A 67-year-old woman presented with multiple painful nodules that had developed on her scalp, face, and neck over the course of 1 year. She also had a few nodules on her trunk and hip. There was no associated bleeding, ulceration, or drainage from the lesions. She had no systemic symptoms. The patient reported that she’d had a similar lesion on her frontal scalp about 15 years earlier, and it was excised completely. (She was not aware of the diagnosis.) She indicated that her mother and son had similar lesions in the past.

Her medical history was remarkable for diabetes and hypertension, which were well controlled on metformin and lisinopril, respectively. The patient had cancer of the left breast that was treated with mastectomy and chemotherapy 3 years prior.

On physical examination, the patient had multiple firm, rubbery, tender nodules with tan or pink hue, measuring 1 to 1.5 cm. The nodules were located on the left side of her chin and right preauricular area (FIGURE 1), as well as the right sides of her neck and hip. Most of the nodules were solitary; the preauricular area had 2 clustered pink lesions. The largest nodule was located on the patient’s chin and had overlying telangiectasias.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Definitive diagnosis was made by shave biopsy of the left hip lesion. Histopathology demonstrated various-sized discrete aggregates of basaloid cell nests in a jigsaw puzzle–like configuration (FIGURE 2), surrounded by rims of homogenous eosinophilic material. Histologic findings were consistent with cylindroma.¹

Rare with a female predominance. Solitary cylindromas occur sporadically and usually affect middle-aged and elderly patients. Incidence is rare, but there is a female predominance of 6 to 9:1.² Clinical appearance shows a slow-growing, firm mass that can range from a few millimeters to a few centimeters in diameter. The masses can have a pink or blue hue and usually are nontender unless there is nerve impingement.²

If multiple tumors are present or the patient has a family history of similar lesions, the disorder is likely inherited in an autosomal dominant pattern (with variable expression), which can be associated with Brooke-Spiegler syndrome. This syndrome is related to a mutation of the cylindromatosis gene on chromosome 16. This is a tumor suppressor gene, inactivation of which can lead to uninhibited action of NF-kB which increases resistance to apoptosis and carcinogenesis.³ This results in production of cylindromas, trichoepitheliomas, and spiradenomas.³

Rarely, cylindromas can undergo malignant transformation; signs include ulceration, bleeding, rapid growth, or color change.² In these cases, appropriate imaging such as computed tomography, magnetic resonance imaging, or positron emission tomography should be sought as there have been case reports of cylindroma extension to bone, as well as metastases to sites including the lymph nodes, thyroid, liver, lungs, bones, and meninges.⁴

Lipomas and pilar cysts comprise the differential

Lipomas are soft, painless, flesh-colored masses that typically appear on the trunk and arms but are uncommon on the face. Telangiectasias are not seen.

Continue to: Pilar cysts

Pilar cysts can mimic cylindromas in clinical presentation. Derived from the root sheath of hair follicles, they typically appear on the scalp but rarely on the face. Pilar cysts are slow growing, firm, and whitish in color⁵; several cysts can appear at a time.

Pilomatricomas are firm skin masses—usually < 3 cm in size—that can vary in color. There may be an extrusion of calcified material within the nodules, which does not occur in cylindromas.

Sebaceous adenomas are yellowish papules, usually < 1 cm in size, that appear on the head and neck area.⁶

Making the diagnosis. The clinical appearance of cylindromas and their location will point to the diagnosis, as will a family history of similar lesions. Ultimately, the diagnosis is confirmed by biopsy.

Treatment mainstay includes excision

Complete excision of all lesions is key due to the possibility of malignant transformation and metastasis. Options for removal include electrodesiccation, curettage, cryosurgery,³ high-dose radiation, and the use of a CO₂ laser.² For multiple large tumors, or ones in cosmetically sensitive areas, consider referral to Dermatology or Plastic Surgery. Further imaging should be sought to rule out extension to bone or metastasis. Patients with multiple cylindromas and Brooke-Spiegler syndrome need lifelong follow-up to monitor for recurrence and malignant transformation.^3,7,8

Continue to: Our patient...

Our patient underwent complete excision of the left hip lesion. Other trunk lesions were excised serially. The patient was referred to a surgeon specializing in Mohs micrographic surgery for excision of the facial lesions. The patient and her family members were referred for genetic testing.

CORRESPONDENCE
Zeeshan Afzal, MD, McAllen Family Medicine Residency Program, University of Texas Rio Grande Valley, 205 E Toronto Ave, McAllen, TX 78503; [email protected]

A 67-year-old woman presented with multiple painful nodules that had developed on her scalp, face, and neck over the course of 1 year. She also had a few nodules on her trunk and hip. There was no associated bleeding, ulceration, or drainage from the lesions. She had no systemic symptoms. The patient reported that she’d had a similar lesion on her frontal scalp about 15 years earlier, and it was excised completely. (She was not aware of the diagnosis.) She indicated that her mother and son had similar lesions in the past.

Her medical history was remarkable for diabetes and hypertension, which were well controlled on metformin and lisinopril, respectively. The patient had cancer of the left breast that was treated with mastectomy and chemotherapy 3 years prior.

On physical examination, the patient had multiple firm, rubbery, tender nodules with tan or pink hue, measuring 1 to 1.5 cm. The nodules were located on the left side of her chin and right preauricular area (FIGURE 1), as well as the right sides of her neck and hip. Most of the nodules were solitary; the preauricular area had 2 clustered pink lesions. The largest nodule was located on the patient’s chin and had overlying telangiectasias.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Definitive diagnosis was made by shave biopsy of the left hip lesion. Histopathology demonstrated various-sized discrete aggregates of basaloid cell nests in a jigsaw puzzle–like configuration (FIGURE 2), surrounded by rims of homogenous eosinophilic material. Histologic findings were consistent with cylindroma.¹

Rare with a female predominance. Solitary cylindromas occur sporadically and usually affect middle-aged and elderly patients. Incidence is rare, but there is a female predominance of 6 to 9:1.² Clinical appearance shows a slow-growing, firm mass that can range from a few millimeters to a few centimeters in diameter. The masses can have a pink or blue hue and usually are nontender unless there is nerve impingement.²

If multiple tumors are present or the patient has a family history of similar lesions, the disorder is likely inherited in an autosomal dominant pattern (with variable expression), which can be associated with Brooke-Spiegler syndrome. This syndrome is related to a mutation of the cylindromatosis gene on chromosome 16. This is a tumor suppressor gene, inactivation of which can lead to uninhibited action of NF-kB which increases resistance to apoptosis and carcinogenesis.³ This results in production of cylindromas, trichoepitheliomas, and spiradenomas.³

Rarely, cylindromas can undergo malignant transformation; signs include ulceration, bleeding, rapid growth, or color change.² In these cases, appropriate imaging such as computed tomography, magnetic resonance imaging, or positron emission tomography should be sought as there have been case reports of cylindroma extension to bone, as well as metastases to sites including the lymph nodes, thyroid, liver, lungs, bones, and meninges.⁴

Lipomas and pilar cysts comprise the differential

Lipomas are soft, painless, flesh-colored masses that typically appear on the trunk and arms but are uncommon on the face. Telangiectasias are not seen.

Continue to: Pilar cysts

Pilar cysts can mimic cylindromas in clinical presentation. Derived from the root sheath of hair follicles, they typically appear on the scalp but rarely on the face. Pilar cysts are slow growing, firm, and whitish in color⁵; several cysts can appear at a time.

Pilomatricomas are firm skin masses—usually < 3 cm in size—that can vary in color. There may be an extrusion of calcified material within the nodules, which does not occur in cylindromas.

Sebaceous adenomas are yellowish papules, usually < 1 cm in size, that appear on the head and neck area.⁶

Making the diagnosis. The clinical appearance of cylindromas and their location will point to the diagnosis, as will a family history of similar lesions. Ultimately, the diagnosis is confirmed by biopsy.

Treatment mainstay includes excision

Complete excision of all lesions is key due to the possibility of malignant transformation and metastasis. Options for removal include electrodesiccation, curettage, cryosurgery,³ high-dose radiation, and the use of a CO₂ laser.² For multiple large tumors, or ones in cosmetically sensitive areas, consider referral to Dermatology or Plastic Surgery. Further imaging should be sought to rule out extension to bone or metastasis. Patients with multiple cylindromas and Brooke-Spiegler syndrome need lifelong follow-up to monitor for recurrence and malignant transformation.^3,7,8

Continue to: Our patient...

Our patient underwent complete excision of the left hip lesion. Other trunk lesions were excised serially. The patient was referred to a surgeon specializing in Mohs micrographic surgery for excision of the facial lesions. The patient and her family members were referred for genetic testing.

CORRESPONDENCE
Zeeshan Afzal, MD, McAllen Family Medicine Residency Program, University of Texas Rio Grande Valley, 205 E Toronto Ave, McAllen, TX 78503; [email protected]

A 67-year-old woman presented with multiple painful nodules that had developed on her scalp, face, and neck over the course of 1 year. She also had a few nodules on her trunk and hip. There was no associated bleeding, ulceration, or drainage from the lesions. She had no systemic symptoms. The patient reported that she’d had a similar lesion on her frontal scalp about 15 years earlier, and it was excised completely. (She was not aware of the diagnosis.) She indicated that her mother and son had similar lesions in the past.

Her medical history was remarkable for diabetes and hypertension, which were well controlled on metformin and lisinopril, respectively. The patient had cancer of the left breast that was treated with mastectomy and chemotherapy 3 years prior.

On physical examination, the patient had multiple firm, rubbery, tender nodules with tan or pink hue, measuring 1 to 1.5 cm. The nodules were located on the left side of her chin and right preauricular area (FIGURE 1), as well as the right sides of her neck and hip. Most of the nodules were solitary; the preauricular area had 2 clustered pink lesions. The largest nodule was located on the patient’s chin and had overlying telangiectasias.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Definitive diagnosis was made by shave biopsy of the left hip lesion. Histopathology demonstrated various-sized discrete aggregates of basaloid cell nests in a jigsaw puzzle–like configuration (FIGURE 2), surrounded by rims of homogenous eosinophilic material. Histologic findings were consistent with cylindroma.¹

Rare with a female predominance. Solitary cylindromas occur sporadically and usually affect middle-aged and elderly patients. Incidence is rare, but there is a female predominance of 6 to 9:1.² Clinical appearance shows a slow-growing, firm mass that can range from a few millimeters to a few centimeters in diameter. The masses can have a pink or blue hue and usually are nontender unless there is nerve impingement.²

If multiple tumors are present or the patient has a family history of similar lesions, the disorder is likely inherited in an autosomal dominant pattern (with variable expression), which can be associated with Brooke-Spiegler syndrome. This syndrome is related to a mutation of the cylindromatosis gene on chromosome 16. This is a tumor suppressor gene, inactivation of which can lead to uninhibited action of NF-kB which increases resistance to apoptosis and carcinogenesis.³ This results in production of cylindromas, trichoepitheliomas, and spiradenomas.³

Rarely, cylindromas can undergo malignant transformation; signs include ulceration, bleeding, rapid growth, or color change.² In these cases, appropriate imaging such as computed tomography, magnetic resonance imaging, or positron emission tomography should be sought as there have been case reports of cylindroma extension to bone, as well as metastases to sites including the lymph nodes, thyroid, liver, lungs, bones, and meninges.⁴

Lipomas and pilar cysts comprise the differential

Lipomas are soft, painless, flesh-colored masses that typically appear on the trunk and arms but are uncommon on the face. Telangiectasias are not seen.

Continue to: Pilar cysts

Pilar cysts can mimic cylindromas in clinical presentation. Derived from the root sheath of hair follicles, they typically appear on the scalp but rarely on the face. Pilar cysts are slow growing, firm, and whitish in color⁵; several cysts can appear at a time.

Pilomatricomas are firm skin masses—usually < 3 cm in size—that can vary in color. There may be an extrusion of calcified material within the nodules, which does not occur in cylindromas.

Sebaceous adenomas are yellowish papules, usually < 1 cm in size, that appear on the head and neck area.⁶

Making the diagnosis. The clinical appearance of cylindromas and their location will point to the diagnosis, as will a family history of similar lesions. Ultimately, the diagnosis is confirmed by biopsy.

Treatment mainstay includes excision

Complete excision of all lesions is key due to the possibility of malignant transformation and metastasis. Options for removal include electrodesiccation, curettage, cryosurgery,³ high-dose radiation, and the use of a CO₂ laser.² For multiple large tumors, or ones in cosmetically sensitive areas, consider referral to Dermatology or Plastic Surgery. Further imaging should be sought to rule out extension to bone or metastasis. Patients with multiple cylindromas and Brooke-Spiegler syndrome need lifelong follow-up to monitor for recurrence and malignant transformation.^3,7,8

Continue to: Our patient...

Our patient underwent complete excision of the left hip lesion. Other trunk lesions were excised serially. The patient was referred to a surgeon specializing in Mohs micrographic surgery for excision of the facial lesions. The patient and her family members were referred for genetic testing.

CORRESPONDENCE
Zeeshan Afzal, MD, McAllen Family Medicine Residency Program, University of Texas Rio Grande Valley, 205 E Toronto Ave, McAllen, TX 78503; [email protected]

Watch Now.

Mantle cell lymphoma (MCL) is a rare, often aggressive form of non-Hodgkin lymphoma that develops when the body makes abnormal B-cells, and it is typically diagnosed at a later stage of disease. In this video series, Dr. Andre Goy sits down with Drs. Matthew Matasar and Peter Martin to discuss diagnosis, treatment, and unmet needs in MCL.

This video roundtable was produced by the Custom Programs division. The faculty received modest honoraria from Custom Programs for participating in this roundtable.

The faculty was solely responsible for the content presented.

Disclosures

Dr. Goy is on the speaker’s bureau and reports grant/research support from Acerta, Genentech, Kite/Gilead, Janssen, Pharmacyclics, and Takeda, and stocks/shares with COTA.

Dr. Matasar reports stock and other ownership interests with Merck; receiving honoraria from Bayer, Genentech, GlaxoSmithKline, Janssen, Pharmacyclics, Roche, and Seattle Genetics; consulting or advisory roles with Bayer, Genentech, Daiichi Sankyo, Juno Therapeutics, Merck, Roche, Rocket Medical, Seattle Genetics, and Teva; and research funding from Bayer, Genentech, GlaxoSmithKline, Janssen, Pharmacyclics, Roche, Rocket Medical, and Seattle Genetics.

Dr. Martin reports consulting for AstraZeneca, Bayer, Celgene, and Janssen.

Watch Now.

Watch Now.

Mantle cell lymphoma (MCL) is a rare, often aggressive form of non-Hodgkin lymphoma that develops when the body makes abnormal B-cells, and it is typically diagnosed at a later stage of disease. In this video series, Dr. Andre Goy sits down with Drs. Matthew Matasar and Peter Martin to discuss diagnosis, treatment, and unmet needs in MCL.

This video roundtable was produced by the Custom Programs division. The faculty received modest honoraria from Custom Programs for participating in this roundtable.

The faculty was solely responsible for the content presented.

Disclosures

Dr. Goy is on the speaker’s bureau and reports grant/research support from Acerta, Genentech, Kite/Gilead, Janssen, Pharmacyclics, and Takeda, and stocks/shares with COTA.

Dr. Matasar reports stock and other ownership interests with Merck; receiving honoraria from Bayer, Genentech, GlaxoSmithKline, Janssen, Pharmacyclics, Roche, and Seattle Genetics; consulting or advisory roles with Bayer, Genentech, Daiichi Sankyo, Juno Therapeutics, Merck, Roche, Rocket Medical, Seattle Genetics, and Teva; and research funding from Bayer, Genentech, GlaxoSmithKline, Janssen, Pharmacyclics, Roche, Rocket Medical, and Seattle Genetics.

Dr. Martin reports consulting for AstraZeneca, Bayer, Celgene, and Janssen.

Watch Now.

Watch Now.

Mantle cell lymphoma (MCL) is a rare, often aggressive form of non-Hodgkin lymphoma that develops when the body makes abnormal B-cells, and it is typically diagnosed at a later stage of disease. In this video series, Dr. Andre Goy sits down with Drs. Matthew Matasar and Peter Martin to discuss diagnosis, treatment, and unmet needs in MCL.

This video roundtable was produced by the Custom Programs division. The faculty received modest honoraria from Custom Programs for participating in this roundtable.

The faculty was solely responsible for the content presented.

Disclosures

Dr. Goy is on the speaker’s bureau and reports grant/research support from Acerta, Genentech, Kite/Gilead, Janssen, Pharmacyclics, and Takeda, and stocks/shares with COTA.

Dr. Matasar reports stock and other ownership interests with Merck; receiving honoraria from Bayer, Genentech, GlaxoSmithKline, Janssen, Pharmacyclics, Roche, and Seattle Genetics; consulting or advisory roles with Bayer, Genentech, Daiichi Sankyo, Juno Therapeutics, Merck, Roche, Rocket Medical, Seattle Genetics, and Teva; and research funding from Bayer, Genentech, GlaxoSmithKline, Janssen, Pharmacyclics, Roche, Rocket Medical, and Seattle Genetics.

Dr. Martin reports consulting for AstraZeneca, Bayer, Celgene, and Janssen.

Watch Now.

PHILADELPHIA – A disproportionate number of breakthrough strokes were observed among patients receiving rivaroxaban for nonvalvular atrial fibrillation in a stroke unit, according to a small, single-center, retrospective study presented at the annual meeting of the American Academy of Neurology.

The researchers reviewed all patients presenting to a tertiary care stroke unit in Australia from January 2015 to June 2018.

A total of 56 patients (median age was 74 years; 61% were male) had received direct oral anticoagulant (DOAC) therapy and then had an ischemic stroke. Of those patients, 37 (66%) had strokes while receiving the treatment; 14 patients (25%) had a stroke after recently stopping a DOAC, often prior to a medical procedure; and 5 patients (9%) were not adherent to their DOAC regimen.

Of the 37 patients who had strokes during DOAC treatment, 48% were on rivaroxaban, 9% were on dabigatran, and 9% were on apixaban, Fiona Chan, MD, of The Princess Alexandra Hospital, Brisbane, Australia, and coinvestigators reported in a poster presentation.

While these findings need to be replicated in a larger study, they do “raise concern for inadequate stroke prevention within this cohort,” they said.

Moreover, the findings illustrate the importance of bridging anticoagulation prior to procedures, when appropriate, to minimize stroke risk, they added, as 25% of the strokes had occurred in patients who recently stopped the DOACs due to procedures.

To determine which DOAC was most often associated with breakthrough ischemic strokes in patients with nonvalvular atrial fibrillation, the investigators compared the proportion of DOACs prescribed in Australia to the proportion of observed strokes in their cohort.

Despite accounting for about 51% of Australian DOAC prescriptions, rivaroxaban represented nearly 73% of breakthrough strokes among the patients who had strokes while receiving the treatment (P = .001), the investigators reported.

Conversely, apixaban accounted for about 35% of prescriptions but 14% of the breakthrough strokes (P = .0007), while dabigatran accounted for 14% of prescriptions and 14% of the strokes (P = 0.99), the investigators said in their poster.

One limitation of this retrospective study is that the patient cohort came from a single specialized center, and may not reflect the true incidence of nonvalvular atrial fibrillation across Australia, the researchers noted.

Dr. Chan and coinvestigators reported that they had no relevant financial disclosures.

SOURCE: Chan F et al. AAN 2019. P1.3-001.

PHILADELPHIA – A disproportionate number of breakthrough strokes were observed among patients receiving rivaroxaban for nonvalvular atrial fibrillation in a stroke unit, according to a small, single-center, retrospective study presented at the annual meeting of the American Academy of Neurology.

The researchers reviewed all patients presenting to a tertiary care stroke unit in Australia from January 2015 to June 2018.

A total of 56 patients (median age was 74 years; 61% were male) had received direct oral anticoagulant (DOAC) therapy and then had an ischemic stroke. Of those patients, 37 (66%) had strokes while receiving the treatment; 14 patients (25%) had a stroke after recently stopping a DOAC, often prior to a medical procedure; and 5 patients (9%) were not adherent to their DOAC regimen.

Of the 37 patients who had strokes during DOAC treatment, 48% were on rivaroxaban, 9% were on dabigatran, and 9% were on apixaban, Fiona Chan, MD, of The Princess Alexandra Hospital, Brisbane, Australia, and coinvestigators reported in a poster presentation.

While these findings need to be replicated in a larger study, they do “raise concern for inadequate stroke prevention within this cohort,” they said.

Moreover, the findings illustrate the importance of bridging anticoagulation prior to procedures, when appropriate, to minimize stroke risk, they added, as 25% of the strokes had occurred in patients who recently stopped the DOACs due to procedures.

To determine which DOAC was most often associated with breakthrough ischemic strokes in patients with nonvalvular atrial fibrillation, the investigators compared the proportion of DOACs prescribed in Australia to the proportion of observed strokes in their cohort.

Despite accounting for about 51% of Australian DOAC prescriptions, rivaroxaban represented nearly 73% of breakthrough strokes among the patients who had strokes while receiving the treatment (P = .001), the investigators reported.

Conversely, apixaban accounted for about 35% of prescriptions but 14% of the breakthrough strokes (P = .0007), while dabigatran accounted for 14% of prescriptions and 14% of the strokes (P = 0.99), the investigators said in their poster.

One limitation of this retrospective study is that the patient cohort came from a single specialized center, and may not reflect the true incidence of nonvalvular atrial fibrillation across Australia, the researchers noted.

Dr. Chan and coinvestigators reported that they had no relevant financial disclosures.

SOURCE: Chan F et al. AAN 2019. P1.3-001.

PHILADELPHIA – A disproportionate number of breakthrough strokes were observed among patients receiving rivaroxaban for nonvalvular atrial fibrillation in a stroke unit, according to a small, single-center, retrospective study presented at the annual meeting of the American Academy of Neurology.

The researchers reviewed all patients presenting to a tertiary care stroke unit in Australia from January 2015 to June 2018.

A total of 56 patients (median age was 74 years; 61% were male) had received direct oral anticoagulant (DOAC) therapy and then had an ischemic stroke. Of those patients, 37 (66%) had strokes while receiving the treatment; 14 patients (25%) had a stroke after recently stopping a DOAC, often prior to a medical procedure; and 5 patients (9%) were not adherent to their DOAC regimen.

Of the 37 patients who had strokes during DOAC treatment, 48% were on rivaroxaban, 9% were on dabigatran, and 9% were on apixaban, Fiona Chan, MD, of The Princess Alexandra Hospital, Brisbane, Australia, and coinvestigators reported in a poster presentation.

While these findings need to be replicated in a larger study, they do “raise concern for inadequate stroke prevention within this cohort,” they said.

Moreover, the findings illustrate the importance of bridging anticoagulation prior to procedures, when appropriate, to minimize stroke risk, they added, as 25% of the strokes had occurred in patients who recently stopped the DOACs due to procedures.

To determine which DOAC was most often associated with breakthrough ischemic strokes in patients with nonvalvular atrial fibrillation, the investigators compared the proportion of DOACs prescribed in Australia to the proportion of observed strokes in their cohort.

Despite accounting for about 51% of Australian DOAC prescriptions, rivaroxaban represented nearly 73% of breakthrough strokes among the patients who had strokes while receiving the treatment (P = .001), the investigators reported.

Conversely, apixaban accounted for about 35% of prescriptions but 14% of the breakthrough strokes (P = .0007), while dabigatran accounted for 14% of prescriptions and 14% of the strokes (P = 0.99), the investigators said in their poster.

One limitation of this retrospective study is that the patient cohort came from a single specialized center, and may not reflect the true incidence of nonvalvular atrial fibrillation across Australia, the researchers noted.

Dr. Chan and coinvestigators reported that they had no relevant financial disclosures.

SOURCE: Chan F et al. AAN 2019. P1.3-001.

Philadelphia – Adoptive transfer of donor-derived T cells represents a potentially life-saving treatment of severely immunocompromised patients with progressive multifocal leukoencephalopathy (PML).

Courtesy NIH/NINDS

“We think this strategy has real potential to be one of the first effective treatments for PML,” Erin Beck, MD, PhD, said during a press conference at the annual meeting of the American Academy of Neurology.

In a pilot study including 12 patients with PML, the 7 who survived had substantial neurological improvement after treatment with this immunotherapeutic approach, said Dr. Beck of the National Institute of Neurological Disorders and Stroke.

“This was very encouraging to us because these patients were worsening at the time of their treatment and we did not expect them to do well,” she said.

There were no serious adverse events related to treatment, which suggests the approach is safe for patients with PML, according to Dr. Beck.

“This is a phenomenal breakthrough,” Natalia S. Rost, MD, MPH, chair of the meeting’s science committee, said at the press conference. “Giving a diagnosis of PML to a patient is basically giving them a death sentence, and it’s one of the most dreaded scenarios in our clinical practice.”

PML, an opportunistic infection of the central nervous system caused by JC polyomavirus, is usually fatal unless adaptive immunity to JC polyomavirus can be restored, Dr. Beck said.

Cases of PML surged in the 1980s and 1990s as a result of the HIV/AIDS epidemic, she said, and an increase in cases has been observed more recently related to new immunosuppressive treatments for cancer and autoimmune diseases.

The pilot study described by Dr. Beck included 12 patients with refractory PML who underwent adoptive transfer of polyomavirus-specific T cells (PyVSTs) that were generated from partially matched first-degree relatives of the patients. Up to three infusions were given at least 28 days apart.

Although five patients died of PML, the remaining seven patients stabilized and in some cases experienced significant neurological improvement, according to the investigators. Two of the seven died of PML a year after their final infusion.

No overt immune reconstitution inflammatory syndrome (IRIS) was observed in treated patients.

It’s not clear to date which PML patients may be most likely to benefit from this treatment approach because there were no differences in age, sex, baseline leukocyte count numbers, or time since their initial diagnosis between responders and nonresponders, Dr. Beck said.

However, patients who died tended to have much higher JC virus copy numbers in their spinal fluid, as did some patients who were enrolled but died before they could receive any treatment, she added.

“That high range, I think, is a very bad prognostic sign,” Dr. Beck said. “A number in the lower range doesn’t mean a good prognosis, but it means potentially that you could respond to a treatment such as this one.”

The study was funded by National Institute of Neurological Disorders and Stroke. The investigators disclosed no conflicts related to the study.

SOURCE: Cortese I et al. AAN 2019, Abstract Plen01.002.

Philadelphia – Adoptive transfer of donor-derived T cells represents a potentially life-saving treatment of severely immunocompromised patients with progressive multifocal leukoencephalopathy (PML).

Courtesy NIH/NINDS

“We think this strategy has real potential to be one of the first effective treatments for PML,” Erin Beck, MD, PhD, said during a press conference at the annual meeting of the American Academy of Neurology.

In a pilot study including 12 patients with PML, the 7 who survived had substantial neurological improvement after treatment with this immunotherapeutic approach, said Dr. Beck of the National Institute of Neurological Disorders and Stroke.

“This was very encouraging to us because these patients were worsening at the time of their treatment and we did not expect them to do well,” she said.

There were no serious adverse events related to treatment, which suggests the approach is safe for patients with PML, according to Dr. Beck.

“This is a phenomenal breakthrough,” Natalia S. Rost, MD, MPH, chair of the meeting’s science committee, said at the press conference. “Giving a diagnosis of PML to a patient is basically giving them a death sentence, and it’s one of the most dreaded scenarios in our clinical practice.”

PML, an opportunistic infection of the central nervous system caused by JC polyomavirus, is usually fatal unless adaptive immunity to JC polyomavirus can be restored, Dr. Beck said.

Cases of PML surged in the 1980s and 1990s as a result of the HIV/AIDS epidemic, she said, and an increase in cases has been observed more recently related to new immunosuppressive treatments for cancer and autoimmune diseases.

The pilot study described by Dr. Beck included 12 patients with refractory PML who underwent adoptive transfer of polyomavirus-specific T cells (PyVSTs) that were generated from partially matched first-degree relatives of the patients. Up to three infusions were given at least 28 days apart.

Although five patients died of PML, the remaining seven patients stabilized and in some cases experienced significant neurological improvement, according to the investigators. Two of the seven died of PML a year after their final infusion.

No overt immune reconstitution inflammatory syndrome (IRIS) was observed in treated patients.

It’s not clear to date which PML patients may be most likely to benefit from this treatment approach because there were no differences in age, sex, baseline leukocyte count numbers, or time since their initial diagnosis between responders and nonresponders, Dr. Beck said.

However, patients who died tended to have much higher JC virus copy numbers in their spinal fluid, as did some patients who were enrolled but died before they could receive any treatment, she added.

“That high range, I think, is a very bad prognostic sign,” Dr. Beck said. “A number in the lower range doesn’t mean a good prognosis, but it means potentially that you could respond to a treatment such as this one.”

The study was funded by National Institute of Neurological Disorders and Stroke. The investigators disclosed no conflicts related to the study.

SOURCE: Cortese I et al. AAN 2019, Abstract Plen01.002.

Philadelphia – Adoptive transfer of donor-derived T cells represents a potentially life-saving treatment of severely immunocompromised patients with progressive multifocal leukoencephalopathy (PML).

Courtesy NIH/NINDS

“We think this strategy has real potential to be one of the first effective treatments for PML,” Erin Beck, MD, PhD, said during a press conference at the annual meeting of the American Academy of Neurology.

In a pilot study including 12 patients with PML, the 7 who survived had substantial neurological improvement after treatment with this immunotherapeutic approach, said Dr. Beck of the National Institute of Neurological Disorders and Stroke.

“This was very encouraging to us because these patients were worsening at the time of their treatment and we did not expect them to do well,” she said.

There were no serious adverse events related to treatment, which suggests the approach is safe for patients with PML, according to Dr. Beck.

“This is a phenomenal breakthrough,” Natalia S. Rost, MD, MPH, chair of the meeting’s science committee, said at the press conference. “Giving a diagnosis of PML to a patient is basically giving them a death sentence, and it’s one of the most dreaded scenarios in our clinical practice.”

PML, an opportunistic infection of the central nervous system caused by JC polyomavirus, is usually fatal unless adaptive immunity to JC polyomavirus can be restored, Dr. Beck said.

Cases of PML surged in the 1980s and 1990s as a result of the HIV/AIDS epidemic, she said, and an increase in cases has been observed more recently related to new immunosuppressive treatments for cancer and autoimmune diseases.

The pilot study described by Dr. Beck included 12 patients with refractory PML who underwent adoptive transfer of polyomavirus-specific T cells (PyVSTs) that were generated from partially matched first-degree relatives of the patients. Up to three infusions were given at least 28 days apart.

Although five patients died of PML, the remaining seven patients stabilized and in some cases experienced significant neurological improvement, according to the investigators. Two of the seven died of PML a year after their final infusion.

No overt immune reconstitution inflammatory syndrome (IRIS) was observed in treated patients.

It’s not clear to date which PML patients may be most likely to benefit from this treatment approach because there were no differences in age, sex, baseline leukocyte count numbers, or time since their initial diagnosis between responders and nonresponders, Dr. Beck said.

However, patients who died tended to have much higher JC virus copy numbers in their spinal fluid, as did some patients who were enrolled but died before they could receive any treatment, she added.

“That high range, I think, is a very bad prognostic sign,” Dr. Beck said. “A number in the lower range doesn’t mean a good prognosis, but it means potentially that you could respond to a treatment such as this one.”

The study was funded by National Institute of Neurological Disorders and Stroke. The investigators disclosed no conflicts related to the study.

SOURCE: Cortese I et al. AAN 2019, Abstract Plen01.002.

The number of U.S. measles cases in 2019 rose by 60 during the week ending May 3, which puts the new postelimination high at 764 cases for the year, according to the Centers for Disease Control and Prevention.

The CDC is currently tracking nine measles outbreaks in six states. The largest outbreak this year has been in New York City, mainly Brooklyn, which has almost half (367) of all cases in the country. An outbreak in New York’s Rockland County has resulted in another 109 cases so far this year. California is experiencing outbreaks in three counties – Butte, Los Angeles, and Sacramento – and the state was up to 40 confirmed cases as of May 1. The other states with outbreaks are Michigan, New Jersey, Georgia, and Maryland.

Twenty-three states now have reported measles cases in 2019, as officials in Pittsburgh reported Pennsylvania’s first case on April 30. Four additional cases in the area were reported on May 2 by the Allegheny County Health Department. A measles outbreak is “defined as three or more cases” by the CDC, but the situation in Pennsylvania is not yet being reported as such.

One Pennsylvania legislator in the state, Rep. Daryl Metcalfe (R) of Butler County, has authored a bill that would “bar health care practitioners and facilities and insurance companies from denying care if parents refuse or delay” recommended vaccinations, PennLive.com reported.

Pennsylvania Governor Tom Wolf (D) said that the “bill would put children, pregnant women, and vulnerable patients at risk of being exposed to horrific diseases – at the doctor’s office.”

[email protected]

The number of U.S. measles cases in 2019 rose by 60 during the week ending May 3, which puts the new postelimination high at 764 cases for the year, according to the Centers for Disease Control and Prevention.

The CDC is currently tracking nine measles outbreaks in six states. The largest outbreak this year has been in New York City, mainly Brooklyn, which has almost half (367) of all cases in the country. An outbreak in New York’s Rockland County has resulted in another 109 cases so far this year. California is experiencing outbreaks in three counties – Butte, Los Angeles, and Sacramento – and the state was up to 40 confirmed cases as of May 1. The other states with outbreaks are Michigan, New Jersey, Georgia, and Maryland.

Twenty-three states now have reported measles cases in 2019, as officials in Pittsburgh reported Pennsylvania’s first case on April 30. Four additional cases in the area were reported on May 2 by the Allegheny County Health Department. A measles outbreak is “defined as three or more cases” by the CDC, but the situation in Pennsylvania is not yet being reported as such.

One Pennsylvania legislator in the state, Rep. Daryl Metcalfe (R) of Butler County, has authored a bill that would “bar health care practitioners and facilities and insurance companies from denying care if parents refuse or delay” recommended vaccinations, PennLive.com reported.

Pennsylvania Governor Tom Wolf (D) said that the “bill would put children, pregnant women, and vulnerable patients at risk of being exposed to horrific diseases – at the doctor’s office.”

[email protected]

The number of U.S. measles cases in 2019 rose by 60 during the week ending May 3, which puts the new postelimination high at 764 cases for the year, according to the Centers for Disease Control and Prevention.

The CDC is currently tracking nine measles outbreaks in six states. The largest outbreak this year has been in New York City, mainly Brooklyn, which has almost half (367) of all cases in the country. An outbreak in New York’s Rockland County has resulted in another 109 cases so far this year. California is experiencing outbreaks in three counties – Butte, Los Angeles, and Sacramento – and the state was up to 40 confirmed cases as of May 1. The other states with outbreaks are Michigan, New Jersey, Georgia, and Maryland.

Twenty-three states now have reported measles cases in 2019, as officials in Pittsburgh reported Pennsylvania’s first case on April 30. Four additional cases in the area were reported on May 2 by the Allegheny County Health Department. A measles outbreak is “defined as three or more cases” by the CDC, but the situation in Pennsylvania is not yet being reported as such.

One Pennsylvania legislator in the state, Rep. Daryl Metcalfe (R) of Butler County, has authored a bill that would “bar health care practitioners and facilities and insurance companies from denying care if parents refuse or delay” recommended vaccinations, PennLive.com reported.

Pennsylvania Governor Tom Wolf (D) said that the “bill would put children, pregnant women, and vulnerable patients at risk of being exposed to horrific diseases – at the doctor’s office.”

[email protected]

For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.

Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.

ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.

Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.

Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
 

SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.

For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.

Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.

ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.

Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.

Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
 

SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.

For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.

Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.

ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.

Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.

Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
 

SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.

Philadelphia – OV101 (gaboxadol), a type A gamma-aminobutyric acid receptor agonist, was safe, well tolerated, and improved clinical outcomes in a phase 2 trial of adults and adolescents with Angelman syndrome, according to results of a study presented at the annual meeting of the American Academy of Neurology.

Clinician-rated clinical global impressions of improvement (CGI-I) were improved versus placebo in the randomized study, as were other outcomes in post hoc analyses, including measures of sleep and motor function, said Alexander Kolevzon, MD, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai, New York.

This study of OV101 was a genetics-driven trial for the rare genetic disorder, which is caused by mutations in UBE3A and characterized by seizures, speech impairments, profound intellectual disability, gait problems, and anxiety, Dr. Kolevzon said in a press conference.

“The only treatments that exist are really very symptomatically driven,” Dr. Kolevzon said. “Here, we are taking a genetics-first approach. Having identified the gene, there is some understanding of what the underlying biology is, and it seems to relate to deficits in tonic inhibition.”

OV101 is a delta-selective type A gamma-aminobutyric acid receptor agonist that may potentially normalize the tonic inhibition that is decreased in Angelman syndrome. “What we think this compound is doing is actually reversing the deficits of tonic inhibition, and sort of restoring that state to these patients,” Dr. Kolevzon said in the press conference.

A total of 78 patients completed the phase 2, randomized study, known as STARS, which had a primary endpoint of safety and tolerability over 12 weeks of treatment with OV101 once daily, twice daily, or placebo. The mean age of the 87 patients who enrolled and had at least one dose of study drug was 22.6 years.

Most adverse events were mild, and frequencies of specific adverse events were similar for OV101 and placebo treatment groups, according to Dr. Kolevzon and his coinvestigators.

Improvements in motor function, sleep, and behavior were seen in a series of exploratory analyses, including global improvement at week 12, as captured by CGI-I, which was significantly improved for daily OV101 versus placebo (P = .0006).

These phase 2 results have informed discussions of which specific endpoints might be incorporated into the design of a planned phase 3 trial in pediatric patients. The CGI-I may be especially useful to measure clinical improvement in Angelman syndrome, which is a very “heterogeneous” disorder, Dr. Kolevzon said in the press conference.

“Every child has a different composite of symptoms, so that is the big challenge,” Dr. Kolevzon said. “I do not think we are going to have one singular outcome. The idea is to have a global measure that really captures heterogeneity across each trial and allows for children to be compared to their baseline, and each as their own control, in essence, but with specific domains in mind.”

Funding for the study came from Ovid Therapeutics. Dr. Kolevzon reported disclosures related to Ovid Therapeutics, as well as Coronis Neurosciences, 5AM Ventures, SEMA4, LabCorp, and AMO Pharma.

Philadelphia – OV101 (gaboxadol), a type A gamma-aminobutyric acid receptor agonist, was safe, well tolerated, and improved clinical outcomes in a phase 2 trial of adults and adolescents with Angelman syndrome, according to results of a study presented at the annual meeting of the American Academy of Neurology.

Clinician-rated clinical global impressions of improvement (CGI-I) were improved versus placebo in the randomized study, as were other outcomes in post hoc analyses, including measures of sleep and motor function, said Alexander Kolevzon, MD, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai, New York.

This study of OV101 was a genetics-driven trial for the rare genetic disorder, which is caused by mutations in UBE3A and characterized by seizures, speech impairments, profound intellectual disability, gait problems, and anxiety, Dr. Kolevzon said in a press conference.

“The only treatments that exist are really very symptomatically driven,” Dr. Kolevzon said. “Here, we are taking a genetics-first approach. Having identified the gene, there is some understanding of what the underlying biology is, and it seems to relate to deficits in tonic inhibition.”

OV101 is a delta-selective type A gamma-aminobutyric acid receptor agonist that may potentially normalize the tonic inhibition that is decreased in Angelman syndrome. “What we think this compound is doing is actually reversing the deficits of tonic inhibition, and sort of restoring that state to these patients,” Dr. Kolevzon said in the press conference.

A total of 78 patients completed the phase 2, randomized study, known as STARS, which had a primary endpoint of safety and tolerability over 12 weeks of treatment with OV101 once daily, twice daily, or placebo. The mean age of the 87 patients who enrolled and had at least one dose of study drug was 22.6 years.

Most adverse events were mild, and frequencies of specific adverse events were similar for OV101 and placebo treatment groups, according to Dr. Kolevzon and his coinvestigators.

Improvements in motor function, sleep, and behavior were seen in a series of exploratory analyses, including global improvement at week 12, as captured by CGI-I, which was significantly improved for daily OV101 versus placebo (P = .0006).

These phase 2 results have informed discussions of which specific endpoints might be incorporated into the design of a planned phase 3 trial in pediatric patients. The CGI-I may be especially useful to measure clinical improvement in Angelman syndrome, which is a very “heterogeneous” disorder, Dr. Kolevzon said in the press conference.

“Every child has a different composite of symptoms, so that is the big challenge,” Dr. Kolevzon said. “I do not think we are going to have one singular outcome. The idea is to have a global measure that really captures heterogeneity across each trial and allows for children to be compared to their baseline, and each as their own control, in essence, but with specific domains in mind.”

Funding for the study came from Ovid Therapeutics. Dr. Kolevzon reported disclosures related to Ovid Therapeutics, as well as Coronis Neurosciences, 5AM Ventures, SEMA4, LabCorp, and AMO Pharma.

Philadelphia – OV101 (gaboxadol), a type A gamma-aminobutyric acid receptor agonist, was safe, well tolerated, and improved clinical outcomes in a phase 2 trial of adults and adolescents with Angelman syndrome, according to results of a study presented at the annual meeting of the American Academy of Neurology.

Clinician-rated clinical global impressions of improvement (CGI-I) were improved versus placebo in the randomized study, as were other outcomes in post hoc analyses, including measures of sleep and motor function, said Alexander Kolevzon, MD, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai, New York.

This study of OV101 was a genetics-driven trial for the rare genetic disorder, which is caused by mutations in UBE3A and characterized by seizures, speech impairments, profound intellectual disability, gait problems, and anxiety, Dr. Kolevzon said in a press conference.

“The only treatments that exist are really very symptomatically driven,” Dr. Kolevzon said. “Here, we are taking a genetics-first approach. Having identified the gene, there is some understanding of what the underlying biology is, and it seems to relate to deficits in tonic inhibition.”

OV101 is a delta-selective type A gamma-aminobutyric acid receptor agonist that may potentially normalize the tonic inhibition that is decreased in Angelman syndrome. “What we think this compound is doing is actually reversing the deficits of tonic inhibition, and sort of restoring that state to these patients,” Dr. Kolevzon said in the press conference.

A total of 78 patients completed the phase 2, randomized study, known as STARS, which had a primary endpoint of safety and tolerability over 12 weeks of treatment with OV101 once daily, twice daily, or placebo. The mean age of the 87 patients who enrolled and had at least one dose of study drug was 22.6 years.

Most adverse events were mild, and frequencies of specific adverse events were similar for OV101 and placebo treatment groups, according to Dr. Kolevzon and his coinvestigators.

Improvements in motor function, sleep, and behavior were seen in a series of exploratory analyses, including global improvement at week 12, as captured by CGI-I, which was significantly improved for daily OV101 versus placebo (P = .0006).

These phase 2 results have informed discussions of which specific endpoints might be incorporated into the design of a planned phase 3 trial in pediatric patients. The CGI-I may be especially useful to measure clinical improvement in Angelman syndrome, which is a very “heterogeneous” disorder, Dr. Kolevzon said in the press conference.

“Every child has a different composite of symptoms, so that is the big challenge,” Dr. Kolevzon said. “I do not think we are going to have one singular outcome. The idea is to have a global measure that really captures heterogeneity across each trial and allows for children to be compared to their baseline, and each as their own control, in essence, but with specific domains in mind.”

Funding for the study came from Ovid Therapeutics. Dr. Kolevzon reported disclosures related to Ovid Therapeutics, as well as Coronis Neurosciences, 5AM Ventures, SEMA4, LabCorp, and AMO Pharma.

PHILADELPHIA – Oligomeric alpha synuclein levels in tears can help clinicians distinguish between patients with Parkinson’s disease and healthy controls, according to research presented at the annual meeting of the American Academy of Neurology. Chemokine (C-C motif) ligand 2 (CCL2), a cytokine, may be used for the same purpose, according to researchers.

Lacrimal glands have high numbers of cholinergic and other neurons. Parasympathetic and sympathetic neural pathways stimulate the tears that lacrimal grands secrete. It is possible that the production, packaging, and secretion of proteins into tears may alter when nerve function in the lacrimal glands and cornea changes. This idea may be tested by collecting reflex tears (i.e., stimulated tears provoked by an unanesthetized Schirmer’s test).

Mark Lew, MD, professor of clinical neurology at University of Southern California, Los Angeles, and colleagues previously studied patients using basal tears collected from an anesthetized Schirmer’s test. To examine whether the protein composition of reflex tears differs in patients with Parkinson’s disease, compared with healthy controls, they collected reflex tears from 85 patients with Parkinson’s disease and 80 age- and sex-matched healthy controls using an unanesthetized Schirmer’s test. The researchers pooled samples from both eyes to analyze alpha synuclein, CCL2, and total protein using enzyme-linked immunosorbent assays or multiplex ELISA.


Eligible participants were aged 30-85 years and had a Montreal Cognitive Assessment (MoCA) score of 21 or higher. Patients with Parkinson’s disease had a lower MoCA score than controls did, although it was still in the normal range. Tear flow was significantly decreased in patients with Parkinson’s disease, compared with controls.

Dr. Lew and colleagues found that the amount of oligomeric alpha synuclein was increased nearly 400% in the tears of patients with Parkinson’s disease, compared with those of healthy controls (4.21 ng/mg tear protein vs. 0.90 ng/mg tear protein). This difference was statistically significant. Similarly, CCL2 was significantly increased in the tears of patients with Parkinson’s disease, compared with those of healthy controls (165.8 pg/mg tear protein vs. 116.3 pg/mg tear protein). Among men, Parkinson’s disease was associated with greater rises in oligomeric alpha synuclein (4.95 ng/mg tear protein vs. 0.89 ng/mg tear protein in healthy controls) and CCL2 (201.5 pg/mg tear protein vs. 117.9 pg/mg tear protein in healthy controls) than in women. The origin of sex differences in these biomarker values requires further study, the investigators said.

Dr. Lew reported receiving research support from the Parkinson’s Study Group, the Michael J. Fox Foundation, Biotie Therapies, NeuroDerm, Enterin, Pharm2B Fellowship Grants, Allergan, and Medtronic.

[email protected]

SOURCE: Lew M et al. AAN 2019, Abstract S10.001

PHILADELPHIA – Oligomeric alpha synuclein levels in tears can help clinicians distinguish between patients with Parkinson’s disease and healthy controls, according to research presented at the annual meeting of the American Academy of Neurology. Chemokine (C-C motif) ligand 2 (CCL2), a cytokine, may be used for the same purpose, according to researchers.

Lacrimal glands have high numbers of cholinergic and other neurons. Parasympathetic and sympathetic neural pathways stimulate the tears that lacrimal grands secrete. It is possible that the production, packaging, and secretion of proteins into tears may alter when nerve function in the lacrimal glands and cornea changes. This idea may be tested by collecting reflex tears (i.e., stimulated tears provoked by an unanesthetized Schirmer’s test).

Mark Lew, MD, professor of clinical neurology at University of Southern California, Los Angeles, and colleagues previously studied patients using basal tears collected from an anesthetized Schirmer’s test. To examine whether the protein composition of reflex tears differs in patients with Parkinson’s disease, compared with healthy controls, they collected reflex tears from 85 patients with Parkinson’s disease and 80 age- and sex-matched healthy controls using an unanesthetized Schirmer’s test. The researchers pooled samples from both eyes to analyze alpha synuclein, CCL2, and total protein using enzyme-linked immunosorbent assays or multiplex ELISA.


Eligible participants were aged 30-85 years and had a Montreal Cognitive Assessment (MoCA) score of 21 or higher. Patients with Parkinson’s disease had a lower MoCA score than controls did, although it was still in the normal range. Tear flow was significantly decreased in patients with Parkinson’s disease, compared with controls.

Dr. Lew and colleagues found that the amount of oligomeric alpha synuclein was increased nearly 400% in the tears of patients with Parkinson’s disease, compared with those of healthy controls (4.21 ng/mg tear protein vs. 0.90 ng/mg tear protein). This difference was statistically significant. Similarly, CCL2 was significantly increased in the tears of patients with Parkinson’s disease, compared with those of healthy controls (165.8 pg/mg tear protein vs. 116.3 pg/mg tear protein). Among men, Parkinson’s disease was associated with greater rises in oligomeric alpha synuclein (4.95 ng/mg tear protein vs. 0.89 ng/mg tear protein in healthy controls) and CCL2 (201.5 pg/mg tear protein vs. 117.9 pg/mg tear protein in healthy controls) than in women. The origin of sex differences in these biomarker values requires further study, the investigators said.

Dr. Lew reported receiving research support from the Parkinson’s Study Group, the Michael J. Fox Foundation, Biotie Therapies, NeuroDerm, Enterin, Pharm2B Fellowship Grants, Allergan, and Medtronic.

[email protected]

SOURCE: Lew M et al. AAN 2019, Abstract S10.001

PHILADELPHIA – Oligomeric alpha synuclein levels in tears can help clinicians distinguish between patients with Parkinson’s disease and healthy controls, according to research presented at the annual meeting of the American Academy of Neurology. Chemokine (C-C motif) ligand 2 (CCL2), a cytokine, may be used for the same purpose, according to researchers.

Lacrimal glands have high numbers of cholinergic and other neurons. Parasympathetic and sympathetic neural pathways stimulate the tears that lacrimal grands secrete. It is possible that the production, packaging, and secretion of proteins into tears may alter when nerve function in the lacrimal glands and cornea changes. This idea may be tested by collecting reflex tears (i.e., stimulated tears provoked by an unanesthetized Schirmer’s test).

Mark Lew, MD, professor of clinical neurology at University of Southern California, Los Angeles, and colleagues previously studied patients using basal tears collected from an anesthetized Schirmer’s test. To examine whether the protein composition of reflex tears differs in patients with Parkinson’s disease, compared with healthy controls, they collected reflex tears from 85 patients with Parkinson’s disease and 80 age- and sex-matched healthy controls using an unanesthetized Schirmer’s test. The researchers pooled samples from both eyes to analyze alpha synuclein, CCL2, and total protein using enzyme-linked immunosorbent assays or multiplex ELISA.


Eligible participants were aged 30-85 years and had a Montreal Cognitive Assessment (MoCA) score of 21 or higher. Patients with Parkinson’s disease had a lower MoCA score than controls did, although it was still in the normal range. Tear flow was significantly decreased in patients with Parkinson’s disease, compared with controls.

Dr. Lew and colleagues found that the amount of oligomeric alpha synuclein was increased nearly 400% in the tears of patients with Parkinson’s disease, compared with those of healthy controls (4.21 ng/mg tear protein vs. 0.90 ng/mg tear protein). This difference was statistically significant. Similarly, CCL2 was significantly increased in the tears of patients with Parkinson’s disease, compared with those of healthy controls (165.8 pg/mg tear protein vs. 116.3 pg/mg tear protein). Among men, Parkinson’s disease was associated with greater rises in oligomeric alpha synuclein (4.95 ng/mg tear protein vs. 0.89 ng/mg tear protein in healthy controls) and CCL2 (201.5 pg/mg tear protein vs. 117.9 pg/mg tear protein in healthy controls) than in women. The origin of sex differences in these biomarker values requires further study, the investigators said.

Dr. Lew reported receiving research support from the Parkinson’s Study Group, the Michael J. Fox Foundation, Biotie Therapies, NeuroDerm, Enterin, Pharm2B Fellowship Grants, Allergan, and Medtronic.

[email protected]

SOURCE: Lew M et al. AAN 2019, Abstract S10.001

Stand Up To Cancer has awarded 1- and 2-year grants to five teams conducting cancer research.

Alan D’Andrea, MD, of the Dana-Farber Cancer Institute in Boston and Juan Cubillos-Ruiz, PhD, of Weill Cornell Medicine in New York won a 2-year grant totaling $250,000.

Dr. Cubillos-Ruiz and Dr. D’Andrea will use this funding to evaluate gene signatures controlled by phospholipid messengers and endoplasmic reticulum stress in responding and nonresponding ovarian cancer patients, and the team will use tumor organoids to test whether pharmacological inhibition of these pathways can fight ovarian cancer.

Denada Dibra, PhD, of the University of Texas MD Anderson Cancer Center in Houston and Peter Lee, MD, of City of Hope in Duarte, Calif., won a 1-year grant of $250,000.

Dr. Lee and Dr. Dibra will use mouse models to study how TP53 may influence the tumor microenvironment in triple-negative breast cancer and to characterize tumor cells and immune cells in the tumor tissue.

Maximilian Diehn, MD, PhD, of Stanford (Calif.) University and Aaron Hata, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston won a 2-year grant totaling $225,000.

Dr. Hata and Dr. Diehn will work on developing a novel method for analyzing cell-free RNA associated with resistance to tyrosine kinase inhibitors in patients with non–small cell lung cancer. The team’s goal is to develop a noninvasive approach to better characterize tumors and detect phenotypic changes during treatment.

Sarah Tasian, MD, of Children’s Hospital of Philadelphia and Kimberly Stegmaier, MD, of the Dana-Farber Cancer Institute won a 2-year grant totaling $250,000, which was funded with support from the Emily Whitehead Foundation.

Dr. Stegmaier and Dr. Tasian will test chimeric antigen receptor T cells targeting two or more neoantigens in preclinical models of childhood Down syndrome–associated acute lymphoblastic leukemia and Ph-like acute lymphoblastic leukemia.

Robert Vonderheide, MD, of the University of Pennsylvania Abramson Cancer Center in Philadelphia and Vinod Balachandran, MD, of Memorial Sloan Kettering Cancer Center in New York won a 2-year grant totaling $225,000.

Dr. Balachandran and Dr. Vonderheide will analyze short- and long-term pancreatic cancer survivors, patients with primary resected pancreatic cancers and patients with mKRAS lung and colon cancers to evaluate how mKRAS immunogenicity may affect outcomes.



Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Stand Up To Cancer has awarded 1- and 2-year grants to five teams conducting cancer research.

Alan D’Andrea, MD, of the Dana-Farber Cancer Institute in Boston and Juan Cubillos-Ruiz, PhD, of Weill Cornell Medicine in New York won a 2-year grant totaling $250,000.

Dr. Cubillos-Ruiz and Dr. D’Andrea will use this funding to evaluate gene signatures controlled by phospholipid messengers and endoplasmic reticulum stress in responding and nonresponding ovarian cancer patients, and the team will use tumor organoids to test whether pharmacological inhibition of these pathways can fight ovarian cancer.

Denada Dibra, PhD, of the University of Texas MD Anderson Cancer Center in Houston and Peter Lee, MD, of City of Hope in Duarte, Calif., won a 1-year grant of $250,000.

Dr. Lee and Dr. Dibra will use mouse models to study how TP53 may influence the tumor microenvironment in triple-negative breast cancer and to characterize tumor cells and immune cells in the tumor tissue.

Maximilian Diehn, MD, PhD, of Stanford (Calif.) University and Aaron Hata, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston won a 2-year grant totaling $225,000.

Dr. Hata and Dr. Diehn will work on developing a novel method for analyzing cell-free RNA associated with resistance to tyrosine kinase inhibitors in patients with non–small cell lung cancer. The team’s goal is to develop a noninvasive approach to better characterize tumors and detect phenotypic changes during treatment.

Sarah Tasian, MD, of Children’s Hospital of Philadelphia and Kimberly Stegmaier, MD, of the Dana-Farber Cancer Institute won a 2-year grant totaling $250,000, which was funded with support from the Emily Whitehead Foundation.

Dr. Stegmaier and Dr. Tasian will test chimeric antigen receptor T cells targeting two or more neoantigens in preclinical models of childhood Down syndrome–associated acute lymphoblastic leukemia and Ph-like acute lymphoblastic leukemia.

Robert Vonderheide, MD, of the University of Pennsylvania Abramson Cancer Center in Philadelphia and Vinod Balachandran, MD, of Memorial Sloan Kettering Cancer Center in New York won a 2-year grant totaling $225,000.

Dr. Balachandran and Dr. Vonderheide will analyze short- and long-term pancreatic cancer survivors, patients with primary resected pancreatic cancers and patients with mKRAS lung and colon cancers to evaluate how mKRAS immunogenicity may affect outcomes.



Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Stand Up To Cancer has awarded 1- and 2-year grants to five teams conducting cancer research.

Alan D’Andrea, MD, of the Dana-Farber Cancer Institute in Boston and Juan Cubillos-Ruiz, PhD, of Weill Cornell Medicine in New York won a 2-year grant totaling $250,000.

Dr. Cubillos-Ruiz and Dr. D’Andrea will use this funding to evaluate gene signatures controlled by phospholipid messengers and endoplasmic reticulum stress in responding and nonresponding ovarian cancer patients, and the team will use tumor organoids to test whether pharmacological inhibition of these pathways can fight ovarian cancer.

Denada Dibra, PhD, of the University of Texas MD Anderson Cancer Center in Houston and Peter Lee, MD, of City of Hope in Duarte, Calif., won a 1-year grant of $250,000.

Dr. Lee and Dr. Dibra will use mouse models to study how TP53 may influence the tumor microenvironment in triple-negative breast cancer and to characterize tumor cells and immune cells in the tumor tissue.

Maximilian Diehn, MD, PhD, of Stanford (Calif.) University and Aaron Hata, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston won a 2-year grant totaling $225,000.

Dr. Hata and Dr. Diehn will work on developing a novel method for analyzing cell-free RNA associated with resistance to tyrosine kinase inhibitors in patients with non–small cell lung cancer. The team’s goal is to develop a noninvasive approach to better characterize tumors and detect phenotypic changes during treatment.

Sarah Tasian, MD, of Children’s Hospital of Philadelphia and Kimberly Stegmaier, MD, of the Dana-Farber Cancer Institute won a 2-year grant totaling $250,000, which was funded with support from the Emily Whitehead Foundation.

Dr. Stegmaier and Dr. Tasian will test chimeric antigen receptor T cells targeting two or more neoantigens in preclinical models of childhood Down syndrome–associated acute lymphoblastic leukemia and Ph-like acute lymphoblastic leukemia.

Robert Vonderheide, MD, of the University of Pennsylvania Abramson Cancer Center in Philadelphia and Vinod Balachandran, MD, of Memorial Sloan Kettering Cancer Center in New York won a 2-year grant totaling $225,000.

Dr. Balachandran and Dr. Vonderheide will analyze short- and long-term pancreatic cancer survivors, patients with primary resected pancreatic cancers and patients with mKRAS lung and colon cancers to evaluate how mKRAS immunogenicity may affect outcomes.



Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

The prognostic influence of estrogen receptor-beta (ESR2) expression in breast cancer – favorable versus unfavorable – appears to hinge on tumor TP53 mutational status, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.

Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.

Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).

Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.

In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.

In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.

Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.

SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.

The prognostic influence of estrogen receptor-beta (ESR2) expression in breast cancer – favorable versus unfavorable – appears to hinge on tumor TP53 mutational status, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.

Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.

Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).

Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.

In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.

In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.

Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.

SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.

The prognostic influence of estrogen receptor-beta (ESR2) expression in breast cancer – favorable versus unfavorable – appears to hinge on tumor TP53 mutational status, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.

Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.

Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).

Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.

In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.

In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.

Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.

SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.