Traditionally, a physician develops a differential diagnosis based primarily (>70%) on the history and the physical examination of a patient.¹ While modern medicine has developed with new technological devices and a growing number of diagnostic tests, one must not forget the value of a thorough physical examination.

Case

A 21-year-old woman, in previous good health, presented to the ED with the chief complaint of shortness of breath. She stated that she woke up with acute dyspnea and a stabbing pain on the left side of her thorax, related to her breathing. The patient looked distressed upon presentation.

Her vital signs at presentation were: blood pressure, 150/85 mm Hg; heart rate, 120 beats/min; respiratory rate, 22 breaths/min; and temperature, 100.6°F. Oxygen saturation was 100% on room air.

During physical examination, a loud ticking noise was heard originating from the thorax, even without a stethoscope (an example of the sound can be heard at https://www.youtube.com/watch?v=mXJHtJeL1mM). During auscultation, the ticking noise was prominent in early systole and audible over all parts of the thorax. The sound was only heard when the patient was in the supine position and disappeared when she sat up. It persisted when the patient was holding her breath. Breath sounds were equal and clear bilaterally. There was no subcutaneous emphysema palpable over the thorax or neck region.

Discussion

These loud intermittent noises originating from the thorax were described for the first time at the beginning of the 19th century.^2,3 However, it was Louis Virgil Hamman whose name would be linked to this physical examination finding. In 1937 he described typical clicking, crackling, and popping sounds over the precordium, synchronized with the heartbeat. This was usually in combination with subcutaneous emphysema in the neck region. Hamman presumed that the symptoms were due to mediastinal air caused by rupture alveoli or bronchioles, resulting in interstitial emphysema of the lung parenchyma. In addition, air could leak into the pleural space, causing a pneumothorax. He concluded that the clinical findings were pathognomonic for spontaneous mediastinal emphysema, and this physical examination finding became known as the “Hamman sign”.^4-11

Conclusion

The Hamman sign is a rare clinical examination finding in left-sided pneumothorax or pneumomediastinum, in which a ticking or crackling noise is heard over the thorax. This is mostly synchronous with the heartbeat and not related to respiration. It is caused by a small amount of accumulated air in the pleural space, which is being displaced by cardiac contractions during the cardiac cycle. Although typically small, pneumothoraces have a good prognosis. Recognition of the Hamman sign is important, and physicians must realize that even a normal chest X-ray does not rule out the diagnosis.

Traditionally, a physician develops a differential diagnosis based primarily (>70%) on the history and the physical examination of a patient.¹ While modern medicine has developed with new technological devices and a growing number of diagnostic tests, one must not forget the value of a thorough physical examination.

Case

A 21-year-old woman, in previous good health, presented to the ED with the chief complaint of shortness of breath. She stated that she woke up with acute dyspnea and a stabbing pain on the left side of her thorax, related to her breathing. The patient looked distressed upon presentation.

Her vital signs at presentation were: blood pressure, 150/85 mm Hg; heart rate, 120 beats/min; respiratory rate, 22 breaths/min; and temperature, 100.6°F. Oxygen saturation was 100% on room air.

During physical examination, a loud ticking noise was heard originating from the thorax, even without a stethoscope (an example of the sound can be heard at https://www.youtube.com/watch?v=mXJHtJeL1mM). During auscultation, the ticking noise was prominent in early systole and audible over all parts of the thorax. The sound was only heard when the patient was in the supine position and disappeared when she sat up. It persisted when the patient was holding her breath. Breath sounds were equal and clear bilaterally. There was no subcutaneous emphysema palpable over the thorax or neck region.

Discussion

These loud intermittent noises originating from the thorax were described for the first time at the beginning of the 19th century.^2,3 However, it was Louis Virgil Hamman whose name would be linked to this physical examination finding. In 1937 he described typical clicking, crackling, and popping sounds over the precordium, synchronized with the heartbeat. This was usually in combination with subcutaneous emphysema in the neck region. Hamman presumed that the symptoms were due to mediastinal air caused by rupture alveoli or bronchioles, resulting in interstitial emphysema of the lung parenchyma. In addition, air could leak into the pleural space, causing a pneumothorax. He concluded that the clinical findings were pathognomonic for spontaneous mediastinal emphysema, and this physical examination finding became known as the “Hamman sign”.^4-11

Conclusion

The Hamman sign is a rare clinical examination finding in left-sided pneumothorax or pneumomediastinum, in which a ticking or crackling noise is heard over the thorax. This is mostly synchronous with the heartbeat and not related to respiration. It is caused by a small amount of accumulated air in the pleural space, which is being displaced by cardiac contractions during the cardiac cycle. Although typically small, pneumothoraces have a good prognosis. Recognition of the Hamman sign is important, and physicians must realize that even a normal chest X-ray does not rule out the diagnosis.

Traditionally, a physician develops a differential diagnosis based primarily (>70%) on the history and the physical examination of a patient.¹ While modern medicine has developed with new technological devices and a growing number of diagnostic tests, one must not forget the value of a thorough physical examination.

Case

A 21-year-old woman, in previous good health, presented to the ED with the chief complaint of shortness of breath. She stated that she woke up with acute dyspnea and a stabbing pain on the left side of her thorax, related to her breathing. The patient looked distressed upon presentation.

Her vital signs at presentation were: blood pressure, 150/85 mm Hg; heart rate, 120 beats/min; respiratory rate, 22 breaths/min; and temperature, 100.6°F. Oxygen saturation was 100% on room air.

During physical examination, a loud ticking noise was heard originating from the thorax, even without a stethoscope (an example of the sound can be heard at https://www.youtube.com/watch?v=mXJHtJeL1mM). During auscultation, the ticking noise was prominent in early systole and audible over all parts of the thorax. The sound was only heard when the patient was in the supine position and disappeared when she sat up. It persisted when the patient was holding her breath. Breath sounds were equal and clear bilaterally. There was no subcutaneous emphysema palpable over the thorax or neck region.

Discussion

These loud intermittent noises originating from the thorax were described for the first time at the beginning of the 19th century.^2,3 However, it was Louis Virgil Hamman whose name would be linked to this physical examination finding. In 1937 he described typical clicking, crackling, and popping sounds over the precordium, synchronized with the heartbeat. This was usually in combination with subcutaneous emphysema in the neck region. Hamman presumed that the symptoms were due to mediastinal air caused by rupture alveoli or bronchioles, resulting in interstitial emphysema of the lung parenchyma. In addition, air could leak into the pleural space, causing a pneumothorax. He concluded that the clinical findings were pathognomonic for spontaneous mediastinal emphysema, and this physical examination finding became known as the “Hamman sign”.^4-11

Conclusion

The Hamman sign is a rare clinical examination finding in left-sided pneumothorax or pneumomediastinum, in which a ticking or crackling noise is heard over the thorax. This is mostly synchronous with the heartbeat and not related to respiration. It is caused by a small amount of accumulated air in the pleural space, which is being displaced by cardiac contractions during the cardiac cycle. Although typically small, pneumothoraces have a good prognosis. Recognition of the Hamman sign is important, and physicians must realize that even a normal chest X-ray does not rule out the diagnosis.

More patients had newly diagnosed HIV and hepatitis C virus (HCV) infection during an automated-laboratory-order HIV/HCV screening algorithm than with a nurse-order HIV/HCV screening algorithm, according to the results of a retrospective before/after comparison study of the two electronic health record (EHR)–based protocols.

©Getty Images

The results of nurse-order HIV/HCV screening in the 5-month period of March 1, 2016, through July 31, 2016, were compared to the subsequently adopted automated-laboratory-order system results from March 1, 2017, through July 31, 2017, according to Douglas A.E. White, MD, and his colleagues at Highland Hospital Emergency Department, Oakland, Calif.

Via the EHR, nurses were instructed to offer screening to all adults aged 18-75 years unless they were known to be HIV- or HCV-positive, unable to verbally consent (e.g., language barriers, intoxication), or medically unstable. Exclusion was at the discretion of the triage nurse. Using a drop-down menu, nurses could choose “accepts” or “declines” for HIV and HCV testing, according to patient response. Choosing “accepts” automatically ordered the test, according to the report (Ann Emerg Med. 2018 Oct;72[4]:438-48).

Automated-laboratory-order HIV/HCV screening was integrated into clinical care. With this protocol, the EHR-automated annual HIV/hepatitis C virus screening was performed on adult patients aged 18-75 years who had laboratory tests ordered. The EHR was configured to automatically order an HIV or HCV test for age-eligible patients who had any test ordered that required laboratory processing of whole blood (excluding point-of-care tests such as for lactate or glucose level) or a urine or urethral swab for chlamydia or gonorrhea testing, according to the researchers.

There were 20,975 and 19,887 unique, age-eligible patients during the nurse-order HIV/HCV virus screening algorithm and automated-laboratory-order HIV/HCV screening algorithm study periods, respectively. A total of 4,121 patients (19.6%) were screened for HIV and 2,968 (14.2%) patients were screened for HCV during the nurse-order period vs. 6,736 (33.9%) patients screened for HIV and 6,972 (35.1%) screened for HCV during the automated-laboratory-order period.

Overall, HIV screening increased from 19.6% to 33.9% and HCV screening, from 14.2% to 35.1% using the automated vs. the nurse-ordered EHR-based algorithm.

“An automated electronic health record algorithm that links nontargeted opt-out HIV and hepatitis C virus screening to physician laboratory ordering more effectively screens ED patients, provides results before discharge, minimizes repeated screening, and diagnoses more new infections than an algorithm that relies on nursing staff to offer screening. Because most EDs in the United States now use EHR systems, this model can be easily replicated and should be considered the standard for future programs,” the researchers concluded.

This work was supported, in part, by grant funding through the FOCUS program, Gilead Sciences, which also has provided funding to various of the authors of the study.

[email protected]

SOURCE: White DAE et al. Ann Emerg Med. 2018 Oct;72[4]:438-48.

More patients had newly diagnosed HIV and hepatitis C virus (HCV) infection during an automated-laboratory-order HIV/HCV screening algorithm than with a nurse-order HIV/HCV screening algorithm, according to the results of a retrospective before/after comparison study of the two electronic health record (EHR)–based protocols.

©Getty Images

The results of nurse-order HIV/HCV screening in the 5-month period of March 1, 2016, through July 31, 2016, were compared to the subsequently adopted automated-laboratory-order system results from March 1, 2017, through July 31, 2017, according to Douglas A.E. White, MD, and his colleagues at Highland Hospital Emergency Department, Oakland, Calif.

Via the EHR, nurses were instructed to offer screening to all adults aged 18-75 years unless they were known to be HIV- or HCV-positive, unable to verbally consent (e.g., language barriers, intoxication), or medically unstable. Exclusion was at the discretion of the triage nurse. Using a drop-down menu, nurses could choose “accepts” or “declines” for HIV and HCV testing, according to patient response. Choosing “accepts” automatically ordered the test, according to the report (Ann Emerg Med. 2018 Oct;72[4]:438-48).

Automated-laboratory-order HIV/HCV screening was integrated into clinical care. With this protocol, the EHR-automated annual HIV/hepatitis C virus screening was performed on adult patients aged 18-75 years who had laboratory tests ordered. The EHR was configured to automatically order an HIV or HCV test for age-eligible patients who had any test ordered that required laboratory processing of whole blood (excluding point-of-care tests such as for lactate or glucose level) or a urine or urethral swab for chlamydia or gonorrhea testing, according to the researchers.

There were 20,975 and 19,887 unique, age-eligible patients during the nurse-order HIV/HCV virus screening algorithm and automated-laboratory-order HIV/HCV screening algorithm study periods, respectively. A total of 4,121 patients (19.6%) were screened for HIV and 2,968 (14.2%) patients were screened for HCV during the nurse-order period vs. 6,736 (33.9%) patients screened for HIV and 6,972 (35.1%) screened for HCV during the automated-laboratory-order period.

Overall, HIV screening increased from 19.6% to 33.9% and HCV screening, from 14.2% to 35.1% using the automated vs. the nurse-ordered EHR-based algorithm.

“An automated electronic health record algorithm that links nontargeted opt-out HIV and hepatitis C virus screening to physician laboratory ordering more effectively screens ED patients, provides results before discharge, minimizes repeated screening, and diagnoses more new infections than an algorithm that relies on nursing staff to offer screening. Because most EDs in the United States now use EHR systems, this model can be easily replicated and should be considered the standard for future programs,” the researchers concluded.

This work was supported, in part, by grant funding through the FOCUS program, Gilead Sciences, which also has provided funding to various of the authors of the study.

[email protected]

SOURCE: White DAE et al. Ann Emerg Med. 2018 Oct;72[4]:438-48.

More patients had newly diagnosed HIV and hepatitis C virus (HCV) infection during an automated-laboratory-order HIV/HCV screening algorithm than with a nurse-order HIV/HCV screening algorithm, according to the results of a retrospective before/after comparison study of the two electronic health record (EHR)–based protocols.

©Getty Images

The results of nurse-order HIV/HCV screening in the 5-month period of March 1, 2016, through July 31, 2016, were compared to the subsequently adopted automated-laboratory-order system results from March 1, 2017, through July 31, 2017, according to Douglas A.E. White, MD, and his colleagues at Highland Hospital Emergency Department, Oakland, Calif.

Via the EHR, nurses were instructed to offer screening to all adults aged 18-75 years unless they were known to be HIV- or HCV-positive, unable to verbally consent (e.g., language barriers, intoxication), or medically unstable. Exclusion was at the discretion of the triage nurse. Using a drop-down menu, nurses could choose “accepts” or “declines” for HIV and HCV testing, according to patient response. Choosing “accepts” automatically ordered the test, according to the report (Ann Emerg Med. 2018 Oct;72[4]:438-48).

Automated-laboratory-order HIV/HCV screening was integrated into clinical care. With this protocol, the EHR-automated annual HIV/hepatitis C virus screening was performed on adult patients aged 18-75 years who had laboratory tests ordered. The EHR was configured to automatically order an HIV or HCV test for age-eligible patients who had any test ordered that required laboratory processing of whole blood (excluding point-of-care tests such as for lactate or glucose level) or a urine or urethral swab for chlamydia or gonorrhea testing, according to the researchers.

There were 20,975 and 19,887 unique, age-eligible patients during the nurse-order HIV/HCV virus screening algorithm and automated-laboratory-order HIV/HCV screening algorithm study periods, respectively. A total of 4,121 patients (19.6%) were screened for HIV and 2,968 (14.2%) patients were screened for HCV during the nurse-order period vs. 6,736 (33.9%) patients screened for HIV and 6,972 (35.1%) screened for HCV during the automated-laboratory-order period.

Overall, HIV screening increased from 19.6% to 33.9% and HCV screening, from 14.2% to 35.1% using the automated vs. the nurse-ordered EHR-based algorithm.

“An automated electronic health record algorithm that links nontargeted opt-out HIV and hepatitis C virus screening to physician laboratory ordering more effectively screens ED patients, provides results before discharge, minimizes repeated screening, and diagnoses more new infections than an algorithm that relies on nursing staff to offer screening. Because most EDs in the United States now use EHR systems, this model can be easily replicated and should be considered the standard for future programs,” the researchers concluded.

This work was supported, in part, by grant funding through the FOCUS program, Gilead Sciences, which also has provided funding to various of the authors of the study.

[email protected]

SOURCE: White DAE et al. Ann Emerg Med. 2018 Oct;72[4]:438-48.

CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.

“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.

“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”

Dr. Kornik showed a chart of the many conditions that cause vaginal or vulvar pruritus, falling within a variety of categories: inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.

Contact dermatitis

The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.

Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.

• Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
• Laundry products, such as fabric softeners or dryer sheets.
• Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
• Over-the-counter itch products, such as those containing benzocaine.
• Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
• Heat-related irritants, such as use of hair dryers and heating pads.
• Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.

It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”

She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).

“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”

The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.

“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”

Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.

One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.

Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.

Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.

Lichen sclerosus

Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.

“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”

Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.

There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*

If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*

Lichen simplex chronicus

Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.

Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.

Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.

Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.

If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.

Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.

Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.

She reported no financial disclosures.

Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.

CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.

“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.

“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”

Dr. Kornik showed a chart of the many conditions that cause vaginal or vulvar pruritus, falling within a variety of categories: inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.

Contact dermatitis

The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.

Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.

• Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
• Laundry products, such as fabric softeners or dryer sheets.
• Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
• Over-the-counter itch products, such as those containing benzocaine.
• Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
• Heat-related irritants, such as use of hair dryers and heating pads.
• Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.

It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”

She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).

“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”

The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.

“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”

Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.

One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.

Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.

Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.

Lichen sclerosus

Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.

“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”

Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.

There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*

If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*

Lichen simplex chronicus

Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.

Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.

Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.

Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.

If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.

Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.

Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.

She reported no financial disclosures.

Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.

CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.

“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.

“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”

Dr. Kornik showed a chart of the many conditions that cause vaginal or vulvar pruritus, falling within a variety of categories: inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.

Contact dermatitis

The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.

Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.

• Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
• Laundry products, such as fabric softeners or dryer sheets.
• Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
• Over-the-counter itch products, such as those containing benzocaine.
• Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
• Heat-related irritants, such as use of hair dryers and heating pads.
• Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.

It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”

She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).

“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”

The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.

“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”

Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.

One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.

Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.

Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.

Lichen sclerosus

Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.

“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”

Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.

There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*

If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*

Lichen simplex chronicus

Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.

Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.

Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.

Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.

If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.

Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.

Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.

She reported no financial disclosures.

Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.

PHILADELPHIA – A low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet was associated with improvement in fecal incontinence in 64.6% of patients who received dietary training, according to recent research presented at the American College of Gastroenterology annual meeting.

Jeff Craven/MDedge News

“In this case series, the low-FODMAP diet improved fecal incontinence in two-thirds of patients with fecal incontinence and loose stools,” Stacy Menees, MD, MS, assistant professor at the University of Michigan in Ann Arbor, said in her presentation.

Dr. Menees and her colleagues performed a retrospective chart review of 65 patients in the Michigan Bowel Control clinic with fecal incontinence (FI) “without alarming features” who were recommended a low FODMAP diet and received formal dietary teaching between August 2012 and December 2017. Patients received the teaching from a Michigan Medicine gastrointestinal dietitian. The dietitians performed a semi-quantitative analysis of patient response, including complete response, Dr. Menees said.

If we are going to help people with fecal incontinence, the key is to concentrate on the area of their stool consistency,” she explained. “We know that foods high in fermentable oligo-, di-, and monosaccharides and polyols, otherwise known as FODMAPS, can cause diarrhea and urgency.”

These FODMAP foods can include fruits with fructose exceeding glucose, fructan-containing vegetables, wheat-based products, sorbitol- and lactose-containing foods, and raffinose-containing foods, Dr. Menees said.

“We know from observations in data and research from the Monash University and our own group that patients with irritable bowel syndrome who are on a [low-]FODMAP diet [get relief from] their symptoms,” she added.

Most of the patients were female, and most were white. The mean age was 61.9 years, and mean body mass index was 26.7 kg/m². Among the patients, 27.7% had irritable bowel syndrome (IBS), 9.2% had inflammatory bowel disease (IBD), 16.9% had diabetes mellitus, and 20% had a prior cholecystectomy.

With regard to reports of loose stool and FI, 46.1% of patients said they had loose stool daily with a mean of 2.8 loose bowel movements daily. More than half of the patients (60.5%) reported FI daily; 37.8% said they experienced weekly FI, and 4.6% reported monthly FI. The number of patients reporting FI was higher than 100% because some patients reported in the chart that they had FI daily or weekly, Dr. Menees said.

FI improvement was reported by 64.6% of patients, with 88.1% of responders having a greater than 50% reduction in FI and 35.7% of patients experiencing complete resolution of FI. There were no serious adverse events in the study, Dr. Menees noted.

“The three patients with postinfection IBS and fecal incontinence had no response to a low-FODMAP diet,” she said. “Our dietitians noted that onion and garlic were the triggers that were most often identified.”

Limitations include the retrospective chart review design and small number of patients, which may overestimate or underestimate the study results, and the fact that the study was done at a tertiary care center, Dr. Menees said.

“We are nearing the completion of a confirmatory, prospective, pilot randomized clinical trial to confirm the efficacy of a low-FODMAP diet in patients who suffer from fecal incontinence and loose stools,” she concluded.

Dr. Menees reports being a consultant for Synergy.

Use AGA’s patient education materials to help your patients better understand the low-FODMAP diet, which can be found at http://ow.ly/Xfqj30maODu

SOURCE: Menees SB et al. ACG 2018. Presentation 9.

PHILADELPHIA – A low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet was associated with improvement in fecal incontinence in 64.6% of patients who received dietary training, according to recent research presented at the American College of Gastroenterology annual meeting.

Jeff Craven/MDedge News

“In this case series, the low-FODMAP diet improved fecal incontinence in two-thirds of patients with fecal incontinence and loose stools,” Stacy Menees, MD, MS, assistant professor at the University of Michigan in Ann Arbor, said in her presentation.

Dr. Menees and her colleagues performed a retrospective chart review of 65 patients in the Michigan Bowel Control clinic with fecal incontinence (FI) “without alarming features” who were recommended a low FODMAP diet and received formal dietary teaching between August 2012 and December 2017. Patients received the teaching from a Michigan Medicine gastrointestinal dietitian. The dietitians performed a semi-quantitative analysis of patient response, including complete response, Dr. Menees said.

If we are going to help people with fecal incontinence, the key is to concentrate on the area of their stool consistency,” she explained. “We know that foods high in fermentable oligo-, di-, and monosaccharides and polyols, otherwise known as FODMAPS, can cause diarrhea and urgency.”

These FODMAP foods can include fruits with fructose exceeding glucose, fructan-containing vegetables, wheat-based products, sorbitol- and lactose-containing foods, and raffinose-containing foods, Dr. Menees said.

“We know from observations in data and research from the Monash University and our own group that patients with irritable bowel syndrome who are on a [low-]FODMAP diet [get relief from] their symptoms,” she added.

Most of the patients were female, and most were white. The mean age was 61.9 years, and mean body mass index was 26.7 kg/m². Among the patients, 27.7% had irritable bowel syndrome (IBS), 9.2% had inflammatory bowel disease (IBD), 16.9% had diabetes mellitus, and 20% had a prior cholecystectomy.

With regard to reports of loose stool and FI, 46.1% of patients said they had loose stool daily with a mean of 2.8 loose bowel movements daily. More than half of the patients (60.5%) reported FI daily; 37.8% said they experienced weekly FI, and 4.6% reported monthly FI. The number of patients reporting FI was higher than 100% because some patients reported in the chart that they had FI daily or weekly, Dr. Menees said.

FI improvement was reported by 64.6% of patients, with 88.1% of responders having a greater than 50% reduction in FI and 35.7% of patients experiencing complete resolution of FI. There were no serious adverse events in the study, Dr. Menees noted.

“The three patients with postinfection IBS and fecal incontinence had no response to a low-FODMAP diet,” she said. “Our dietitians noted that onion and garlic were the triggers that were most often identified.”

Limitations include the retrospective chart review design and small number of patients, which may overestimate or underestimate the study results, and the fact that the study was done at a tertiary care center, Dr. Menees said.

“We are nearing the completion of a confirmatory, prospective, pilot randomized clinical trial to confirm the efficacy of a low-FODMAP diet in patients who suffer from fecal incontinence and loose stools,” she concluded.

Dr. Menees reports being a consultant for Synergy.

Use AGA’s patient education materials to help your patients better understand the low-FODMAP diet, which can be found at http://ow.ly/Xfqj30maODu

SOURCE: Menees SB et al. ACG 2018. Presentation 9.

PHILADELPHIA – A low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet was associated with improvement in fecal incontinence in 64.6% of patients who received dietary training, according to recent research presented at the American College of Gastroenterology annual meeting.

Jeff Craven/MDedge News

“In this case series, the low-FODMAP diet improved fecal incontinence in two-thirds of patients with fecal incontinence and loose stools,” Stacy Menees, MD, MS, assistant professor at the University of Michigan in Ann Arbor, said in her presentation.

Dr. Menees and her colleagues performed a retrospective chart review of 65 patients in the Michigan Bowel Control clinic with fecal incontinence (FI) “without alarming features” who were recommended a low FODMAP diet and received formal dietary teaching between August 2012 and December 2017. Patients received the teaching from a Michigan Medicine gastrointestinal dietitian. The dietitians performed a semi-quantitative analysis of patient response, including complete response, Dr. Menees said.

If we are going to help people with fecal incontinence, the key is to concentrate on the area of their stool consistency,” she explained. “We know that foods high in fermentable oligo-, di-, and monosaccharides and polyols, otherwise known as FODMAPS, can cause diarrhea and urgency.”

These FODMAP foods can include fruits with fructose exceeding glucose, fructan-containing vegetables, wheat-based products, sorbitol- and lactose-containing foods, and raffinose-containing foods, Dr. Menees said.

“We know from observations in data and research from the Monash University and our own group that patients with irritable bowel syndrome who are on a [low-]FODMAP diet [get relief from] their symptoms,” she added.

Most of the patients were female, and most were white. The mean age was 61.9 years, and mean body mass index was 26.7 kg/m². Among the patients, 27.7% had irritable bowel syndrome (IBS), 9.2% had inflammatory bowel disease (IBD), 16.9% had diabetes mellitus, and 20% had a prior cholecystectomy.

With regard to reports of loose stool and FI, 46.1% of patients said they had loose stool daily with a mean of 2.8 loose bowel movements daily. More than half of the patients (60.5%) reported FI daily; 37.8% said they experienced weekly FI, and 4.6% reported monthly FI. The number of patients reporting FI was higher than 100% because some patients reported in the chart that they had FI daily or weekly, Dr. Menees said.

FI improvement was reported by 64.6% of patients, with 88.1% of responders having a greater than 50% reduction in FI and 35.7% of patients experiencing complete resolution of FI. There were no serious adverse events in the study, Dr. Menees noted.

“The three patients with postinfection IBS and fecal incontinence had no response to a low-FODMAP diet,” she said. “Our dietitians noted that onion and garlic were the triggers that were most often identified.”

Limitations include the retrospective chart review design and small number of patients, which may overestimate or underestimate the study results, and the fact that the study was done at a tertiary care center, Dr. Menees said.

“We are nearing the completion of a confirmatory, prospective, pilot randomized clinical trial to confirm the efficacy of a low-FODMAP diet in patients who suffer from fecal incontinence and loose stools,” she concluded.

Dr. Menees reports being a consultant for Synergy.

Use AGA’s patient education materials to help your patients better understand the low-FODMAP diet, which can be found at http://ow.ly/Xfqj30maODu

SOURCE: Menees SB et al. ACG 2018. Presentation 9.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

A holiday from bisphosphonates may help reduce atypical femur fracture risk. Also today, most dermatologic drugs are safe for breastfeeding mothers, impressive HbA1c and weight control from a new novel drug, and short-term NSAIDs appear safe for high-risk patients.

A holiday from bisphosphonates may help reduce atypical femur fracture risk. Also today, most dermatologic drugs are safe for breastfeeding mothers, impressive HbA1c and weight control from a new novel drug, and short-term NSAIDs appear safe for high-risk patients.

A holiday from bisphosphonates may help reduce atypical femur fracture risk. Also today, most dermatologic drugs are safe for breastfeeding mothers, impressive HbA1c and weight control from a new novel drug, and short-term NSAIDs appear safe for high-risk patients.

Switching breathing tubes may save more lives. A study funded by the National Heart, Lung, and Blood Institute shows that when a laryngeal tube instead of an endotracheal tube is used to open and access the airway in someone who has suffered cardiac arrest, the patient is more likely to survive.

The Pragmatic Airway Resuscitation Trial, a multicenter study conducted by the Resuscitation Outcomes Consortium, compared survival rates among 3,000 adults treated for cardiac arrest by paramedic crews from 27  emergency medical service (EMS) agencies. In half the cases, the EMS team used the newer laryngeal tube, and the other half used traditional endotracheal intubation.

Outcomes were significantly better in the laryngeal group: 18.3% of patients survived 3 days in the hospital compared with 15.4% of the endotracheal group. Moreover, 10.8% of the laryngeal group survived to discharge compared with 8.1% of the other group. The proportion of patients surviving with good brain function was also higher in the laryngeal group.

Switching breathing tubes may save more lives. A study funded by the National Heart, Lung, and Blood Institute shows that when a laryngeal tube instead of an endotracheal tube is used to open and access the airway in someone who has suffered cardiac arrest, the patient is more likely to survive.

The Pragmatic Airway Resuscitation Trial, a multicenter study conducted by the Resuscitation Outcomes Consortium, compared survival rates among 3,000 adults treated for cardiac arrest by paramedic crews from 27  emergency medical service (EMS) agencies. In half the cases, the EMS team used the newer laryngeal tube, and the other half used traditional endotracheal intubation.

Outcomes were significantly better in the laryngeal group: 18.3% of patients survived 3 days in the hospital compared with 15.4% of the endotracheal group. Moreover, 10.8% of the laryngeal group survived to discharge compared with 8.1% of the other group. The proportion of patients surviving with good brain function was also higher in the laryngeal group.

Switching breathing tubes may save more lives. A study funded by the National Heart, Lung, and Blood Institute shows that when a laryngeal tube instead of an endotracheal tube is used to open and access the airway in someone who has suffered cardiac arrest, the patient is more likely to survive.

The Pragmatic Airway Resuscitation Trial, a multicenter study conducted by the Resuscitation Outcomes Consortium, compared survival rates among 3,000 adults treated for cardiac arrest by paramedic crews from 27  emergency medical service (EMS) agencies. In half the cases, the EMS team used the newer laryngeal tube, and the other half used traditional endotracheal intubation.

Outcomes were significantly better in the laryngeal group: 18.3% of patients survived 3 days in the hospital compared with 15.4% of the endotracheal group. Moreover, 10.8% of the laryngeal group survived to discharge compared with 8.1% of the other group. The proportion of patients surviving with good brain function was also higher in the laryngeal group.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.