.

[email protected]

On Twitter @Alz_Gal

An implanted vagus nerve stimulator like that used for epilepsy treatment reduced inflammatory markers and significantly improved symptoms and function in a small cohort of patients with rheumatoid arthritis.

After 42 days, almost 30% of patients had achieved disease remission, Frieda A. Koopman, MD, and her colleagues reported in the July issue of the Proceedings of the National Academy of Science (doi: 10.1073/pnas.1605635113). The improvements disappeared rapidly when the devices were turned off, but were quickly reestablished after stimulation resumed.

“This first-in-class study supports a conceptual framework for further studies of electronic medical devices in diseases currently treated with drugs, an approach termed ‘bioelectronic medicine,’” wrote Dr. Koopman of the University of Amsterdam, and her coauthors.

The team built on evidence of what they termed a “reflex neural circuit” in the vagus that strongly influences the production of inflammatory cytokines. Animal studies showed that electrical stimulation of the vagus nerve encouraged choline acetyltransferase–positive T cells to secrete acetylcholine in the spleen and other tissues. Acetylcholine binds to a class of nicotinic receptors on monocytes, macrophages, and stromal cells, and inhibits their inflammatory response.

“Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in experimental models of endotoxemia, sepsis, colitis, and other preclinical animal models of inflammatory syndromes,” the team noted.

The group reported on two human studies, totaling 25 patients. The first comprised seven patients with epilepsy who received the implanted vagus nerve stimulator for medically refractory seizures. None of these patients had a history of RA or any other inflammatory disease. The second group was all patients with active RA.

Each epilepsy patient contributed peripheral blood for study, which was collected before, during and after the implantation surgery. The team studied inflammatory markers by adding endotoxin to the samples. Those collected after the patient had been exposed to a single 30-second stimulation at 20 Hertz showed significantly inhibited production of TNF-alpha, compared with that seen in unexposed blood. Interleukin (IL)-6 and IL-1beta was also inhibited significantly by vagus nerve stimulation.

The next study involved 17 patients who had active RA, but not epilepsy. Of these, seven had failed methotrexate but were naïve to biologics; the rest had failed methotrexate and at least two biologics from different classes. Their average disease duration was 11 years.

The 86-day study gradually titrated the stimulation dose, but even at its highest, stimulation was far less than what is typically employed in epilepsy, “in which current is delivered at 60-second intervals, followed by an off interval of 5-180 minutes, repeated continuously,” the investigators wrote. “Thus, epilepsy patients may receive electrical current delivery for up to 240 minutes daily. Preclinical studies have established that stimulation of the inflammatory reflex for as little as 60 seconds confers significant inhibition of cytokine production for up to 24 hours.”

There was a 14-day post-implantation washout period with no stimulation, followed by 28 days of treatment titration. During that time, stimulation was ramped up from single 60-second stimulation with electric pulses of 250-microseconds duration at 10 Hertz and an output current between 0.25-2.0 milliamps, to the highest amperage tolerated (up to 2.0 milliamps).

That dose was the treatment target, and delivered once daily for 60 seconds in 250-microsecond pulse widths at 10 Hertz. At day 28, patients who had not had good clinical response according to EULAR response criteria, had their stimulation increased to four times daily.

In the group of seven methotrexate-resistant patients, two received electric current pulses four times daily. In the group of 10 methotrexate- and biologic-resistant patients, 6 received the four-dose stimulation.

On day 42, TNF-alpha levels in cultured peripheral blood were significantly reduced from baseline.

At that time, the vagus nerve stimulator was turned off for 14 days. By the end of the silent period, TNF-alpha levels had risen significantly from the day 42 levels. The stimulator was restarted on day 56. By day 84, after 28 more days of stimulation, TNF-alpha levels had again decreased significantly.

Symptoms and function as measured by the Disease Activity Score 28 followed a similar trajectory, improving during the initial treatment, worsening during the period of no stimulation, and improving again when stimulation was restarted. Symptom and function scores correlated positively with change in TNF levels.

The investigators also assessed the response rates according to American College of Rheumatology criteria. At day 42, 71% of those in the methotrexate-resistant group had achieved a 20% response; 57% a 50% response; and 28.6% a 70% response. Response was not as dramatic in the group resistant to both drug classes: rates were 70%, 30%, and 0%.

By day 42, nearly 30% of patients overall achieved remission, which was defined as a DAS28 score of less than 2.6. This constituted improvement in all the score components, including tender joint count, swollen joint count, patient’s assessment of pain, patient’s global assessment, physician’s global assessment, and C-reactive protein.

Finally, the investigators noted decreased levels of most serum cytokines. Most, including serum TNF, IL-10, IL-12p70, IL-13, IL-1alpha, IL-1beta, IL-2, IL-4, IL-5, and TNF-a-beta, were below 1 pg/ml.

Adverse events were common (16 patients) but reported as mild-moderate. The included hoarseness (5), hypoesthesia (4), parasthesia (2), dyspnea (2), and bradycardia (1), among others. There were no implantation-related infections. One patient reported postimplantation pain.

SetPoint Medical, of Valencia, Calif., makes the device and conducted the study. Dr. Koopman made no financial disclosures. However, several of the other authors are employees of Set Point, and of GlaxoSmithKline, which holds equity interest in the company.

[email protected]

On Twitter @Alz_Gal

An implanted vagus nerve stimulator like that used for epilepsy treatment reduced inflammatory markers and significantly improved symptoms and function in a small cohort of patients with rheumatoid arthritis.

After 42 days, almost 30% of patients had achieved disease remission, Frieda A. Koopman, MD, and her colleagues reported in the July issue of the Proceedings of the National Academy of Science (doi: 10.1073/pnas.1605635113). The improvements disappeared rapidly when the devices were turned off, but were quickly reestablished after stimulation resumed.

“This first-in-class study supports a conceptual framework for further studies of electronic medical devices in diseases currently treated with drugs, an approach termed ‘bioelectronic medicine,’” wrote Dr. Koopman of the University of Amsterdam, and her coauthors.

The team built on evidence of what they termed a “reflex neural circuit” in the vagus that strongly influences the production of inflammatory cytokines. Animal studies showed that electrical stimulation of the vagus nerve encouraged choline acetyltransferase–positive T cells to secrete acetylcholine in the spleen and other tissues. Acetylcholine binds to a class of nicotinic receptors on monocytes, macrophages, and stromal cells, and inhibits their inflammatory response.

“Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in experimental models of endotoxemia, sepsis, colitis, and other preclinical animal models of inflammatory syndromes,” the team noted.

The group reported on two human studies, totaling 25 patients. The first comprised seven patients with epilepsy who received the implanted vagus nerve stimulator for medically refractory seizures. None of these patients had a history of RA or any other inflammatory disease. The second group was all patients with active RA.

Each epilepsy patient contributed peripheral blood for study, which was collected before, during and after the implantation surgery. The team studied inflammatory markers by adding endotoxin to the samples. Those collected after the patient had been exposed to a single 30-second stimulation at 20 Hertz showed significantly inhibited production of TNF-alpha, compared with that seen in unexposed blood. Interleukin (IL)-6 and IL-1beta was also inhibited significantly by vagus nerve stimulation.

The next study involved 17 patients who had active RA, but not epilepsy. Of these, seven had failed methotrexate but were naïve to biologics; the rest had failed methotrexate and at least two biologics from different classes. Their average disease duration was 11 years.

The 86-day study gradually titrated the stimulation dose, but even at its highest, stimulation was far less than what is typically employed in epilepsy, “in which current is delivered at 60-second intervals, followed by an off interval of 5-180 minutes, repeated continuously,” the investigators wrote. “Thus, epilepsy patients may receive electrical current delivery for up to 240 minutes daily. Preclinical studies have established that stimulation of the inflammatory reflex for as little as 60 seconds confers significant inhibition of cytokine production for up to 24 hours.”

There was a 14-day post-implantation washout period with no stimulation, followed by 28 days of treatment titration. During that time, stimulation was ramped up from single 60-second stimulation with electric pulses of 250-microseconds duration at 10 Hertz and an output current between 0.25-2.0 milliamps, to the highest amperage tolerated (up to 2.0 milliamps).

That dose was the treatment target, and delivered once daily for 60 seconds in 250-microsecond pulse widths at 10 Hertz. At day 28, patients who had not had good clinical response according to EULAR response criteria, had their stimulation increased to four times daily.

In the group of seven methotrexate-resistant patients, two received electric current pulses four times daily. In the group of 10 methotrexate- and biologic-resistant patients, 6 received the four-dose stimulation.

On day 42, TNF-alpha levels in cultured peripheral blood were significantly reduced from baseline.

At that time, the vagus nerve stimulator was turned off for 14 days. By the end of the silent period, TNF-alpha levels had risen significantly from the day 42 levels. The stimulator was restarted on day 56. By day 84, after 28 more days of stimulation, TNF-alpha levels had again decreased significantly.

Symptoms and function as measured by the Disease Activity Score 28 followed a similar trajectory, improving during the initial treatment, worsening during the period of no stimulation, and improving again when stimulation was restarted. Symptom and function scores correlated positively with change in TNF levels.

The investigators also assessed the response rates according to American College of Rheumatology criteria. At day 42, 71% of those in the methotrexate-resistant group had achieved a 20% response; 57% a 50% response; and 28.6% a 70% response. Response was not as dramatic in the group resistant to both drug classes: rates were 70%, 30%, and 0%.

By day 42, nearly 30% of patients overall achieved remission, which was defined as a DAS28 score of less than 2.6. This constituted improvement in all the score components, including tender joint count, swollen joint count, patient’s assessment of pain, patient’s global assessment, physician’s global assessment, and C-reactive protein.

Finally, the investigators noted decreased levels of most serum cytokines. Most, including serum TNF, IL-10, IL-12p70, IL-13, IL-1alpha, IL-1beta, IL-2, IL-4, IL-5, and TNF-a-beta, were below 1 pg/ml.

Adverse events were common (16 patients) but reported as mild-moderate. The included hoarseness (5), hypoesthesia (4), parasthesia (2), dyspnea (2), and bradycardia (1), among others. There were no implantation-related infections. One patient reported postimplantation pain.

SetPoint Medical, of Valencia, Calif., makes the device and conducted the study. Dr. Koopman made no financial disclosures. However, several of the other authors are employees of Set Point, and of GlaxoSmithKline, which holds equity interest in the company.

[email protected]

On Twitter @Alz_Gal

CHICAGO – Women with clinical early-stage breast cancer and a positive sentinel lymph node who receive breast-conserving therapy can safely skip an axillary lymph node dissection (ALND), and therefore avoid its associated morbidity, confirms long-term follow-up of the Z0011 trial conducted by the American College of Surgeons Oncology Group and the Alliance for Clinical Trials in Oncology.

The phase III trial enrolled 891 women with clinical T1-2,N0,M0 disease who underwent lumpectomy and were found to have sentinel node involvement. They were randomized to ALND or no further surgery, followed by whole-breast radiation therapy and, in most cases, systemic adjuvant therapy.

The trial was closed early because of low rates of accrual and events. Results at 6.3 years of follow-up showed that compared with peers who had an ALND, the women who skipped this surgery did not have inferior 5-year rates of locoregional recurrence or overall survival (JAMA. 2011;305:569-75).

“The study, however, like most breast cancer studies, contained mostly postmenopausal women with hormone receptor–positive tumors who are known to have late recurrences, and it was criticized for short follow-up,” commented first author Armando E. Giuliano, MD, executive vice chair of surgical oncology in the department of surgery, and associate director of surgical oncology in the Samuel Oschin Comprehensive Cancer Institute, Los Angeles.

In an update of the findings, now with a median follow-up of 9.3 years, the groups were statistically indistinguishable with respect to 10-year rates of the same outcomes, he reported at the annual meeting of the American Society of Clinical Oncology.

“This study... shows that sentinel node biopsy alone provides excellent 10-year locoregional control and survival comparable to completion axillary lymph node dissection for these patients, even with long-term follow-up,” he maintained. “Routine use of axillary lymph node dissection should be abandoned.”

“This was designed as a noninferiority trial, and I would suggest that based on the data we have seen, even if they had hit their target accrual, the outcomes would not be different,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston. “Clearly, even before today’s presentation, Z0011 has been identified as a practice-changing trial, as evidenced by the NCCN guidelines.”

In fact, a study last year showed that among patients in the general U.S. population meeting the trial’s enrollment criteria, the use of sentinel lymph node dissection alone has increased significantly since the Z0011 results were first reported (J Am Coll Surg. 2015;221:71-81).

“However, I would highlight that we have also seen an increase in omission of axillary lymph node dissection for patients who do not meet the Z0011 criteria to include those not planned for radiotherapy, those receiving APBI [accelerated partial breast irradiation], and those undergoing mastectomy,” she added. “I highlight these examples specifically because it’s been suggested that one of the reasons the patients on the trial have outstanding regional control is because of the radiation administered as part of their breast-conserving therapy.”

“We will obtain additional data on the locoregional management of these early-stage patients with clinically node-negative breast cancer,” Dr. Mittendorf predicted, pointing to the similar POSNOC trial (which is comparing systemic therapy with versus without axillary treatment) and SOUND trial (which is comparing sentinel node dissection versus no axillary surgery).

In Z0011, all women had tumor in sentinel nodes detected with hematoxylin and eosin staining. Those with sentinel node tumor detected only by immunohistochemistry were excluded, as were those who had matted nodes, three or more involved sentinel nodes, or planned third-field (nodal) irradiation.

Overall, 27.4% of the patients in the ALND group had additional positive nodes removed beyond their sentinel nodes. “There is no reason to suspect that women with sentinel node biopsy [only] had fewer involved nodes than the women treated with axillary lymph node dissection,” Dr. Giuliano commented; thus, a similar share of the former group likely had residual axillary disease that went unresected.

The updated findings showed that the women received ALND and the women who did not were statistically indistinguishable with respect to the 10-year rate of locoregional recurrence (6.2% and 5.3%). Of note, only a single regional recurrence was seen after the initial 5 years of follow-up, and it occurred in the group that did not have ALND.

The groups treated with and without ALND were also statistically indistinguishable with respect to 10-year rates of disease-free survival (78.2% and 80.2%), locoregional recurrence–free survival (81.2% and 83.0%), and overall survival (83.6% and 86.3%).

In multivariate analysis, omission of ALND did not significantly predict locoregional recurrence or overall survival, reported Dr. Giuliano. Additionally, stratified analysis showed that the lack of difference in overall survival between study groups was the same whether tumors had hormone receptors or not.

In a related analysis of radiation protocol deviations in a subset of women from the trial, 11% did not receive any radiation therapy, while 18.9% received third-field radiation, with equal distribution of the latter between study groups (J Clin Oncol. 2014;32:3600-6). Omission of radiation was associated with an increased risk of local recurrence and death, but it did not affect nodal recurrences. Receipt of third-field radiation did not influence survival.

[email protected]

CHICAGO – Women with clinical early-stage breast cancer and a positive sentinel lymph node who receive breast-conserving therapy can safely skip an axillary lymph node dissection (ALND), and therefore avoid its associated morbidity, confirms long-term follow-up of the Z0011 trial conducted by the American College of Surgeons Oncology Group and the Alliance for Clinical Trials in Oncology.

The phase III trial enrolled 891 women with clinical T1-2,N0,M0 disease who underwent lumpectomy and were found to have sentinel node involvement. They were randomized to ALND or no further surgery, followed by whole-breast radiation therapy and, in most cases, systemic adjuvant therapy.

The trial was closed early because of low rates of accrual and events. Results at 6.3 years of follow-up showed that compared with peers who had an ALND, the women who skipped this surgery did not have inferior 5-year rates of locoregional recurrence or overall survival (JAMA. 2011;305:569-75).

“The study, however, like most breast cancer studies, contained mostly postmenopausal women with hormone receptor–positive tumors who are known to have late recurrences, and it was criticized for short follow-up,” commented first author Armando E. Giuliano, MD, executive vice chair of surgical oncology in the department of surgery, and associate director of surgical oncology in the Samuel Oschin Comprehensive Cancer Institute, Los Angeles.

In an update of the findings, now with a median follow-up of 9.3 years, the groups were statistically indistinguishable with respect to 10-year rates of the same outcomes, he reported at the annual meeting of the American Society of Clinical Oncology.

“This study... shows that sentinel node biopsy alone provides excellent 10-year locoregional control and survival comparable to completion axillary lymph node dissection for these patients, even with long-term follow-up,” he maintained. “Routine use of axillary lymph node dissection should be abandoned.”

“This was designed as a noninferiority trial, and I would suggest that based on the data we have seen, even if they had hit their target accrual, the outcomes would not be different,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston. “Clearly, even before today’s presentation, Z0011 has been identified as a practice-changing trial, as evidenced by the NCCN guidelines.”

In fact, a study last year showed that among patients in the general U.S. population meeting the trial’s enrollment criteria, the use of sentinel lymph node dissection alone has increased significantly since the Z0011 results were first reported (J Am Coll Surg. 2015;221:71-81).

“However, I would highlight that we have also seen an increase in omission of axillary lymph node dissection for patients who do not meet the Z0011 criteria to include those not planned for radiotherapy, those receiving APBI [accelerated partial breast irradiation], and those undergoing mastectomy,” she added. “I highlight these examples specifically because it’s been suggested that one of the reasons the patients on the trial have outstanding regional control is because of the radiation administered as part of their breast-conserving therapy.”

“We will obtain additional data on the locoregional management of these early-stage patients with clinically node-negative breast cancer,” Dr. Mittendorf predicted, pointing to the similar POSNOC trial (which is comparing systemic therapy with versus without axillary treatment) and SOUND trial (which is comparing sentinel node dissection versus no axillary surgery).

In Z0011, all women had tumor in sentinel nodes detected with hematoxylin and eosin staining. Those with sentinel node tumor detected only by immunohistochemistry were excluded, as were those who had matted nodes, three or more involved sentinel nodes, or planned third-field (nodal) irradiation.

Overall, 27.4% of the patients in the ALND group had additional positive nodes removed beyond their sentinel nodes. “There is no reason to suspect that women with sentinel node biopsy [only] had fewer involved nodes than the women treated with axillary lymph node dissection,” Dr. Giuliano commented; thus, a similar share of the former group likely had residual axillary disease that went unresected.

The updated findings showed that the women received ALND and the women who did not were statistically indistinguishable with respect to the 10-year rate of locoregional recurrence (6.2% and 5.3%). Of note, only a single regional recurrence was seen after the initial 5 years of follow-up, and it occurred in the group that did not have ALND.

The groups treated with and without ALND were also statistically indistinguishable with respect to 10-year rates of disease-free survival (78.2% and 80.2%), locoregional recurrence–free survival (81.2% and 83.0%), and overall survival (83.6% and 86.3%).

In multivariate analysis, omission of ALND did not significantly predict locoregional recurrence or overall survival, reported Dr. Giuliano. Additionally, stratified analysis showed that the lack of difference in overall survival between study groups was the same whether tumors had hormone receptors or not.

In a related analysis of radiation protocol deviations in a subset of women from the trial, 11% did not receive any radiation therapy, while 18.9% received third-field radiation, with equal distribution of the latter between study groups (J Clin Oncol. 2014;32:3600-6). Omission of radiation was associated with an increased risk of local recurrence and death, but it did not affect nodal recurrences. Receipt of third-field radiation did not influence survival.

[email protected]

CHICAGO – Women with clinical early-stage breast cancer and a positive sentinel lymph node who receive breast-conserving therapy can safely skip an axillary lymph node dissection (ALND), and therefore avoid its associated morbidity, confirms long-term follow-up of the Z0011 trial conducted by the American College of Surgeons Oncology Group and the Alliance for Clinical Trials in Oncology.

The phase III trial enrolled 891 women with clinical T1-2,N0,M0 disease who underwent lumpectomy and were found to have sentinel node involvement. They were randomized to ALND or no further surgery, followed by whole-breast radiation therapy and, in most cases, systemic adjuvant therapy.

The trial was closed early because of low rates of accrual and events. Results at 6.3 years of follow-up showed that compared with peers who had an ALND, the women who skipped this surgery did not have inferior 5-year rates of locoregional recurrence or overall survival (JAMA. 2011;305:569-75).

“The study, however, like most breast cancer studies, contained mostly postmenopausal women with hormone receptor–positive tumors who are known to have late recurrences, and it was criticized for short follow-up,” commented first author Armando E. Giuliano, MD, executive vice chair of surgical oncology in the department of surgery, and associate director of surgical oncology in the Samuel Oschin Comprehensive Cancer Institute, Los Angeles.

In an update of the findings, now with a median follow-up of 9.3 years, the groups were statistically indistinguishable with respect to 10-year rates of the same outcomes, he reported at the annual meeting of the American Society of Clinical Oncology.

“This study... shows that sentinel node biopsy alone provides excellent 10-year locoregional control and survival comparable to completion axillary lymph node dissection for these patients, even with long-term follow-up,” he maintained. “Routine use of axillary lymph node dissection should be abandoned.”

“This was designed as a noninferiority trial, and I would suggest that based on the data we have seen, even if they had hit their target accrual, the outcomes would not be different,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston. “Clearly, even before today’s presentation, Z0011 has been identified as a practice-changing trial, as evidenced by the NCCN guidelines.”

In fact, a study last year showed that among patients in the general U.S. population meeting the trial’s enrollment criteria, the use of sentinel lymph node dissection alone has increased significantly since the Z0011 results were first reported (J Am Coll Surg. 2015;221:71-81).

“However, I would highlight that we have also seen an increase in omission of axillary lymph node dissection for patients who do not meet the Z0011 criteria to include those not planned for radiotherapy, those receiving APBI [accelerated partial breast irradiation], and those undergoing mastectomy,” she added. “I highlight these examples specifically because it’s been suggested that one of the reasons the patients on the trial have outstanding regional control is because of the radiation administered as part of their breast-conserving therapy.”

“We will obtain additional data on the locoregional management of these early-stage patients with clinically node-negative breast cancer,” Dr. Mittendorf predicted, pointing to the similar POSNOC trial (which is comparing systemic therapy with versus without axillary treatment) and SOUND trial (which is comparing sentinel node dissection versus no axillary surgery).

In Z0011, all women had tumor in sentinel nodes detected with hematoxylin and eosin staining. Those with sentinel node tumor detected only by immunohistochemistry were excluded, as were those who had matted nodes, three or more involved sentinel nodes, or planned third-field (nodal) irradiation.

Overall, 27.4% of the patients in the ALND group had additional positive nodes removed beyond their sentinel nodes. “There is no reason to suspect that women with sentinel node biopsy [only] had fewer involved nodes than the women treated with axillary lymph node dissection,” Dr. Giuliano commented; thus, a similar share of the former group likely had residual axillary disease that went unresected.

The updated findings showed that the women received ALND and the women who did not were statistically indistinguishable with respect to the 10-year rate of locoregional recurrence (6.2% and 5.3%). Of note, only a single regional recurrence was seen after the initial 5 years of follow-up, and it occurred in the group that did not have ALND.

The groups treated with and without ALND were also statistically indistinguishable with respect to 10-year rates of disease-free survival (78.2% and 80.2%), locoregional recurrence–free survival (81.2% and 83.0%), and overall survival (83.6% and 86.3%).

In multivariate analysis, omission of ALND did not significantly predict locoregional recurrence or overall survival, reported Dr. Giuliano. Additionally, stratified analysis showed that the lack of difference in overall survival between study groups was the same whether tumors had hormone receptors or not.

In a related analysis of radiation protocol deviations in a subset of women from the trial, 11% did not receive any radiation therapy, while 18.9% received third-field radiation, with equal distribution of the latter between study groups (J Clin Oncol. 2014;32:3600-6). Omission of radiation was associated with an increased risk of local recurrence and death, but it did not affect nodal recurrences. Receipt of third-field radiation did not influence survival.

[email protected]

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed its review of the PI3Kδ inhibitor idelalisib (Zyedelig) and concluded that the drug’s benefits outweigh its risks in the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma.

However, the PRAC also confirmed that the drug increases the risk of serious infections, including Pneumocystis jirovecii pneumonia.

And the committee updated its previous recommendations to manage this risk.

The PRAC’s recommendations will now be sent to the Committee for Medicinal Products for Human Use, which will adopt the EMA’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all member states of the European Union (EU).

About idelalisib

In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

About the review

The PRAC’s review of idelalisib began after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indications for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

PRAC’s recommendations

The PRAC noted that, although the aforementioned trials did not all use idelalisib as currently authorized, the risk of serious infection is considered relevant to the authorized use.

Therefore, the PRAC recommends that all patients treated with idelalisib receive antibiotics to prevent Pneumocystis jirovecii pneumonia during treatment and for up to 2 to 6 months after treatment has stopped.

Patients should also be monitored for infection and have regular blood tests for white cell counts because low counts can increase their risk of infection.

Furthermore, idelalisib should not be started in patients with a generalized infection.

At the beginning of its review, the PRAC had said idelalisib should not be started in patients with previously untreated CLL and 17p deletion or TP53 mutation.

Now, the PRAC has concluded that idelalisib can be initiated in these patients, provided they cannot take any alternative treatment and that the recommended measures to prevent infection are followed.