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.

In 1961 before Congress, and in 1962 at Rice University, Houston, President John F. Kennedy called on America to land a man on the moon and bring him back safely, and to look beyond the moon as well, and pursue an ambitious space exploration program. He challenged the country to think and act boldly, telling Americans in his speech at Rice that “we choose to go the moon in this decade and do the other things, not because they are easy, but because they are hard.”

When Neil Armstrong and Buzz Aldrin set foot on the moon in 1969 – even before President Kennedy’s 10-year deadline had arrived – the country’s primary moonshot was realized. The President had inspired the nation, teams of engineers and others had collectively met daunting technological challenges, and space consequently was more open to us than ever before.

In looking at the field of obstetrics and how far it has come in the past 50 years, since the 1960s, it is similarly astonishing and inspiring to reflect on what extraordinary advances we have made. Who would have thought that the fetus would become such a visible and intimate patient – one who, like the mother, can be interrogated, monitored, and sometimes treated before birth? Who would have thought we would be utilizing genomic studies in a now well-established field of prenatal diagnosis, or that fetal therapy would become a field in and of itself?

Our specialty has advanced through a series of moonshots that have been inspired and driven by technological advancement and by our continually bold goals and vision for the health and well-being of women and their offspring. We have taken on ambitious challenges, achieved many goals, and embraced advancements in practice only to then set new targets that previously were unimaginable.

Yet just as our country’s space exploration program has faced disappointments, so has our field. It is sobering, for instance, that we have made only incremental improvements in prematurity and infant mortality, and that the age-old maternal problem of preeclampsia is still with us. We also face new challenges, such as the rising rate of maternal obesity and diabetes, which threaten both maternal and fetal health.

President Kennedy spoke of having “examined where we are strong, and where we are not.” Such self-reflection and assessment is a critical underpinning of advancement in fields across all of science, medicine, and health care, and in our specialty, it is a process that has driven ambitious new research efforts to improve fetal and maternal health.

A step back to more in-depth fundamental research on the biomolecular mechanisms of premature labor and diabetes-associated birth defects, for instance, as well as new efforts to approach fetal surgery less invasively, are positioning us to both conquer our disappointments and achieve ambitious new moonshots.

The fetus as our patient

Fifty years ago, in 1966, a seminal paper in the Lancet reported that amniotic fluid cells could be cultured and were suitable for karyotyping (1[7434]:383-5). The tapping and examination of amniotic fluid had been reported on sporadically for many decades, for various clinical purposes, but by and large the fetal compartment was not invaded or directly examined. The fetus was instead the hopeful beneficiary of pregnancy care that focused on the mother. Fetal outcome was clouded in mystery, known only at birth.

With the Lancet report, prenatal detection of chromosomal disorders began to feel achievable, and the 1960s marked the beginning of a journey first through invasive methods of prenatal diagnosis and then through increasingly non-invasive approaches.

In 1970, just several years after the report on chromosome analysis of amniotic-fluid cells, another landmark paper in the New England Journal of Medicine described 162 amniocenteses performed between the 13th and 18th weeks of gestation and the detection of 10 cases of Down syndrome, as well as a few other cases of metabolic and other disorders (282[11]:596-9). This report provided an impetus for broader use of the procedure to detect neural tube defects, Down syndrome, and other abnormalities.

The adoption of amniocentesis for prenatal diagnosis still took some time, however. The procedure was used primarily early on to determine fetal lung maturity, and to predict the ability of the fetus to survive after delivery.

At the time, it was widely praised as an advanced method for evaluating the fetus. Yet, looking back, the early years of the procedure seem primitive. The procedure was done late in pregnancy and it was performed blindly, with the puncture site located either with external palpation of the uterus or with the assistance of static ultrasound. Patients who had scans would usually visit the radiologist, who would mark on the patient’s abdomen a suggested location for needle insertion. Upon the patient’s return, the obstetrician would then insert a needle into that spot, blindly and likely after the fetus had moved.

The development and adoption of real-time ultrasound was a revolutionary achievement. Ultrasound-guided amniocentesis was first described in 1972, 14 years after Ian Donald’s seminal paper introducing obstetric ultrasound was published in the Lancet (1958 Jun 7;1[7032]:1188-95).

As real-time ultrasound made its way into practice, it marked the true realization of a moonshot for obstetrics.

Not only could we simultaneously visualize the needle tip and place the needle safety, but we could see the real-time movement of the fetus, its activity, and the surrounding pockets of fluid. It was like looking up into the sky and seeing the stars for the first time. We could see fetal arrhythmia – not only hear it. With this window into the fetal compartment, we could visualize the fetal bowel migrating into the chest cavity due to a hole (hernia) in the diaphragm. We could visualize other malformations as well.

Chorionic villus sampling (CVS) was technically more difficult and took longer to evolve. For years, through the early 1980s, it was performed only at select centers throughout the country. Patients traveled for the procedure and faced relatively significant risks of complications.

By the end of the 1980s, however, with successive improvements in equipment and technique (including development of a transabdominal approach in addition to transvaginal) the procedure was deemed safe, effective, and acceptable for routine use. Fetoscopy, pioneered by John Hobbins, MD, and his colleagues at Yale University, New Haven, Conn., had also advanced and was being used to diagnose sickle cell anemia, Tay-Sachs disease, congenital fetal skin diseases, and other disorders.

With these advances and with our newfound ability to obtain and analyze a tissue sample earlier in pregnancy – even before a woman shared the news of her pregnancy, in some cases – it seemed that we had achieved our goals and may have even reached past the moon.

Yet there were other moonshots being pursued, including initiatives to make prenatal diagnosis less invasive. The discovery in 1997 of cell-free fetal DNA in maternal plasma and serum, for instance, was a pivotal development that opened the door for noninvasive prenatal testing.

This, and other advances in areas from biochemistry to ultrasound to genomic analysis, led to an array of prenatal diagnostic tools that today enable women and their physicians to assess the genetic, chromosomal, and biophysical aspects of their fetus considerably before the time of viability, and from both the maternal side and directly in the fetal compartment.

First-trimester screening is a current option, and we now have the ability to more selectively perform amniocentesis and CVS based on probability testing, and not solely on maternal age. Ultrasound technology now encompasses color Doppler, 3D and 4D imaging, and other techniques that can be used to assess the placenta, various structures inside the brain, and the heart, as well as blood flow through the ductus venosus.

Parents have called for and welcomed having the option of assessing the fetus in greater detail, and of having either assurance when anomalies are excluded or the opportunity to plan and make decisions when anomalies are detected.

Fetal surgery has been a natural extension of our unprecedented access to the fetus. Our ability to visualize malformations and their evolution led to animal studies that advanced our interest in arresting, correcting, or reversing fetal anomalies through in-utero interventions. In 1981, surgeons performed the first human open fetal surgery to correct congenital hydronephrosis.

Today, we can employ endoscopic laser ablation or laser coagulation to treat severe twin-to-twin syndrome, for instance, as well as other surgical techniques to repair defects such as congenital diaphragmatic hernia, lower urinary tract obstruction, and myelomeningocele. Such advances were unimaginable decades ago.

Old foes and new threats

Despite these advances in diagnosis and care, obstetrics faces unrealized moonshots – lingering challenges that, 50 years ago, we would have predicted would have been solved. Who would have thought that we would still have as high an infant mortality rate as we do, and that we would not be further along in solving the problem of prematurity? Our progress has been only incremental.

Fifty years ago, we lacked an understanding of the basic biology of preterm labor. Prematurity was viewed simply as term labor occurring too early, and many efforts were made over the years to halt the premature labor process through the use of various drugs and other therapeutics, with variable and minimally impactful levels of success.

In the last 25 years, and especially in the last decade, we have made greater efforts to better understand the biology of premature labor – to elucidate how and why it occurs – and we have come to understand that premature labor is very different physiologically from term labor.

Thanks to the work at the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), led by Roberto Romero, MD, attention has consequently shifted toward prediction, identification of women at highest risk, and prevention of the onset of premature labor among those deemed to be at highest risk.

Cervical length in the mid-trimester is now a well-verified predictor of preterm birth, and vaginal progesterone has been shown to benefit women without other known risk factors who are diagnosed with a shortened cervical length.

We have consequently seen the preterm birth rate decline a bit. In 2013, the last year for which we have complete data, the preterm birth rate dropped to 11.4%, down from a high of 12.8% in 2006, according to the Centers for Disease Control and Prevention.

Infant mortality similarly remains unacceptably high, due largely to the high preterm birth rate and to our failure to significantly alter the prevalence of birth defects. In 2010, according to the CDC, the infant mortality rate in the U.S. was 6.1 deaths per 1,000 live births (compared with 6.87 in 2005), and the United States ranked 26th in infant mortality among countries belonging to the Organisation for Economic Co-operation and Development, despite the fact that we spend a significant portion of our gross domestic product (17.5% in 2014) on health care.

Birth defects have taken over as a leading cause of infant mortality after early newborn life, and while we’ve made some advancements in understanding and diagnosing them, the majority of causes of birth defects are still unknown.

On the maternal side of obstetrical care, our progress has similarly been more modest than we have hoped for. Preeclampsia remains a problem, for instance. Despite decades of research into its pathogenesis, our advancements have been only incremental, and the condition – particularly its severe form – continues to be a vexing and high-risk problem.

Added to such age-old foes, moreover, are the growing threats of maternal obesity and diabetes, two closely related and often chronic conditions that affect not only the health of the mother but the in-utero environment and the health of the fetus. Today, more than one-third of all adults in the U.S., and 34% of women aged 20-39 years, are obese, and almost 10% of the U.S. population has diabetes.

Both conditions are on the rise, and obstetrics is confronting an epidemic of “diabesity” that would not necessarily have been predicted 50 years ago. It is particularly alarming given our growing knowledge of how obesity can be programmed in-utero and essentially passed on from generation to generation, of how diabetes can negatively affect perinatal outcomes, and of how the two conditions can have an additive effect on fetal complications.

Achieving new moonshots

Concerted efforts in the past several decades to step back and try to understand the basic biology and physiology of term labor and of premature labor have better positioned our specialty to achieve the moonshot of significantly reducing the incidence of preterm birth.

Establishment in the mid-1980s of the NICHD’s Perinatology Research Branch was a major development in this regard, helping to build and direct research efforts, including basic laboratory science, toward questions about what triggers and propagates labor. There has been notable progress in the past decade, in particular, and our specialty is now on the right path toward development of therapeutic interventions for preventing prematurity.

Additionally, the NICHD’s recently launched Human Placenta Project is building upon the branch-sponsored animal and cell culture model systems of the placenta to allow researchers, for the first time, to monitor human placental health in real time. By more fully understanding the role of the placenta in health and disease, we will be able to better evaluate pregnancy risks and improve pregnancy outcomes.

We also are learning through research in the University of Maryland Birth Defects Research Laboratory, which I am privileged to direct, and at other facilities, that maternal hyperglycemia is a teratogen, creating insults that can trigger a series of developmental fetal defects. By studying the biomolecular mechanisms of hyperglycemia-induced birth defects and developing “molecular maps,” we expect to be able to develop strategies for preventing or mitigating the development of such anomalies. I hope and expect that these future advancements, combined with reductions in prematurity, will significantly impact the infant mortality rate.

Fetal therapy and surgery will also continue to advance, with a much more minimally invasive approach taken in the next 50 years to addressing the fetal condition without putting the mother at increased risk. Just as surgery in other fields has moved from open laparotomy to minimally invasive techniques, I believe we will develop endoscopic or laparoscopic means of correcting the various problems in-utero, such as the repair of neural tube defects and diaphragmatic hernias. It already appears likely that a fetoscopic approach to treating myelomeningocele can reduce maternal morbidity while achieving infant neurological outcomes that are at least as good as outcomes achieved with open fetal surgery.

We’re in a much different position than we were 50 years ago in that we have two patients – the mother and the fetus – with whom we can closely work. We also have a relatively new and urgent obligation to place our attention not only on women’s reproductive health, but on the general gynecologic state. Ob.gyns. often are the only primary care physicians whom women see for routine care, and the quality of our attention to their weight and their diabetes risk factors will have far-reaching consequences, both for them and for their offspring.

As we have since the 1960s, we will continue to set new moonshots and meet new challenges, working with each other and with our patients to evaluate where we are strong and where we must improve. We will persistently harness the power of technology, choosing to do the things that “are hard,” while stepping back as needed to ask and address fundamental questions.

As a result, I can envision the next 50 years as a revolutionary time period for obstetrics – a time in which current problems and disorders are abated or eliminated through a combination of genomics, microbiomics, and other technological advances. Someday in the future, we will look back on some of our many achievements and marvel at how we have transformed the unimaginable to reality.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at obnews@frontlinemedcom.com.

Select advances through the years

1960s

1965: Siemens Corp. introduces first real-time ultrasound scanner.

1966: Lancet paper reports that amniotic fluid cells can be cultured and karyotyped.

1970s

1970: New England Journal of Medicine paper describes mid-trimester amniocenteses and detection of Down syndrome cases.

1972: Ultrasound-guided amniocentesis first described.

1973: Fetoscopy introduced.

1980s

1981: First human open fetal surgery to correct congenital hydronephrosis.

Early 1980s: Chorionic villus sampling introduced at select centers.

1985: Color Doppler incorporated into ultrasound.

1990s

1990: Embryoscopy first described.

Mid-1990s: 3D/4D ultrasound begins to assume major role in ob.gyn. imaging.1997: Discovery of cell-free fetal DNA in maternal plasma.

2000s

2003: MOMS (Management of Myelomeningocele Study) was launched.

2010s

2012: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support cell-free DNA screening for women at increased risk of fetal aneuploidy.

2013: Preterm birth rate drops to 11.4%

2014: Diabetes incidence marks a 4-fold increase since 1980.

In 1961 before Congress, and in 1962 at Rice University, Houston, President John F. Kennedy called on America to land a man on the moon and bring him back safely, and to look beyond the moon as well, and pursue an ambitious space exploration program. He challenged the country to think and act boldly, telling Americans in his speech at Rice that “we choose to go the moon in this decade and do the other things, not because they are easy, but because they are hard.”

When Neil Armstrong and Buzz Aldrin set foot on the moon in 1969 – even before President Kennedy’s 10-year deadline had arrived – the country’s primary moonshot was realized. The President had inspired the nation, teams of engineers and others had collectively met daunting technological challenges, and space consequently was more open to us than ever before.

In looking at the field of obstetrics and how far it has come in the past 50 years, since the 1960s, it is similarly astonishing and inspiring to reflect on what extraordinary advances we have made. Who would have thought that the fetus would become such a visible and intimate patient – one who, like the mother, can be interrogated, monitored, and sometimes treated before birth? Who would have thought we would be utilizing genomic studies in a now well-established field of prenatal diagnosis, or that fetal therapy would become a field in and of itself?

Our specialty has advanced through a series of moonshots that have been inspired and driven by technological advancement and by our continually bold goals and vision for the health and well-being of women and their offspring. We have taken on ambitious challenges, achieved many goals, and embraced advancements in practice only to then set new targets that previously were unimaginable.

Yet just as our country’s space exploration program has faced disappointments, so has our field. It is sobering, for instance, that we have made only incremental improvements in prematurity and infant mortality, and that the age-old maternal problem of preeclampsia is still with us. We also face new challenges, such as the rising rate of maternal obesity and diabetes, which threaten both maternal and fetal health.

President Kennedy spoke of having “examined where we are strong, and where we are not.” Such self-reflection and assessment is a critical underpinning of advancement in fields across all of science, medicine, and health care, and in our specialty, it is a process that has driven ambitious new research efforts to improve fetal and maternal health.

A step back to more in-depth fundamental research on the biomolecular mechanisms of premature labor and diabetes-associated birth defects, for instance, as well as new efforts to approach fetal surgery less invasively, are positioning us to both conquer our disappointments and achieve ambitious new moonshots.

The fetus as our patient

Fifty years ago, in 1966, a seminal paper in the Lancet reported that amniotic fluid cells could be cultured and were suitable for karyotyping (1[7434]:383-5). The tapping and examination of amniotic fluid had been reported on sporadically for many decades, for various clinical purposes, but by and large the fetal compartment was not invaded or directly examined. The fetus was instead the hopeful beneficiary of pregnancy care that focused on the mother. Fetal outcome was clouded in mystery, known only at birth.

With the Lancet report, prenatal detection of chromosomal disorders began to feel achievable, and the 1960s marked the beginning of a journey first through invasive methods of prenatal diagnosis and then through increasingly non-invasive approaches.

In 1970, just several years after the report on chromosome analysis of amniotic-fluid cells, another landmark paper in the New England Journal of Medicine described 162 amniocenteses performed between the 13th and 18th weeks of gestation and the detection of 10 cases of Down syndrome, as well as a few other cases of metabolic and other disorders (282[11]:596-9). This report provided an impetus for broader use of the procedure to detect neural tube defects, Down syndrome, and other abnormalities.

The adoption of amniocentesis for prenatal diagnosis still took some time, however. The procedure was used primarily early on to determine fetal lung maturity, and to predict the ability of the fetus to survive after delivery.

At the time, it was widely praised as an advanced method for evaluating the fetus. Yet, looking back, the early years of the procedure seem primitive. The procedure was done late in pregnancy and it was performed blindly, with the puncture site located either with external palpation of the uterus or with the assistance of static ultrasound. Patients who had scans would usually visit the radiologist, who would mark on the patient’s abdomen a suggested location for needle insertion. Upon the patient’s return, the obstetrician would then insert a needle into that spot, blindly and likely after the fetus had moved.

The development and adoption of real-time ultrasound was a revolutionary achievement. Ultrasound-guided amniocentesis was first described in 1972, 14 years after Ian Donald’s seminal paper introducing obstetric ultrasound was published in the Lancet (1958 Jun 7;1[7032]:1188-95).

As real-time ultrasound made its way into practice, it marked the true realization of a moonshot for obstetrics.

Not only could we simultaneously visualize the needle tip and place the needle safety, but we could see the real-time movement of the fetus, its activity, and the surrounding pockets of fluid. It was like looking up into the sky and seeing the stars for the first time. We could see fetal arrhythmia – not only hear it. With this window into the fetal compartment, we could visualize the fetal bowel migrating into the chest cavity due to a hole (hernia) in the diaphragm. We could visualize other malformations as well.

Chorionic villus sampling (CVS) was technically more difficult and took longer to evolve. For years, through the early 1980s, it was performed only at select centers throughout the country. Patients traveled for the procedure and faced relatively significant risks of complications.

By the end of the 1980s, however, with successive improvements in equipment and technique (including development of a transabdominal approach in addition to transvaginal) the procedure was deemed safe, effective, and acceptable for routine use. Fetoscopy, pioneered by John Hobbins, MD, and his colleagues at Yale University, New Haven, Conn., had also advanced and was being used to diagnose sickle cell anemia, Tay-Sachs disease, congenital fetal skin diseases, and other disorders.

With these advances and with our newfound ability to obtain and analyze a tissue sample earlier in pregnancy – even before a woman shared the news of her pregnancy, in some cases – it seemed that we had achieved our goals and may have even reached past the moon.

Yet there were other moonshots being pursued, including initiatives to make prenatal diagnosis less invasive. The discovery in 1997 of cell-free fetal DNA in maternal plasma and serum, for instance, was a pivotal development that opened the door for noninvasive prenatal testing.

This, and other advances in areas from biochemistry to ultrasound to genomic analysis, led to an array of prenatal diagnostic tools that today enable women and their physicians to assess the genetic, chromosomal, and biophysical aspects of their fetus considerably before the time of viability, and from both the maternal side and directly in the fetal compartment.

First-trimester screening is a current option, and we now have the ability to more selectively perform amniocentesis and CVS based on probability testing, and not solely on maternal age. Ultrasound technology now encompasses color Doppler, 3D and 4D imaging, and other techniques that can be used to assess the placenta, various structures inside the brain, and the heart, as well as blood flow through the ductus venosus.

Parents have called for and welcomed having the option of assessing the fetus in greater detail, and of having either assurance when anomalies are excluded or the opportunity to plan and make decisions when anomalies are detected.

Fetal surgery has been a natural extension of our unprecedented access to the fetus. Our ability to visualize malformations and their evolution led to animal studies that advanced our interest in arresting, correcting, or reversing fetal anomalies through in-utero interventions. In 1981, surgeons performed the first human open fetal surgery to correct congenital hydronephrosis.

Today, we can employ endoscopic laser ablation or laser coagulation to treat severe twin-to-twin syndrome, for instance, as well as other surgical techniques to repair defects such as congenital diaphragmatic hernia, lower urinary tract obstruction, and myelomeningocele. Such advances were unimaginable decades ago.

Old foes and new threats

Despite these advances in diagnosis and care, obstetrics faces unrealized moonshots – lingering challenges that, 50 years ago, we would have predicted would have been solved. Who would have thought that we would still have as high an infant mortality rate as we do, and that we would not be further along in solving the problem of prematurity? Our progress has been only incremental.

Fifty years ago, we lacked an understanding of the basic biology of preterm labor. Prematurity was viewed simply as term labor occurring too early, and many efforts were made over the years to halt the premature labor process through the use of various drugs and other therapeutics, with variable and minimally impactful levels of success.

In the last 25 years, and especially in the last decade, we have made greater efforts to better understand the biology of premature labor – to elucidate how and why it occurs – and we have come to understand that premature labor is very different physiologically from term labor.

Thanks to the work at the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), led by Roberto Romero, MD, attention has consequently shifted toward prediction, identification of women at highest risk, and prevention of the onset of premature labor among those deemed to be at highest risk.

Cervical length in the mid-trimester is now a well-verified predictor of preterm birth, and vaginal progesterone has been shown to benefit women without other known risk factors who are diagnosed with a shortened cervical length.

We have consequently seen the preterm birth rate decline a bit. In 2013, the last year for which we have complete data, the preterm birth rate dropped to 11.4%, down from a high of 12.8% in 2006, according to the Centers for Disease Control and Prevention.

Infant mortality similarly remains unacceptably high, due largely to the high preterm birth rate and to our failure to significantly alter the prevalence of birth defects. In 2010, according to the CDC, the infant mortality rate in the U.S. was 6.1 deaths per 1,000 live births (compared with 6.87 in 2005), and the United States ranked 26th in infant mortality among countries belonging to the Organisation for Economic Co-operation and Development, despite the fact that we spend a significant portion of our gross domestic product (17.5% in 2014) on health care.

Birth defects have taken over as a leading cause of infant mortality after early newborn life, and while we’ve made some advancements in understanding and diagnosing them, the majority of causes of birth defects are still unknown.

On the maternal side of obstetrical care, our progress has similarly been more modest than we have hoped for. Preeclampsia remains a problem, for instance. Despite decades of research into its pathogenesis, our advancements have been only incremental, and the condition – particularly its severe form – continues to be a vexing and high-risk problem.

Added to such age-old foes, moreover, are the growing threats of maternal obesity and diabetes, two closely related and often chronic conditions that affect not only the health of the mother but the in-utero environment and the health of the fetus. Today, more than one-third of all adults in the U.S., and 34% of women aged 20-39 years, are obese, and almost 10% of the U.S. population has diabetes.

Both conditions are on the rise, and obstetrics is confronting an epidemic of “diabesity” that would not necessarily have been predicted 50 years ago. It is particularly alarming given our growing knowledge of how obesity can be programmed in-utero and essentially passed on from generation to generation, of how diabetes can negatively affect perinatal outcomes, and of how the two conditions can have an additive effect on fetal complications.

Achieving new moonshots

Concerted efforts in the past several decades to step back and try to understand the basic biology and physiology of term labor and of premature labor have better positioned our specialty to achieve the moonshot of significantly reducing the incidence of preterm birth.

Establishment in the mid-1980s of the NICHD’s Perinatology Research Branch was a major development in this regard, helping to build and direct research efforts, including basic laboratory science, toward questions about what triggers and propagates labor. There has been notable progress in the past decade, in particular, and our specialty is now on the right path toward development of therapeutic interventions for preventing prematurity.

Additionally, the NICHD’s recently launched Human Placenta Project is building upon the branch-sponsored animal and cell culture model systems of the placenta to allow researchers, for the first time, to monitor human placental health in real time. By more fully understanding the role of the placenta in health and disease, we will be able to better evaluate pregnancy risks and improve pregnancy outcomes.

We also are learning through research in the University of Maryland Birth Defects Research Laboratory, which I am privileged to direct, and at other facilities, that maternal hyperglycemia is a teratogen, creating insults that can trigger a series of developmental fetal defects. By studying the biomolecular mechanisms of hyperglycemia-induced birth defects and developing “molecular maps,” we expect to be able to develop strategies for preventing or mitigating the development of such anomalies. I hope and expect that these future advancements, combined with reductions in prematurity, will significantly impact the infant mortality rate.

Fetal therapy and surgery will also continue to advance, with a much more minimally invasive approach taken in the next 50 years to addressing the fetal condition without putting the mother at increased risk. Just as surgery in other fields has moved from open laparotomy to minimally invasive techniques, I believe we will develop endoscopic or laparoscopic means of correcting the various problems in-utero, such as the repair of neural tube defects and diaphragmatic hernias. It already appears likely that a fetoscopic approach to treating myelomeningocele can reduce maternal morbidity while achieving infant neurological outcomes that are at least as good as outcomes achieved with open fetal surgery.

We’re in a much different position than we were 50 years ago in that we have two patients – the mother and the fetus – with whom we can closely work. We also have a relatively new and urgent obligation to place our attention not only on women’s reproductive health, but on the general gynecologic state. Ob.gyns. often are the only primary care physicians whom women see for routine care, and the quality of our attention to their weight and their diabetes risk factors will have far-reaching consequences, both for them and for their offspring.

As we have since the 1960s, we will continue to set new moonshots and meet new challenges, working with each other and with our patients to evaluate where we are strong and where we must improve. We will persistently harness the power of technology, choosing to do the things that “are hard,” while stepping back as needed to ask and address fundamental questions.

As a result, I can envision the next 50 years as a revolutionary time period for obstetrics – a time in which current problems and disorders are abated or eliminated through a combination of genomics, microbiomics, and other technological advances. Someday in the future, we will look back on some of our many achievements and marvel at how we have transformed the unimaginable to reality.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at obnews@frontlinemedcom.com.

Select advances through the years

1960s

1965: Siemens Corp. introduces first real-time ultrasound scanner.

1966: Lancet paper reports that amniotic fluid cells can be cultured and karyotyped.

1970s

1970: New England Journal of Medicine paper describes mid-trimester amniocenteses and detection of Down syndrome cases.

1972: Ultrasound-guided amniocentesis first described.

1973: Fetoscopy introduced.

1980s

1981: First human open fetal surgery to correct congenital hydronephrosis.

Early 1980s: Chorionic villus sampling introduced at select centers.

1985: Color Doppler incorporated into ultrasound.

1990s

1990: Embryoscopy first described.

Mid-1990s: 3D/4D ultrasound begins to assume major role in ob.gyn. imaging.1997: Discovery of cell-free fetal DNA in maternal plasma.

2000s

2003: MOMS (Management of Myelomeningocele Study) was launched.

2010s

2012: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support cell-free DNA screening for women at increased risk of fetal aneuploidy.

2013: Preterm birth rate drops to 11.4%

2014: Diabetes incidence marks a 4-fold increase since 1980.

In 1961 before Congress, and in 1962 at Rice University, Houston, President John F. Kennedy called on America to land a man on the moon and bring him back safely, and to look beyond the moon as well, and pursue an ambitious space exploration program. He challenged the country to think and act boldly, telling Americans in his speech at Rice that “we choose to go the moon in this decade and do the other things, not because they are easy, but because they are hard.”

When Neil Armstrong and Buzz Aldrin set foot on the moon in 1969 – even before President Kennedy’s 10-year deadline had arrived – the country’s primary moonshot was realized. The President had inspired the nation, teams of engineers and others had collectively met daunting technological challenges, and space consequently was more open to us than ever before.

In looking at the field of obstetrics and how far it has come in the past 50 years, since the 1960s, it is similarly astonishing and inspiring to reflect on what extraordinary advances we have made. Who would have thought that the fetus would become such a visible and intimate patient – one who, like the mother, can be interrogated, monitored, and sometimes treated before birth? Who would have thought we would be utilizing genomic studies in a now well-established field of prenatal diagnosis, or that fetal therapy would become a field in and of itself?

Our specialty has advanced through a series of moonshots that have been inspired and driven by technological advancement and by our continually bold goals and vision for the health and well-being of women and their offspring. We have taken on ambitious challenges, achieved many goals, and embraced advancements in practice only to then set new targets that previously were unimaginable.

Yet just as our country’s space exploration program has faced disappointments, so has our field. It is sobering, for instance, that we have made only incremental improvements in prematurity and infant mortality, and that the age-old maternal problem of preeclampsia is still with us. We also face new challenges, such as the rising rate of maternal obesity and diabetes, which threaten both maternal and fetal health.

President Kennedy spoke of having “examined where we are strong, and where we are not.” Such self-reflection and assessment is a critical underpinning of advancement in fields across all of science, medicine, and health care, and in our specialty, it is a process that has driven ambitious new research efforts to improve fetal and maternal health.

A step back to more in-depth fundamental research on the biomolecular mechanisms of premature labor and diabetes-associated birth defects, for instance, as well as new efforts to approach fetal surgery less invasively, are positioning us to both conquer our disappointments and achieve ambitious new moonshots.

The fetus as our patient

Fifty years ago, in 1966, a seminal paper in the Lancet reported that amniotic fluid cells could be cultured and were suitable for karyotyping (1[7434]:383-5). The tapping and examination of amniotic fluid had been reported on sporadically for many decades, for various clinical purposes, but by and large the fetal compartment was not invaded or directly examined. The fetus was instead the hopeful beneficiary of pregnancy care that focused on the mother. Fetal outcome was clouded in mystery, known only at birth.

With the Lancet report, prenatal detection of chromosomal disorders began to feel achievable, and the 1960s marked the beginning of a journey first through invasive methods of prenatal diagnosis and then through increasingly non-invasive approaches.

In 1970, just several years after the report on chromosome analysis of amniotic-fluid cells, another landmark paper in the New England Journal of Medicine described 162 amniocenteses performed between the 13th and 18th weeks of gestation and the detection of 10 cases of Down syndrome, as well as a few other cases of metabolic and other disorders (282[11]:596-9). This report provided an impetus for broader use of the procedure to detect neural tube defects, Down syndrome, and other abnormalities.

The adoption of amniocentesis for prenatal diagnosis still took some time, however. The procedure was used primarily early on to determine fetal lung maturity, and to predict the ability of the fetus to survive after delivery.

At the time, it was widely praised as an advanced method for evaluating the fetus. Yet, looking back, the early years of the procedure seem primitive. The procedure was done late in pregnancy and it was performed blindly, with the puncture site located either with external palpation of the uterus or with the assistance of static ultrasound. Patients who had scans would usually visit the radiologist, who would mark on the patient’s abdomen a suggested location for needle insertion. Upon the patient’s return, the obstetrician would then insert a needle into that spot, blindly and likely after the fetus had moved.

The development and adoption of real-time ultrasound was a revolutionary achievement. Ultrasound-guided amniocentesis was first described in 1972, 14 years after Ian Donald’s seminal paper introducing obstetric ultrasound was published in the Lancet (1958 Jun 7;1[7032]:1188-95).

As real-time ultrasound made its way into practice, it marked the true realization of a moonshot for obstetrics.

Not only could we simultaneously visualize the needle tip and place the needle safety, but we could see the real-time movement of the fetus, its activity, and the surrounding pockets of fluid. It was like looking up into the sky and seeing the stars for the first time. We could see fetal arrhythmia – not only hear it. With this window into the fetal compartment, we could visualize the fetal bowel migrating into the chest cavity due to a hole (hernia) in the diaphragm. We could visualize other malformations as well.

Chorionic villus sampling (CVS) was technically more difficult and took longer to evolve. For years, through the early 1980s, it was performed only at select centers throughout the country. Patients traveled for the procedure and faced relatively significant risks of complications.

By the end of the 1980s, however, with successive improvements in equipment and technique (including development of a transabdominal approach in addition to transvaginal) the procedure was deemed safe, effective, and acceptable for routine use. Fetoscopy, pioneered by John Hobbins, MD, and his colleagues at Yale University, New Haven, Conn., had also advanced and was being used to diagnose sickle cell anemia, Tay-Sachs disease, congenital fetal skin diseases, and other disorders.

With these advances and with our newfound ability to obtain and analyze a tissue sample earlier in pregnancy – even before a woman shared the news of her pregnancy, in some cases – it seemed that we had achieved our goals and may have even reached past the moon.

Yet there were other moonshots being pursued, including initiatives to make prenatal diagnosis less invasive. The discovery in 1997 of cell-free fetal DNA in maternal plasma and serum, for instance, was a pivotal development that opened the door for noninvasive prenatal testing.

This, and other advances in areas from biochemistry to ultrasound to genomic analysis, led to an array of prenatal diagnostic tools that today enable women and their physicians to assess the genetic, chromosomal, and biophysical aspects of their fetus considerably before the time of viability, and from both the maternal side and directly in the fetal compartment.

First-trimester screening is a current option, and we now have the ability to more selectively perform amniocentesis and CVS based on probability testing, and not solely on maternal age. Ultrasound technology now encompasses color Doppler, 3D and 4D imaging, and other techniques that can be used to assess the placenta, various structures inside the brain, and the heart, as well as blood flow through the ductus venosus.

Parents have called for and welcomed having the option of assessing the fetus in greater detail, and of having either assurance when anomalies are excluded or the opportunity to plan and make decisions when anomalies are detected.

Fetal surgery has been a natural extension of our unprecedented access to the fetus. Our ability to visualize malformations and their evolution led to animal studies that advanced our interest in arresting, correcting, or reversing fetal anomalies through in-utero interventions. In 1981, surgeons performed the first human open fetal surgery to correct congenital hydronephrosis.

Today, we can employ endoscopic laser ablation or laser coagulation to treat severe twin-to-twin syndrome, for instance, as well as other surgical techniques to repair defects such as congenital diaphragmatic hernia, lower urinary tract obstruction, and myelomeningocele. Such advances were unimaginable decades ago.

Old foes and new threats

Despite these advances in diagnosis and care, obstetrics faces unrealized moonshots – lingering challenges that, 50 years ago, we would have predicted would have been solved. Who would have thought that we would still have as high an infant mortality rate as we do, and that we would not be further along in solving the problem of prematurity? Our progress has been only incremental.

Fifty years ago, we lacked an understanding of the basic biology of preterm labor. Prematurity was viewed simply as term labor occurring too early, and many efforts were made over the years to halt the premature labor process through the use of various drugs and other therapeutics, with variable and minimally impactful levels of success.

In the last 25 years, and especially in the last decade, we have made greater efforts to better understand the biology of premature labor – to elucidate how and why it occurs – and we have come to understand that premature labor is very different physiologically from term labor.

Thanks to the work at the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), led by Roberto Romero, MD, attention has consequently shifted toward prediction, identification of women at highest risk, and prevention of the onset of premature labor among those deemed to be at highest risk.

Cervical length in the mid-trimester is now a well-verified predictor of preterm birth, and vaginal progesterone has been shown to benefit women without other known risk factors who are diagnosed with a shortened cervical length.

We have consequently seen the preterm birth rate decline a bit. In 2013, the last year for which we have complete data, the preterm birth rate dropped to 11.4%, down from a high of 12.8% in 2006, according to the Centers for Disease Control and Prevention.

Infant mortality similarly remains unacceptably high, due largely to the high preterm birth rate and to our failure to significantly alter the prevalence of birth defects. In 2010, according to the CDC, the infant mortality rate in the U.S. was 6.1 deaths per 1,000 live births (compared with 6.87 in 2005), and the United States ranked 26th in infant mortality among countries belonging to the Organisation for Economic Co-operation and Development, despite the fact that we spend a significant portion of our gross domestic product (17.5% in 2014) on health care.

Birth defects have taken over as a leading cause of infant mortality after early newborn life, and while we’ve made some advancements in understanding and diagnosing them, the majority of causes of birth defects are still unknown.

On the maternal side of obstetrical care, our progress has similarly been more modest than we have hoped for. Preeclampsia remains a problem, for instance. Despite decades of research into its pathogenesis, our advancements have been only incremental, and the condition – particularly its severe form – continues to be a vexing and high-risk problem.

Added to such age-old foes, moreover, are the growing threats of maternal obesity and diabetes, two closely related and often chronic conditions that affect not only the health of the mother but the in-utero environment and the health of the fetus. Today, more than one-third of all adults in the U.S., and 34% of women aged 20-39 years, are obese, and almost 10% of the U.S. population has diabetes.

Both conditions are on the rise, and obstetrics is confronting an epidemic of “diabesity” that would not necessarily have been predicted 50 years ago. It is particularly alarming given our growing knowledge of how obesity can be programmed in-utero and essentially passed on from generation to generation, of how diabetes can negatively affect perinatal outcomes, and of how the two conditions can have an additive effect on fetal complications.

Achieving new moonshots

Concerted efforts in the past several decades to step back and try to understand the basic biology and physiology of term labor and of premature labor have better positioned our specialty to achieve the moonshot of significantly reducing the incidence of preterm birth.

Establishment in the mid-1980s of the NICHD’s Perinatology Research Branch was a major development in this regard, helping to build and direct research efforts, including basic laboratory science, toward questions about what triggers and propagates labor. There has been notable progress in the past decade, in particular, and our specialty is now on the right path toward development of therapeutic interventions for preventing prematurity.

Additionally, the NICHD’s recently launched Human Placenta Project is building upon the branch-sponsored animal and cell culture model systems of the placenta to allow researchers, for the first time, to monitor human placental health in real time. By more fully understanding the role of the placenta in health and disease, we will be able to better evaluate pregnancy risks and improve pregnancy outcomes.

We also are learning through research in the University of Maryland Birth Defects Research Laboratory, which I am privileged to direct, and at other facilities, that maternal hyperglycemia is a teratogen, creating insults that can trigger a series of developmental fetal defects. By studying the biomolecular mechanisms of hyperglycemia-induced birth defects and developing “molecular maps,” we expect to be able to develop strategies for preventing or mitigating the development of such anomalies. I hope and expect that these future advancements, combined with reductions in prematurity, will significantly impact the infant mortality rate.

Fetal therapy and surgery will also continue to advance, with a much more minimally invasive approach taken in the next 50 years to addressing the fetal condition without putting the mother at increased risk. Just as surgery in other fields has moved from open laparotomy to minimally invasive techniques, I believe we will develop endoscopic or laparoscopic means of correcting the various problems in-utero, such as the repair of neural tube defects and diaphragmatic hernias. It already appears likely that a fetoscopic approach to treating myelomeningocele can reduce maternal morbidity while achieving infant neurological outcomes that are at least as good as outcomes achieved with open fetal surgery.

We’re in a much different position than we were 50 years ago in that we have two patients – the mother and the fetus – with whom we can closely work. We also have a relatively new and urgent obligation to place our attention not only on women’s reproductive health, but on the general gynecologic state. Ob.gyns. often are the only primary care physicians whom women see for routine care, and the quality of our attention to their weight and their diabetes risk factors will have far-reaching consequences, both for them and for their offspring.

As we have since the 1960s, we will continue to set new moonshots and meet new challenges, working with each other and with our patients to evaluate where we are strong and where we must improve. We will persistently harness the power of technology, choosing to do the things that “are hard,” while stepping back as needed to ask and address fundamental questions.

As a result, I can envision the next 50 years as a revolutionary time period for obstetrics – a time in which current problems and disorders are abated or eliminated through a combination of genomics, microbiomics, and other technological advances. Someday in the future, we will look back on some of our many achievements and marvel at how we have transformed the unimaginable to reality.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at obnews@frontlinemedcom.com.

Select advances through the years

1960s

1965: Siemens Corp. introduces first real-time ultrasound scanner.

1966: Lancet paper reports that amniotic fluid cells can be cultured and karyotyped.

1970s

1970: New England Journal of Medicine paper describes mid-trimester amniocenteses and detection of Down syndrome cases.

1972: Ultrasound-guided amniocentesis first described.

1973: Fetoscopy introduced.

1980s

1981: First human open fetal surgery to correct congenital hydronephrosis.

Early 1980s: Chorionic villus sampling introduced at select centers.

1985: Color Doppler incorporated into ultrasound.

1990s

1990: Embryoscopy first described.

Mid-1990s: 3D/4D ultrasound begins to assume major role in ob.gyn. imaging.1997: Discovery of cell-free fetal DNA in maternal plasma.

2000s

2003: MOMS (Management of Myelomeningocele Study) was launched.

2010s

2012: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine support cell-free DNA screening for women at increased risk of fetal aneuploidy.

2013: Preterm birth rate drops to 11.4%

2014: Diabetes incidence marks a 4-fold increase since 1980.