ORLANDO – Patients with atrial fibrillation (AF) should be screened for obstructive sleep apnea (OSA), because this information may be useful in guiding ablation strategies, according to results of a prospective study.

The study, which associated OSA in AF with a high relative rate of non–pulmonary vein (PV) triggers, has contributed to the “growing body of evidence implicating sleep apnea in atrial remodeling and promotion of the AF substrate,” Elad Anter, MD, associate director of the clinical electrophysiology laboratory at Beth Israel Deaconess Medical Center, Boston, reported at the annual International AF Symposium.

Despite the close association between OSA and AF, it has been unclear whether OSA is a causative factor. Dr. Anter suggested that mechanistic association is strengthening, however.

It has been hypothesized that OSA generates AF substrate through negative intrathoracic pressure changes and autonomic nervous system activation. But Dr. Anter reported that there is more recent and compelling evidence that the repetitive occlusions produced by OSA result in remodeling of the atria, producing scar tissue that slows conduction and produces susceptibility to reentry AF.

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[email protected]

ORLANDO – Patients with atrial fibrillation (AF) should be screened for obstructive sleep apnea (OSA), because this information may be useful in guiding ablation strategies, according to results of a prospective study.

The study, which associated OSA in AF with a high relative rate of non–pulmonary vein (PV) triggers, has contributed to the “growing body of evidence implicating sleep apnea in atrial remodeling and promotion of the AF substrate,” Elad Anter, MD, associate director of the clinical electrophysiology laboratory at Beth Israel Deaconess Medical Center, Boston, reported at the annual International AF Symposium.

Despite the close association between OSA and AF, it has been unclear whether OSA is a causative factor. Dr. Anter suggested that mechanistic association is strengthening, however.

It has been hypothesized that OSA generates AF substrate through negative intrathoracic pressure changes and autonomic nervous system activation. But Dr. Anter reported that there is more recent and compelling evidence that the repetitive occlusions produced by OSA result in remodeling of the atria, producing scar tissue that slows conduction and produces susceptibility to reentry AF.

copyright designer491/Thinkstock

[email protected]

ORLANDO – Patients with atrial fibrillation (AF) should be screened for obstructive sleep apnea (OSA), because this information may be useful in guiding ablation strategies, according to results of a prospective study.

The study, which associated OSA in AF with a high relative rate of non–pulmonary vein (PV) triggers, has contributed to the “growing body of evidence implicating sleep apnea in atrial remodeling and promotion of the AF substrate,” Elad Anter, MD, associate director of the clinical electrophysiology laboratory at Beth Israel Deaconess Medical Center, Boston, reported at the annual International AF Symposium.

Despite the close association between OSA and AF, it has been unclear whether OSA is a causative factor. Dr. Anter suggested that mechanistic association is strengthening, however.

It has been hypothesized that OSA generates AF substrate through negative intrathoracic pressure changes and autonomic nervous system activation. But Dr. Anter reported that there is more recent and compelling evidence that the repetitive occlusions produced by OSA result in remodeling of the atria, producing scar tissue that slows conduction and produces susceptibility to reentry AF.

copyright designer491/Thinkstock

[email protected]

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

To the Editor:

Pemphigus foliaceus is a rare autoimmune blistering disorder that typically presents with crusted scaly erosions in a seborrheic distribution. We describe a case of pemphigus foliaceus localized to the right cheek of 10 years’ duration that spread to other areas. With a PubMed search of articles indexed for MEDLINE yielding only 14 cases of localized pemphigus foliaceus (Table), it represents an extremely rare entity that often is a diagnostic challenge and may be a harbinger for disseminated disease months to years after the inciting lesion appears.

A 51-year-old woman presented with an asymptomatic cutaneous eruption that had remained localized to the right cheek for 10 years before it increased in size and new lesions developed on the left cheek, chest, and upper back. No inciting factors, such as contactants, insect bites, infections, medications, or recent travel were identified. On physical examination a well-demarcated, hypertrophic, verrucouslike plaque with central pink atrophy and exfoliative scale involved the right malar and submalar regions but spared the mucocutaneous junctions of the face (Figure 1). Subtle dark brown papules, some with overlying scale, speckled the left cheek, right jawline, chest, and upper back. The oral cavity was clear.

Leading differentials included hypertrophic discoid lupus erythematosus and pemphigus vegetans. Other considerations included sarcoidosis, granuloma faciale, lupus vulgaris, disseminated coccidioidomycosis or blastomycosis, and squamous cell carcinoma.

An initial biopsy revealed a lymphocytic lichenoid dermatitis with epidermal hyperplasia and scattered eosinophils for which the following differentials were provided: insect bite, hypertrophic lichen planus, prurigo nodularis superimposed on rosacea, and allergic contact dermatitis. Under these histologic diagnoses, tacrolimus ointment 0.03%, topical mid-potency corticosteroid, and a combination of oral doxycycline and metronidazole gel 1% were prescribed but failed to ameliorate her condition.

Because the clinical differentials were vast and noncorrelative with the original pathology, additional biopsies were performed: one from the edge of the large malar plaque, which was transected for hematoxylin and eosin (H&E) and tissue cultures; one perilesional to the large malar plaque for direct immunofluorescence (DIF); and one from the papule on the right jawline for H&E. Tissue cultures were negative for fungal and mycobacterial organisms. Both specimens submitted for H&E showed the prominent epidermal hyperplasia and lymphocytic dermal infiltrate noted on the original H&E but also demonstrated intragranular acantholysis (Figure 2). The DIF revealed intercellular IgG and C3 deposition throughout the epidermis (Figure 3). Indirect immunofluorescence was negative, but enzyme-linked immunosorbent assay detected circulating antidesmoglein-1 but not antidesmoglein-3 autoantibodies. Other serologies including antinuclear antibody, anti–double-stranded DNA, antihistone, anti–Sjögren syndrome A, and anti–Sjögren syndrome B antibodies were negative.

The diagnosis of localized pemphigus foliaceus was made and management with oral prednisone and mycophenolate mofetil resulted in improvement within weeks.

Localized pemphigus foliaceus is extremely rare with only 14 cases reported in the literature (Table).^1-10 Its diagnosis is challenging, as the clinical presentation simulates various entities and the histological features and serological markers are difficult to capture.

Localized pemphigus foliaceus typically presents as an isolated, erythematous, scaly, crusted plaque involving the nose, cheek, or scalp and may mimic several conditions including contact dermatitis, seborrheic dermatitis, rosacea, cutaneous sarcoidosis, discoid lupus erythematosus, lupus vulgaris, impetigo contagiosa, solar keratosis, and nonmelanoma skin cancer.^1-10

The predilection for sun-exposed areas suggests UV radiation may induce binding of antidesmoglein-1 autoantibodies with subsequent cytokine-mediated inflammation and acantholysis at these sites.^11-13 Similarly, the immunomodulatory agent imiquimod has been reported to induce pemphigus foliaceus at its application sites.⁶

When pemphigus foliaceus is clinically discernible, the histology and DIF are in accordance with the clinical diagnosis 53.8% of the time.¹³ In cases of localized pemphigus foliaceus in which the diagnosis is more elusive, many biopsies often are needed to capture the characteristic intragranular acantholysis; this feature often is so subtle that unless the diagnosis is suspected, it is underappreciated or undetectable. In chronic lesions, it may be masked by secondary changes such as acanthosis, hyperkeratosis, and parakeratosis.¹⁴

In pemphigus foliaceus, detection of circulating antidesmoglein-1 autoantibodies by enzyme-linked immunosorbent assay is slightly more sensitive and specific compared to indirect immunofluorescence, but both correlate with disease activity.^15,16 The low or absent autoantibody titers in localized pemphigus foliaceus may reflect its limited involvement, but dissemination of the disease with subsequent elevation of autoantibody titers may occur months to years after initial presentation,^1,2,9 as was the case with our patient.

The majority of localized pemphigus foliaceus cases require systemic prednisone, sometimes in conjunction with nonsteroidal immunosuppressants or topical high-potency corticosteroids.^1-3,5,6,8-10 One case was efficaciously managed with tacrolimus ointment 0.1%.⁷

Localized pemphigus foliaceus is a rare and challenging entity that must be a diagnostic consideration for any chronic focal plaque on the face or scalp, as it may herald disseminated disease.

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Immediate antiretroviral therapy reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count, according to a study in The Lancet HIV. The authors said this is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count.

Postmenopausal status was not associated with a greater risk of unprotected sex in a population of high-risk HIV-positive Kenyan women, a recent study showed.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Immediate antiretroviral therapy reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count, according to a study in The Lancet HIV. The authors said this is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count.

Postmenopausal status was not associated with a greater risk of unprotected sex in a population of high-risk HIV-positive Kenyan women, a recent study showed.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

Immediate antiretroviral therapy reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count, according to a study in The Lancet HIV. The authors said this is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count.

Postmenopausal status was not associated with a greater risk of unprotected sex in a population of high-risk HIV-positive Kenyan women, a recent study showed.

copyright alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

The discussion this month focuses on an exciting new ingredient that is showing great promise as a topical antiaging agent. For years we have known that aging skin needs more collagen, elastin, and hyaluronic acid. It is time to add a new player to the antiaging team – heparan sulfate (HS). New studies have shown that lower levels of HS are associated with aged skin. This is what you need to know.

Significance of HS

Endogenous HS, an essential glycosaminoglycan (GAG), contributes to skin development and homeostasis, and thus actively promotes skin health.¹ GAGs such as HS and hyaluronic acid are well known as endogenous superhydrators that bind and retain water, thus contributing to skin hydration as well as preserving the structural integrity of collagen and elastin fibers. Specifically, HS and its protein-bound forms (HS proteoglycans such as syndecan, glypican, and perlecan) – the most common constituents on the cell surface and in the extracellular matrix (ECM) – play an important role in cutaneous cell proliferation, migration, communication, and activation as well as collagen fiber development, basement membrane regeneration, granulation tissue formation, and cell adhesion related to wound healing.¹ This results from their capacity to bind, store, present, degrade, and amplify growth factors and cytokines.

Conclusion

Heparan sulfate does appear to be a novel viable antiaging option. Endogenous heparan sulfate is involved in skin defense against pathogens, dehydrated/dried skin, redness, and wound healing. Theoretically, then, HS analogs should be able to modulate these processes. More research is necessary to determine if this is the case, however. In the meantime, HS analogs are extremely well tolerated by all patients and especially those with sensitive skin, which is often the case with aging skin. Further, HS analogs promote skin hydration, providing resistance to compressive forces as well as keeping skin looking healthy. Anecdotally, I can report that I have been using the Senté Dermal Repair Cream in my rosacea patients without any problems. I think HS analogs represent a good option for patients who cannot tolerate retinoids.

Resources

1. J Drugs Dermatol. 2015 Jul;14(7):669-74.

2. Proteoglycans in Skin Aging, in “Textbook of Aging Skin” (Heidelberg, Berlin: Springer-Verlag, pp. 109-120).

3. Joint Bone Spine. 2016 Sep 20. doi: 10.1016/j.jbspin.2016.06.012.

4. Ann Chir Plast Esthet. 2010 Oct;55(5):421-8.

5. Int Wound J. 2015 Apr;12(2):169-72.

6. Int Wound J. 2016 Feb;13(1):35-8.

7. ISRN Orthop. 2012 Jan 17. doi: 10.5402/2012/504151.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

The discussion this month focuses on an exciting new ingredient that is showing great promise as a topical antiaging agent. For years we have known that aging skin needs more collagen, elastin, and hyaluronic acid. It is time to add a new player to the antiaging team – heparan sulfate (HS). New studies have shown that lower levels of HS are associated with aged skin. This is what you need to know.

Significance of HS

Endogenous HS, an essential glycosaminoglycan (GAG), contributes to skin development and homeostasis, and thus actively promotes skin health.¹ GAGs such as HS and hyaluronic acid are well known as endogenous superhydrators that bind and retain water, thus contributing to skin hydration as well as preserving the structural integrity of collagen and elastin fibers. Specifically, HS and its protein-bound forms (HS proteoglycans such as syndecan, glypican, and perlecan) – the most common constituents on the cell surface and in the extracellular matrix (ECM) – play an important role in cutaneous cell proliferation, migration, communication, and activation as well as collagen fiber development, basement membrane regeneration, granulation tissue formation, and cell adhesion related to wound healing.¹ This results from their capacity to bind, store, present, degrade, and amplify growth factors and cytokines.

Conclusion

Heparan sulfate does appear to be a novel viable antiaging option. Endogenous heparan sulfate is involved in skin defense against pathogens, dehydrated/dried skin, redness, and wound healing. Theoretically, then, HS analogs should be able to modulate these processes. More research is necessary to determine if this is the case, however. In the meantime, HS analogs are extremely well tolerated by all patients and especially those with sensitive skin, which is often the case with aging skin. Further, HS analogs promote skin hydration, providing resistance to compressive forces as well as keeping skin looking healthy. Anecdotally, I can report that I have been using the Senté Dermal Repair Cream in my rosacea patients without any problems. I think HS analogs represent a good option for patients who cannot tolerate retinoids.

Resources

1. J Drugs Dermatol. 2015 Jul;14(7):669-74.

2. Proteoglycans in Skin Aging, in “Textbook of Aging Skin” (Heidelberg, Berlin: Springer-Verlag, pp. 109-120).

3. Joint Bone Spine. 2016 Sep 20. doi: 10.1016/j.jbspin.2016.06.012.

4. Ann Chir Plast Esthet. 2010 Oct;55(5):421-8.

5. Int Wound J. 2015 Apr;12(2):169-72.

6. Int Wound J. 2016 Feb;13(1):35-8.

7. ISRN Orthop. 2012 Jan 17. doi: 10.5402/2012/504151.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

The discussion this month focuses on an exciting new ingredient that is showing great promise as a topical antiaging agent. For years we have known that aging skin needs more collagen, elastin, and hyaluronic acid. It is time to add a new player to the antiaging team – heparan sulfate (HS). New studies have shown that lower levels of HS are associated with aged skin. This is what you need to know.

Significance of HS

Endogenous HS, an essential glycosaminoglycan (GAG), contributes to skin development and homeostasis, and thus actively promotes skin health.¹ GAGs such as HS and hyaluronic acid are well known as endogenous superhydrators that bind and retain water, thus contributing to skin hydration as well as preserving the structural integrity of collagen and elastin fibers. Specifically, HS and its protein-bound forms (HS proteoglycans such as syndecan, glypican, and perlecan) – the most common constituents on the cell surface and in the extracellular matrix (ECM) – play an important role in cutaneous cell proliferation, migration, communication, and activation as well as collagen fiber development, basement membrane regeneration, granulation tissue formation, and cell adhesion related to wound healing.¹ This results from their capacity to bind, store, present, degrade, and amplify growth factors and cytokines.

Conclusion

Heparan sulfate does appear to be a novel viable antiaging option. Endogenous heparan sulfate is involved in skin defense against pathogens, dehydrated/dried skin, redness, and wound healing. Theoretically, then, HS analogs should be able to modulate these processes. More research is necessary to determine if this is the case, however. In the meantime, HS analogs are extremely well tolerated by all patients and especially those with sensitive skin, which is often the case with aging skin. Further, HS analogs promote skin hydration, providing resistance to compressive forces as well as keeping skin looking healthy. Anecdotally, I can report that I have been using the Senté Dermal Repair Cream in my rosacea patients without any problems. I think HS analogs represent a good option for patients who cannot tolerate retinoids.

Resources

1. J Drugs Dermatol. 2015 Jul;14(7):669-74.

2. Proteoglycans in Skin Aging, in “Textbook of Aging Skin” (Heidelberg, Berlin: Springer-Verlag, pp. 109-120).

3. Joint Bone Spine. 2016 Sep 20. doi: 10.1016/j.jbspin.2016.06.012.

4. Ann Chir Plast Esthet. 2010 Oct;55(5):421-8.

5. Int Wound J. 2015 Apr;12(2):169-72.

6. Int Wound J. 2016 Feb;13(1):35-8.

7. ISRN Orthop. 2012 Jan 17. doi: 10.5402/2012/504151.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

Take-Home Points

• Patients sustaining DRFs commonly have associated ligament injuries and chondral damage as well.
• Many of these associated injuries do not seem to affect outcomes up to 1 year after surgery.
• Plain radiographs have a 74% sensitivity and 73% specificity for detecting intra-articular fractures.
• ”Minor” injuries identified incidentally by arthroscopy during fixation of DRFs may not require dedicated treatment.
• The optimal treatment for high-grade ligament or chondral injuries in patients with DRFs remains incompletely understood.

Distal radius fracture (DRF) is one of the most common upper extremity injuries, with up to 20% to 50% requiring surgical fixation.¹ With increasing use of wrist arthroscopy to assist in managing these fractures,^2-6 it has become easier to accurately assess concomitant wrist ligament injuries. Reported injury rates are 18% to 86% for the scapholunate interosseous ligament (SLIL),^7,8 5% to 29% for the lunotriquetral ligament (LTL),^8,9 and 17% to 60% for the triangular fibrocartilage complex (TFCC).^10,11 Reported chondral injury rates range from 18% to 60%.^7,9,12 Despite the common occurrence of these injuries, it is unclear how they affect outcomes and how aggressively they should be treated when detected during fracture surgery.

As the use of arthroscopy in DRF management becomes more common, surgeons often must decide how to treat ligamentous/chondral injuries incidentally discovered during surgery. To date, only 1 study prospectively evaluated how these injuries affect DRF outcomes,⁸ though it did not use a validated, patient-based outcome measure.

We conducted a study to address a common clinical scenario: When arthroscopy is used to assist with intra-articular reduction during DRF fixation, how should the surgeon respond to incidentally identified ligament and chondral injuries? Specifically, we wanted to address 3 questions: What is the overall incidence of SLIL, TFCC, and chondral surface injuries in patients undergoing operative fracture fixation? On initial injury films, do any radiographic parameters predict specific soft-tissue injuries or ultimate functional outcomes? Do wrist ligament and chondral injuries affect patient-rated outcomes (disability, pain) and objective measures (range of motion [ROM], grip strength, pinch strength) up to 1 year after fracture surgery?

Materials and Methods

Patient Selection/Population

This observational, prognostic study was approved by our Institutional Review Board. Inclusion criteria were age over 18 years, isolated acute operatively treated DRF (surgery within 14 days of injury), and informed consent. All patients were treated by the same surgeon. Exclusion criteria were open DRF, dorsal shear pattern, fractures requiring dorsal arthrotomy for reduction because of significant intra-articular damage, prior ipsilateral DRF, and prior SLIL or TFCC injury.

Surgery was indicated according to general radiographic parameters as measured on postreduction films: radial height, <8 mm; radial inclination, <15°; positive ulnar variance, >3 mm, or 3 mm more than contralateral side; dorsal tilt, >10°; and volar tilt, >15°. With these parameters within acceptable limits, surgery was also indicated when fractures were deemed unstable and likely to displace because of dorsal tilt >20°, dorsal comminution, intra-articular step-off of ≥2 mm on the posterior-anterior (PA) film, associated ulnar fracture, and age >60 years.¹³Over a 2-year period, 42 patients (12 male, 30 female) met the inclusion criteria and were enrolled in the study. The dominant arm was affected in 17 patients (40%). Mean (SD) age at time of injury was 56.6 (16.4) years (median, 54 years; range, 20-85 years).

Operative Technique

During surgery, damage to the SLIL, the TFCC, and chondral surfaces (scaphoid, lunate, scaphoid fossa, lunate fossa) and to the intra-articular extension of the DRF was assessed and recorded. Wrist arthroscopy was performed with the 3, 4 portal as the primary portal. When significant damage to the TFCC warranted débridement, the 6R (radial) portal was used as an accessory portal. As a midcarpal portal was not used for SLIL assessment, we used a novel classification system: 0 = no injury, normal-appearing ligament without hemorrhage and smooth transition from scaphoid to lunate surface except for slight concave indentation at the ligament; 1 = attenuation, no visible tear with convex shape of ligament with or without hemorrhage; 2 = partial tear with or without step-off at junction between scaphoid and lunate, but 2.7-mm arthroscope cannot “drive through” to midcarpal joint; and 3 = complete tear with positive “drive-through” sign. TFCC injuries were classified according to the system described by Palmer¹⁴: Avulsions were central (1A), ulnar (1B), distal (1C), or radial (1D). The trampoline test was performed through a 6R portal by using a probe to evaluate ligament tension/laxity. In some cases, a 6R portal was deemed unnecessary, and a modified trampoline test was performed—tension/laxity/displacement was evaluated by manually palpating at the fovea and observing TFCC motion with the arthroscope. When appropriate, the TFCC was débrided with a shaver through the 6R portal. In cases of significant instability at the SLIL interval, two 0.062-inch K-wires were placed percutaneously through the scaphoid and lunate, and one was placed from the scaphoid to the capitate.

All DRFs underwent internal fixation with a locked volar plate. When necessary, K-wires and/or a locked radial column plate was used for additional fixation. External fixation was not used. The postoperative protocol began with a dorsal wrist splint placed on the patient in the operating room and worn for 10 to 14 days. At the first postoperative visit, the patient received a removable splint that was to be worn at all times except during showers, therapy, and home exercises. Occupational therapy, initiated the week of the first postoperative visit, consisted of active and passive ROM exercises. At 6 weeks, the splint was removed and strengthening initiated.

Outcome Measures

Our primary outcome measure was the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire at 1 year.¹⁵ Secondary outcome measures were visual analog scale (VAS) pain rating, ROM, and radiographic measurements. Patients returned for evaluation 2, 6, 12, 24, and 52 weeks after surgery. At each follow-up visit, the DASH questionnaire and the pain VAS were administered, and ROM and strength were measured. Patient-reported pain was recorded on a standard VAS and measured on a scale from 0 (no pain) to 10 (worst possible pain). Wrist flexion and extension and radioulnar deviation were assessed with a goniometer. Forearm supination and pronation were assessed with the elbow flexed 90° at the patient’s side. Grip strength was measured with a calibrated Jamar dynamometer (Sammons Preston Rolyan), and lateral pinch strength was measured with a hydraulic pinch gauge (Sammons Preston Rolyan). The average of 3 trials for both hands was recorded for all strength measurements.

Radiographs were obtained on presentation. When appropriate, the fracture was manually reduced with a hematoma block, and postreduction radiographs were obtained. Then, radiographs were obtained at each postoperative visit until union. Radial height, radial inclination, tilt, and ulnar variance were measured on preoperative and postoperative radiographs according to standard methods.¹⁶ Radiographs were used to classify the fracture patterns according to the AO/ASIF (Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation) classification. Union was determined by radiographic healing, absence of tenderness to palpation, absence of pain with motion, and continued functional improvement.

Data Analysis

To evaluate for relationships between patient injury parameters and outcome measures, we used a 1-way analysis of variance seeking statistically significant differences between groups. Patients were divided into 4 groups: no ligament injuries; isolated SLIL injuries; isolated TFCC injuries; and both SLIL and TFCC injuries. These injury classification categories were then evaluated independently against our chosen outcome measures, which included DASH and VAS pain scores, ROM, and grip/pinch strength.

To determine the optimal sample size, we performed a power analysis to estimate the number of patients required to detect a clinically significant difference in DASH scores at 1 year among the 4 groups. According to the literature, standard deviations of DASH scores in healthy volunteers range from 10 to 15,¹⁷ consistent with values found in other recent trials of patients with DRFs.¹⁸ The recent literature on DASH construct validity has established a DASH score difference of 19 as representing a disability change being “much better or much worse.”¹⁹ As such, power analysis for a 1-way analysis of variance among 4 categories, detecting a DASH score difference of 19 with a standard deviation ranging from 10 to 15, would require 28 to 60 patients to detect a difference with an α of 0.05 and a power of 0.8.

In addition, radiographic parameters at time of injury were compared with injury characteristics to assess for significant relationships. Multivariate linear regression analysis was performed to evaluate radial height, radial inclination, and volar tilt as possible predictors of SLIL injury, TFCC injury, and chondral surface damage. A statistically significant result was defined as a correlation with P < .05.

Results

Of the 42 patients included in the study, 11 (26%) had no ligament injuries, 10 (24%) had isolated SLIL injuries, 12 (29%) had isolated TFCC injuries, and 9 (21%) had injuries to both the SLIL and the TFCC. In addition, in 12 patients (29%), the articular cartilage had visible damage (Table 1).

In all patients, bony union occurred. After union, 1 patient underwent hardware removal for hardware-related pain. The same patient had a dorsal ulnar cutaneous nerve neurolysis at the ulnar styloid fixation site. Another patient developed a partial extensor pollicis longus tear from a prominent dorsal screw tip.

All patients returned for their 2- and 6-week follow-ups. At 1 year, 30 patients (71%) returned for follow-up, 11 could not be contacted, and 1 was removed because of an olecranon fracture from a subsequent fall.

Regarding the primary outcome measure, mean DASH score at 1-year follow-up was 30.8 for the group without injuries, 10.8 for the group with SLIL injuries, 14.7 for the group with TFCC injuries, and 21.9 for the group with SLIL and TFCC injuries (Table 2).

Discussion

Use of wrist arthroscopy in DRF management has allowed assessment of the incidence of intra-articular injuries, including ligament and chondral surface injuries. Although the literature on the incidence of these injuries has been expanding, their clinical significance remains unclear.

Authors have postulated that some patients do not do well after DRF repair because of undetected ligament injuries. With the current trend of internal fixation, locked plating, and early motion—contrasting with older trends of prolonged immobilization in a cast or external fixation—concerns have been raised that early mobilization results in inadequate treatment of ligament injuries. However, data from the present study suggest no significant morbidity from early mobilization despite the presence of ligament injuries in more than half of all operatively treated DRFs. It is possible morbidity was not appreciated, as most patients with DRFs end up with some stiffness, which masks the effects of ligament injuries during healing.

We found no correlation between injury radiographic parameters, observed soft-tissue injuries, or final subjective outcomes. Interestingly, in this study, there was some discordance between the appearance of intra-articular fractures on radiographs and the direct arthroscopic observation of intra-articular fracture extension. With the present data and with arthroscopic visualization as the gold standard, radiographs had 74% sensitivity and 73% specificity for detecting intra-articular fractures (the corresponding positive predictive value was 83%, and the negative predictive value was 61%). As we typically rely on radiographs as the primary tool in assessing the articular component of a fracture, these results should be taken into account when basing management decisions exclusively on static injury films.

Observational studies of arthroscopy in DRFs have revealed a wide range of injury rates: For SLILs, the average injury rate was 44%; for LTLs, 13%; for TFCCs, 43%; and for chondral surfaces, 32% (Table 4).

Am J Orthop. 2017;46(1):E41-E46. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Patients sustaining DRFs commonly have associated ligament injuries and chondral damage as well.
• Many of these associated injuries do not seem to affect outcomes up to 1 year after surgery.
• Plain radiographs have a 74% sensitivity and 73% specificity for detecting intra-articular fractures.
• ”Minor” injuries identified incidentally by arthroscopy during fixation of DRFs may not require dedicated treatment.
• The optimal treatment for high-grade ligament or chondral injuries in patients with DRFs remains incompletely understood.

Distal radius fracture (DRF) is one of the most common upper extremity injuries, with up to 20% to 50% requiring surgical fixation.¹ With increasing use of wrist arthroscopy to assist in managing these fractures,^2-6 it has become easier to accurately assess concomitant wrist ligament injuries. Reported injury rates are 18% to 86% for the scapholunate interosseous ligament (SLIL),^7,8 5% to 29% for the lunotriquetral ligament (LTL),^8,9 and 17% to 60% for the triangular fibrocartilage complex (TFCC).^10,11 Reported chondral injury rates range from 18% to 60%.^7,9,12 Despite the common occurrence of these injuries, it is unclear how they affect outcomes and how aggressively they should be treated when detected during fracture surgery.

As the use of arthroscopy in DRF management becomes more common, surgeons often must decide how to treat ligamentous/chondral injuries incidentally discovered during surgery. To date, only 1 study prospectively evaluated how these injuries affect DRF outcomes,⁸ though it did not use a validated, patient-based outcome measure.

We conducted a study to address a common clinical scenario: When arthroscopy is used to assist with intra-articular reduction during DRF fixation, how should the surgeon respond to incidentally identified ligament and chondral injuries? Specifically, we wanted to address 3 questions: What is the overall incidence of SLIL, TFCC, and chondral surface injuries in patients undergoing operative fracture fixation? On initial injury films, do any radiographic parameters predict specific soft-tissue injuries or ultimate functional outcomes? Do wrist ligament and chondral injuries affect patient-rated outcomes (disability, pain) and objective measures (range of motion [ROM], grip strength, pinch strength) up to 1 year after fracture surgery?

Materials and Methods

Patient Selection/Population

This observational, prognostic study was approved by our Institutional Review Board. Inclusion criteria were age over 18 years, isolated acute operatively treated DRF (surgery within 14 days of injury), and informed consent. All patients were treated by the same surgeon. Exclusion criteria were open DRF, dorsal shear pattern, fractures requiring dorsal arthrotomy for reduction because of significant intra-articular damage, prior ipsilateral DRF, and prior SLIL or TFCC injury.

Surgery was indicated according to general radiographic parameters as measured on postreduction films: radial height, <8 mm; radial inclination, <15°; positive ulnar variance, >3 mm, or 3 mm more than contralateral side; dorsal tilt, >10°; and volar tilt, >15°. With these parameters within acceptable limits, surgery was also indicated when fractures were deemed unstable and likely to displace because of dorsal tilt >20°, dorsal comminution, intra-articular step-off of ≥2 mm on the posterior-anterior (PA) film, associated ulnar fracture, and age >60 years.¹³Over a 2-year period, 42 patients (12 male, 30 female) met the inclusion criteria and were enrolled in the study. The dominant arm was affected in 17 patients (40%). Mean (SD) age at time of injury was 56.6 (16.4) years (median, 54 years; range, 20-85 years).

Operative Technique

During surgery, damage to the SLIL, the TFCC, and chondral surfaces (scaphoid, lunate, scaphoid fossa, lunate fossa) and to the intra-articular extension of the DRF was assessed and recorded. Wrist arthroscopy was performed with the 3, 4 portal as the primary portal. When significant damage to the TFCC warranted débridement, the 6R (radial) portal was used as an accessory portal. As a midcarpal portal was not used for SLIL assessment, we used a novel classification system: 0 = no injury, normal-appearing ligament without hemorrhage and smooth transition from scaphoid to lunate surface except for slight concave indentation at the ligament; 1 = attenuation, no visible tear with convex shape of ligament with or without hemorrhage; 2 = partial tear with or without step-off at junction between scaphoid and lunate, but 2.7-mm arthroscope cannot “drive through” to midcarpal joint; and 3 = complete tear with positive “drive-through” sign. TFCC injuries were classified according to the system described by Palmer¹⁴: Avulsions were central (1A), ulnar (1B), distal (1C), or radial (1D). The trampoline test was performed through a 6R portal by using a probe to evaluate ligament tension/laxity. In some cases, a 6R portal was deemed unnecessary, and a modified trampoline test was performed—tension/laxity/displacement was evaluated by manually palpating at the fovea and observing TFCC motion with the arthroscope. When appropriate, the TFCC was débrided with a shaver through the 6R portal. In cases of significant instability at the SLIL interval, two 0.062-inch K-wires were placed percutaneously through the scaphoid and lunate, and one was placed from the scaphoid to the capitate.

All DRFs underwent internal fixation with a locked volar plate. When necessary, K-wires and/or a locked radial column plate was used for additional fixation. External fixation was not used. The postoperative protocol began with a dorsal wrist splint placed on the patient in the operating room and worn for 10 to 14 days. At the first postoperative visit, the patient received a removable splint that was to be worn at all times except during showers, therapy, and home exercises. Occupational therapy, initiated the week of the first postoperative visit, consisted of active and passive ROM exercises. At 6 weeks, the splint was removed and strengthening initiated.

Outcome Measures

Our primary outcome measure was the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire at 1 year.¹⁵ Secondary outcome measures were visual analog scale (VAS) pain rating, ROM, and radiographic measurements. Patients returned for evaluation 2, 6, 12, 24, and 52 weeks after surgery. At each follow-up visit, the DASH questionnaire and the pain VAS were administered, and ROM and strength were measured. Patient-reported pain was recorded on a standard VAS and measured on a scale from 0 (no pain) to 10 (worst possible pain). Wrist flexion and extension and radioulnar deviation were assessed with a goniometer. Forearm supination and pronation were assessed with the elbow flexed 90° at the patient’s side. Grip strength was measured with a calibrated Jamar dynamometer (Sammons Preston Rolyan), and lateral pinch strength was measured with a hydraulic pinch gauge (Sammons Preston Rolyan). The average of 3 trials for both hands was recorded for all strength measurements.

Radiographs were obtained on presentation. When appropriate, the fracture was manually reduced with a hematoma block, and postreduction radiographs were obtained. Then, radiographs were obtained at each postoperative visit until union. Radial height, radial inclination, tilt, and ulnar variance were measured on preoperative and postoperative radiographs according to standard methods.¹⁶ Radiographs were used to classify the fracture patterns according to the AO/ASIF (Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation) classification. Union was determined by radiographic healing, absence of tenderness to palpation, absence of pain with motion, and continued functional improvement.

Data Analysis

To evaluate for relationships between patient injury parameters and outcome measures, we used a 1-way analysis of variance seeking statistically significant differences between groups. Patients were divided into 4 groups: no ligament injuries; isolated SLIL injuries; isolated TFCC injuries; and both SLIL and TFCC injuries. These injury classification categories were then evaluated independently against our chosen outcome measures, which included DASH and VAS pain scores, ROM, and grip/pinch strength.

To determine the optimal sample size, we performed a power analysis to estimate the number of patients required to detect a clinically significant difference in DASH scores at 1 year among the 4 groups. According to the literature, standard deviations of DASH scores in healthy volunteers range from 10 to 15,¹⁷ consistent with values found in other recent trials of patients with DRFs.¹⁸ The recent literature on DASH construct validity has established a DASH score difference of 19 as representing a disability change being “much better or much worse.”¹⁹ As such, power analysis for a 1-way analysis of variance among 4 categories, detecting a DASH score difference of 19 with a standard deviation ranging from 10 to 15, would require 28 to 60 patients to detect a difference with an α of 0.05 and a power of 0.8.

In addition, radiographic parameters at time of injury were compared with injury characteristics to assess for significant relationships. Multivariate linear regression analysis was performed to evaluate radial height, radial inclination, and volar tilt as possible predictors of SLIL injury, TFCC injury, and chondral surface damage. A statistically significant result was defined as a correlation with P < .05.

Results

Of the 42 patients included in the study, 11 (26%) had no ligament injuries, 10 (24%) had isolated SLIL injuries, 12 (29%) had isolated TFCC injuries, and 9 (21%) had injuries to both the SLIL and the TFCC. In addition, in 12 patients (29%), the articular cartilage had visible damage (Table 1).

In all patients, bony union occurred. After union, 1 patient underwent hardware removal for hardware-related pain. The same patient had a dorsal ulnar cutaneous nerve neurolysis at the ulnar styloid fixation site. Another patient developed a partial extensor pollicis longus tear from a prominent dorsal screw tip.

All patients returned for their 2- and 6-week follow-ups. At 1 year, 30 patients (71%) returned for follow-up, 11 could not be contacted, and 1 was removed because of an olecranon fracture from a subsequent fall.

Regarding the primary outcome measure, mean DASH score at 1-year follow-up was 30.8 for the group without injuries, 10.8 for the group with SLIL injuries, 14.7 for the group with TFCC injuries, and 21.9 for the group with SLIL and TFCC injuries (Table 2).

Discussion

Use of wrist arthroscopy in DRF management has allowed assessment of the incidence of intra-articular injuries, including ligament and chondral surface injuries. Although the literature on the incidence of these injuries has been expanding, their clinical significance remains unclear.

Authors have postulated that some patients do not do well after DRF repair because of undetected ligament injuries. With the current trend of internal fixation, locked plating, and early motion—contrasting with older trends of prolonged immobilization in a cast or external fixation—concerns have been raised that early mobilization results in inadequate treatment of ligament injuries. However, data from the present study suggest no significant morbidity from early mobilization despite the presence of ligament injuries in more than half of all operatively treated DRFs. It is possible morbidity was not appreciated, as most patients with DRFs end up with some stiffness, which masks the effects of ligament injuries during healing.

We found no correlation between injury radiographic parameters, observed soft-tissue injuries, or final subjective outcomes. Interestingly, in this study, there was some discordance between the appearance of intra-articular fractures on radiographs and the direct arthroscopic observation of intra-articular fracture extension. With the present data and with arthroscopic visualization as the gold standard, radiographs had 74% sensitivity and 73% specificity for detecting intra-articular fractures (the corresponding positive predictive value was 83%, and the negative predictive value was 61%). As we typically rely on radiographs as the primary tool in assessing the articular component of a fracture, these results should be taken into account when basing management decisions exclusively on static injury films.

Observational studies of arthroscopy in DRFs have revealed a wide range of injury rates: For SLILs, the average injury rate was 44%; for LTLs, 13%; for TFCCs, 43%; and for chondral surfaces, 32% (Table 4).

Am J Orthop. 2017;46(1):E41-E46. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Patients sustaining DRFs commonly have associated ligament injuries and chondral damage as well.
• Many of these associated injuries do not seem to affect outcomes up to 1 year after surgery.
• Plain radiographs have a 74% sensitivity and 73% specificity for detecting intra-articular fractures.
• ”Minor” injuries identified incidentally by arthroscopy during fixation of DRFs may not require dedicated treatment.
• The optimal treatment for high-grade ligament or chondral injuries in patients with DRFs remains incompletely understood.

Distal radius fracture (DRF) is one of the most common upper extremity injuries, with up to 20% to 50% requiring surgical fixation.¹ With increasing use of wrist arthroscopy to assist in managing these fractures,^2-6 it has become easier to accurately assess concomitant wrist ligament injuries. Reported injury rates are 18% to 86% for the scapholunate interosseous ligament (SLIL),^7,8 5% to 29% for the lunotriquetral ligament (LTL),^8,9 and 17% to 60% for the triangular fibrocartilage complex (TFCC).^10,11 Reported chondral injury rates range from 18% to 60%.^7,9,12 Despite the common occurrence of these injuries, it is unclear how they affect outcomes and how aggressively they should be treated when detected during fracture surgery.

As the use of arthroscopy in DRF management becomes more common, surgeons often must decide how to treat ligamentous/chondral injuries incidentally discovered during surgery. To date, only 1 study prospectively evaluated how these injuries affect DRF outcomes,⁸ though it did not use a validated, patient-based outcome measure.

We conducted a study to address a common clinical scenario: When arthroscopy is used to assist with intra-articular reduction during DRF fixation, how should the surgeon respond to incidentally identified ligament and chondral injuries? Specifically, we wanted to address 3 questions: What is the overall incidence of SLIL, TFCC, and chondral surface injuries in patients undergoing operative fracture fixation? On initial injury films, do any radiographic parameters predict specific soft-tissue injuries or ultimate functional outcomes? Do wrist ligament and chondral injuries affect patient-rated outcomes (disability, pain) and objective measures (range of motion [ROM], grip strength, pinch strength) up to 1 year after fracture surgery?

Materials and Methods

Patient Selection/Population

This observational, prognostic study was approved by our Institutional Review Board. Inclusion criteria were age over 18 years, isolated acute operatively treated DRF (surgery within 14 days of injury), and informed consent. All patients were treated by the same surgeon. Exclusion criteria were open DRF, dorsal shear pattern, fractures requiring dorsal arthrotomy for reduction because of significant intra-articular damage, prior ipsilateral DRF, and prior SLIL or TFCC injury.

Surgery was indicated according to general radiographic parameters as measured on postreduction films: radial height, <8 mm; radial inclination, <15°; positive ulnar variance, >3 mm, or 3 mm more than contralateral side; dorsal tilt, >10°; and volar tilt, >15°. With these parameters within acceptable limits, surgery was also indicated when fractures were deemed unstable and likely to displace because of dorsal tilt >20°, dorsal comminution, intra-articular step-off of ≥2 mm on the posterior-anterior (PA) film, associated ulnar fracture, and age >60 years.¹³Over a 2-year period, 42 patients (12 male, 30 female) met the inclusion criteria and were enrolled in the study. The dominant arm was affected in 17 patients (40%). Mean (SD) age at time of injury was 56.6 (16.4) years (median, 54 years; range, 20-85 years).

Operative Technique

During surgery, damage to the SLIL, the TFCC, and chondral surfaces (scaphoid, lunate, scaphoid fossa, lunate fossa) and to the intra-articular extension of the DRF was assessed and recorded. Wrist arthroscopy was performed with the 3, 4 portal as the primary portal. When significant damage to the TFCC warranted débridement, the 6R (radial) portal was used as an accessory portal. As a midcarpal portal was not used for SLIL assessment, we used a novel classification system: 0 = no injury, normal-appearing ligament without hemorrhage and smooth transition from scaphoid to lunate surface except for slight concave indentation at the ligament; 1 = attenuation, no visible tear with convex shape of ligament with or without hemorrhage; 2 = partial tear with or without step-off at junction between scaphoid and lunate, but 2.7-mm arthroscope cannot “drive through” to midcarpal joint; and 3 = complete tear with positive “drive-through” sign. TFCC injuries were classified according to the system described by Palmer¹⁴: Avulsions were central (1A), ulnar (1B), distal (1C), or radial (1D). The trampoline test was performed through a 6R portal by using a probe to evaluate ligament tension/laxity. In some cases, a 6R portal was deemed unnecessary, and a modified trampoline test was performed—tension/laxity/displacement was evaluated by manually palpating at the fovea and observing TFCC motion with the arthroscope. When appropriate, the TFCC was débrided with a shaver through the 6R portal. In cases of significant instability at the SLIL interval, two 0.062-inch K-wires were placed percutaneously through the scaphoid and lunate, and one was placed from the scaphoid to the capitate.

All DRFs underwent internal fixation with a locked volar plate. When necessary, K-wires and/or a locked radial column plate was used for additional fixation. External fixation was not used. The postoperative protocol began with a dorsal wrist splint placed on the patient in the operating room and worn for 10 to 14 days. At the first postoperative visit, the patient received a removable splint that was to be worn at all times except during showers, therapy, and home exercises. Occupational therapy, initiated the week of the first postoperative visit, consisted of active and passive ROM exercises. At 6 weeks, the splint was removed and strengthening initiated.

Outcome Measures

Our primary outcome measure was the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire at 1 year.¹⁵ Secondary outcome measures were visual analog scale (VAS) pain rating, ROM, and radiographic measurements. Patients returned for evaluation 2, 6, 12, 24, and 52 weeks after surgery. At each follow-up visit, the DASH questionnaire and the pain VAS were administered, and ROM and strength were measured. Patient-reported pain was recorded on a standard VAS and measured on a scale from 0 (no pain) to 10 (worst possible pain). Wrist flexion and extension and radioulnar deviation were assessed with a goniometer. Forearm supination and pronation were assessed with the elbow flexed 90° at the patient’s side. Grip strength was measured with a calibrated Jamar dynamometer (Sammons Preston Rolyan), and lateral pinch strength was measured with a hydraulic pinch gauge (Sammons Preston Rolyan). The average of 3 trials for both hands was recorded for all strength measurements.

Radiographs were obtained on presentation. When appropriate, the fracture was manually reduced with a hematoma block, and postreduction radiographs were obtained. Then, radiographs were obtained at each postoperative visit until union. Radial height, radial inclination, tilt, and ulnar variance were measured on preoperative and postoperative radiographs according to standard methods.¹⁶ Radiographs were used to classify the fracture patterns according to the AO/ASIF (Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation) classification. Union was determined by radiographic healing, absence of tenderness to palpation, absence of pain with motion, and continued functional improvement.

Data Analysis

To evaluate for relationships between patient injury parameters and outcome measures, we used a 1-way analysis of variance seeking statistically significant differences between groups. Patients were divided into 4 groups: no ligament injuries; isolated SLIL injuries; isolated TFCC injuries; and both SLIL and TFCC injuries. These injury classification categories were then evaluated independently against our chosen outcome measures, which included DASH and VAS pain scores, ROM, and grip/pinch strength.

To determine the optimal sample size, we performed a power analysis to estimate the number of patients required to detect a clinically significant difference in DASH scores at 1 year among the 4 groups. According to the literature, standard deviations of DASH scores in healthy volunteers range from 10 to 15,¹⁷ consistent with values found in other recent trials of patients with DRFs.¹⁸ The recent literature on DASH construct validity has established a DASH score difference of 19 as representing a disability change being “much better or much worse.”¹⁹ As such, power analysis for a 1-way analysis of variance among 4 categories, detecting a DASH score difference of 19 with a standard deviation ranging from 10 to 15, would require 28 to 60 patients to detect a difference with an α of 0.05 and a power of 0.8.

In addition, radiographic parameters at time of injury were compared with injury characteristics to assess for significant relationships. Multivariate linear regression analysis was performed to evaluate radial height, radial inclination, and volar tilt as possible predictors of SLIL injury, TFCC injury, and chondral surface damage. A statistically significant result was defined as a correlation with P < .05.

Results

Of the 42 patients included in the study, 11 (26%) had no ligament injuries, 10 (24%) had isolated SLIL injuries, 12 (29%) had isolated TFCC injuries, and 9 (21%) had injuries to both the SLIL and the TFCC. In addition, in 12 patients (29%), the articular cartilage had visible damage (Table 1).

In all patients, bony union occurred. After union, 1 patient underwent hardware removal for hardware-related pain. The same patient had a dorsal ulnar cutaneous nerve neurolysis at the ulnar styloid fixation site. Another patient developed a partial extensor pollicis longus tear from a prominent dorsal screw tip.

All patients returned for their 2- and 6-week follow-ups. At 1 year, 30 patients (71%) returned for follow-up, 11 could not be contacted, and 1 was removed because of an olecranon fracture from a subsequent fall.

Regarding the primary outcome measure, mean DASH score at 1-year follow-up was 30.8 for the group without injuries, 10.8 for the group with SLIL injuries, 14.7 for the group with TFCC injuries, and 21.9 for the group with SLIL and TFCC injuries (Table 2).

Discussion

Use of wrist arthroscopy in DRF management has allowed assessment of the incidence of intra-articular injuries, including ligament and chondral surface injuries. Although the literature on the incidence of these injuries has been expanding, their clinical significance remains unclear.

Authors have postulated that some patients do not do well after DRF repair because of undetected ligament injuries. With the current trend of internal fixation, locked plating, and early motion—contrasting with older trends of prolonged immobilization in a cast or external fixation—concerns have been raised that early mobilization results in inadequate treatment of ligament injuries. However, data from the present study suggest no significant morbidity from early mobilization despite the presence of ligament injuries in more than half of all operatively treated DRFs. It is possible morbidity was not appreciated, as most patients with DRFs end up with some stiffness, which masks the effects of ligament injuries during healing.

We found no correlation between injury radiographic parameters, observed soft-tissue injuries, or final subjective outcomes. Interestingly, in this study, there was some discordance between the appearance of intra-articular fractures on radiographs and the direct arthroscopic observation of intra-articular fracture extension. With the present data and with arthroscopic visualization as the gold standard, radiographs had 74% sensitivity and 73% specificity for detecting intra-articular fractures (the corresponding positive predictive value was 83%, and the negative predictive value was 61%). As we typically rely on radiographs as the primary tool in assessing the articular component of a fracture, these results should be taken into account when basing management decisions exclusively on static injury films.

Observational studies of arthroscopy in DRFs have revealed a wide range of injury rates: For SLILs, the average injury rate was 44%; for LTLs, 13%; for TFCCs, 43%; and for chondral surfaces, 32% (Table 4).

Am J Orthop. 2017;46(1):E41-E46. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

NEW ORLEANS – Clinicians may not be prescribing enough statins and/or aspirin therapy for the HIV-infected population at highest risk for atherosclerotic cardiovascular disease, according to the results of a large retrospective study from an HIV clinic in New York.

“We need to shift our paradigm for care – from ‘take antiretrovirals and that’s it’ – to a focus on the whole patient and chronic conditions,” Emma Kaplan-Lewis, MD, said during a poster presentation at an annual scientific meeting on infectious diseases. Risk of cardiovascular events increases 1.5-fold among people with HIV treated with antiretroviral therapy, compared with the uninfected population, she noted.

Damian McNamara/Frontline Medical News

NEW ORLEANS – Clinicians may not be prescribing enough statins and/or aspirin therapy for the HIV-infected population at highest risk for atherosclerotic cardiovascular disease, according to the results of a large retrospective study from an HIV clinic in New York.

“We need to shift our paradigm for care – from ‘take antiretrovirals and that’s it’ – to a focus on the whole patient and chronic conditions,” Emma Kaplan-Lewis, MD, said during a poster presentation at an annual scientific meeting on infectious diseases. Risk of cardiovascular events increases 1.5-fold among people with HIV treated with antiretroviral therapy, compared with the uninfected population, she noted.

Damian McNamara/Frontline Medical News

NEW ORLEANS – Clinicians may not be prescribing enough statins and/or aspirin therapy for the HIV-infected population at highest risk for atherosclerotic cardiovascular disease, according to the results of a large retrospective study from an HIV clinic in New York.

“We need to shift our paradigm for care – from ‘take antiretrovirals and that’s it’ – to a focus on the whole patient and chronic conditions,” Emma Kaplan-Lewis, MD, said during a poster presentation at an annual scientific meeting on infectious diseases. Risk of cardiovascular events increases 1.5-fold among people with HIV treated with antiretroviral therapy, compared with the uninfected population, she noted.

Damian McNamara/Frontline Medical News

Antihemophilic factor

Some young hemophilia patients may not be sticking to their prophylaxis regimens for psychosocial reasons, according to research published in PLOS ONE.

The study included 78 hemophilia patients, ages 12 to 25, treated at 13 centers in England and Wales.

“This research has a specific focus on young people rather than including patients of all age groups,” said study author Sandra Van Os, a PhD student at the University of Hertfordshire in Hatfield, UK.

“This is important since young people are likely to have had a very different experience than the older generations due to the revolutionary improvements in treatment achieved during the past 2 decades. Another key issue is rather than asking parents or healthcare professionals to estimate adherence as previous studies have done, this study asked young people directly.”

The results showed that 18% of the patients did not adhere to their prophylaxis regimens. Most non-adherence was due to forgetting treatment rather than intentionally skipping it.

But there were a few psychosocial reasons for non-adherence. Patients reported non-adherence due to a lack of social support and the perceived impact of prophylaxis on their everyday lives.

Patients also lacked understanding about the effectiveness of prophylaxis and its importance in treating hemophilia.

The patients were more likely to adhere to treatment when they perceived the need for prophylaxis to be greater than their concern over taking it.

And the study suggested a strong emotional reaction to a bleed may encourage young people to adhere to their treatment regimen.

“Interestingly, the findings suggest that, in addition to social support and treatment beliefs, emotional responses in relation to hemophilia, such as fear, anger, or distress, may also contribute to better adherence,” van Os said.

“It is important that patients receive sufficient and appropriate social support in order to stay on track with their treatment. It will also be beneficial to reduce potential concerns about prophylaxis and to assess whether patients understand their treatment sufficiently well and the role they themselves have to play in its effectiveness.”

This research was supported by external, peer-reviewed funding from the Bayer Haemophilia Awards Programme (Caregiver Award awarded to van Os).

Antihemophilic factor

Some young hemophilia patients may not be sticking to their prophylaxis regimens for psychosocial reasons, according to research published in PLOS ONE.

The study included 78 hemophilia patients, ages 12 to 25, treated at 13 centers in England and Wales.

“This research has a specific focus on young people rather than including patients of all age groups,” said study author Sandra Van Os, a PhD student at the University of Hertfordshire in Hatfield, UK.

“This is important since young people are likely to have had a very different experience than the older generations due to the revolutionary improvements in treatment achieved during the past 2 decades. Another key issue is rather than asking parents or healthcare professionals to estimate adherence as previous studies have done, this study asked young people directly.”

The results showed that 18% of the patients did not adhere to their prophylaxis regimens. Most non-adherence was due to forgetting treatment rather than intentionally skipping it.

But there were a few psychosocial reasons for non-adherence. Patients reported non-adherence due to a lack of social support and the perceived impact of prophylaxis on their everyday lives.

Patients also lacked understanding about the effectiveness of prophylaxis and its importance in treating hemophilia.

The patients were more likely to adhere to treatment when they perceived the need for prophylaxis to be greater than their concern over taking it.

And the study suggested a strong emotional reaction to a bleed may encourage young people to adhere to their treatment regimen.

“Interestingly, the findings suggest that, in addition to social support and treatment beliefs, emotional responses in relation to hemophilia, such as fear, anger, or distress, may also contribute to better adherence,” van Os said.

“It is important that patients receive sufficient and appropriate social support in order to stay on track with their treatment. It will also be beneficial to reduce potential concerns about prophylaxis and to assess whether patients understand their treatment sufficiently well and the role they themselves have to play in its effectiveness.”

This research was supported by external, peer-reviewed funding from the Bayer Haemophilia Awards Programme (Caregiver Award awarded to van Os).

Antihemophilic factor

Some young hemophilia patients may not be sticking to their prophylaxis regimens for psychosocial reasons, according to research published in PLOS ONE.

The study included 78 hemophilia patients, ages 12 to 25, treated at 13 centers in England and Wales.

“This research has a specific focus on young people rather than including patients of all age groups,” said study author Sandra Van Os, a PhD student at the University of Hertfordshire in Hatfield, UK.

“This is important since young people are likely to have had a very different experience than the older generations due to the revolutionary improvements in treatment achieved during the past 2 decades. Another key issue is rather than asking parents or healthcare professionals to estimate adherence as previous studies have done, this study asked young people directly.”

The results showed that 18% of the patients did not adhere to their prophylaxis regimens. Most non-adherence was due to forgetting treatment rather than intentionally skipping it.

But there were a few psychosocial reasons for non-adherence. Patients reported non-adherence due to a lack of social support and the perceived impact of prophylaxis on their everyday lives.

Patients also lacked understanding about the effectiveness of prophylaxis and its importance in treating hemophilia.

The patients were more likely to adhere to treatment when they perceived the need for prophylaxis to be greater than their concern over taking it.

And the study suggested a strong emotional reaction to a bleed may encourage young people to adhere to their treatment regimen.

“Interestingly, the findings suggest that, in addition to social support and treatment beliefs, emotional responses in relation to hemophilia, such as fear, anger, or distress, may also contribute to better adherence,” van Os said.

“It is important that patients receive sufficient and appropriate social support in order to stay on track with their treatment. It will also be beneficial to reduce potential concerns about prophylaxis and to assess whether patients understand their treatment sufficiently well and the role they themselves have to play in its effectiveness.”

This research was supported by external, peer-reviewed funding from the Bayer Haemophilia Awards Programme (Caregiver Award awarded to van Os).

Layla Richards, the first person
treated with UCART19
Photo courtesy of GOSH

New research suggests that “universal,” donor-derived, chimeric antigen receptor (CAR) T cells may be a viable treatment option for very young children who do not have sufficient healthy T cells for autologous CAR T-cell therapy.

The universal CAR T-cell therapy, known as UCART19, was given to 2 infants with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) who had previously

exhausted all other treatment options.

Both infants achieved remission after UCART19 and were able to proceed to transplant.

Both were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19, respectively.

Waseem Qasim, MBBS, PhD, of University College London’s Institute of Child Health and Great Ormond Street Hospital (GOSH) in London, UK, and his colleagues reported these results in Science Translational Medicine.

About the therapy

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases. The cells are programmed to target CD19 and be insensitive to alemtuzumab. That way, a patient can receive alemtuzumab to prevent rejection of HLA-mismatched cells.

UCART19 was under development by Cellectis but is now being developed by Servier and Pfizer Inc. Pfizer has exclusive rights to develop and commercialize UCART19 in the US, while Servier retains exclusive rights for all other countries.

In Science Translational Medicine, Dr Qasim and his colleagues reported results in the first patients ever treated with UCART19. That research was funded, in part, by Cellectis.

Subject 1

The first patient was an 11-month-old, mixed-race infant with high-risk, t(11;19), CD19+ B-ALL. She had already failed chemotherapy, an allogeneic hematopoietic stem cell transplant (HSCT), and blinatumomab.

Prior to UCART19, she received a dose of vincristine and asparaginase and 7 days of dexamethasone, followed by cytoreduction with fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose of UCART19 (4.6 × 10⁶/kg).

The patient had neutrophil recovery by day 30, although this was dependent on granulocyte colony-stimulating factor. After that, she developed multilineage cytopenia that persisted until she underwent a second allogeneic HSCT.

Prior to the second HSCT, the patient achieved cytogenetic and molecular remission but also developed grade 2 skin graft-vs-host disease. This was managed with systemic steroids.

The child received rituximab and conditioning with antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa, and total body irradiation, followed by an HSCT from the original mismatched, unrelated donor.

The child achieved a complete remission and has remained minimal residual disease-negative, with full donor chimerism and normalized lymphocyte profiles, at 18 months after UCART19.

Results with this patient were previously reported by GOSH in November 2015 and at the 2015 ASH Annual Meeting.

Subject 2

The second patient was a 16-month-old Caucasian infant who had been diagnosed at 4 weeks of age with high-risk, congenital, mixed lineage leukemia–rearranged B-ALL.

She had already undergone HSCT from a matched, unrelated donor but relapsed. She did not respond to subsequent blinatumomab.

After these failed treatments, the patient received fludarabine, cyclophosphamide, and alemtuzumab, followed by a single infusion of UCART19 (4.0 × 10⁶/kg).

She developed an erythematous rash after treatment, but this was immediately responsive to topical steroids.

The child achieved donor-derived neutrophil recovery and went on to receive a transplant from the same matched, unrelated donor as her previous HSCT.

The child received the transplant within 10 weeks of UCART19 therapy, after receiving rituximab and conditioning with antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation.

At 12 months after UCART19, the child remains minimal residual disease-negative and “clinically well.”

“Both infants who have had this treatment have been at home for some time and are doing well,” Dr Qasim said. “We continue to monitor them closely, and, while we have reduced the frequency of their hospital visits and checks, we will still need to keep an eye on them for some time.”
 
Dr Qasim added that there are phase 1 trials of UCART19 underway for children and adults with chronic lymphocytic leukemia and acute lymphoblastic leukemia.

Layla Richards, the first person
treated with UCART19
Photo courtesy of GOSH

New research suggests that “universal,” donor-derived, chimeric antigen receptor (CAR) T cells may be a viable treatment option for very young children who do not have sufficient healthy T cells for autologous CAR T-cell therapy.

The universal CAR T-cell therapy, known as UCART19, was given to 2 infants with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) who had previously

exhausted all other treatment options.

Both infants achieved remission after UCART19 and were able to proceed to transplant.

Both were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19, respectively.

Waseem Qasim, MBBS, PhD, of University College London’s Institute of Child Health and Great Ormond Street Hospital (GOSH) in London, UK, and his colleagues reported these results in Science Translational Medicine.

About the therapy

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases. The cells are programmed to target CD19 and be insensitive to alemtuzumab. That way, a patient can receive alemtuzumab to prevent rejection of HLA-mismatched cells.

UCART19 was under development by Cellectis but is now being developed by Servier and Pfizer Inc. Pfizer has exclusive rights to develop and commercialize UCART19 in the US, while Servier retains exclusive rights for all other countries.

In Science Translational Medicine, Dr Qasim and his colleagues reported results in the first patients ever treated with UCART19. That research was funded, in part, by Cellectis.

Subject 1

The first patient was an 11-month-old, mixed-race infant with high-risk, t(11;19), CD19+ B-ALL. She had already failed chemotherapy, an allogeneic hematopoietic stem cell transplant (HSCT), and blinatumomab.

Prior to UCART19, she received a dose of vincristine and asparaginase and 7 days of dexamethasone, followed by cytoreduction with fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose of UCART19 (4.6 × 10⁶/kg).

The patient had neutrophil recovery by day 30, although this was dependent on granulocyte colony-stimulating factor. After that, she developed multilineage cytopenia that persisted until she underwent a second allogeneic HSCT.

Prior to the second HSCT, the patient achieved cytogenetic and molecular remission but also developed grade 2 skin graft-vs-host disease. This was managed with systemic steroids.

The child received rituximab and conditioning with antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa, and total body irradiation, followed by an HSCT from the original mismatched, unrelated donor.

The child achieved a complete remission and has remained minimal residual disease-negative, with full donor chimerism and normalized lymphocyte profiles, at 18 months after UCART19.

Results with this patient were previously reported by GOSH in November 2015 and at the 2015 ASH Annual Meeting.

Subject 2

The second patient was a 16-month-old Caucasian infant who had been diagnosed at 4 weeks of age with high-risk, congenital, mixed lineage leukemia–rearranged B-ALL.

She had already undergone HSCT from a matched, unrelated donor but relapsed. She did not respond to subsequent blinatumomab.

After these failed treatments, the patient received fludarabine, cyclophosphamide, and alemtuzumab, followed by a single infusion of UCART19 (4.0 × 10⁶/kg).

She developed an erythematous rash after treatment, but this was immediately responsive to topical steroids.

The child achieved donor-derived neutrophil recovery and went on to receive a transplant from the same matched, unrelated donor as her previous HSCT.

The child received the transplant within 10 weeks of UCART19 therapy, after receiving rituximab and conditioning with antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation.

At 12 months after UCART19, the child remains minimal residual disease-negative and “clinically well.”

“Both infants who have had this treatment have been at home for some time and are doing well,” Dr Qasim said. “We continue to monitor them closely, and, while we have reduced the frequency of their hospital visits and checks, we will still need to keep an eye on them for some time.”
 
Dr Qasim added that there are phase 1 trials of UCART19 underway for children and adults with chronic lymphocytic leukemia and acute lymphoblastic leukemia.

Layla Richards, the first person
treated with UCART19
Photo courtesy of GOSH

New research suggests that “universal,” donor-derived, chimeric antigen receptor (CAR) T cells may be a viable treatment option for very young children who do not have sufficient healthy T cells for autologous CAR T-cell therapy.

The universal CAR T-cell therapy, known as UCART19, was given to 2 infants with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) who had previously

exhausted all other treatment options.

Both infants achieved remission after UCART19 and were able to proceed to transplant.

Both were still alive and leukemia-free at last follow-up—12 months and 18 months after UCART19, respectively.

Waseem Qasim, MBBS, PhD, of University College London’s Institute of Child Health and Great Ormond Street Hospital (GOSH) in London, UK, and his colleagues reported these results in Science Translational Medicine.

About the therapy

UCART19 consists of donor T cells modified using transcription activator-like effector nucleases. The cells are programmed to target CD19 and be insensitive to alemtuzumab. That way, a patient can receive alemtuzumab to prevent rejection of HLA-mismatched cells.

UCART19 was under development by Cellectis but is now being developed by Servier and Pfizer Inc. Pfizer has exclusive rights to develop and commercialize UCART19 in the US, while Servier retains exclusive rights for all other countries.

In Science Translational Medicine, Dr Qasim and his colleagues reported results in the first patients ever treated with UCART19. That research was funded, in part, by Cellectis.

Subject 1

The first patient was an 11-month-old, mixed-race infant with high-risk, t(11;19), CD19+ B-ALL. She had already failed chemotherapy, an allogeneic hematopoietic stem cell transplant (HSCT), and blinatumomab.

Prior to UCART19, she received a dose of vincristine and asparaginase and 7 days of dexamethasone, followed by cytoreduction with fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose of UCART19 (4.6 × 10⁶/kg).

The patient had neutrophil recovery by day 30, although this was dependent on granulocyte colony-stimulating factor. After that, she developed multilineage cytopenia that persisted until she underwent a second allogeneic HSCT.

Prior to the second HSCT, the patient achieved cytogenetic and molecular remission but also developed grade 2 skin graft-vs-host disease. This was managed with systemic steroids.

The child received rituximab and conditioning with antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa, and total body irradiation, followed by an HSCT from the original mismatched, unrelated donor.

The child achieved a complete remission and has remained minimal residual disease-negative, with full donor chimerism and normalized lymphocyte profiles, at 18 months after UCART19.

Results with this patient were previously reported by GOSH in November 2015 and at the 2015 ASH Annual Meeting.

Subject 2

The second patient was a 16-month-old Caucasian infant who had been diagnosed at 4 weeks of age with high-risk, congenital, mixed lineage leukemia–rearranged B-ALL.

She had already undergone HSCT from a matched, unrelated donor but relapsed. She did not respond to subsequent blinatumomab.

After these failed treatments, the patient received fludarabine, cyclophosphamide, and alemtuzumab, followed by a single infusion of UCART19 (4.0 × 10⁶/kg).

She developed an erythematous rash after treatment, but this was immediately responsive to topical steroids.

The child achieved donor-derived neutrophil recovery and went on to receive a transplant from the same matched, unrelated donor as her previous HSCT.

The child received the transplant within 10 weeks of UCART19 therapy, after receiving rituximab and conditioning with antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation.

At 12 months after UCART19, the child remains minimal residual disease-negative and “clinically well.”

“Both infants who have had this treatment have been at home for some time and are doing well,” Dr Qasim said. “We continue to monitor them closely, and, while we have reduced the frequency of their hospital visits and checks, we will still need to keep an eye on them for some time.”
 
Dr Qasim added that there are phase 1 trials of UCART19 underway for children and adults with chronic lymphocytic leukemia and acute lymphoblastic leukemia.

Blood samples
Photo by Graham Colm

Roche has announced the launch of its cobas m 511 integrated hematology analyzer in countries that recognize the CE mark.*

The cobas m 511 combines 3 components of the hematology testing process—a digital morphology analyzer, cell counter, and classifier—into a single system that prepares, stains, and analyzes microscopy blood slides.

Roche said cobas m 511 provides greater accuracy and consistency than current technologies by identifying, counting, isolating, and categorizing blood cells, then presenting the digital images of all these cell types.

The company said this automation and digitalization reduces the need for resource-intensive manual microscope reviews, supports clinicians to share challenging cases around the world, and enables the delivery of quicker results, which ultimately aid patient diagnoses.

The cobas m 511 uses Bloodhound® technology for printing, staining, and imaging. This technology uses 30 µL of blood to print a monolayer onto the slide, stains for further analysis of the morphology, and enables classification of cells displayed on a viewing station.

Unlike the indirect methods commonly used in blood analysis today, the cobas m 511 images individual cells directly.

Based on these direct images, the Bloodhound® technology counts, analyzes morphology, and then classifies every cell in the viewing area to provide a standard complete blood count and 5-part differential and reticulocyte count.

While hematologists will continue to have the option of looking at slides under their microscopes, the cobas m 511 provides cell-by-cell images that, in many cases, may eliminate the need for microscopic review.

“With this launch, patients will benefit from a faster and more accurate diagnosis of blood diseases as diverse as anemia and leukemia,” said Roland Diggelmann, CEO of Roche Diagnostics.

“We are entering a new area of innovation with Roche in hematology testing, supporting customers with integrated and efficient laboratory solutions, which deliver increased medical value.”

Blood samples
Photo by Graham Colm

Roche has announced the launch of its cobas m 511 integrated hematology analyzer in countries that recognize the CE mark.*

The cobas m 511 combines 3 components of the hematology testing process—a digital morphology analyzer, cell counter, and classifier—into a single system that prepares, stains, and analyzes microscopy blood slides.

Roche said cobas m 511 provides greater accuracy and consistency than current technologies by identifying, counting, isolating, and categorizing blood cells, then presenting the digital images of all these cell types.

The company said this automation and digitalization reduces the need for resource-intensive manual microscope reviews, supports clinicians to share challenging cases around the world, and enables the delivery of quicker results, which ultimately aid patient diagnoses.

The cobas m 511 uses Bloodhound® technology for printing, staining, and imaging. This technology uses 30 µL of blood to print a monolayer onto the slide, stains for further analysis of the morphology, and enables classification of cells displayed on a viewing station.

Unlike the indirect methods commonly used in blood analysis today, the cobas m 511 images individual cells directly.

Based on these direct images, the Bloodhound® technology counts, analyzes morphology, and then classifies every cell in the viewing area to provide a standard complete blood count and 5-part differential and reticulocyte count.

While hematologists will continue to have the option of looking at slides under their microscopes, the cobas m 511 provides cell-by-cell images that, in many cases, may eliminate the need for microscopic review.

“With this launch, patients will benefit from a faster and more accurate diagnosis of blood diseases as diverse as anemia and leukemia,” said Roland Diggelmann, CEO of Roche Diagnostics.

“We are entering a new area of innovation with Roche in hematology testing, supporting customers with integrated and efficient laboratory solutions, which deliver increased medical value.”

Blood samples
Photo by Graham Colm

Roche has announced the launch of its cobas m 511 integrated hematology analyzer in countries that recognize the CE mark.*

The cobas m 511 combines 3 components of the hematology testing process—a digital morphology analyzer, cell counter, and classifier—into a single system that prepares, stains, and analyzes microscopy blood slides.

Roche said cobas m 511 provides greater accuracy and consistency than current technologies by identifying, counting, isolating, and categorizing blood cells, then presenting the digital images of all these cell types.

The company said this automation and digitalization reduces the need for resource-intensive manual microscope reviews, supports clinicians to share challenging cases around the world, and enables the delivery of quicker results, which ultimately aid patient diagnoses.

The cobas m 511 uses Bloodhound® technology for printing, staining, and imaging. This technology uses 30 µL of blood to print a monolayer onto the slide, stains for further analysis of the morphology, and enables classification of cells displayed on a viewing station.

Unlike the indirect methods commonly used in blood analysis today, the cobas m 511 images individual cells directly.

Based on these direct images, the Bloodhound® technology counts, analyzes morphology, and then classifies every cell in the viewing area to provide a standard complete blood count and 5-part differential and reticulocyte count.

While hematologists will continue to have the option of looking at slides under their microscopes, the cobas m 511 provides cell-by-cell images that, in many cases, may eliminate the need for microscopic review.

“With this launch, patients will benefit from a faster and more accurate diagnosis of blood diseases as diverse as anemia and leukemia,” said Roland Diggelmann, CEO of Roche Diagnostics.

“We are entering a new area of innovation with Roche in hematology testing, supporting customers with integrated and efficient laboratory solutions, which deliver increased medical value.”

Before he assumed his position as U.S. Surgeon General, Vivek Murthy, MD, says, he stopped by to say good-bye to his colleagues. The nurses had 1 parting request: If you can only do 1 thing as Surgeon General, please do something about the addiction crisis in America.

Thus, for the first time, a U.S. Surgeon General has dedicated a report to substance misuse and related disorders, calling these issues one of America’s most pressing public health concerns. “I am issuing a new call to action,” he says in the foreword, “to end the public health crisis of addiction.” Nearly 21 million Americans suffer from substance use disorders—more than the number of people who have all cancers combined.

Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health offers an in-depth look at the science of substance use disorders and addiction, with chapters on neurobiology, prevention, treatment, recovery, health systems integration, and recommendations for the future.

One of the findings is that substance use disorder treatment in the U.S. remains “largely separate” from the rest of health care and serves only a fraction of those in need of treatment. An estimated 1 in 7 people in the U.S. develops a substance use disorder at some point in their lives, yet only 1 in 10 receives treatment. Many factors contribute to this treatment gap, including the stigma associated with drug and alcohol addiction.

There has been progress: The Obama administration has invested in research, development, and evaluation of programs to prevent and treat substance misuse and substance use disorders, as well as support recovery, the report says.

“It’s time to change how we view addiction,” said Dr. Murthy. “Not as a moral failing, but as a chronic illness that must be treated with skill, urgency and compassion. The way we address this crisis is a test for America.”

Before he assumed his position as U.S. Surgeon General, Vivek Murthy, MD, says, he stopped by to say good-bye to his colleagues. The nurses had 1 parting request: If you can only do 1 thing as Surgeon General, please do something about the addiction crisis in America.

Thus, for the first time, a U.S. Surgeon General has dedicated a report to substance misuse and related disorders, calling these issues one of America’s most pressing public health concerns. “I am issuing a new call to action,” he says in the foreword, “to end the public health crisis of addiction.” Nearly 21 million Americans suffer from substance use disorders—more than the number of people who have all cancers combined.

Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health offers an in-depth look at the science of substance use disorders and addiction, with chapters on neurobiology, prevention, treatment, recovery, health systems integration, and recommendations for the future.

One of the findings is that substance use disorder treatment in the U.S. remains “largely separate” from the rest of health care and serves only a fraction of those in need of treatment. An estimated 1 in 7 people in the U.S. develops a substance use disorder at some point in their lives, yet only 1 in 10 receives treatment. Many factors contribute to this treatment gap, including the stigma associated with drug and alcohol addiction.

There has been progress: The Obama administration has invested in research, development, and evaluation of programs to prevent and treat substance misuse and substance use disorders, as well as support recovery, the report says.

“It’s time to change how we view addiction,” said Dr. Murthy. “Not as a moral failing, but as a chronic illness that must be treated with skill, urgency and compassion. The way we address this crisis is a test for America.”

Before he assumed his position as U.S. Surgeon General, Vivek Murthy, MD, says, he stopped by to say good-bye to his colleagues. The nurses had 1 parting request: If you can only do 1 thing as Surgeon General, please do something about the addiction crisis in America.

Thus, for the first time, a U.S. Surgeon General has dedicated a report to substance misuse and related disorders, calling these issues one of America’s most pressing public health concerns. “I am issuing a new call to action,” he says in the foreword, “to end the public health crisis of addiction.” Nearly 21 million Americans suffer from substance use disorders—more than the number of people who have all cancers combined.

Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health offers an in-depth look at the science of substance use disorders and addiction, with chapters on neurobiology, prevention, treatment, recovery, health systems integration, and recommendations for the future.

One of the findings is that substance use disorder treatment in the U.S. remains “largely separate” from the rest of health care and serves only a fraction of those in need of treatment. An estimated 1 in 7 people in the U.S. develops a substance use disorder at some point in their lives, yet only 1 in 10 receives treatment. Many factors contribute to this treatment gap, including the stigma associated with drug and alcohol addiction.

There has been progress: The Obama administration has invested in research, development, and evaluation of programs to prevent and treat substance misuse and substance use disorders, as well as support recovery, the report says.

“It’s time to change how we view addiction,” said Dr. Murthy. “Not as a moral failing, but as a chronic illness that must be treated with skill, urgency and compassion. The way we address this crisis is a test for America.”