A reduction in portal hepatic pressure gradient (PPG) soon after implantation of a transjugular intrahepatic portosystemic shunt (TIPS) greater than 60% was associated with improved ascites control at 6 weeks in a study published in Hepatology.

“The probability of ascites resolution is much higher if PPG reduction exceeded 60% of PPG before TIPS,” wrote the researchers, led by co–first authors Alexander Queck, MD, a postdoctoral researcher in the department of internal medicine at University Hospital Frankfurt (Germany) and Goethe University Frankfurt, and Louise Schwierz, MD, of the department of internal medicine in the University Hospital Bonn (Germany). “This study suggests that, even in patients with uncomplicated TIPS insertion, a short-term follow-up 6 weeks after TIPS should be scheduled to be able to predict their course of disease.”

Alexander Raths/Fotolia

The authors investigated the decrease of PPG in a single-center, retrospective analysis of 341 patients with liver cirrhosis undergoing TIPS insertion for recurrent or refractory ascites between March 1994 and July 2015. During each procedure, portal and inferior vena cava pressures were invasively measured and correlated with patients’ outcomes and ascites progression over time. In 241 patients, or 71%, chronic alcohol consumption was the reason for cirrhosis development, followed by 13% with chronic viral hepatitis (n = 43). Median survival after TIPS insertion was 102 weeks, and 19 patients received liver transplants over time.

Median portal pressure before TIPS placement was 28 mm Hg, which decreased to a median of 21 mm Hg after TIPS. Median PPG levels were 19 mm Hg before TIPS and 8 mm Hg immediately after TIPS placement.

At the time of TIPS placement, 65 patients, or 19%, had hepatic encephalopathy, and nine had severe hepatic encephalopathy. Six weeks after TIPS, two had episodes of hepatic encephalopathy.

After 6 weeks, ascites significantly improved through TIPS insertion. About 47% had a complete resolution of ascites at 6 weeks, whereas 29% had ascites detectable only by ultrasound and 24% of patients still needed large-volume paracentesis. There was an association between extent of PPG reduction and ascites resolution: Median PPG reduction was 55% of initial PPG in patients with persistence of severe ascites, 58% in patients with ascites detected by ultrasound, and 65% in patients with complete resolution of ascites at 6 weeks after TIPS.

Ascites resolved in 54% of patients with higher PPG reduction (60% or above), compared with 39% of patients with lower PPG reduction (below 60%). Ascites that was detected by ultrasound in another 27% of patients with higher PPG reduction, compared with 31% of patients with lower PPG reduction. In addition, persistent severe ascites was seen in 19% of patients with higher PPG reduction, compared with 30% of patients with lower PPG reduction.

The authors also noted the importance of timing follow-up evaluation: They noted that post-TIPS follow-up is a frequent question and not yet standardized; in this study, they found that, with follow-up at 6 weeks, they could “clearly stratify the course post TIPS” and this could “detect patients at high risk of unstable course of disease.”

PPG reduction of more than 60% after TIPS correlated with resolution of severe ascites 6 weeks after TIPS, the study authors concluded.

A reduction in portal hepatic pressure gradient (PPG) soon after implantation of a transjugular intrahepatic portosystemic shunt (TIPS) greater than 60% was associated with improved ascites control at 6 weeks in a study published in Hepatology.

“The probability of ascites resolution is much higher if PPG reduction exceeded 60% of PPG before TIPS,” wrote the researchers, led by co–first authors Alexander Queck, MD, a postdoctoral researcher in the department of internal medicine at University Hospital Frankfurt (Germany) and Goethe University Frankfurt, and Louise Schwierz, MD, of the department of internal medicine in the University Hospital Bonn (Germany). “This study suggests that, even in patients with uncomplicated TIPS insertion, a short-term follow-up 6 weeks after TIPS should be scheduled to be able to predict their course of disease.”

Alexander Raths/Fotolia

The authors investigated the decrease of PPG in a single-center, retrospective analysis of 341 patients with liver cirrhosis undergoing TIPS insertion for recurrent or refractory ascites between March 1994 and July 2015. During each procedure, portal and inferior vena cava pressures were invasively measured and correlated with patients’ outcomes and ascites progression over time. In 241 patients, or 71%, chronic alcohol consumption was the reason for cirrhosis development, followed by 13% with chronic viral hepatitis (n = 43). Median survival after TIPS insertion was 102 weeks, and 19 patients received liver transplants over time.

Median portal pressure before TIPS placement was 28 mm Hg, which decreased to a median of 21 mm Hg after TIPS. Median PPG levels were 19 mm Hg before TIPS and 8 mm Hg immediately after TIPS placement.

At the time of TIPS placement, 65 patients, or 19%, had hepatic encephalopathy, and nine had severe hepatic encephalopathy. Six weeks after TIPS, two had episodes of hepatic encephalopathy.

After 6 weeks, ascites significantly improved through TIPS insertion. About 47% had a complete resolution of ascites at 6 weeks, whereas 29% had ascites detectable only by ultrasound and 24% of patients still needed large-volume paracentesis. There was an association between extent of PPG reduction and ascites resolution: Median PPG reduction was 55% of initial PPG in patients with persistence of severe ascites, 58% in patients with ascites detected by ultrasound, and 65% in patients with complete resolution of ascites at 6 weeks after TIPS.

Ascites resolved in 54% of patients with higher PPG reduction (60% or above), compared with 39% of patients with lower PPG reduction (below 60%). Ascites that was detected by ultrasound in another 27% of patients with higher PPG reduction, compared with 31% of patients with lower PPG reduction. In addition, persistent severe ascites was seen in 19% of patients with higher PPG reduction, compared with 30% of patients with lower PPG reduction.

The authors also noted the importance of timing follow-up evaluation: They noted that post-TIPS follow-up is a frequent question and not yet standardized; in this study, they found that, with follow-up at 6 weeks, they could “clearly stratify the course post TIPS” and this could “detect patients at high risk of unstable course of disease.”

PPG reduction of more than 60% after TIPS correlated with resolution of severe ascites 6 weeks after TIPS, the study authors concluded.

A reduction in portal hepatic pressure gradient (PPG) soon after implantation of a transjugular intrahepatic portosystemic shunt (TIPS) greater than 60% was associated with improved ascites control at 6 weeks in a study published in Hepatology.

“The probability of ascites resolution is much higher if PPG reduction exceeded 60% of PPG before TIPS,” wrote the researchers, led by co–first authors Alexander Queck, MD, a postdoctoral researcher in the department of internal medicine at University Hospital Frankfurt (Germany) and Goethe University Frankfurt, and Louise Schwierz, MD, of the department of internal medicine in the University Hospital Bonn (Germany). “This study suggests that, even in patients with uncomplicated TIPS insertion, a short-term follow-up 6 weeks after TIPS should be scheduled to be able to predict their course of disease.”

Alexander Raths/Fotolia

The authors investigated the decrease of PPG in a single-center, retrospective analysis of 341 patients with liver cirrhosis undergoing TIPS insertion for recurrent or refractory ascites between March 1994 and July 2015. During each procedure, portal and inferior vena cava pressures were invasively measured and correlated with patients’ outcomes and ascites progression over time. In 241 patients, or 71%, chronic alcohol consumption was the reason for cirrhosis development, followed by 13% with chronic viral hepatitis (n = 43). Median survival after TIPS insertion was 102 weeks, and 19 patients received liver transplants over time.

Median portal pressure before TIPS placement was 28 mm Hg, which decreased to a median of 21 mm Hg after TIPS. Median PPG levels were 19 mm Hg before TIPS and 8 mm Hg immediately after TIPS placement.

At the time of TIPS placement, 65 patients, or 19%, had hepatic encephalopathy, and nine had severe hepatic encephalopathy. Six weeks after TIPS, two had episodes of hepatic encephalopathy.

After 6 weeks, ascites significantly improved through TIPS insertion. About 47% had a complete resolution of ascites at 6 weeks, whereas 29% had ascites detectable only by ultrasound and 24% of patients still needed large-volume paracentesis. There was an association between extent of PPG reduction and ascites resolution: Median PPG reduction was 55% of initial PPG in patients with persistence of severe ascites, 58% in patients with ascites detected by ultrasound, and 65% in patients with complete resolution of ascites at 6 weeks after TIPS.

Ascites resolved in 54% of patients with higher PPG reduction (60% or above), compared with 39% of patients with lower PPG reduction (below 60%). Ascites that was detected by ultrasound in another 27% of patients with higher PPG reduction, compared with 31% of patients with lower PPG reduction. In addition, persistent severe ascites was seen in 19% of patients with higher PPG reduction, compared with 30% of patients with lower PPG reduction.

The authors also noted the importance of timing follow-up evaluation: They noted that post-TIPS follow-up is a frequent question and not yet standardized; in this study, they found that, with follow-up at 6 weeks, they could “clearly stratify the course post TIPS” and this could “detect patients at high risk of unstable course of disease.”

PPG reduction of more than 60% after TIPS correlated with resolution of severe ascites 6 weeks after TIPS, the study authors concluded.

The sun protection factor (SPF) value indicates to consumers the level of protection that a given sunscreen formulation provides against erythemally effective UV radiation (UVR). ¹ In vivo SPF testing, the gold standard for determining SPF, yields highly variable results and can harm human test participants. ² In vitro SPF testing methodologies have been under development for years but none have (yet) replaced the in vivo test required by national and international regulatory agencies.

Recent European studies have shown strong data to support a highly standardized in vitro method,¹ now under development by the International Organization for Standardization (ISO)—potentially to serve as a new SPF determination standard.^1,3 Academia and industry should follow this example and actively take steps to develop and validate a suitable replacement for in vivo SPF testing.

In Vivo SPF Testing

The in vivo SPF test involves comparing doses of UVR necessary to induce erythema in human participants with and without sunscreen applied.² Although this method has long been the standard for SPF determination, it is associated with the following major disadvantages:

• Cost: The in vivo test is expensive.
• Variability: Results of the test are subject to high interlaboratory variability due to the inherent subjectivity of identifying erythema, the variable skin types of human participants, and other laboratory-dependent factors.² A study found that the average coefficient of variation for SPF values obtained from 3 or 4 laboratories to be 20%—with values exceeding 50% in some cases. With that level of variability, the same sunscreen may be labeled SPF 30, SPF 50, or SPF 50+, thereby posing a health risk to consumers who rely on the accuracy of such claims. In fact, Miksa et al² concluded that “the largest obstacle to a reliable SPF assessment for consumer health is the in vivo SPF test itself.”
• Ethical concerns: Human participants are intentionally exposed to harmful UVR until sunburn is achieved. For that reason, there have been calls to abandon the practice of in vivo testing.¹

Alternatives to In Vivo SPF Testing

There has been international interest in developing in silico and in vitro alternatives to the in vivo SPF test. These options are attractive because they are relatively inexpensive; avoid exposing human participants to harmful UVR; and have the potential to be more accurate and more reproducible than in vivo tests.

In Vitro Protocols—Many such in vitro tests exist; all generally involve applying a layer of sunscreen to an artificial substrate, exposing it to UVR from a solar simulator, and measuring the UVR transmittance through the product and film by spectrophotometry.¹ Prior shortcomings of this method have included suboptimal reproducibility, lack of data on substrate and product properties, and lack of demonstrated equivalency to in vivo SPF testing.⁴

In Silico Protocols—These tests use data on the UV spectra of sunscreen filters, physical characteristics of sunscreen films on skin, and the unique photoinstability of filters to calculate expected UVR transmittance and SPF of sunscreens based on their ingredients.⁵ Reports have shown high correlation with in vivo values. Results are not subject to random error; reproducibility is theoretically perfect.⁵

Regulatory Agencies and In Vitro Testing

In the United States, sunscreens are regulated as over-the-counter drugs. In vivo testing is the only US Food and Drug Administration (FDA)–approved method for determining SPF for labeling purposes.¹ In a 2007 Proposed Rule and a 2011 Final Rule, the FDA stated that in vitro SPF tests were an inadequate alternative to in vivo tests because of their shortcomings.^4,6

Acknowledging the potential benefits of in vitro testing, the FDA wrote that it would consider in vitro alternatives if equivalency to the in vivo test could be proved.⁶ The agency has not published an official stance on in vitro SPF testing since those statements in 2007 and 2011. Of note, the FDA deems in vitro testing sufficient for making claims of broad-spectrum coverage.⁴

In contrast to the regulatory scenario in the United States, Europe regulates sunscreens as cosmetics, and the European Union (EU) has banned animal testing of cosmetics,⁷ which poses a problem for the development of new sunscreens. It is not surprising, therefore, that in 2006 the European Commission (the executive arm of the EU) published a mandate that in vitro SPF testing methods be actively developed due to ethical concerns associated with in vivo methods.⁸ In 2017, the International Organization for Standardization released specific validation criteria for proposed in vitro tests to facilitate the eventual approval of such methods.¹

Progress of In Vitro Methods

In recent years, advances in in vitro SPF testing methods have addressed shortcomings noted previously by the FDA, which has led to notably improved reproducibility of results and correlation with in vivo values, in large part due to strict standardization of protocols,¹ such as tight temperature control of samples, a multisubstrate approach, robotic product application to ensure even distribution, and pre-irradiation of sunscreen samples.

With these improvements, a 2018 study demonstrated an in vitro SPF testing methodology that exceeded published ISO validation criteria for emulsion-type products.¹ This method was found to have low interlaboratory variability and high correlation with in vivo SPF values (Pearson r=0.88). Importantly, the authors noted that the consistency and reliability of in vitro SPF testing requires broad institution of a single unified method.¹

The method described in the 2018 study¹ has been accepted by the ISO Technical Committee and is undergoing further development³; it is expected to be approved by the European Committee for Standardization. After approval, adoption by member nations of the EU will require individual action, representing the next regulatory hurdle for in vitro SPF testing in Europe.

Final Thoughts and Future Steps

Recent data confirm the potential viability of in vitro testing as a primary method of determining SPF values.¹ Although ISO has moved forward with development of this method, the FDA has been quiet on in vitro SPF testing since 2011.⁴ The agency has, however, acknowledged the disadvantages of in vivo broad-spectrum testing, including exposure of human participants to harmful UVR and poor interlaboratory reproducibility.⁶

Given the technical developments and substantial potential benefits of in vitro testing, we believe that it is time for the FDA to revisit this matter. We propose that the FDA take 2 steps toward in vitro testing. First, publish specific validation criteria that would be deemed necessary for approval of such a test, similar to what ISO published in 2017. Second, thoroughly assess new data supporting the viability of available in vitro testing to determine if the FDA’s stated position that in vitro testing is inadequate remains true.

Although these 2 steps will be important to the process, adoption of an in vitro standard will require more than statements from the FDA. Additional funding should be allocated to researchers who are studying in vitro methodologies, and companies that profit from the multibillion-dollar sunscreen industry should be encouraged to invest in the development of more accurate and more ethical alternatives to in vivo SPF testing.

In vitro SPF testing is inexpensive, avoids the moral quandary of intentionally sunburning human participants, and is more reliable than in vivo testing. It is time for the FDA to facilitate the efforts of academia and industry in taking concrete steps toward approval of an in vitro alternative to in vivo SPF testing.

The sun protection factor (SPF) value indicates to consumers the level of protection that a given sunscreen formulation provides against erythemally effective UV radiation (UVR). ¹ In vivo SPF testing, the gold standard for determining SPF, yields highly variable results and can harm human test participants. ² In vitro SPF testing methodologies have been under development for years but none have (yet) replaced the in vivo test required by national and international regulatory agencies.

Recent European studies have shown strong data to support a highly standardized in vitro method,¹ now under development by the International Organization for Standardization (ISO)—potentially to serve as a new SPF determination standard.^1,3 Academia and industry should follow this example and actively take steps to develop and validate a suitable replacement for in vivo SPF testing.

In Vivo SPF Testing

The in vivo SPF test involves comparing doses of UVR necessary to induce erythema in human participants with and without sunscreen applied.² Although this method has long been the standard for SPF determination, it is associated with the following major disadvantages:

• Cost: The in vivo test is expensive.
• Variability: Results of the test are subject to high interlaboratory variability due to the inherent subjectivity of identifying erythema, the variable skin types of human participants, and other laboratory-dependent factors.² A study found that the average coefficient of variation for SPF values obtained from 3 or 4 laboratories to be 20%—with values exceeding 50% in some cases. With that level of variability, the same sunscreen may be labeled SPF 30, SPF 50, or SPF 50+, thereby posing a health risk to consumers who rely on the accuracy of such claims. In fact, Miksa et al² concluded that “the largest obstacle to a reliable SPF assessment for consumer health is the in vivo SPF test itself.”
• Ethical concerns: Human participants are intentionally exposed to harmful UVR until sunburn is achieved. For that reason, there have been calls to abandon the practice of in vivo testing.¹

Alternatives to In Vivo SPF Testing

There has been international interest in developing in silico and in vitro alternatives to the in vivo SPF test. These options are attractive because they are relatively inexpensive; avoid exposing human participants to harmful UVR; and have the potential to be more accurate and more reproducible than in vivo tests.

In Vitro Protocols—Many such in vitro tests exist; all generally involve applying a layer of sunscreen to an artificial substrate, exposing it to UVR from a solar simulator, and measuring the UVR transmittance through the product and film by spectrophotometry.¹ Prior shortcomings of this method have included suboptimal reproducibility, lack of data on substrate and product properties, and lack of demonstrated equivalency to in vivo SPF testing.⁴

In Silico Protocols—These tests use data on the UV spectra of sunscreen filters, physical characteristics of sunscreen films on skin, and the unique photoinstability of filters to calculate expected UVR transmittance and SPF of sunscreens based on their ingredients.⁵ Reports have shown high correlation with in vivo values. Results are not subject to random error; reproducibility is theoretically perfect.⁵

Regulatory Agencies and In Vitro Testing

In the United States, sunscreens are regulated as over-the-counter drugs. In vivo testing is the only US Food and Drug Administration (FDA)–approved method for determining SPF for labeling purposes.¹ In a 2007 Proposed Rule and a 2011 Final Rule, the FDA stated that in vitro SPF tests were an inadequate alternative to in vivo tests because of their shortcomings.^4,6

Acknowledging the potential benefits of in vitro testing, the FDA wrote that it would consider in vitro alternatives if equivalency to the in vivo test could be proved.⁶ The agency has not published an official stance on in vitro SPF testing since those statements in 2007 and 2011. Of note, the FDA deems in vitro testing sufficient for making claims of broad-spectrum coverage.⁴

In contrast to the regulatory scenario in the United States, Europe regulates sunscreens as cosmetics, and the European Union (EU) has banned animal testing of cosmetics,⁷ which poses a problem for the development of new sunscreens. It is not surprising, therefore, that in 2006 the European Commission (the executive arm of the EU) published a mandate that in vitro SPF testing methods be actively developed due to ethical concerns associated with in vivo methods.⁸ In 2017, the International Organization for Standardization released specific validation criteria for proposed in vitro tests to facilitate the eventual approval of such methods.¹

Progress of In Vitro Methods

In recent years, advances in in vitro SPF testing methods have addressed shortcomings noted previously by the FDA, which has led to notably improved reproducibility of results and correlation with in vivo values, in large part due to strict standardization of protocols,¹ such as tight temperature control of samples, a multisubstrate approach, robotic product application to ensure even distribution, and pre-irradiation of sunscreen samples.

With these improvements, a 2018 study demonstrated an in vitro SPF testing methodology that exceeded published ISO validation criteria for emulsion-type products.¹ This method was found to have low interlaboratory variability and high correlation with in vivo SPF values (Pearson r=0.88). Importantly, the authors noted that the consistency and reliability of in vitro SPF testing requires broad institution of a single unified method.¹

The method described in the 2018 study¹ has been accepted by the ISO Technical Committee and is undergoing further development³; it is expected to be approved by the European Committee for Standardization. After approval, adoption by member nations of the EU will require individual action, representing the next regulatory hurdle for in vitro SPF testing in Europe.

Final Thoughts and Future Steps

Recent data confirm the potential viability of in vitro testing as a primary method of determining SPF values.¹ Although ISO has moved forward with development of this method, the FDA has been quiet on in vitro SPF testing since 2011.⁴ The agency has, however, acknowledged the disadvantages of in vivo broad-spectrum testing, including exposure of human participants to harmful UVR and poor interlaboratory reproducibility.⁶

Given the technical developments and substantial potential benefits of in vitro testing, we believe that it is time for the FDA to revisit this matter. We propose that the FDA take 2 steps toward in vitro testing. First, publish specific validation criteria that would be deemed necessary for approval of such a test, similar to what ISO published in 2017. Second, thoroughly assess new data supporting the viability of available in vitro testing to determine if the FDA’s stated position that in vitro testing is inadequate remains true.

Although these 2 steps will be important to the process, adoption of an in vitro standard will require more than statements from the FDA. Additional funding should be allocated to researchers who are studying in vitro methodologies, and companies that profit from the multibillion-dollar sunscreen industry should be encouraged to invest in the development of more accurate and more ethical alternatives to in vivo SPF testing.

In vitro SPF testing is inexpensive, avoids the moral quandary of intentionally sunburning human participants, and is more reliable than in vivo testing. It is time for the FDA to facilitate the efforts of academia and industry in taking concrete steps toward approval of an in vitro alternative to in vivo SPF testing.

The sun protection factor (SPF) value indicates to consumers the level of protection that a given sunscreen formulation provides against erythemally effective UV radiation (UVR). ¹ In vivo SPF testing, the gold standard for determining SPF, yields highly variable results and can harm human test participants. ² In vitro SPF testing methodologies have been under development for years but none have (yet) replaced the in vivo test required by national and international regulatory agencies.

Recent European studies have shown strong data to support a highly standardized in vitro method,¹ now under development by the International Organization for Standardization (ISO)—potentially to serve as a new SPF determination standard.^1,3 Academia and industry should follow this example and actively take steps to develop and validate a suitable replacement for in vivo SPF testing.

In Vivo SPF Testing

The in vivo SPF test involves comparing doses of UVR necessary to induce erythema in human participants with and without sunscreen applied.² Although this method has long been the standard for SPF determination, it is associated with the following major disadvantages:

• Cost: The in vivo test is expensive.
• Variability: Results of the test are subject to high interlaboratory variability due to the inherent subjectivity of identifying erythema, the variable skin types of human participants, and other laboratory-dependent factors.² A study found that the average coefficient of variation for SPF values obtained from 3 or 4 laboratories to be 20%—with values exceeding 50% in some cases. With that level of variability, the same sunscreen may be labeled SPF 30, SPF 50, or SPF 50+, thereby posing a health risk to consumers who rely on the accuracy of such claims. In fact, Miksa et al² concluded that “the largest obstacle to a reliable SPF assessment for consumer health is the in vivo SPF test itself.”
• Ethical concerns: Human participants are intentionally exposed to harmful UVR until sunburn is achieved. For that reason, there have been calls to abandon the practice of in vivo testing.¹

Alternatives to In Vivo SPF Testing

There has been international interest in developing in silico and in vitro alternatives to the in vivo SPF test. These options are attractive because they are relatively inexpensive; avoid exposing human participants to harmful UVR; and have the potential to be more accurate and more reproducible than in vivo tests.

In Vitro Protocols—Many such in vitro tests exist; all generally involve applying a layer of sunscreen to an artificial substrate, exposing it to UVR from a solar simulator, and measuring the UVR transmittance through the product and film by spectrophotometry.¹ Prior shortcomings of this method have included suboptimal reproducibility, lack of data on substrate and product properties, and lack of demonstrated equivalency to in vivo SPF testing.⁴

In Silico Protocols—These tests use data on the UV spectra of sunscreen filters, physical characteristics of sunscreen films on skin, and the unique photoinstability of filters to calculate expected UVR transmittance and SPF of sunscreens based on their ingredients.⁵ Reports have shown high correlation with in vivo values. Results are not subject to random error; reproducibility is theoretically perfect.⁵

Regulatory Agencies and In Vitro Testing

In the United States, sunscreens are regulated as over-the-counter drugs. In vivo testing is the only US Food and Drug Administration (FDA)–approved method for determining SPF for labeling purposes.¹ In a 2007 Proposed Rule and a 2011 Final Rule, the FDA stated that in vitro SPF tests were an inadequate alternative to in vivo tests because of their shortcomings.^4,6

Acknowledging the potential benefits of in vitro testing, the FDA wrote that it would consider in vitro alternatives if equivalency to the in vivo test could be proved.⁶ The agency has not published an official stance on in vitro SPF testing since those statements in 2007 and 2011. Of note, the FDA deems in vitro testing sufficient for making claims of broad-spectrum coverage.⁴

In contrast to the regulatory scenario in the United States, Europe regulates sunscreens as cosmetics, and the European Union (EU) has banned animal testing of cosmetics,⁷ which poses a problem for the development of new sunscreens. It is not surprising, therefore, that in 2006 the European Commission (the executive arm of the EU) published a mandate that in vitro SPF testing methods be actively developed due to ethical concerns associated with in vivo methods.⁸ In 2017, the International Organization for Standardization released specific validation criteria for proposed in vitro tests to facilitate the eventual approval of such methods.¹

Progress of In Vitro Methods

In recent years, advances in in vitro SPF testing methods have addressed shortcomings noted previously by the FDA, which has led to notably improved reproducibility of results and correlation with in vivo values, in large part due to strict standardization of protocols,¹ such as tight temperature control of samples, a multisubstrate approach, robotic product application to ensure even distribution, and pre-irradiation of sunscreen samples.

With these improvements, a 2018 study demonstrated an in vitro SPF testing methodology that exceeded published ISO validation criteria for emulsion-type products.¹ This method was found to have low interlaboratory variability and high correlation with in vivo SPF values (Pearson r=0.88). Importantly, the authors noted that the consistency and reliability of in vitro SPF testing requires broad institution of a single unified method.¹

The method described in the 2018 study¹ has been accepted by the ISO Technical Committee and is undergoing further development³; it is expected to be approved by the European Committee for Standardization. After approval, adoption by member nations of the EU will require individual action, representing the next regulatory hurdle for in vitro SPF testing in Europe.

Final Thoughts and Future Steps

Recent data confirm the potential viability of in vitro testing as a primary method of determining SPF values.¹ Although ISO has moved forward with development of this method, the FDA has been quiet on in vitro SPF testing since 2011.⁴ The agency has, however, acknowledged the disadvantages of in vivo broad-spectrum testing, including exposure of human participants to harmful UVR and poor interlaboratory reproducibility.⁶

Given the technical developments and substantial potential benefits of in vitro testing, we believe that it is time for the FDA to revisit this matter. We propose that the FDA take 2 steps toward in vitro testing. First, publish specific validation criteria that would be deemed necessary for approval of such a test, similar to what ISO published in 2017. Second, thoroughly assess new data supporting the viability of available in vitro testing to determine if the FDA’s stated position that in vitro testing is inadequate remains true.

Although these 2 steps will be important to the process, adoption of an in vitro standard will require more than statements from the FDA. Additional funding should be allocated to researchers who are studying in vitro methodologies, and companies that profit from the multibillion-dollar sunscreen industry should be encouraged to invest in the development of more accurate and more ethical alternatives to in vivo SPF testing.

In vitro SPF testing is inexpensive, avoids the moral quandary of intentionally sunburning human participants, and is more reliable than in vivo testing. It is time for the FDA to facilitate the efforts of academia and industry in taking concrete steps toward approval of an in vitro alternative to in vivo SPF testing.

To the Editor:

There is increasing evidence supporting the use of the human papillomavirus (HPV) vaccine in the treatment of recalcitrant common warts.¹ We describe a potential complication associated with HPV vaccine treatment of warts that would be of interest to dermatologists.

A 70-year-old woman presented with a plantar wart measuring 6 mm in diameter at the base of the right hallux of 5 years’ duration. Prior failed therapies for wart removal included multiple paring treatments, cryotherapy, and topical salicylic acid 40% to 60%. The patient had no notable comorbidities; no history of gout; and no known risk factors for gout, such as hypertension, renal insufficiency, diuretic use, obesity, family history, or trauma.

Prior reports cited effective treatment of recalcitrant warts with recombinant HPV vaccines, both intralesionally¹ and intramuscularly.^2,3 With this knowledge in mind, we administered an intralesional injection with 0.1-mL recombinant HPV 9-valent vaccine to the patient’s plantar wart. Gradual erythema and swelling of the right first metatarsophalangeal joint developed over the next 7 days. Synovial fluid analysis demonstrated negatively birefringent crystals. The patient commenced treatment with colchicine and indomethacin and improved over the next 5 days. The wart resolved 3 months later and required no further treatment.

Prophylactic quadrivalent HPV vaccines have shown efficacy in treating HPV-associated precancerous and cancerous lesions.⁴ Case reports have suggested that HPV vaccines may be an effective treatment option for recalcitrant warts,^1-3,5 especially in cases that do not respond to traditional treatment. It is possible that the mechanism of wart treatment involves overlap in the antigenic epitopes of the HPV types targeted by the vaccine vs the HPV types responsible for causing warts.² Papillomaviruslike particles, based on the L1 capsid protein, can induce a specific CD8⁺ activation signal, leading to a vaccine-induced cytotoxic T-cell response that targets the wart cells with HPV-like antigens.⁶ The HPV vaccine contains aluminium, which has been shown to activate NLRP3 inflammasome,⁵ which may trigger gout by increasing monosodium urate crystal deposition via IL-1β production.⁷ This may lead to an increased risk for gout flares, an adverse effect of the HPV vaccine. This finding is supported by other studies of aluminium-containing vaccines that show an association with gout.⁶ It is noted that these vaccines are mostly delivered intramuscularly or subcutaneously in some cases.

We reported a case of gout triggered by intralesional HPV vaccine treatment of warts. It is unclear whether the gout was induced by the vaccine itself or whether it was due to trauma caused by the intralesional injection near the joint space. Based on our findings, we recommend that patients receiving intralesional injections for wart treatment be advised of this potential adverse effect, especially if they have risk factors for gout or have a history of gout.

To the Editor:

There is increasing evidence supporting the use of the human papillomavirus (HPV) vaccine in the treatment of recalcitrant common warts.¹ We describe a potential complication associated with HPV vaccine treatment of warts that would be of interest to dermatologists.

A 70-year-old woman presented with a plantar wart measuring 6 mm in diameter at the base of the right hallux of 5 years’ duration. Prior failed therapies for wart removal included multiple paring treatments, cryotherapy, and topical salicylic acid 40% to 60%. The patient had no notable comorbidities; no history of gout; and no known risk factors for gout, such as hypertension, renal insufficiency, diuretic use, obesity, family history, or trauma.

Prior reports cited effective treatment of recalcitrant warts with recombinant HPV vaccines, both intralesionally¹ and intramuscularly.^2,3 With this knowledge in mind, we administered an intralesional injection with 0.1-mL recombinant HPV 9-valent vaccine to the patient’s plantar wart. Gradual erythema and swelling of the right first metatarsophalangeal joint developed over the next 7 days. Synovial fluid analysis demonstrated negatively birefringent crystals. The patient commenced treatment with colchicine and indomethacin and improved over the next 5 days. The wart resolved 3 months later and required no further treatment.

Prophylactic quadrivalent HPV vaccines have shown efficacy in treating HPV-associated precancerous and cancerous lesions.⁴ Case reports have suggested that HPV vaccines may be an effective treatment option for recalcitrant warts,^1-3,5 especially in cases that do not respond to traditional treatment. It is possible that the mechanism of wart treatment involves overlap in the antigenic epitopes of the HPV types targeted by the vaccine vs the HPV types responsible for causing warts.² Papillomaviruslike particles, based on the L1 capsid protein, can induce a specific CD8⁺ activation signal, leading to a vaccine-induced cytotoxic T-cell response that targets the wart cells with HPV-like antigens.⁶ The HPV vaccine contains aluminium, which has been shown to activate NLRP3 inflammasome,⁵ which may trigger gout by increasing monosodium urate crystal deposition via IL-1β production.⁷ This may lead to an increased risk for gout flares, an adverse effect of the HPV vaccine. This finding is supported by other studies of aluminium-containing vaccines that show an association with gout.⁶ It is noted that these vaccines are mostly delivered intramuscularly or subcutaneously in some cases.

We reported a case of gout triggered by intralesional HPV vaccine treatment of warts. It is unclear whether the gout was induced by the vaccine itself or whether it was due to trauma caused by the intralesional injection near the joint space. Based on our findings, we recommend that patients receiving intralesional injections for wart treatment be advised of this potential adverse effect, especially if they have risk factors for gout or have a history of gout.

To the Editor:

There is increasing evidence supporting the use of the human papillomavirus (HPV) vaccine in the treatment of recalcitrant common warts.¹ We describe a potential complication associated with HPV vaccine treatment of warts that would be of interest to dermatologists.

A 70-year-old woman presented with a plantar wart measuring 6 mm in diameter at the base of the right hallux of 5 years’ duration. Prior failed therapies for wart removal included multiple paring treatments, cryotherapy, and topical salicylic acid 40% to 60%. The patient had no notable comorbidities; no history of gout; and no known risk factors for gout, such as hypertension, renal insufficiency, diuretic use, obesity, family history, or trauma.

Prior reports cited effective treatment of recalcitrant warts with recombinant HPV vaccines, both intralesionally¹ and intramuscularly.^2,3 With this knowledge in mind, we administered an intralesional injection with 0.1-mL recombinant HPV 9-valent vaccine to the patient’s plantar wart. Gradual erythema and swelling of the right first metatarsophalangeal joint developed over the next 7 days. Synovial fluid analysis demonstrated negatively birefringent crystals. The patient commenced treatment with colchicine and indomethacin and improved over the next 5 days. The wart resolved 3 months later and required no further treatment.

Prophylactic quadrivalent HPV vaccines have shown efficacy in treating HPV-associated precancerous and cancerous lesions.⁴ Case reports have suggested that HPV vaccines may be an effective treatment option for recalcitrant warts,^1-3,5 especially in cases that do not respond to traditional treatment. It is possible that the mechanism of wart treatment involves overlap in the antigenic epitopes of the HPV types targeted by the vaccine vs the HPV types responsible for causing warts.² Papillomaviruslike particles, based on the L1 capsid protein, can induce a specific CD8⁺ activation signal, leading to a vaccine-induced cytotoxic T-cell response that targets the wart cells with HPV-like antigens.⁶ The HPV vaccine contains aluminium, which has been shown to activate NLRP3 inflammasome,⁵ which may trigger gout by increasing monosodium urate crystal deposition via IL-1β production.⁷ This may lead to an increased risk for gout flares, an adverse effect of the HPV vaccine. This finding is supported by other studies of aluminium-containing vaccines that show an association with gout.⁶ It is noted that these vaccines are mostly delivered intramuscularly or subcutaneously in some cases.

We reported a case of gout triggered by intralesional HPV vaccine treatment of warts. It is unclear whether the gout was induced by the vaccine itself or whether it was due to trauma caused by the intralesional injection near the joint space. Based on our findings, we recommend that patients receiving intralesional injections for wart treatment be advised of this potential adverse effect, especially if they have risk factors for gout or have a history of gout.

PORTLAND, ORE. – If you’re uncomfortable asking new dermatology patients about their sexual orientation and gender identity, they’re likely to sense your unease.

“From the patient perspective, there’s nothing more awkward than having an awkward provider asking awkward questions,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said at the annual meeting of the Pacific Dermatologic Association.

In 2014, Sean Cahill, PhD, and Harvey Makadon, MD, published an article recommending the inclusion of sexual orientation and gender identity questions in electronic medical records, a practice that Dr. Yeung characterized as “the most patient-centered way to collect sexual orientation and gender identity information. The most important thing is to ask routinely on an intake form where they fill it out themselves. All electronic medical records have the capacity to do so.”

On the other hand, when asking new patients about their sexual orientation and gender identity in person, it’s important to normalize the discussion and ask in an inclusive way, said Dr. Yeung, who was the lead author on published recommendations on dermatologic care for LGBTQ persons published in the Journal of the American Academy of Dermatology. “For example, I always say, ‘I’m Howa Yeung. I use him pronouns,’ ” he said. “ ‘How should I address you?’ Then they will tell you. Allow people to lead the way.”

Other suggested tips in the JAAD article include to avoid using terms such as “sir” or “miss” until the patient’s gender identify is ascertained. Instead, use gender-neutral terms such as “they” or “the patient” when referring to new patients. Do not use the pronoun “it.” If a patient’s name does not match a name in the medical record, ask, “What is the name on your insurance/records?” and avoid assuming gender(s) of a patient’s partner or parents. Instead, consider asking, “Who did you bring with you today?” “Are you in a relationship?” “What are the names of your parents?”

Normalizing questions about the patient’s sexual history is also key. “I tell patients that I routinely ask about sexual history for patients with similar skin issues because it helps me provide the best care for them,” Dr. Yeung said. “I also discuss confidentiality and documentation.”

Dr. Yeung reported having no relevant disclosures.

PORTLAND, ORE. – If you’re uncomfortable asking new dermatology patients about their sexual orientation and gender identity, they’re likely to sense your unease.

“From the patient perspective, there’s nothing more awkward than having an awkward provider asking awkward questions,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said at the annual meeting of the Pacific Dermatologic Association.

In 2014, Sean Cahill, PhD, and Harvey Makadon, MD, published an article recommending the inclusion of sexual orientation and gender identity questions in electronic medical records, a practice that Dr. Yeung characterized as “the most patient-centered way to collect sexual orientation and gender identity information. The most important thing is to ask routinely on an intake form where they fill it out themselves. All electronic medical records have the capacity to do so.”

On the other hand, when asking new patients about their sexual orientation and gender identity in person, it’s important to normalize the discussion and ask in an inclusive way, said Dr. Yeung, who was the lead author on published recommendations on dermatologic care for LGBTQ persons published in the Journal of the American Academy of Dermatology. “For example, I always say, ‘I’m Howa Yeung. I use him pronouns,’ ” he said. “ ‘How should I address you?’ Then they will tell you. Allow people to lead the way.”

Other suggested tips in the JAAD article include to avoid using terms such as “sir” or “miss” until the patient’s gender identify is ascertained. Instead, use gender-neutral terms such as “they” or “the patient” when referring to new patients. Do not use the pronoun “it.” If a patient’s name does not match a name in the medical record, ask, “What is the name on your insurance/records?” and avoid assuming gender(s) of a patient’s partner or parents. Instead, consider asking, “Who did you bring with you today?” “Are you in a relationship?” “What are the names of your parents?”

Normalizing questions about the patient’s sexual history is also key. “I tell patients that I routinely ask about sexual history for patients with similar skin issues because it helps me provide the best care for them,” Dr. Yeung said. “I also discuss confidentiality and documentation.”

Dr. Yeung reported having no relevant disclosures.

PORTLAND, ORE. – If you’re uncomfortable asking new dermatology patients about their sexual orientation and gender identity, they’re likely to sense your unease.

“From the patient perspective, there’s nothing more awkward than having an awkward provider asking awkward questions,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said at the annual meeting of the Pacific Dermatologic Association.

In 2014, Sean Cahill, PhD, and Harvey Makadon, MD, published an article recommending the inclusion of sexual orientation and gender identity questions in electronic medical records, a practice that Dr. Yeung characterized as “the most patient-centered way to collect sexual orientation and gender identity information. The most important thing is to ask routinely on an intake form where they fill it out themselves. All electronic medical records have the capacity to do so.”

On the other hand, when asking new patients about their sexual orientation and gender identity in person, it’s important to normalize the discussion and ask in an inclusive way, said Dr. Yeung, who was the lead author on published recommendations on dermatologic care for LGBTQ persons published in the Journal of the American Academy of Dermatology. “For example, I always say, ‘I’m Howa Yeung. I use him pronouns,’ ” he said. “ ‘How should I address you?’ Then they will tell you. Allow people to lead the way.”

Other suggested tips in the JAAD article include to avoid using terms such as “sir” or “miss” until the patient’s gender identify is ascertained. Instead, use gender-neutral terms such as “they” or “the patient” when referring to new patients. Do not use the pronoun “it.” If a patient’s name does not match a name in the medical record, ask, “What is the name on your insurance/records?” and avoid assuming gender(s) of a patient’s partner or parents. Instead, consider asking, “Who did you bring with you today?” “Are you in a relationship?” “What are the names of your parents?”

Normalizing questions about the patient’s sexual history is also key. “I tell patients that I routinely ask about sexual history for patients with similar skin issues because it helps me provide the best care for them,” Dr. Yeung said. “I also discuss confidentiality and documentation.”

Dr. Yeung reported having no relevant disclosures.

Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.

The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.

“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
 

Various hypotheses

In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.

“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”

AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
 

Seasonal factors involved?

Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.

The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.

They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.

AML cases per month were standardized to months of equal length.

Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.

Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
 

Long-term trend

A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.

Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”

The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.

January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).

The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
 

Potential role of viruses

“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”

With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”

“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”

As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori  and lymphomas.”

Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.

“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
 

New research network

Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.

As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.

To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.

“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.

Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.

Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.

The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.

“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
 

Various hypotheses

In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.

“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”

AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
 

Seasonal factors involved?

Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.

The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.

They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.

AML cases per month were standardized to months of equal length.

Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.

Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
 

Long-term trend

A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.

Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”

The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.

January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).

The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
 

Potential role of viruses

“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”

With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”

“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”

As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori  and lymphomas.”

Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.

“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
 

New research network

Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.

As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.

To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.

“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.

Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.

Most diagnoses of acute myeloid leukemia (AML) are made during January. This finding strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development or proliferation of the disease, which points to prevention opportunities. This was the conclusion of an international study led by a team from the Jiménez Díaz Foundation University Hospital Health Research Institute (IIS-FJD) in Madrid, in collaboration with colleagues from the University of Bristol, England. Their work was published in the British Journal of Haematology.

The study’s aim was to investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age. To do so, the researchers examined 26,472 cases of AML diagnosed in Spain between 2004 and 2015. They found seasonality in the diagnosis of this type of leukemia. This “could point to there being an underlying seasonal etiology at play,” noted one of the main authors of the study, Juan Manuel Alonso, MD, a physician in the IIS-FJD’s department of hematology and hemotherapy.

“The environmental triggers involved could be radiation, pollution, allergens, or infectious agents like viruses. We’re leaning toward viruses, because there are already distinct solid tumor and hematologic cancers that are caused by them and because, in the winter months, there’s an increased incidence of cancers due to viral infections,” Dr. Alonso said in an interview. “The etiological mechanism should be different from that exerted by chronic viral pressure, because here we’re dealing with an acute and aggressive disease that probably needs a short incubation period.”
 

Various hypotheses

In an interview, David Martínez, MD, a hematologist at La Fe University Hospital in Valencia, Spain, described the research as “an extremely well done and much-discussed study on AML, a disease that appears to be diagnosed more frequently at a certain time of year – namely, January.

“There’s no clear explanation for this finding,” Dr. Martínez said. “Several possible reasons have been put forward and are being talked about. The one that seems to hold the most water is the hypothesis that infectious agents and environmental factors may have a greater influence. This is because the idea that they’re involved in neoplastic diseases is nothing new. In fact, there are a lot of publications and a good amount of scientific evidence that link viral infections and environmental factors with the development of oncologic diseases.”

AML is a rare disease yet is responsible for many cancer-related deaths. Mutations that cause AML can occur due to an inherited mutant gene or exposure to certain carcinogens, such as chemotherapy, radiotherapy, ionizing radiation, tobacco, and benzene. These findings are broadly similar to those of a large U.S.-based study by Calip et al., who found a peak of adult AML diagnoses during December and January from 1992 to 2008. Previous smaller studies have provided conflicting evidence, likely due to lower power or to the use of less advanced statistical approaches.
 

Seasonal factors involved?

Demonstration of seasonal variation in the occurrence of AML would, firstly, provide supportive evidence of etiology by seasonal factors, such as infectious agents or environmental factors, and, secondly, focus research onto the etiologic role of such factors.

The current study used population-based data on cases of AML occurring in Spain from a nationwide hospital discharge registry for the years 2004 to 2015. “This is, to our knowledge, the largest study aimed at investigating the potential seasonal and long-term trends in AML incidence in an overall population and in subgroups according to sex and age while employing novel statistical models with serial dependence for discrete-valued time series,” wrote the researchers.

They extracted information from the register of each case about the date of admission, discharge date, the anonymous identifier for each patient, International Classification of Diseases (ICD)–9 codes, sex, and date of birth, from which they derived age groups as described for the at-risk population. For patients hospitalized on more than one occasion, only the record corresponding to their first diagnosis of AML was selected.

AML cases per month were standardized to months of equal length.

Age/sex-standardized monthly incidence rates of AML were calculated using the census of Spanish population in 2010 as a “standard” population. Age-standardized and sex-standardized monthly incidence rates of AML were calculated.

Nine separate time-series decompositions were performed as an initial exploratory analysis on the monthly incidence rates of AML using data for all cases and data for each sex and age group. Nine separate Poisson generalized linear autoregressive moving average (GLARMA) models were fitted to evaluate the temporal dynamics in AML incidence using data for all cases, and data for each sex and age group.
 

Long-term trend

A total of 26,472 patients with a first diagnosis of active AML were hospitalized in Spain and registered at the country’s Minimum Basic Data Set (CMBD) during 2004-2015. In the end, there were 26,475 patients in the study population; a greater proportion of cases were male (56.0%), and the median age at diagnosis was 67 years.

Seasonal and trend decomposition using Loess decomposition of the incidence rates observed in the overall population exhibited seasonal fluctuation with a peak in January. A slight upward trend was apparent from visual inspection with an upturn in early 2005 and a downturn at the end of 2013. As for the differences by sex groups and age groups, Dr. Alonso said, “For both sexes and in age groups 5-19, 20-49, and 50-64 years, we found that the results were identical to those found in the overall population.”

The final model included an upward linear long-term trend, as well as the variables monthly seasonality and December 2015. The estimated monthly long-term trend implies that the monthly incidence rates of AML diagnoses annually increased by 0.4% (95% confidence interval [CI], 0.2%-0.6%; P = .0011), given that the other covariates are held constant.

January displayed the highest incidence rate of AML, with a minimum average difference of 7%, when compared with February (95% CI, 2%-12%; P = .0143) and a maximum average difference of 16%, compared with November (95% CI, 11%-21%; P < .0001) and August (95% CI, 10%-21%; P < .0001).

The incidence rate of AML for December 2015 was 0.43 (95% CI, 0.34-0.54; P < .0001) times the average incidence rate for the rest of the study period.
 

Potential role of viruses

“We have to keep in mind that infectious agents (viral infections) and environmental factors (allergens) don’t disappear in the warmer months,” Dr. Martínez added. “There are just other viruses and different factors. We don’t know the role or the weight that each one of the factors has, either individually or specifically, in the development of AML. In addition, we know that AML is a very heterogeneous disease and that various factors, including genetic ones, can be involved in its etiopathogenesis.”

With respect to the stem cell theory in this leukemia, Dr. Alonso emphasized that, “in theory, the virus could fit into it with no problem. That said, any other environmental agent could also produce the described phenomenon where the rapid proliferation of quiescent leukemic stem cells is stimulated, thereby hastening the diagnosis.”

“Should the etiological factor be found,” Dr. Martínez noted, “we can try to reduce exposure and thereby decrease the incidence of AML. On the other hand, discovering how the environmental factor stimulates the proliferation of quiescent leukemic [stem] cells could enhance our knowledge about the regulation of that.”

As to whether there is evidence for the involvement of infections in other hematologic malignancies, Dr. Martínez reported, “This has already been seen. And this study shows other examples (Epstein-Barr virus and human T-cell lymphotropic virus type 1 with lymphomas), and there could also be Helicobacter pylori  and lymphomas.”

Outside of hematology, human papillomavirus has been associated with cervical cancer, tobacco with lung cancer, sun with skin cancer, and diet with the development of some solid neoplasms.

“The study speaks about the concept of a latency period. To accept the idea that a factor or virus that’s more prevalent in winter produces, on its own, AML in a few weeks or months means accepting the idea of a very short latency period – something that’s not usually the case. For that, another explanation is given: An abnormal immune response or that a seasonal infectious agent can be capable of promoting leukemogenesis. These are also hypotheses to be explored in the future,” suggested Dr. Martínez.
 

New research network

Several potential limitations of this study should be considered. One limitation is that AML cases were obtained from the CMBD registry as defined by ICD-9, and no other AML classifications were available. Another limitation is that information on the date of onset of clinical symptoms was not available for analysis. In addition, a further limitation related to the source of their data may have led the researchers to underestimate the incidence rates of AML in older patients, as only hospitalized patients were captured in their study.

As for continuing the research, the results make it necessary to carry out complementary epidemiologic studies that will examine the association between seasonal risk factors and the increased diagnosis of AML during winter months.

To go forward, the first step would be to secure funding. For this purpose, a network is being put together featuring collaborators from other world-renowned research groups that are at the top of their respective disciplines. Through this network, they hope to be able to apply together for public research grants from countries in Europe and elsewhere as well as to establish collaborations with various companies in the private sector.

“This could open up new therapeutic avenues in the future, as we could try to force leukemic stem cells to divide, thereby reducing the resistance that the standard treatments usually demonstrate,” Dr. Alonso concluded.

Dr. Alonso received research funding from Incyte, Pfizer International, and Astellas Pharma outside the present work. Dr. Martínez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish edition. A version of the article appeared on Medscape.com.

Some members of the American Academy of Pediatrics say its association leadership is blocking discussion about a resolution asking for a “rigorous systematic review” of gender-affirming care guidelines.

At issue is 2018 guidance that states children can undergo hormonal therapy after they are deemed appropriate candidates following a thorough mental health evaluation.

Critics say minors under age 18 may be getting “fast-tracked” to hormonal treatment too quickly or inappropriately and can end up regretting the decision and facing medical conditions like sterility.

Five AAP members, which has a total membership of around 67,000 pediatricians in the United States and Canada, this year penned Resolution 27, calling for a possible update of the guidelines following consultation with stakeholders that include mental health and medical clinicians, parents, and patients “with diverse views and experiences.”

Those members and others in written comments on a members-only website accuse the AAP of deliberately silencing debate on the issue and changing resolution rules. Any AAP member can submit a resolution for consideration by the group’s leadership at its annual policy meeting.

This year, the AAP sent an email to members stating it would not allow comments on resolutions that had not been “sponsored” by one of the group’s 66 chapters or 88 internal committees, councils, or sections.

That’s why comments were not allowed on Resolution 27, said Mark Del Monte, the AAP’s CEO. A second attempt to get sponsorship during the annual leadership forum, held earlier this month in Chicago, also failed, he noted. Mr. Del Monte told this news organization that changes to the resolution process are made every year and that no rule changes were directly associated with Resolution 27.

But one of the resolution’s authors said there was sponsorship when members first drafted the suggestion. Julia Mason, MD, a board member for the Society for Evidence-based Gender Medicine and a pediatrician in private practice in Gresham, Ore., says an AAP chapter president agreed to second Resolution 27 but backed off after attending a different AAP meeting. Dr. Mason did not name the member.

On Aug. 10, AAP President Moira Szilagyi, MD, PhD, wrote in a blog on the AAP website – after the AAP leadership meeting in Chicago – that the lack of sponsorship “meant no one was willing to support their proposal.”

The AAP Leadership Council’s 154 voting entities approved 48 resolutions at the meeting, all of which will be referred to the AAP Board of Directors for potential, but not definite, action as the Board only takes resolutions under advisement, Mr. Del Monte notes.

In an email allowing members to comment on a resolution (number 28) regarding education support for caring for transgender patients, 23 chose to support Resolution 27 instead.

“I am wholeheartedly in support of Resolution 27, which interestingly has been removed from the list of resolutions for member comment,” one comment read. “I can no longer trust the AAP to provide medical evidence-based education with regard to care for transgender individuals.” 

“We don’t need a formal resolution to look at the evidence around the care of transgender young people. Evaluating the evidence behind our recommendations, which the unsponsored resolution called for, is a routine part of the Academy’s policy-writing process,” wrote Dr. Szilagyi in her blog.

Mr. Del Monte says that “the 2018 policy is under review now.”

So far, “the evidence that we have seen reinforces our policy that gender-affirming care is the correct approach,” Mr. Del Monte stresses. “It is supported by every mainstream medical society in the world and is the standard of care,” he maintains.

Among those societies is the World Professional Association for Transgender Health, which in the draft of its latest Standards of Care (SOC8) – the first new guidance on the issue for 10 years – reportedly lowers the age for “top surgery” to 15 years.

The final SOC8 will most likely be published to coincide with WPATH’s annual meeting in September in Montreal.

Opponents plan to protest outside the AAP’s annual meeting, in Anaheim in October, Dr. Mason says.

“I’m concerned that kids with a transient gender identity are being funneled into medicalization that does not serve them,” Dr. Mason says. “I am worried that the trans identity is valued over the possibility of desistance,” she adds, admitting that her goal is to have fewer children transition gender.

Last summer, AAP found itself in hot water on the same topic when it barred SEGM from having a booth at the AAP annual meeting in 2021, as reported by this news organization.

A version of this article first appeared on Medscape.com.

Some members of the American Academy of Pediatrics say its association leadership is blocking discussion about a resolution asking for a “rigorous systematic review” of gender-affirming care guidelines.

At issue is 2018 guidance that states children can undergo hormonal therapy after they are deemed appropriate candidates following a thorough mental health evaluation.

Critics say minors under age 18 may be getting “fast-tracked” to hormonal treatment too quickly or inappropriately and can end up regretting the decision and facing medical conditions like sterility.

Five AAP members, which has a total membership of around 67,000 pediatricians in the United States and Canada, this year penned Resolution 27, calling for a possible update of the guidelines following consultation with stakeholders that include mental health and medical clinicians, parents, and patients “with diverse views and experiences.”

Those members and others in written comments on a members-only website accuse the AAP of deliberately silencing debate on the issue and changing resolution rules. Any AAP member can submit a resolution for consideration by the group’s leadership at its annual policy meeting.

This year, the AAP sent an email to members stating it would not allow comments on resolutions that had not been “sponsored” by one of the group’s 66 chapters or 88 internal committees, councils, or sections.

That’s why comments were not allowed on Resolution 27, said Mark Del Monte, the AAP’s CEO. A second attempt to get sponsorship during the annual leadership forum, held earlier this month in Chicago, also failed, he noted. Mr. Del Monte told this news organization that changes to the resolution process are made every year and that no rule changes were directly associated with Resolution 27.

But one of the resolution’s authors said there was sponsorship when members first drafted the suggestion. Julia Mason, MD, a board member for the Society for Evidence-based Gender Medicine and a pediatrician in private practice in Gresham, Ore., says an AAP chapter president agreed to second Resolution 27 but backed off after attending a different AAP meeting. Dr. Mason did not name the member.

On Aug. 10, AAP President Moira Szilagyi, MD, PhD, wrote in a blog on the AAP website – after the AAP leadership meeting in Chicago – that the lack of sponsorship “meant no one was willing to support their proposal.”

The AAP Leadership Council’s 154 voting entities approved 48 resolutions at the meeting, all of which will be referred to the AAP Board of Directors for potential, but not definite, action as the Board only takes resolutions under advisement, Mr. Del Monte notes.

In an email allowing members to comment on a resolution (number 28) regarding education support for caring for transgender patients, 23 chose to support Resolution 27 instead.

“I am wholeheartedly in support of Resolution 27, which interestingly has been removed from the list of resolutions for member comment,” one comment read. “I can no longer trust the AAP to provide medical evidence-based education with regard to care for transgender individuals.” 

“We don’t need a formal resolution to look at the evidence around the care of transgender young people. Evaluating the evidence behind our recommendations, which the unsponsored resolution called for, is a routine part of the Academy’s policy-writing process,” wrote Dr. Szilagyi in her blog.

Mr. Del Monte says that “the 2018 policy is under review now.”

So far, “the evidence that we have seen reinforces our policy that gender-affirming care is the correct approach,” Mr. Del Monte stresses. “It is supported by every mainstream medical society in the world and is the standard of care,” he maintains.

Among those societies is the World Professional Association for Transgender Health, which in the draft of its latest Standards of Care (SOC8) – the first new guidance on the issue for 10 years – reportedly lowers the age for “top surgery” to 15 years.

The final SOC8 will most likely be published to coincide with WPATH’s annual meeting in September in Montreal.

Opponents plan to protest outside the AAP’s annual meeting, in Anaheim in October, Dr. Mason says.

“I’m concerned that kids with a transient gender identity are being funneled into medicalization that does not serve them,” Dr. Mason says. “I am worried that the trans identity is valued over the possibility of desistance,” she adds, admitting that her goal is to have fewer children transition gender.

Last summer, AAP found itself in hot water on the same topic when it barred SEGM from having a booth at the AAP annual meeting in 2021, as reported by this news organization.

A version of this article first appeared on Medscape.com.

Some members of the American Academy of Pediatrics say its association leadership is blocking discussion about a resolution asking for a “rigorous systematic review” of gender-affirming care guidelines.

At issue is 2018 guidance that states children can undergo hormonal therapy after they are deemed appropriate candidates following a thorough mental health evaluation.

Critics say minors under age 18 may be getting “fast-tracked” to hormonal treatment too quickly or inappropriately and can end up regretting the decision and facing medical conditions like sterility.

Five AAP members, which has a total membership of around 67,000 pediatricians in the United States and Canada, this year penned Resolution 27, calling for a possible update of the guidelines following consultation with stakeholders that include mental health and medical clinicians, parents, and patients “with diverse views and experiences.”

Those members and others in written comments on a members-only website accuse the AAP of deliberately silencing debate on the issue and changing resolution rules. Any AAP member can submit a resolution for consideration by the group’s leadership at its annual policy meeting.

This year, the AAP sent an email to members stating it would not allow comments on resolutions that had not been “sponsored” by one of the group’s 66 chapters or 88 internal committees, councils, or sections.

That’s why comments were not allowed on Resolution 27, said Mark Del Monte, the AAP’s CEO. A second attempt to get sponsorship during the annual leadership forum, held earlier this month in Chicago, also failed, he noted. Mr. Del Monte told this news organization that changes to the resolution process are made every year and that no rule changes were directly associated with Resolution 27.

But one of the resolution’s authors said there was sponsorship when members first drafted the suggestion. Julia Mason, MD, a board member for the Society for Evidence-based Gender Medicine and a pediatrician in private practice in Gresham, Ore., says an AAP chapter president agreed to second Resolution 27 but backed off after attending a different AAP meeting. Dr. Mason did not name the member.

On Aug. 10, AAP President Moira Szilagyi, MD, PhD, wrote in a blog on the AAP website – after the AAP leadership meeting in Chicago – that the lack of sponsorship “meant no one was willing to support their proposal.”

The AAP Leadership Council’s 154 voting entities approved 48 resolutions at the meeting, all of which will be referred to the AAP Board of Directors for potential, but not definite, action as the Board only takes resolutions under advisement, Mr. Del Monte notes.

In an email allowing members to comment on a resolution (number 28) regarding education support for caring for transgender patients, 23 chose to support Resolution 27 instead.

“I am wholeheartedly in support of Resolution 27, which interestingly has been removed from the list of resolutions for member comment,” one comment read. “I can no longer trust the AAP to provide medical evidence-based education with regard to care for transgender individuals.” 

“We don’t need a formal resolution to look at the evidence around the care of transgender young people. Evaluating the evidence behind our recommendations, which the unsponsored resolution called for, is a routine part of the Academy’s policy-writing process,” wrote Dr. Szilagyi in her blog.

Mr. Del Monte says that “the 2018 policy is under review now.”

So far, “the evidence that we have seen reinforces our policy that gender-affirming care is the correct approach,” Mr. Del Monte stresses. “It is supported by every mainstream medical society in the world and is the standard of care,” he maintains.

Among those societies is the World Professional Association for Transgender Health, which in the draft of its latest Standards of Care (SOC8) – the first new guidance on the issue for 10 years – reportedly lowers the age for “top surgery” to 15 years.

The final SOC8 will most likely be published to coincide with WPATH’s annual meeting in September in Montreal.

Opponents plan to protest outside the AAP’s annual meeting, in Anaheim in October, Dr. Mason says.

“I’m concerned that kids with a transient gender identity are being funneled into medicalization that does not serve them,” Dr. Mason says. “I am worried that the trans identity is valued over the possibility of desistance,” she adds, admitting that her goal is to have fewer children transition gender.

Last summer, AAP found itself in hot water on the same topic when it barred SEGM from having a booth at the AAP annual meeting in 2021, as reported by this news organization.

A version of this article first appeared on Medscape.com.

In the United States, uterine cancer is the fourth most common cancer among women, behind breast, lung/bronchus, and colorectal cancer. There are expected to be almost 66,000 new cases of uterine cancer in 2022.¹ The majority of uterine cancers are endometrioid in histology and tend to be low grade, diagnosed at an early stage, and have a good prognosis. While our molecular understanding of endometrial cancers (EC) has changed significantly in recent years, low-grade endometrioid adenocarcinomas have historically been described as type 1 ECs. Type 1 ECs are typically caused by excess estrogen exposure (often unopposed or lacking progesterone protection) and are preceded by endometrial hyperplasia. Excess estrogen can come from exogenous sources (such as unopposed estrogen replacement therapy or tamoxifen, a commonly used treatment in estrogen receptor–positive breast cancer that acts as an estrogen agonist in the endometrium in postmenopausal patients) or endogenous ones (such as obesity).

Peripheral adipose tissue converts androgens into estrogens; paired with the decreased levels of sex hormone–binding globulin seen in obesity, there is more unbound or free serum estrogen (specifically estradiol) in obese women. Estrogen acts on the endometrium to cause proliferation and, if unopposed or imbalanced in relation to progesterone exposure, can ultimately lead to hyperplasia and malignancy.

Footnote: vaginal estrogen therapy

There are no randomized trials assessing the safety of vaginal estrogen preparations or their effect on oncologic outcomes in EC survivors. Observational data from the Women’s Health Initiative showed no increased risk of endometrial cancer in patients who used vaginal estrogen with an intact uterus.⁴ A recently published retrospective study among 244 gynecologic cancer survivors found low rates of disease recurrence and adverse outcomes among women who used vaginal estrogen for genitourinary symptoms.⁵ Among EC survivors, the incidence of recurrence was 2.4% for patients with stage I/II disease and 4.3% for stage III/IV disease, with a median follow-up of 80.2 months. While there appears to be some systemic absorption with vaginal estrogen use, this can be quite challenging to measure because of the current sensitivity of serum estradiol and estrone assays. Given the significantly lower serum levels with vaginal estrogen preparations compared with ERT, vaginal estrogen use appears to be safe in EC survivors.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Cancer Stat Facts: Uterine Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed 12 Aug. 2022. https://seer.cancer.gov/statfacts/html/corp.html.

2. Barakat RR et al. J Clin Oncol. 2006;24(4):587-92.

3. Shim SH et al. Eur J Cancer. 2014;50(9):1628-37.

4. Crandall CJ et al. Menopause. 2018 Jan;25(1):11-20.

5. Chambers LM et al. Int J Gynecol Cancer. 2020 Apr;30(4):515-24.

In the United States, uterine cancer is the fourth most common cancer among women, behind breast, lung/bronchus, and colorectal cancer. There are expected to be almost 66,000 new cases of uterine cancer in 2022.¹ The majority of uterine cancers are endometrioid in histology and tend to be low grade, diagnosed at an early stage, and have a good prognosis. While our molecular understanding of endometrial cancers (EC) has changed significantly in recent years, low-grade endometrioid adenocarcinomas have historically been described as type 1 ECs. Type 1 ECs are typically caused by excess estrogen exposure (often unopposed or lacking progesterone protection) and are preceded by endometrial hyperplasia. Excess estrogen can come from exogenous sources (such as unopposed estrogen replacement therapy or tamoxifen, a commonly used treatment in estrogen receptor–positive breast cancer that acts as an estrogen agonist in the endometrium in postmenopausal patients) or endogenous ones (such as obesity).

Peripheral adipose tissue converts androgens into estrogens; paired with the decreased levels of sex hormone–binding globulin seen in obesity, there is more unbound or free serum estrogen (specifically estradiol) in obese women. Estrogen acts on the endometrium to cause proliferation and, if unopposed or imbalanced in relation to progesterone exposure, can ultimately lead to hyperplasia and malignancy.

Footnote: vaginal estrogen therapy

There are no randomized trials assessing the safety of vaginal estrogen preparations or their effect on oncologic outcomes in EC survivors. Observational data from the Women’s Health Initiative showed no increased risk of endometrial cancer in patients who used vaginal estrogen with an intact uterus.⁴ A recently published retrospective study among 244 gynecologic cancer survivors found low rates of disease recurrence and adverse outcomes among women who used vaginal estrogen for genitourinary symptoms.⁵ Among EC survivors, the incidence of recurrence was 2.4% for patients with stage I/II disease and 4.3% for stage III/IV disease, with a median follow-up of 80.2 months. While there appears to be some systemic absorption with vaginal estrogen use, this can be quite challenging to measure because of the current sensitivity of serum estradiol and estrone assays. Given the significantly lower serum levels with vaginal estrogen preparations compared with ERT, vaginal estrogen use appears to be safe in EC survivors.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Cancer Stat Facts: Uterine Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed 12 Aug. 2022. https://seer.cancer.gov/statfacts/html/corp.html.

2. Barakat RR et al. J Clin Oncol. 2006;24(4):587-92.

3. Shim SH et al. Eur J Cancer. 2014;50(9):1628-37.

4. Crandall CJ et al. Menopause. 2018 Jan;25(1):11-20.

5. Chambers LM et al. Int J Gynecol Cancer. 2020 Apr;30(4):515-24.

In the United States, uterine cancer is the fourth most common cancer among women, behind breast, lung/bronchus, and colorectal cancer. There are expected to be almost 66,000 new cases of uterine cancer in 2022.¹ The majority of uterine cancers are endometrioid in histology and tend to be low grade, diagnosed at an early stage, and have a good prognosis. While our molecular understanding of endometrial cancers (EC) has changed significantly in recent years, low-grade endometrioid adenocarcinomas have historically been described as type 1 ECs. Type 1 ECs are typically caused by excess estrogen exposure (often unopposed or lacking progesterone protection) and are preceded by endometrial hyperplasia. Excess estrogen can come from exogenous sources (such as unopposed estrogen replacement therapy or tamoxifen, a commonly used treatment in estrogen receptor–positive breast cancer that acts as an estrogen agonist in the endometrium in postmenopausal patients) or endogenous ones (such as obesity).

Peripheral adipose tissue converts androgens into estrogens; paired with the decreased levels of sex hormone–binding globulin seen in obesity, there is more unbound or free serum estrogen (specifically estradiol) in obese women. Estrogen acts on the endometrium to cause proliferation and, if unopposed or imbalanced in relation to progesterone exposure, can ultimately lead to hyperplasia and malignancy.

Footnote: vaginal estrogen therapy

There are no randomized trials assessing the safety of vaginal estrogen preparations or their effect on oncologic outcomes in EC survivors. Observational data from the Women’s Health Initiative showed no increased risk of endometrial cancer in patients who used vaginal estrogen with an intact uterus.⁴ A recently published retrospective study among 244 gynecologic cancer survivors found low rates of disease recurrence and adverse outcomes among women who used vaginal estrogen for genitourinary symptoms.⁵ Among EC survivors, the incidence of recurrence was 2.4% for patients with stage I/II disease and 4.3% for stage III/IV disease, with a median follow-up of 80.2 months. While there appears to be some systemic absorption with vaginal estrogen use, this can be quite challenging to measure because of the current sensitivity of serum estradiol and estrone assays. Given the significantly lower serum levels with vaginal estrogen preparations compared with ERT, vaginal estrogen use appears to be safe in EC survivors.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Cancer Stat Facts: Uterine Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed 12 Aug. 2022. https://seer.cancer.gov/statfacts/html/corp.html.

2. Barakat RR et al. J Clin Oncol. 2006;24(4):587-92.

3. Shim SH et al. Eur J Cancer. 2014;50(9):1628-37.

4. Crandall CJ et al. Menopause. 2018 Jan;25(1):11-20.

5. Chambers LM et al. Int J Gynecol Cancer. 2020 Apr;30(4):515-24.

Annual prostate cancer screening may be particularly important for Black men, new data suggest.

The data come from a review of 45,834 veterans (aged 55-69 years) who had been diagnosed with prostate cancer. About one-third of these men self-identified as non-Hispanic Black, and the rest were White.

During the study period (2004-2017), 2,465 men (5.4%) died of the disease.

The review found that annual prostate-specific antigen (PSA) screening significantly reduced the risk of dying from prostate cancer among Black men but not White men.

The study was published online in JAMA Oncology.

“These results may be biologically plausible because a shorter screening interval may be valuable for detecting aggressive disease, which is more common in Black men,” say investigators, led by University of California, San Diego, radiation oncology resident Michael Sherer, MD.

“Given that Black men are younger at diagnosis and have worse prostate cancer survival compared with White men,” more intensive screening recommendations “may benefit Black patients,” they write.

The study “conclusions are reasonable,” said Christopher Wallis, MD, PhD, a urologic oncologist at Mount Sinai Hospital in Toronto, when asked for comment.

Annual screening may well have “a greater potential to benefit” Black men, he said. “While we would ideally see randomized data supporting this, those data are unlikely to ever be forthcoming. Thus, this study provides a strong rationale to support the recommendations from many guideline panels (including those from the American Urological Association) that Black men, in the context of shared decision-making, may benefit more from PSA-based prostate cancer screening than the population at large,” he added.

Overall, the findings could help inform screening discussions with Black men, the investigators comments. In its most recent guidance, the U.S. Preventive Services Task Force recommends shared decision-making regarding PSA screening for men aged 55-69 years.
 

Similar screening frequency

For their study, the team reviewed Veterans Health Administration data to assess PSA screening patterns – which they categorized as no screening, less than annual screening, or annual screening – in the 5 years leading up to diagnosis.

They then correlated screening behaviors with the subsequent risk of dying from prostate cancer.

Overall, the reduction in risk of prostate cancer–specific mortality (PCSM) associated with screening was similar among Black men (subdistribution hazard ratio, 0.56; P = .001) and White men (sHR, 0.58; P = .001).

However, on multivariable regression, annual screening, in comparison with some screening, was associated with a significant reduction in the risk of dying from prostate cancer only among Black men (sHR, 0.65; P = .02), not among White men (sHR, 0.91; P = .35).

The cumulative incidence of PCSM among Black men was 4.7% with annual screening but 7.3% with only some screening.

Among White men, the cumulative incidence of PCSM with annual screening was 5.9% vs. 6.9% with less than annual screening.

Screening frequency was similar between Black men and White men. Black men were younger on average (61.8 vs. 63.1 years) and had slightly higher PSA levels at diagnosis but were not more likely to have regional or metastatic disease.

No funding was reported for this study. The investigators have disclosed no relevant financial relationships. Dr. Wallis has received personal fees from Janssen Canada.

A version of this article first appeared on Medscape.com.

Annual prostate cancer screening may be particularly important for Black men, new data suggest.

The data come from a review of 45,834 veterans (aged 55-69 years) who had been diagnosed with prostate cancer. About one-third of these men self-identified as non-Hispanic Black, and the rest were White.

During the study period (2004-2017), 2,465 men (5.4%) died of the disease.

The review found that annual prostate-specific antigen (PSA) screening significantly reduced the risk of dying from prostate cancer among Black men but not White men.

The study was published online in JAMA Oncology.

“These results may be biologically plausible because a shorter screening interval may be valuable for detecting aggressive disease, which is more common in Black men,” say investigators, led by University of California, San Diego, radiation oncology resident Michael Sherer, MD.

“Given that Black men are younger at diagnosis and have worse prostate cancer survival compared with White men,” more intensive screening recommendations “may benefit Black patients,” they write.

The study “conclusions are reasonable,” said Christopher Wallis, MD, PhD, a urologic oncologist at Mount Sinai Hospital in Toronto, when asked for comment.

Annual screening may well have “a greater potential to benefit” Black men, he said. “While we would ideally see randomized data supporting this, those data are unlikely to ever be forthcoming. Thus, this study provides a strong rationale to support the recommendations from many guideline panels (including those from the American Urological Association) that Black men, in the context of shared decision-making, may benefit more from PSA-based prostate cancer screening than the population at large,” he added.

Overall, the findings could help inform screening discussions with Black men, the investigators comments. In its most recent guidance, the U.S. Preventive Services Task Force recommends shared decision-making regarding PSA screening for men aged 55-69 years.
 

Similar screening frequency

For their study, the team reviewed Veterans Health Administration data to assess PSA screening patterns – which they categorized as no screening, less than annual screening, or annual screening – in the 5 years leading up to diagnosis.

They then correlated screening behaviors with the subsequent risk of dying from prostate cancer.

Overall, the reduction in risk of prostate cancer–specific mortality (PCSM) associated with screening was similar among Black men (subdistribution hazard ratio, 0.56; P = .001) and White men (sHR, 0.58; P = .001).

However, on multivariable regression, annual screening, in comparison with some screening, was associated with a significant reduction in the risk of dying from prostate cancer only among Black men (sHR, 0.65; P = .02), not among White men (sHR, 0.91; P = .35).

The cumulative incidence of PCSM among Black men was 4.7% with annual screening but 7.3% with only some screening.

Among White men, the cumulative incidence of PCSM with annual screening was 5.9% vs. 6.9% with less than annual screening.

Screening frequency was similar between Black men and White men. Black men were younger on average (61.8 vs. 63.1 years) and had slightly higher PSA levels at diagnosis but were not more likely to have regional or metastatic disease.

No funding was reported for this study. The investigators have disclosed no relevant financial relationships. Dr. Wallis has received personal fees from Janssen Canada.

A version of this article first appeared on Medscape.com.

Annual prostate cancer screening may be particularly important for Black men, new data suggest.

The data come from a review of 45,834 veterans (aged 55-69 years) who had been diagnosed with prostate cancer. About one-third of these men self-identified as non-Hispanic Black, and the rest were White.

During the study period (2004-2017), 2,465 men (5.4%) died of the disease.

The review found that annual prostate-specific antigen (PSA) screening significantly reduced the risk of dying from prostate cancer among Black men but not White men.

The study was published online in JAMA Oncology.

“These results may be biologically plausible because a shorter screening interval may be valuable for detecting aggressive disease, which is more common in Black men,” say investigators, led by University of California, San Diego, radiation oncology resident Michael Sherer, MD.

“Given that Black men are younger at diagnosis and have worse prostate cancer survival compared with White men,” more intensive screening recommendations “may benefit Black patients,” they write.

The study “conclusions are reasonable,” said Christopher Wallis, MD, PhD, a urologic oncologist at Mount Sinai Hospital in Toronto, when asked for comment.

Annual screening may well have “a greater potential to benefit” Black men, he said. “While we would ideally see randomized data supporting this, those data are unlikely to ever be forthcoming. Thus, this study provides a strong rationale to support the recommendations from many guideline panels (including those from the American Urological Association) that Black men, in the context of shared decision-making, may benefit more from PSA-based prostate cancer screening than the population at large,” he added.

Overall, the findings could help inform screening discussions with Black men, the investigators comments. In its most recent guidance, the U.S. Preventive Services Task Force recommends shared decision-making regarding PSA screening for men aged 55-69 years.
 

Similar screening frequency

For their study, the team reviewed Veterans Health Administration data to assess PSA screening patterns – which they categorized as no screening, less than annual screening, or annual screening – in the 5 years leading up to diagnosis.

They then correlated screening behaviors with the subsequent risk of dying from prostate cancer.

Overall, the reduction in risk of prostate cancer–specific mortality (PCSM) associated with screening was similar among Black men (subdistribution hazard ratio, 0.56; P = .001) and White men (sHR, 0.58; P = .001).

However, on multivariable regression, annual screening, in comparison with some screening, was associated with a significant reduction in the risk of dying from prostate cancer only among Black men (sHR, 0.65; P = .02), not among White men (sHR, 0.91; P = .35).

The cumulative incidence of PCSM among Black men was 4.7% with annual screening but 7.3% with only some screening.

Among White men, the cumulative incidence of PCSM with annual screening was 5.9% vs. 6.9% with less than annual screening.

Screening frequency was similar between Black men and White men. Black men were younger on average (61.8 vs. 63.1 years) and had slightly higher PSA levels at diagnosis but were not more likely to have regional or metastatic disease.

No funding was reported for this study. The investigators have disclosed no relevant financial relationships. Dr. Wallis has received personal fees from Janssen Canada.

A version of this article first appeared on Medscape.com.

Varicella zoster virus (VZV) infection may activate dormant herpes simplex virus (HSV-1), leading to neuroinflammation and accumulation of Alzheimer’s disease (AD)–related proteins in the brain, new research suggests.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” lead author Dana Cairns, PhD, research associate, department of biomedical engineering at Tufts University, Boston, said in a news release.

The findings were published online  in Journal of Alzheimer’s Disease.
 

‘One-two punch’

Previous research has suggested a correlation between HSV-1 and AD and involvement of VZV. However, the sequence of events that the viruses create to set the disease in motion has been unclear.

“We think we now have evidence of those events,” co–senior author David Kaplan, PhD, chair of the department of biomedical engineering at Tufts, said in the release.

Working with co–senior author Ruth Itzhaki, PhD, University of Oxford, United Kingdom, the researchers infected human-induced neural stem cells (hiNSCs) and 3D brain tissue models with HSV-1 and/or VZV. Dr. Itzhaki was one of the first to hypothesize a connection between herpes virus and AD.

The investigators found that HSV-1 infection of hiNSCs induces amyloid-beta and P-tau accumulation: the main components of AD plaques and neurofibrillary tangles, respectively.

On the other hand, VZV infection of cultured hiNSCs did not lead to amyloid-beta and P-tau accumulation but instead resulted in gliosis and increased levels of proinflammatory cytokines.

“Strikingly,” VZV infection of cells quiescently infected with HSV-1 caused reactivation of HSV-1, leading to AD-like changes, including amyloid-beta and P-tau accumulation, the investigators report.

This suggests that VZV is unlikely to be a direct cause of AD but rather acts indirectly via reactivation of HSV-1, they add.

Similar findings emerged in similar experiments using 3D human brain tissue models.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” Dr. Cairns said.

The researchers note that vaccination against VZV has been shown previously to reduce risk for dementia. It is possible, they add, that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.
 

‘A first step’

Heather M. Snyder, PhD, vice president of Medical & Scientific Relations at the Alzheimer’s Association, said that the study “is using artificial systems with the goal of more clearly and more deeply understanding” the assessed associations.

She added that although it is a first step, it may provide valuable direction for follow-up research.

“This is preliminary work that first needs replication, validation, and further development to understand if any association that is uncovered between viruses and Alzheimer’s/dementia has a mechanistic link,” said Dr. Snyder.

She noted that several past studies have sought to help the research field better understand the links between different viruses and Alzheimer’s and other forms of dementia.

“There have been some challenges in evaluating these associations in our current model systems or in individuals for a number of reasons,” said Dr. Snyder.

However, “the COVID-19 pandemic has created an opportunity to examine and investigate the relationships between different viruses and Alzheimer’s and other dementias by following individuals in more common and well-established ways,” she added.

She reported that her organization is “leading and working with a large global network of studies and investigators to address some of these questions” from during and after the COVID pandemic.

“The lessons we learn and share may inform our understanding of how other viruses are, or are not, connected to Alzheimer’s and other dementia,” Dr. Snyder said.

More information on the Alzheimer’s Association International Cohort Study of Chronic Neurological Sequelae of SARS-CoV-2 is available online.

The study was funded by the National Institutes of Health. Dr. Cairns, Dr. Kaplan, Dr. Itzhaki, and Dr. Snyder have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Varicella zoster virus (VZV) infection may activate dormant herpes simplex virus (HSV-1), leading to neuroinflammation and accumulation of Alzheimer’s disease (AD)–related proteins in the brain, new research suggests.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” lead author Dana Cairns, PhD, research associate, department of biomedical engineering at Tufts University, Boston, said in a news release.

The findings were published online  in Journal of Alzheimer’s Disease.
 

‘One-two punch’

Previous research has suggested a correlation between HSV-1 and AD and involvement of VZV. However, the sequence of events that the viruses create to set the disease in motion has been unclear.

“We think we now have evidence of those events,” co–senior author David Kaplan, PhD, chair of the department of biomedical engineering at Tufts, said in the release.

Working with co–senior author Ruth Itzhaki, PhD, University of Oxford, United Kingdom, the researchers infected human-induced neural stem cells (hiNSCs) and 3D brain tissue models with HSV-1 and/or VZV. Dr. Itzhaki was one of the first to hypothesize a connection between herpes virus and AD.

The investigators found that HSV-1 infection of hiNSCs induces amyloid-beta and P-tau accumulation: the main components of AD plaques and neurofibrillary tangles, respectively.

On the other hand, VZV infection of cultured hiNSCs did not lead to amyloid-beta and P-tau accumulation but instead resulted in gliosis and increased levels of proinflammatory cytokines.

“Strikingly,” VZV infection of cells quiescently infected with HSV-1 caused reactivation of HSV-1, leading to AD-like changes, including amyloid-beta and P-tau accumulation, the investigators report.

This suggests that VZV is unlikely to be a direct cause of AD but rather acts indirectly via reactivation of HSV-1, they add.

Similar findings emerged in similar experiments using 3D human brain tissue models.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” Dr. Cairns said.

The researchers note that vaccination against VZV has been shown previously to reduce risk for dementia. It is possible, they add, that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.
 

‘A first step’

Heather M. Snyder, PhD, vice president of Medical & Scientific Relations at the Alzheimer’s Association, said that the study “is using artificial systems with the goal of more clearly and more deeply understanding” the assessed associations.

She added that although it is a first step, it may provide valuable direction for follow-up research.

“This is preliminary work that first needs replication, validation, and further development to understand if any association that is uncovered between viruses and Alzheimer’s/dementia has a mechanistic link,” said Dr. Snyder.

She noted that several past studies have sought to help the research field better understand the links between different viruses and Alzheimer’s and other forms of dementia.

“There have been some challenges in evaluating these associations in our current model systems or in individuals for a number of reasons,” said Dr. Snyder.

However, “the COVID-19 pandemic has created an opportunity to examine and investigate the relationships between different viruses and Alzheimer’s and other dementias by following individuals in more common and well-established ways,” she added.

She reported that her organization is “leading and working with a large global network of studies and investigators to address some of these questions” from during and after the COVID pandemic.

“The lessons we learn and share may inform our understanding of how other viruses are, or are not, connected to Alzheimer’s and other dementia,” Dr. Snyder said.

More information on the Alzheimer’s Association International Cohort Study of Chronic Neurological Sequelae of SARS-CoV-2 is available online.

The study was funded by the National Institutes of Health. Dr. Cairns, Dr. Kaplan, Dr. Itzhaki, and Dr. Snyder have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Varicella zoster virus (VZV) infection may activate dormant herpes simplex virus (HSV-1), leading to neuroinflammation and accumulation of Alzheimer’s disease (AD)–related proteins in the brain, new research suggests.

“Our results suggest one pathway to Alzheimer’s disease, caused by a VZV infection which creates inflammatory triggers that awaken HSV in the brain,” lead author Dana Cairns, PhD, research associate, department of biomedical engineering at Tufts University, Boston, said in a news release.

The findings were published online  in Journal of Alzheimer’s Disease.
 

‘One-two punch’

Previous research has suggested a correlation between HSV-1 and AD and involvement of VZV. However, the sequence of events that the viruses create to set the disease in motion has been unclear.

“We think we now have evidence of those events,” co–senior author David Kaplan, PhD, chair of the department of biomedical engineering at Tufts, said in the release.

Working with co–senior author Ruth Itzhaki, PhD, University of Oxford, United Kingdom, the researchers infected human-induced neural stem cells (hiNSCs) and 3D brain tissue models with HSV-1 and/or VZV. Dr. Itzhaki was one of the first to hypothesize a connection between herpes virus and AD.

The investigators found that HSV-1 infection of hiNSCs induces amyloid-beta and P-tau accumulation: the main components of AD plaques and neurofibrillary tangles, respectively.

On the other hand, VZV infection of cultured hiNSCs did not lead to amyloid-beta and P-tau accumulation but instead resulted in gliosis and increased levels of proinflammatory cytokines.

“Strikingly,” VZV infection of cells quiescently infected with HSV-1 caused reactivation of HSV-1, leading to AD-like changes, including amyloid-beta and P-tau accumulation, the investigators report.

This suggests that VZV is unlikely to be a direct cause of AD but rather acts indirectly via reactivation of HSV-1, they add.

Similar findings emerged in similar experiments using 3D human brain tissue models.

“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble,” Dr. Cairns said.

The researchers note that vaccination against VZV has been shown previously to reduce risk for dementia. It is possible, they add, that the vaccine is helping to stop the cycle of viral reactivation, inflammation, and neuronal damage.
 

‘A first step’

Heather M. Snyder, PhD, vice president of Medical & Scientific Relations at the Alzheimer’s Association, said that the study “is using artificial systems with the goal of more clearly and more deeply understanding” the assessed associations.

She added that although it is a first step, it may provide valuable direction for follow-up research.

“This is preliminary work that first needs replication, validation, and further development to understand if any association that is uncovered between viruses and Alzheimer’s/dementia has a mechanistic link,” said Dr. Snyder.

She noted that several past studies have sought to help the research field better understand the links between different viruses and Alzheimer’s and other forms of dementia.

“There have been some challenges in evaluating these associations in our current model systems or in individuals for a number of reasons,” said Dr. Snyder.

However, “the COVID-19 pandemic has created an opportunity to examine and investigate the relationships between different viruses and Alzheimer’s and other dementias by following individuals in more common and well-established ways,” she added.

She reported that her organization is “leading and working with a large global network of studies and investigators to address some of these questions” from during and after the COVID pandemic.

“The lessons we learn and share may inform our understanding of how other viruses are, or are not, connected to Alzheimer’s and other dementia,” Dr. Snyder said.

More information on the Alzheimer’s Association International Cohort Study of Chronic Neurological Sequelae of SARS-CoV-2 is available online.

The study was funded by the National Institutes of Health. Dr. Cairns, Dr. Kaplan, Dr. Itzhaki, and Dr. Snyder have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.