Celiac disease’s only treatment is far from ideal. Not only is the gluten-free diet hard to follow, costly, and socially isolating, but even adherent patients can suffer persistent and disabling symptoms, Daniel A. Leffler, MD, MS, of Beth Israel Deaconess Medical Center in Boston, and his associates noted. This “high unmet medical need” inspired their discussion of clinical trials in celiac disease at the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3). A summary appears as a Clinical Practice Update in Gastroenterology (2016 Jul 22. doi: 10.1053/j.gastro.2016.07.025).

Celiac is the “outlier among intestinal diseases,” the experts noted. Few randomized trials have assessed nondietary celiac disease therapies, drug developers lack a precedent approval to clarify a “guiding regulatory pathway.” The first step toward bridging these gaps is to better define target populations for clinical trials, meeting attendees agreed. Such groups might include patients with diet-refractory symptoms; newly diagnosed patients who need pharmacologic support for symptom resolution and duodenal healing; patients with asymptomatic mucosal damage, if such damage is shown to cause malignancy; and patients with neurobehavioral disorders that impede gluten avoidance. Medications that enable patients to safely consume gluten could benefit even more, including those who already face “arduous” dietary controls from comorbidities such as type 1 diabetes, the experts added.

Defining “clinical benefit” in pivotal trials of celiac disease also poses a challenge. “While every patient might desire something slightly different, the overarching theme of clinical benefit from the patient’s perspective appears to be quality of life – free of symptoms and inflammation without worry about [gluten] contamination,” attendees emphasized. Indeed, one recent survey found that patients prioritized protection against cross-contamination over being able to consume gluten at will. But initial trials should focus on gastrointestinal symptoms, which are common, affect patients of all ages, and “can be measured in a reasonable time frame,” they concluded.

Unfortunately, defining and measuring atypical symptoms can be difficult, particularly in children and adolescents. In an unpublished study at the Nationwide Children’s Hospital, gastrointestinal symptoms affected 77% of celiac patients, while only about 5% experienced atypical or nongastrointestinal symptoms, the experts noted. Such low percentages could make it difficult to adequately power studies of these nongastrointestinal outcomes. Furthermore, measuring sequelae such as osteoporosis or anemia “would require longer studies, as these conditions do not resolve quickly.”

Phase II and III trials cannot secure marketing approvals without clearly defining and measuring “clinical benefit,” Food and Drug Administration representatives at the meeting noted. Accordingly, diarrhea and abdominal pain will be key patient-reported outcome measures, and pivotal trials of young children with celiac disease will require observer-reported outcomes, attendees agreed. Although both celiac disease and the gluten-free diet profoundly undercut health-related quality of life, this measure is too broad and easily confounded to be a good endpoint in pivotal trials of celiac therapies. Likewise, histology is valuable for relating symptoms to active disease, but mucosal healing is too variable and unpredictable to serve as a primary endpoint, experts noted.

In contrast, serologic tests could serve as enrollment criteria, stratification measures, and endpoints if these tests received the appropriate FDA approvals, experts asserted. The endomysial antibody, tissue transglutaminase antibody, and deamidated gliadin peptide tests are most often used in practice, but have only been approved for diagnosing celiac disease – not as a replacement for biopsy or as a measure of disease progression or therapeutic response, FDA representatives noted. Although drug developers need tools to measure therapeutic efficacy in celiac disease, FDA recommended soliciting advice from its Center for Drug Evaluation and Research before testing these tools or kicking off monitoring studies.

The meeting was supported by the Celiac Disease Foundation and Beyond Celiac, and was sponsored by the FDA Center for Drug Evaluation and Research; the American Gastroenterological Association; the American College of Gastroenterology; the American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the North American Society for the Study of Celiac Disease. Dr. Leffler disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, INOVA Diagnostics, Coronado Biosciences, Pfizer, and GI Supply. One coauthor and senior author, Dr. Sheila Crowe, disclosed ties to Alvine Pharmaceuticals, Ferring, and Celimmune.

Celiac disease’s only treatment is far from ideal. Not only is the gluten-free diet hard to follow, costly, and socially isolating, but even adherent patients can suffer persistent and disabling symptoms, Daniel A. Leffler, MD, MS, of Beth Israel Deaconess Medical Center in Boston, and his associates noted. This “high unmet medical need” inspired their discussion of clinical trials in celiac disease at the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3). A summary appears as a Clinical Practice Update in Gastroenterology (2016 Jul 22. doi: 10.1053/j.gastro.2016.07.025).

Celiac is the “outlier among intestinal diseases,” the experts noted. Few randomized trials have assessed nondietary celiac disease therapies, drug developers lack a precedent approval to clarify a “guiding regulatory pathway.” The first step toward bridging these gaps is to better define target populations for clinical trials, meeting attendees agreed. Such groups might include patients with diet-refractory symptoms; newly diagnosed patients who need pharmacologic support for symptom resolution and duodenal healing; patients with asymptomatic mucosal damage, if such damage is shown to cause malignancy; and patients with neurobehavioral disorders that impede gluten avoidance. Medications that enable patients to safely consume gluten could benefit even more, including those who already face “arduous” dietary controls from comorbidities such as type 1 diabetes, the experts added.

Defining “clinical benefit” in pivotal trials of celiac disease also poses a challenge. “While every patient might desire something slightly different, the overarching theme of clinical benefit from the patient’s perspective appears to be quality of life – free of symptoms and inflammation without worry about [gluten] contamination,” attendees emphasized. Indeed, one recent survey found that patients prioritized protection against cross-contamination over being able to consume gluten at will. But initial trials should focus on gastrointestinal symptoms, which are common, affect patients of all ages, and “can be measured in a reasonable time frame,” they concluded.

Unfortunately, defining and measuring atypical symptoms can be difficult, particularly in children and adolescents. In an unpublished study at the Nationwide Children’s Hospital, gastrointestinal symptoms affected 77% of celiac patients, while only about 5% experienced atypical or nongastrointestinal symptoms, the experts noted. Such low percentages could make it difficult to adequately power studies of these nongastrointestinal outcomes. Furthermore, measuring sequelae such as osteoporosis or anemia “would require longer studies, as these conditions do not resolve quickly.”

Phase II and III trials cannot secure marketing approvals without clearly defining and measuring “clinical benefit,” Food and Drug Administration representatives at the meeting noted. Accordingly, diarrhea and abdominal pain will be key patient-reported outcome measures, and pivotal trials of young children with celiac disease will require observer-reported outcomes, attendees agreed. Although both celiac disease and the gluten-free diet profoundly undercut health-related quality of life, this measure is too broad and easily confounded to be a good endpoint in pivotal trials of celiac therapies. Likewise, histology is valuable for relating symptoms to active disease, but mucosal healing is too variable and unpredictable to serve as a primary endpoint, experts noted.

In contrast, serologic tests could serve as enrollment criteria, stratification measures, and endpoints if these tests received the appropriate FDA approvals, experts asserted. The endomysial antibody, tissue transglutaminase antibody, and deamidated gliadin peptide tests are most often used in practice, but have only been approved for diagnosing celiac disease – not as a replacement for biopsy or as a measure of disease progression or therapeutic response, FDA representatives noted. Although drug developers need tools to measure therapeutic efficacy in celiac disease, FDA recommended soliciting advice from its Center for Drug Evaluation and Research before testing these tools or kicking off monitoring studies.

The meeting was supported by the Celiac Disease Foundation and Beyond Celiac, and was sponsored by the FDA Center for Drug Evaluation and Research; the American Gastroenterological Association; the American College of Gastroenterology; the American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the North American Society for the Study of Celiac Disease. Dr. Leffler disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, INOVA Diagnostics, Coronado Biosciences, Pfizer, and GI Supply. One coauthor and senior author, Dr. Sheila Crowe, disclosed ties to Alvine Pharmaceuticals, Ferring, and Celimmune.

Celiac disease’s only treatment is far from ideal. Not only is the gluten-free diet hard to follow, costly, and socially isolating, but even adherent patients can suffer persistent and disabling symptoms, Daniel A. Leffler, MD, MS, of Beth Israel Deaconess Medical Center in Boston, and his associates noted. This “high unmet medical need” inspired their discussion of clinical trials in celiac disease at the third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics (GREAT 3). A summary appears as a Clinical Practice Update in Gastroenterology (2016 Jul 22. doi: 10.1053/j.gastro.2016.07.025).

Celiac is the “outlier among intestinal diseases,” the experts noted. Few randomized trials have assessed nondietary celiac disease therapies, drug developers lack a precedent approval to clarify a “guiding regulatory pathway.” The first step toward bridging these gaps is to better define target populations for clinical trials, meeting attendees agreed. Such groups might include patients with diet-refractory symptoms; newly diagnosed patients who need pharmacologic support for symptom resolution and duodenal healing; patients with asymptomatic mucosal damage, if such damage is shown to cause malignancy; and patients with neurobehavioral disorders that impede gluten avoidance. Medications that enable patients to safely consume gluten could benefit even more, including those who already face “arduous” dietary controls from comorbidities such as type 1 diabetes, the experts added.

Defining “clinical benefit” in pivotal trials of celiac disease also poses a challenge. “While every patient might desire something slightly different, the overarching theme of clinical benefit from the patient’s perspective appears to be quality of life – free of symptoms and inflammation without worry about [gluten] contamination,” attendees emphasized. Indeed, one recent survey found that patients prioritized protection against cross-contamination over being able to consume gluten at will. But initial trials should focus on gastrointestinal symptoms, which are common, affect patients of all ages, and “can be measured in a reasonable time frame,” they concluded.

Unfortunately, defining and measuring atypical symptoms can be difficult, particularly in children and adolescents. In an unpublished study at the Nationwide Children’s Hospital, gastrointestinal symptoms affected 77% of celiac patients, while only about 5% experienced atypical or nongastrointestinal symptoms, the experts noted. Such low percentages could make it difficult to adequately power studies of these nongastrointestinal outcomes. Furthermore, measuring sequelae such as osteoporosis or anemia “would require longer studies, as these conditions do not resolve quickly.”

Phase II and III trials cannot secure marketing approvals without clearly defining and measuring “clinical benefit,” Food and Drug Administration representatives at the meeting noted. Accordingly, diarrhea and abdominal pain will be key patient-reported outcome measures, and pivotal trials of young children with celiac disease will require observer-reported outcomes, attendees agreed. Although both celiac disease and the gluten-free diet profoundly undercut health-related quality of life, this measure is too broad and easily confounded to be a good endpoint in pivotal trials of celiac therapies. Likewise, histology is valuable for relating symptoms to active disease, but mucosal healing is too variable and unpredictable to serve as a primary endpoint, experts noted.

In contrast, serologic tests could serve as enrollment criteria, stratification measures, and endpoints if these tests received the appropriate FDA approvals, experts asserted. The endomysial antibody, tissue transglutaminase antibody, and deamidated gliadin peptide tests are most often used in practice, but have only been approved for diagnosing celiac disease – not as a replacement for biopsy or as a measure of disease progression or therapeutic response, FDA representatives noted. Although drug developers need tools to measure therapeutic efficacy in celiac disease, FDA recommended soliciting advice from its Center for Drug Evaluation and Research before testing these tools or kicking off monitoring studies.

The meeting was supported by the Celiac Disease Foundation and Beyond Celiac, and was sponsored by the FDA Center for Drug Evaluation and Research; the American Gastroenterological Association; the American College of Gastroenterology; the American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the North American Society for the Study of Celiac Disease. Dr. Leffler disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, INOVA Diagnostics, Coronado Biosciences, Pfizer, and GI Supply. One coauthor and senior author, Dr. Sheila Crowe, disclosed ties to Alvine Pharmaceuticals, Ferring, and Celimmune.

To the Editor:

Vemurafenib is a selective BRAF inhibitor that was approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an approved test. Both malignant and nonmalignant cutaneous findings have been well documented in association with vemurafenib, including squamous cell carcinoma, keratoacanthomas, UVA photosensitivity, keratosis pilaris–like eruptions, seborrheic dermatitis, follicular plugging, follicular hyperkeratosis, and eruptive melanocytic nevi.¹ As more patients with metastatic melanoma are treated with vemurafenib, the use of concomitant palliative or adjuvant radiation therapy with vemurafenib will inevitably occur in greater frequency. Therefore, it is critical to understand the potential cutaneous side effects of this combination.

A predisposition to enhanced radiation dermatitis has been well described with concurrent use of targeted chemotherapies such as the epidermal growth factor receptor inhibitor cetuximab with radiotherapy.² We report a case of radiation dermatitis occurring shortly after initiating radiation therapy in a patient on vemurafenib.

A 53-year-old man with initial stage IIIB melanoma, Breslow depth 2.2 mm with histologic ulceration, and a mitotic index of 2/mm² on the right buttock underwent wide local excision and sentinel lymph node biopsy followed by complete lymph node dissection with a total of 2 of 10 positive lymph nodes. The patient subsequently underwent 1 year of adjuvant high-dose interferon therapy. Four years after his initial presentation he developed metastases to the lungs, pelvis, and both femurs. He was started on oral vemurafenib 960 mg twice daily. Due to painful bony metastases in the pelvis, the patient also was started on concurrent palliative radiation therapy to both femurs, L5 vertebra, and the sacrum 1 day after initiation of vemurafenib. Three days after initiation of radiation therapy at a cumulative radiation dose of 0.75 Gy, the patient developed severe, painful, well-demarcated, erythematous plaques in the anterior and posterior pelvic distribution overlying the radiation field (Figure 1) that subsequently evolved to eroded desquamative plaques with copious transudate. The patient also developed hyperkeratotic papules on the chest and thighs consistent with the keratosis pilaris–like eruptions associated with vemurafenib therapy.¹ Five months later the patient developed worsening neurologic symptoms, and magnetic resonance imaging of the brain revealed multiple brain metastases. Given his disease progression, vemurafenib was discontinued. Ten days later, the patient underwent palliative whole-brain radiation therapy. He received a total dose of 3.25 Gy to the whole brain without any cutaneous sequelae.

The pathophysiology of radiation dermatitis is caused by a dose-dependent loss of basal and endothelial cells following irradiation.³ If surviving basal cells are able to repopulate the basal monolayer, normal skin barrier function is preserved. Dose tolerance is exceeded when cell loss without replacement occurs, resulting in necrosis and clinical evidence of radiation dermatitis, which is characterized by painful erythema or hyperpigmentation followed by desquamation and skin necrosis. In general, occurrence and severity of radiation dermatitis when radiation therapy is used alone in the absence of concurrent chemotherapy is dose dependent, with cutaneous evidence of radiation dermatitis occurring at doses ranging from as low as 2 Gy but most commonly 5 to 10 Gy.⁴ A report of radiation recall dermatitis in 2 patients who received vemurafenib after completing a full course of radiotherapy⁵ supports the hypothesis that vemurafenib is a radiosensitizing medication. Enhanced radiation dermatitis was reported in a single case of a patient on vemurafenib who developed radiation dermatitis after completing 3.25 Gy of radiation to the lumbar spine. Although this case likely depicted enhanced radiation dermatitis secondary to concurrent vemurafenib use, it was inconclusive whether vemurafenib contributed to the cutaneous effect, as the patient developed a cutaneous skin reaction 1 week after receiving a cumulative radiation dose of 3.25 Gy, a level at which radiation alone has been shown to cause skin toxicity.⁶ In our patient, cutaneous manifestations were noted 3 days after initiation of radiation treatment, at which point he had received a total radiation dose of 0.75 Gy, which is well below the threshold commonly recognized to cause radiation-induced skin toxicities. In addition, rechallenge in this patient with higher-dose radiotherapy while off of vemurafenib treatment led to no skin toxicity, despite the common side effects of whole-brain radiation therapy including radiation dermatitis and alopecia.⁷

The exact mechanism of increased radiosensitivity caused by targeted chemotherapies such as cetuximab and vemurafenib is unclear. One possible explanation is that the drug interferes with the mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in controlling cell survival and regeneration following radiation exposure.⁸ Disruption of this signaling pathway through targeted therapies leads to impaired keratinocyte cell survival and recovery, and thus may enhance susceptibility to radiation-induced skin injury (Figure 2). In vivo studies have demonstrated that the epidermal growth factor receptor is activated following UV irradiation in human keratinocytes, leading to activation of the downstream MAPK signal transduction pathway required for cellular proliferation mediated via the RAF family of proteins.^9,10 Further supporting the importance of this pathway in keratinocyte survival and recovery are findings that somatic deletion of BRAF in fibroblasts results in decreased growth factor–induced MAPK activation and enhanced apoptosis,⁸ whereas activated BRAF has been shown to exert protective effects against oxidative stress as well as tumorigenesis.¹¹ The observation that mutant BRAF melanoma cells demonstrated increased radiosensitivity following BRAF inhibition with vemurafenib¹² is consistent with our hypothesis that increased radiosensitivity occurs when signal transduction mediated by MAPK pathway is blocked, thereby inhibiting cell survival. As a result, radiation dermatitis is likely to occur more frequently and at a lower dose when signaling pathways upstream in the MAPK pathway required for keratinocyte regeneration, such as epidermal growth factor receptor and BRAF, are inhibited by targeted therapies. This hypothesis supports the observation that patients on medications that inhibit these signaling pathways, such as cetuximab and vemurafenib, develop enhanced sensitivity to both UV radiation and radiation therapy.

To the Editor:

Vemurafenib is a selective BRAF inhibitor that was approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an approved test. Both malignant and nonmalignant cutaneous findings have been well documented in association with vemurafenib, including squamous cell carcinoma, keratoacanthomas, UVA photosensitivity, keratosis pilaris–like eruptions, seborrheic dermatitis, follicular plugging, follicular hyperkeratosis, and eruptive melanocytic nevi.¹ As more patients with metastatic melanoma are treated with vemurafenib, the use of concomitant palliative or adjuvant radiation therapy with vemurafenib will inevitably occur in greater frequency. Therefore, it is critical to understand the potential cutaneous side effects of this combination.

A predisposition to enhanced radiation dermatitis has been well described with concurrent use of targeted chemotherapies such as the epidermal growth factor receptor inhibitor cetuximab with radiotherapy.² We report a case of radiation dermatitis occurring shortly after initiating radiation therapy in a patient on vemurafenib.

A 53-year-old man with initial stage IIIB melanoma, Breslow depth 2.2 mm with histologic ulceration, and a mitotic index of 2/mm² on the right buttock underwent wide local excision and sentinel lymph node biopsy followed by complete lymph node dissection with a total of 2 of 10 positive lymph nodes. The patient subsequently underwent 1 year of adjuvant high-dose interferon therapy. Four years after his initial presentation he developed metastases to the lungs, pelvis, and both femurs. He was started on oral vemurafenib 960 mg twice daily. Due to painful bony metastases in the pelvis, the patient also was started on concurrent palliative radiation therapy to both femurs, L5 vertebra, and the sacrum 1 day after initiation of vemurafenib. Three days after initiation of radiation therapy at a cumulative radiation dose of 0.75 Gy, the patient developed severe, painful, well-demarcated, erythematous plaques in the anterior and posterior pelvic distribution overlying the radiation field (Figure 1) that subsequently evolved to eroded desquamative plaques with copious transudate. The patient also developed hyperkeratotic papules on the chest and thighs consistent with the keratosis pilaris–like eruptions associated with vemurafenib therapy.¹ Five months later the patient developed worsening neurologic symptoms, and magnetic resonance imaging of the brain revealed multiple brain metastases. Given his disease progression, vemurafenib was discontinued. Ten days later, the patient underwent palliative whole-brain radiation therapy. He received a total dose of 3.25 Gy to the whole brain without any cutaneous sequelae.

The pathophysiology of radiation dermatitis is caused by a dose-dependent loss of basal and endothelial cells following irradiation.³ If surviving basal cells are able to repopulate the basal monolayer, normal skin barrier function is preserved. Dose tolerance is exceeded when cell loss without replacement occurs, resulting in necrosis and clinical evidence of radiation dermatitis, which is characterized by painful erythema or hyperpigmentation followed by desquamation and skin necrosis. In general, occurrence and severity of radiation dermatitis when radiation therapy is used alone in the absence of concurrent chemotherapy is dose dependent, with cutaneous evidence of radiation dermatitis occurring at doses ranging from as low as 2 Gy but most commonly 5 to 10 Gy.⁴ A report of radiation recall dermatitis in 2 patients who received vemurafenib after completing a full course of radiotherapy⁵ supports the hypothesis that vemurafenib is a radiosensitizing medication. Enhanced radiation dermatitis was reported in a single case of a patient on vemurafenib who developed radiation dermatitis after completing 3.25 Gy of radiation to the lumbar spine. Although this case likely depicted enhanced radiation dermatitis secondary to concurrent vemurafenib use, it was inconclusive whether vemurafenib contributed to the cutaneous effect, as the patient developed a cutaneous skin reaction 1 week after receiving a cumulative radiation dose of 3.25 Gy, a level at which radiation alone has been shown to cause skin toxicity.⁶ In our patient, cutaneous manifestations were noted 3 days after initiation of radiation treatment, at which point he had received a total radiation dose of 0.75 Gy, which is well below the threshold commonly recognized to cause radiation-induced skin toxicities. In addition, rechallenge in this patient with higher-dose radiotherapy while off of vemurafenib treatment led to no skin toxicity, despite the common side effects of whole-brain radiation therapy including radiation dermatitis and alopecia.⁷

The exact mechanism of increased radiosensitivity caused by targeted chemotherapies such as cetuximab and vemurafenib is unclear. One possible explanation is that the drug interferes with the mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in controlling cell survival and regeneration following radiation exposure.⁸ Disruption of this signaling pathway through targeted therapies leads to impaired keratinocyte cell survival and recovery, and thus may enhance susceptibility to radiation-induced skin injury (Figure 2). In vivo studies have demonstrated that the epidermal growth factor receptor is activated following UV irradiation in human keratinocytes, leading to activation of the downstream MAPK signal transduction pathway required for cellular proliferation mediated via the RAF family of proteins.^9,10 Further supporting the importance of this pathway in keratinocyte survival and recovery are findings that somatic deletion of BRAF in fibroblasts results in decreased growth factor–induced MAPK activation and enhanced apoptosis,⁸ whereas activated BRAF has been shown to exert protective effects against oxidative stress as well as tumorigenesis.¹¹ The observation that mutant BRAF melanoma cells demonstrated increased radiosensitivity following BRAF inhibition with vemurafenib¹² is consistent with our hypothesis that increased radiosensitivity occurs when signal transduction mediated by MAPK pathway is blocked, thereby inhibiting cell survival. As a result, radiation dermatitis is likely to occur more frequently and at a lower dose when signaling pathways upstream in the MAPK pathway required for keratinocyte regeneration, such as epidermal growth factor receptor and BRAF, are inhibited by targeted therapies. This hypothesis supports the observation that patients on medications that inhibit these signaling pathways, such as cetuximab and vemurafenib, develop enhanced sensitivity to both UV radiation and radiation therapy.

To the Editor:

Vemurafenib is a selective BRAF inhibitor that was approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an approved test. Both malignant and nonmalignant cutaneous findings have been well documented in association with vemurafenib, including squamous cell carcinoma, keratoacanthomas, UVA photosensitivity, keratosis pilaris–like eruptions, seborrheic dermatitis, follicular plugging, follicular hyperkeratosis, and eruptive melanocytic nevi.¹ As more patients with metastatic melanoma are treated with vemurafenib, the use of concomitant palliative or adjuvant radiation therapy with vemurafenib will inevitably occur in greater frequency. Therefore, it is critical to understand the potential cutaneous side effects of this combination.

A predisposition to enhanced radiation dermatitis has been well described with concurrent use of targeted chemotherapies such as the epidermal growth factor receptor inhibitor cetuximab with radiotherapy.² We report a case of radiation dermatitis occurring shortly after initiating radiation therapy in a patient on vemurafenib.

A 53-year-old man with initial stage IIIB melanoma, Breslow depth 2.2 mm with histologic ulceration, and a mitotic index of 2/mm² on the right buttock underwent wide local excision and sentinel lymph node biopsy followed by complete lymph node dissection with a total of 2 of 10 positive lymph nodes. The patient subsequently underwent 1 year of adjuvant high-dose interferon therapy. Four years after his initial presentation he developed metastases to the lungs, pelvis, and both femurs. He was started on oral vemurafenib 960 mg twice daily. Due to painful bony metastases in the pelvis, the patient also was started on concurrent palliative radiation therapy to both femurs, L5 vertebra, and the sacrum 1 day after initiation of vemurafenib. Three days after initiation of radiation therapy at a cumulative radiation dose of 0.75 Gy, the patient developed severe, painful, well-demarcated, erythematous plaques in the anterior and posterior pelvic distribution overlying the radiation field (Figure 1) that subsequently evolved to eroded desquamative plaques with copious transudate. The patient also developed hyperkeratotic papules on the chest and thighs consistent with the keratosis pilaris–like eruptions associated with vemurafenib therapy.¹ Five months later the patient developed worsening neurologic symptoms, and magnetic resonance imaging of the brain revealed multiple brain metastases. Given his disease progression, vemurafenib was discontinued. Ten days later, the patient underwent palliative whole-brain radiation therapy. He received a total dose of 3.25 Gy to the whole brain without any cutaneous sequelae.

The pathophysiology of radiation dermatitis is caused by a dose-dependent loss of basal and endothelial cells following irradiation.³ If surviving basal cells are able to repopulate the basal monolayer, normal skin barrier function is preserved. Dose tolerance is exceeded when cell loss without replacement occurs, resulting in necrosis and clinical evidence of radiation dermatitis, which is characterized by painful erythema or hyperpigmentation followed by desquamation and skin necrosis. In general, occurrence and severity of radiation dermatitis when radiation therapy is used alone in the absence of concurrent chemotherapy is dose dependent, with cutaneous evidence of radiation dermatitis occurring at doses ranging from as low as 2 Gy but most commonly 5 to 10 Gy.⁴ A report of radiation recall dermatitis in 2 patients who received vemurafenib after completing a full course of radiotherapy⁵ supports the hypothesis that vemurafenib is a radiosensitizing medication. Enhanced radiation dermatitis was reported in a single case of a patient on vemurafenib who developed radiation dermatitis after completing 3.25 Gy of radiation to the lumbar spine. Although this case likely depicted enhanced radiation dermatitis secondary to concurrent vemurafenib use, it was inconclusive whether vemurafenib contributed to the cutaneous effect, as the patient developed a cutaneous skin reaction 1 week after receiving a cumulative radiation dose of 3.25 Gy, a level at which radiation alone has been shown to cause skin toxicity.⁶ In our patient, cutaneous manifestations were noted 3 days after initiation of radiation treatment, at which point he had received a total radiation dose of 0.75 Gy, which is well below the threshold commonly recognized to cause radiation-induced skin toxicities. In addition, rechallenge in this patient with higher-dose radiotherapy while off of vemurafenib treatment led to no skin toxicity, despite the common side effects of whole-brain radiation therapy including radiation dermatitis and alopecia.⁷

The exact mechanism of increased radiosensitivity caused by targeted chemotherapies such as cetuximab and vemurafenib is unclear. One possible explanation is that the drug interferes with the mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in controlling cell survival and regeneration following radiation exposure.⁸ Disruption of this signaling pathway through targeted therapies leads to impaired keratinocyte cell survival and recovery, and thus may enhance susceptibility to radiation-induced skin injury (Figure 2). In vivo studies have demonstrated that the epidermal growth factor receptor is activated following UV irradiation in human keratinocytes, leading to activation of the downstream MAPK signal transduction pathway required for cellular proliferation mediated via the RAF family of proteins.^9,10 Further supporting the importance of this pathway in keratinocyte survival and recovery are findings that somatic deletion of BRAF in fibroblasts results in decreased growth factor–induced MAPK activation and enhanced apoptosis,⁸ whereas activated BRAF has been shown to exert protective effects against oxidative stress as well as tumorigenesis.¹¹ The observation that mutant BRAF melanoma cells demonstrated increased radiosensitivity following BRAF inhibition with vemurafenib¹² is consistent with our hypothesis that increased radiosensitivity occurs when signal transduction mediated by MAPK pathway is blocked, thereby inhibiting cell survival. As a result, radiation dermatitis is likely to occur more frequently and at a lower dose when signaling pathways upstream in the MAPK pathway required for keratinocyte regeneration, such as epidermal growth factor receptor and BRAF, are inhibited by targeted therapies. This hypothesis supports the observation that patients on medications that inhibit these signaling pathways, such as cetuximab and vemurafenib, develop enhanced sensitivity to both UV radiation and radiation therapy.

To the Editor:

Topical photodynamic therapy (PDT) is one of several effective treatments of actinic keratoses (AKs). Photodynamic therapy involves selection of a lesion field, application of a photosensitizer drug, incubation for an explicit period of time, and illumination of the area from a light source corresponding to the absorption spectrum of the chosen drug.¹ A photosensitizer drug used in PDT to target AK is aminolevulinic acid (ALA). Aminolevulinic acid converts disease tissue to photoactivatable porphyrins, especially protoporphyrin IX, which has its largest absorption peak (410 nm) in the blue spectrum, with smaller absorption peaks at 505, 540, 580, and 630 nm. Photodynamic therapy treatments historically have been carried out under red light (peak emissions, 630 nm) to improve tissue penetration, which is superior in efficacy when treating Bowen disease and basal cell carcinoma.^1,2 Broadband blue light (peak emission, 417 nm) now is routinely used and has been proven effective in combination with ALA for the treatment of AK.³ It was approved by the US Food and Drug Administration for AKs in 1999.⁴

Photo-onycholysis is a photosensitivity reaction defined as separation of the nail plate from the nail bed. There are 4 different types of photo-onycholysis characterized by appearance and by the number of digits affected: Type I is denoted by the involvement of several fingers, with half-moon–shaped separations of the nail plate. Type II affects a single finger and corresponds to a brown, defined, circular notch opening distally. Type III, which involves several fingers, is defined as round yellow stains in the central portion of the nail that turn red after 5 to 10 days. Type IV has been associated with bullae under the nails.⁵ There have been cases of photo-onycholysis arising after exposure to UV light following ingestion of certain prescription drugs or spontaneously,⁶ and a single case following PDT to the hands with red light.⁵ We report a case of fingernail photo-onycholysis resulting from ALA-PDT for the treatment of perioral AK.

Our case provides evidence for risks involving the development of photo-onycholysis following PDT. We have no reason to believe there was systemic absorption of ALA, as there were no visible vesicles on the arms or hands after the treatment. Negative fungal culture results excluded onychomycosis. It is our hypothesis that the patient touched her face with her fingernails during the 60-minute incubation time prior to ALA-PDT treatment under blue light, inadvertently collecting ALA under the fingernails. Once she exposed her hands to sunlight while gardening after treatment, the nails likely reacted with the ALA in response to the UV radiation, thus triggering photo-onycholysis.

This case represents a report of fingernail photo-onycholysis from ALA-PDT under blue light as well as a report following treatment of AK not located on the hands with PDT. Although the photo-onycholysis did resolve within a few months of treatment, our case demonstrates the importance of counseling patients more specifically about isolating the ALA treatment zone from nontreated areas on the body during incubation. Improper UV light protection following ALA-PDT is known to produce phototoxic reactions and our case supports this outcome.

To the Editor:

Topical photodynamic therapy (PDT) is one of several effective treatments of actinic keratoses (AKs). Photodynamic therapy involves selection of a lesion field, application of a photosensitizer drug, incubation for an explicit period of time, and illumination of the area from a light source corresponding to the absorption spectrum of the chosen drug.¹ A photosensitizer drug used in PDT to target AK is aminolevulinic acid (ALA). Aminolevulinic acid converts disease tissue to photoactivatable porphyrins, especially protoporphyrin IX, which has its largest absorption peak (410 nm) in the blue spectrum, with smaller absorption peaks at 505, 540, 580, and 630 nm. Photodynamic therapy treatments historically have been carried out under red light (peak emissions, 630 nm) to improve tissue penetration, which is superior in efficacy when treating Bowen disease and basal cell carcinoma.^1,2 Broadband blue light (peak emission, 417 nm) now is routinely used and has been proven effective in combination with ALA for the treatment of AK.³ It was approved by the US Food and Drug Administration for AKs in 1999.⁴

Photo-onycholysis is a photosensitivity reaction defined as separation of the nail plate from the nail bed. There are 4 different types of photo-onycholysis characterized by appearance and by the number of digits affected: Type I is denoted by the involvement of several fingers, with half-moon–shaped separations of the nail plate. Type II affects a single finger and corresponds to a brown, defined, circular notch opening distally. Type III, which involves several fingers, is defined as round yellow stains in the central portion of the nail that turn red after 5 to 10 days. Type IV has been associated with bullae under the nails.⁵ There have been cases of photo-onycholysis arising after exposure to UV light following ingestion of certain prescription drugs or spontaneously,⁶ and a single case following PDT to the hands with red light.⁵ We report a case of fingernail photo-onycholysis resulting from ALA-PDT for the treatment of perioral AK.

Our case provides evidence for risks involving the development of photo-onycholysis following PDT. We have no reason to believe there was systemic absorption of ALA, as there were no visible vesicles on the arms or hands after the treatment. Negative fungal culture results excluded onychomycosis. It is our hypothesis that the patient touched her face with her fingernails during the 60-minute incubation time prior to ALA-PDT treatment under blue light, inadvertently collecting ALA under the fingernails. Once she exposed her hands to sunlight while gardening after treatment, the nails likely reacted with the ALA in response to the UV radiation, thus triggering photo-onycholysis.

This case represents a report of fingernail photo-onycholysis from ALA-PDT under blue light as well as a report following treatment of AK not located on the hands with PDT. Although the photo-onycholysis did resolve within a few months of treatment, our case demonstrates the importance of counseling patients more specifically about isolating the ALA treatment zone from nontreated areas on the body during incubation. Improper UV light protection following ALA-PDT is known to produce phototoxic reactions and our case supports this outcome.

To the Editor:

Topical photodynamic therapy (PDT) is one of several effective treatments of actinic keratoses (AKs). Photodynamic therapy involves selection of a lesion field, application of a photosensitizer drug, incubation for an explicit period of time, and illumination of the area from a light source corresponding to the absorption spectrum of the chosen drug.¹ A photosensitizer drug used in PDT to target AK is aminolevulinic acid (ALA). Aminolevulinic acid converts disease tissue to photoactivatable porphyrins, especially protoporphyrin IX, which has its largest absorption peak (410 nm) in the blue spectrum, with smaller absorption peaks at 505, 540, 580, and 630 nm. Photodynamic therapy treatments historically have been carried out under red light (peak emissions, 630 nm) to improve tissue penetration, which is superior in efficacy when treating Bowen disease and basal cell carcinoma.^1,2 Broadband blue light (peak emission, 417 nm) now is routinely used and has been proven effective in combination with ALA for the treatment of AK.³ It was approved by the US Food and Drug Administration for AKs in 1999.⁴

Photo-onycholysis is a photosensitivity reaction defined as separation of the nail plate from the nail bed. There are 4 different types of photo-onycholysis characterized by appearance and by the number of digits affected: Type I is denoted by the involvement of several fingers, with half-moon–shaped separations of the nail plate. Type II affects a single finger and corresponds to a brown, defined, circular notch opening distally. Type III, which involves several fingers, is defined as round yellow stains in the central portion of the nail that turn red after 5 to 10 days. Type IV has been associated with bullae under the nails.⁵ There have been cases of photo-onycholysis arising after exposure to UV light following ingestion of certain prescription drugs or spontaneously,⁶ and a single case following PDT to the hands with red light.⁵ We report a case of fingernail photo-onycholysis resulting from ALA-PDT for the treatment of perioral AK.

Our case provides evidence for risks involving the development of photo-onycholysis following PDT. We have no reason to believe there was systemic absorption of ALA, as there were no visible vesicles on the arms or hands after the treatment. Negative fungal culture results excluded onychomycosis. It is our hypothesis that the patient touched her face with her fingernails during the 60-minute incubation time prior to ALA-PDT treatment under blue light, inadvertently collecting ALA under the fingernails. Once she exposed her hands to sunlight while gardening after treatment, the nails likely reacted with the ALA in response to the UV radiation, thus triggering photo-onycholysis.

This case represents a report of fingernail photo-onycholysis from ALA-PDT under blue light as well as a report following treatment of AK not located on the hands with PDT. Although the photo-onycholysis did resolve within a few months of treatment, our case demonstrates the importance of counseling patients more specifically about isolating the ALA treatment zone from nontreated areas on the body during incubation. Improper UV light protection following ALA-PDT is known to produce phototoxic reactions and our case supports this outcome.

Patients with psoriasis now have several treatment options to help control their disease. Among them are oral therapies. Dr. Gary Goldenberg reviews clearance data on approved therapies and ones on the horizon.

Patients with psoriasis now have several treatment options to help control their disease. Among them are oral therapies. Dr. Gary Goldenberg reviews clearance data on approved therapies and ones on the horizon.

Patients with psoriasis now have several treatment options to help control their disease. Among them are oral therapies. Dr. Gary Goldenberg reviews clearance data on approved therapies and ones on the horizon.

Nonalcoholic fatty liver disease (NAFLD) is associated with a significant increase in the risk of carotid atherosclerosis that appears to be mediated by metabolic factors, according to a retrospective cohort study published in Gastroenterology.

The study of 8,020 adult Korean men without carotid atherosclerosis at baseline showed that men with persistent NAFLD had a 13% greater risk of subclinical carotid atherosclerosis compared with those without NAFLD, after adjustment for age, smoking, alcohol, body mass index, and weight change (95% confidence interval [CI], 1.13-1.35, P less than .001).

Courtesy of Wikimedia / "Nephron" / Creative Commons License

However, this increase in risk was entirely accounted for by metabolic variables including systolic blood pressure, fasting blood glucose, LDL and HDL cholesterol, and triglycerides (Gastroenterology 2016; http://dx.doi.org/10.1053/j.gastro.2016.06.001).

The analysis also showed a significant relationship between the degree of fibrosis and the risk of atherosclerosis; individuals with an NAFLD fibrosis score greater than –1.455 had a 29% higher risk of subclinical carotid atherosclerosis compared to those with a score less than –1.455. Those with a high FIB-4 score had a 43% greater risk of atherosclerosis than did those with a low FIB-4 score, even after adjustment for metabolic factors.

Individuals with a high gamma-glutamyl transferase level also had a higher risk of subclinical carotid atherosclerosis, but this became nonsignificant after adjustment for metabolic variables.

“Although the primary abnormality in NAFLD affects liver structure and function and may result in cirrhosis, liver failure, and hepatocellular carcinoma, the clinical burden of NAFLD is not confined to liver-related morbidity and mortality,” wrote Dong Hyun Sinn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and coauthors. “In our study, the association of persistent NAFLD with the development of carotid atherosclerosis was attenuated after adjusting for metabolic risk factors.”

Overall, 16.8% of individuals with persistent NAFLD developed subclinical carotid atherosclerosis over 3 years, compared to 11.4% of those with regressed NAFLD, 12.2% with developed NAFLD and 13.6% of those with no NAFLD.

The authors noted that regression of NAFLD appeared to reduce the risk of subclinical carotid atherosclerosis to a level that was comparable to that of individuals without NAFLD at baseline.

“This observation highlights the importance of persistent NAFLD as a risk factor and suggests that resolution of NAFLD may reduce the risk of atherosclerotic CVD,” they wrote. “Because lifestyle changes reduce CVD risk, it is possible that the reduced risk of CVD among participants with resolved NAFLD in the present study may be the consequence of lifestyle changes and not the direct consequence of NAFLD resolution.”

No conflicts of interest were declared.

Nonalcoholic fatty liver disease (NAFLD) is associated with a significant increase in the risk of carotid atherosclerosis that appears to be mediated by metabolic factors, according to a retrospective cohort study published in Gastroenterology.

The study of 8,020 adult Korean men without carotid atherosclerosis at baseline showed that men with persistent NAFLD had a 13% greater risk of subclinical carotid atherosclerosis compared with those without NAFLD, after adjustment for age, smoking, alcohol, body mass index, and weight change (95% confidence interval [CI], 1.13-1.35, P less than .001).

Courtesy of Wikimedia / "Nephron" / Creative Commons License

However, this increase in risk was entirely accounted for by metabolic variables including systolic blood pressure, fasting blood glucose, LDL and HDL cholesterol, and triglycerides (Gastroenterology 2016; http://dx.doi.org/10.1053/j.gastro.2016.06.001).

The analysis also showed a significant relationship between the degree of fibrosis and the risk of atherosclerosis; individuals with an NAFLD fibrosis score greater than –1.455 had a 29% higher risk of subclinical carotid atherosclerosis compared to those with a score less than –1.455. Those with a high FIB-4 score had a 43% greater risk of atherosclerosis than did those with a low FIB-4 score, even after adjustment for metabolic factors.

Individuals with a high gamma-glutamyl transferase level also had a higher risk of subclinical carotid atherosclerosis, but this became nonsignificant after adjustment for metabolic variables.

“Although the primary abnormality in NAFLD affects liver structure and function and may result in cirrhosis, liver failure, and hepatocellular carcinoma, the clinical burden of NAFLD is not confined to liver-related morbidity and mortality,” wrote Dong Hyun Sinn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and coauthors. “In our study, the association of persistent NAFLD with the development of carotid atherosclerosis was attenuated after adjusting for metabolic risk factors.”

Overall, 16.8% of individuals with persistent NAFLD developed subclinical carotid atherosclerosis over 3 years, compared to 11.4% of those with regressed NAFLD, 12.2% with developed NAFLD and 13.6% of those with no NAFLD.

The authors noted that regression of NAFLD appeared to reduce the risk of subclinical carotid atherosclerosis to a level that was comparable to that of individuals without NAFLD at baseline.

“This observation highlights the importance of persistent NAFLD as a risk factor and suggests that resolution of NAFLD may reduce the risk of atherosclerotic CVD,” they wrote. “Because lifestyle changes reduce CVD risk, it is possible that the reduced risk of CVD among participants with resolved NAFLD in the present study may be the consequence of lifestyle changes and not the direct consequence of NAFLD resolution.”

No conflicts of interest were declared.

Nonalcoholic fatty liver disease (NAFLD) is associated with a significant increase in the risk of carotid atherosclerosis that appears to be mediated by metabolic factors, according to a retrospective cohort study published in Gastroenterology.

The study of 8,020 adult Korean men without carotid atherosclerosis at baseline showed that men with persistent NAFLD had a 13% greater risk of subclinical carotid atherosclerosis compared with those without NAFLD, after adjustment for age, smoking, alcohol, body mass index, and weight change (95% confidence interval [CI], 1.13-1.35, P less than .001).

Courtesy of Wikimedia / "Nephron" / Creative Commons License

However, this increase in risk was entirely accounted for by metabolic variables including systolic blood pressure, fasting blood glucose, LDL and HDL cholesterol, and triglycerides (Gastroenterology 2016; http://dx.doi.org/10.1053/j.gastro.2016.06.001).

The analysis also showed a significant relationship between the degree of fibrosis and the risk of atherosclerosis; individuals with an NAFLD fibrosis score greater than –1.455 had a 29% higher risk of subclinical carotid atherosclerosis compared to those with a score less than –1.455. Those with a high FIB-4 score had a 43% greater risk of atherosclerosis than did those with a low FIB-4 score, even after adjustment for metabolic factors.

Individuals with a high gamma-glutamyl transferase level also had a higher risk of subclinical carotid atherosclerosis, but this became nonsignificant after adjustment for metabolic variables.

“Although the primary abnormality in NAFLD affects liver structure and function and may result in cirrhosis, liver failure, and hepatocellular carcinoma, the clinical burden of NAFLD is not confined to liver-related morbidity and mortality,” wrote Dong Hyun Sinn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and coauthors. “In our study, the association of persistent NAFLD with the development of carotid atherosclerosis was attenuated after adjusting for metabolic risk factors.”

Overall, 16.8% of individuals with persistent NAFLD developed subclinical carotid atherosclerosis over 3 years, compared to 11.4% of those with regressed NAFLD, 12.2% with developed NAFLD and 13.6% of those with no NAFLD.

The authors noted that regression of NAFLD appeared to reduce the risk of subclinical carotid atherosclerosis to a level that was comparable to that of individuals without NAFLD at baseline.

“This observation highlights the importance of persistent NAFLD as a risk factor and suggests that resolution of NAFLD may reduce the risk of atherosclerotic CVD,” they wrote. “Because lifestyle changes reduce CVD risk, it is possible that the reduced risk of CVD among participants with resolved NAFLD in the present study may be the consequence of lifestyle changes and not the direct consequence of NAFLD resolution.”

No conflicts of interest were declared.

Want to re-visit the 2016 Vascular Annual Meeting, or view it for the first time?

The VAM On-Demand Library includes a wealth of useful information: 100+ audio and slide presentations of abstracts and papers, video recordings of plenaries and special sessions, lists of authors and faculty, links to information on CME credits and more.

The search feature helps locate all sessions related to a particular topic or speaker, and users can download the associated slide presentations. Best of all, these materials are available to refer to again and again.

Cost for this valuable educational resource is $199 for those who attended the annual meeting and $499 for non-attendees. (People who purchased the library before or during VAM were to receive their access codes on Aug. 3 -- remember to check spam or junk folders! -- in an email from the recording vendor, CadmiumCD.)

Contact the SVS Education Department with any questions. Access or purchase the On-Demand Library here.

Want to re-visit the 2016 Vascular Annual Meeting, or view it for the first time?

The VAM On-Demand Library includes a wealth of useful information: 100+ audio and slide presentations of abstracts and papers, video recordings of plenaries and special sessions, lists of authors and faculty, links to information on CME credits and more.

The search feature helps locate all sessions related to a particular topic or speaker, and users can download the associated slide presentations. Best of all, these materials are available to refer to again and again.

Cost for this valuable educational resource is $199 for those who attended the annual meeting and $499 for non-attendees. (People who purchased the library before or during VAM were to receive their access codes on Aug. 3 -- remember to check spam or junk folders! -- in an email from the recording vendor, CadmiumCD.)

Contact the SVS Education Department with any questions. Access or purchase the On-Demand Library here.

Want to re-visit the 2016 Vascular Annual Meeting, or view it for the first time?

The VAM On-Demand Library includes a wealth of useful information: 100+ audio and slide presentations of abstracts and papers, video recordings of plenaries and special sessions, lists of authors and faculty, links to information on CME credits and more.

The search feature helps locate all sessions related to a particular topic or speaker, and users can download the associated slide presentations. Best of all, these materials are available to refer to again and again.

Cost for this valuable educational resource is $199 for those who attended the annual meeting and $499 for non-attendees. (People who purchased the library before or during VAM were to receive their access codes on Aug. 3 -- remember to check spam or junk folders! -- in an email from the recording vendor, CadmiumCD.)

Contact the SVS Education Department with any questions. Access or purchase the On-Demand Library here.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.

The European Commission has proposed regulatory criteria on endocrine-disrupting chemicals that are too strict and so fall short of protecting the public, as they were intended to do, experts contend.

Endocrine-disrupting chemicals cost Europe billions in health care costs each year (Andrology. 2016 Jul;4[4]:565-72).

Published in June, the criteria would require proof that chemicals harm human endocrine health to define them as endocrine-disrupting chemicals (EDCs) – even if data from animal and in vitro studies already suggest so. “Because health effects can take years or even generations to become apparent, this proposal will not protect public health,” the Endocrine Society noted in a sharp formal critique.

Endocrine-disrupting chemicals mimic or block hormones central to brain development, reproduction, metabolism, growth, and other key physiologic processes. The European Union is the largest single economy to regulate EDCs specifically, which more than 1,300 studies have linked to health problems such as infertility, diabetes, obesity, hormone-related cancers, and neurological disorders, the Endocrine Society concluded in a 2015 scientific statement.

Exposure to even low doses of EDCs such as bisphenol A (BPA) can cause adverse effects. But to fulfill the regulatory definition of the European Commission, EDCs would have to meet an even greater burden of proof than carcinogens – a backward step that “defeats the purpose of the regulations – to shield the public from EDCs that pose a threat to human health,” Rémy Slama, PhD, a member of the Society’s European Union Endocrine-Disrupting Chemicals Task Force, stated in an Endocrine Society news release. Of particular concern is the proposal that EDCs must have a single known “mode of action,” which “represents a fundamental misunderstanding of how endocrine signaling works by connecting different organ systems within the body,” said Dr. Slama, senior investigator at Inserm (the National Institute of Health and Medical Research) in Paris.

Deborah M. Kurrasch, PhD, assistant professor and principal investigator at the University of Calgary (Alta.), agreed. The “mode of action” criterion misses the point that EDCs are “messy” compounds that target various proteins and elicit a range of potential cellular responses based on dose, target tissue, and age, she said in an interview. An EDC may lack a single mode of action, or its mode of action may be far harder to pinpoint than its effects on processes such as reproduction, sleep, mood, and growth, she added. “In my opinion, an endocrine-disrupting chemical is one that disrupts the endocrine system. Despite some internal dialogue, the name for this broad and diverse group of chemicals is, and likely will remain, EDCs because the name so accurately describes their one unifying effect – they all perturb normal endocrine function.”

Ultimately, enacting such tight criteria would tie the hands of regulators with regard to newly recognized and even some well-studied EDCs, “despite evidence that they affect endocrine signaling, because their mode of action is not yet known,” Dr. Kurrasch said.

Experts also noted that the EC criteria would keep regulatory bodies from ranking chemicals based on the strength of evidence that they disrupt endocrine function. Instead, the Endocrine Society advocates for a tiered ranking system based on available data. “As the European Parliament and member countries consider whether to implement the European Commission’s criteria, the Society will continue to advocate for criteria that reflect the state of the science,” the organization emphasized.

Dr. Kurrasch is a member of the Endocrine Society and had no other disclosures.