Genitourinary syndrome of menopause (GSM) is the new terminology to describe symptoms occurring secondary to vulvovaginal atrophy.¹ The recent change in terminology originated with a consensus panel comprising the board of directors of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the board of trustees of the North American Menopause Society (NAMS). At a terminology consensus conference in May 2013, these groups determined that the term GSM is medically more accurate and all encompassing than vulvovaginal atrophy. It is also more publicly acceptable.

The symptoms of GSM derive from the hypoestrogenic state most commonly associated with menopause and its effects on the genitourinary tract.² Vaginal symptoms associated with GSM include vaginal or vulvar dryness, discharge, itching, and dyspareunia.³ Histologically, a loss of superficial epithelial cells in the genitourinary tract leads to thinning of the tissue. There is then a loss of vaginal rugae and elasticity, leading to narrowing and shortening of the vagina.

In addition, the vaginal epithelium becomes much more fragile, which can lead to tears, bleeding, and fissures. There is also a loss of the subcutaneous fat of the labia majora, a change that can result in narrowing of the introitus, fusion of the labia majora, and shrinkage of the clitoral prepuce and urethra. The vaginal pH level becomes more alkaline, which may alter vaginal flora and increase the risk of urogenital infections—specifically, urinary tract infection (UTI). Vaginal secretions, largely transudate, from the vaginal vasculature also decrease over time. These changes lead to significant dyspareunia and impairment of sexual function.

In this article, we survey the therapies available for GSM, focusing first on proven treatments such as local estrogen administration and use of ospemifene (Osphena), and then describing an emerging treatment involving the use of fractional CO₂ laser.

How prevalent is GSM?
Approximately half of all postmenopausal women in the United States report atrophy-related symptoms and a significant negative effect on quality of life.^4–6 Few women with these symptoms seek medical attention.

The Vaginal Health: Insights, Views, and Attitudes (VIVA) survey found that 80% of women with genital atrophy considered its impact on their lives to be negative, 75% reported negative consequences in their sexual life, 68% reported that it made them feel less sexual, 33% reported negative effects on their marriage or relationship, and 26% reported a negative impact on their self-esteem.⁷

Another review of the impact of this condition by Nappi and Palacios estimated that, by the year 2025, there will be 1.1 billion women worldwide older than age 50 with specific needs related to GSM.⁸ Nappi and Palacios cite 4 recent surveys that suggest that health care providers need to be more proactive in helping patients disclose their symptoms. The same can be said of other symptoms of the urinary tract, such as urinary frequency, urgency, and incontinence, as well as pelvic floor relaxation.

A recently published international survey on vaginal atrophy not only depicts the extremely high prevalence of the condition but also describes fairly significant differences in attitudes toward symptoms between countries in Europe and North America.⁹ Overall, 77% of respondents, who included more than 4,000 menopausal women, believed that women were uncomfortable discussing symptoms of vaginal atrophy.⁹

Pastore and colleagues, using data from the Women’s Health Initiative (WHI), found the most prevalent urogenital symptoms to be vaginal dryness (27%), vaginal irritation or itching (18.6%), vaginal discharge (11.1%), and dysuria (5.2%).⁴ Unlike vasomotor symptoms of menopause, which tend to decrease over time, GSM does not spontaneously remit and commonly recurs when hormone therapy—the dominant treatment—is withdrawn.

What can we offer our patients?
Vaginal estrogen
The most common therapy used to manage GSM is estrogen. Most recommendations state that if the primary menopausal symptoms are related to vaginal atrophy, then local estrogen administration should be the primary mode of therapy. The Society of Gynecologic Surgeons Systematic Review Group recently concluded that all commercially available vaginal estrogens effectively can relieve common vulvovaginal atrophy−related symptoms and have additional utility in women with urinary urgency, frequency, stress incontinence, urge incontinence, and recurrent UTIs.¹⁰ Although their meta-­analysis clearly demonstrated that estrogen therapy improves the symptoms of GSM, investigators acknowledged that a clearer understanding is needed of the exact risk to the endometrium with sustained use of vaginal estrogen, as well as a more precise assessment of changes in serum estradiol levels.¹⁰

A recent Cochrane review concluded that all forms of local estrogen appear to be equally effective for symptoms of vaginal atrophy.¹¹ One trial cited in the review found significant adverse effects following administration of cream, compared with tablets, causing uterine bleeding, breast pain, and perineal pain.¹¹

Another trial cited in the Cochrane review found significant endometrial overstimulation following use of cream, compared with the vaginal ring. As a treatment of choice, women appeared to favor the estradiol-releasing vaginal ring for ease of use, comfort of product, and overall satisfaction.¹¹

After the release of the WHI data, the US Food and Drug Administration (FDA) released a “black box” warning on postmenopausal hormone use in women, which has significantly reduced the use of both local and systemic estrogen in eligible women. NAMS has recommended that the FDA revisit this warning, calling specifically for an independent commission to scrutinize every major WHI paper to determine whether the data justify the conclusions drawn.¹²

Most data back local estrogen as treatment for GSM
In 2013, the North American Menopause Society (NAMS) issued a position statement noting that the choice of therapy for genitourinary syndrome of menopause (GSM) depends on the severity of symptoms, the efficacy and safety of therapy for the individual patient, and patient preference.¹

To date, estrogen therapy is the most effective treatment for moderate to severe GSM, although a direct comparison of estrogen and ospemifene is lacking. Nonhormonal therapies available without a prescription provide sufficient relief for most women with mild symptoms. When low-dose estrogen is administered locally, a progestin is not indicated for women without a uterus—and generally is not indicated for women with an intact uterus. However, endometrial safety has not been studied in clinical trials beyond 1 year. Data are insufficient to confirm the safety of local estrogen in women with breast cancer.

Future research on the use of the fractional CO₂ laser, which seems to be a promising emerging therapy, may provide clinicians with another option to treat the common and distressing problem of GSM.

Reference
1. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause. 2013;20(9):888–902.

Ospemifene
This estrogen agonist and antagonist selectively stimulates or inhibits estrogen receptors of different target tissues, making it a selective estrogen receptor modulator (SERM). In a study involving 826 postmenopausal women randomly allocated to 30 mg or 60 mg of ospemifene, the 60-mg dose proved to be more effective for improving vulvovaginal atrophy.¹³ Long-term safety studies revealed that ospemifene 60 mg given daily for 52 weeks was well tolerated and not associated with any endometrial- or breast-related safety issues.^13,14 Common adverse effects of ospemifene reported during clinical trials included hot flashes, vaginal discharge, muscle spasms, general discharge, and excessive sweating.¹²

Vaginal lubricants and moisturizers
Nonestrogen water- or silicone-based vaginal lubricants and moisturizers may alleviate vaginal symptoms related to menopause. These products may be particularly helpful for women who do not wish to use hormone therapies.

Vaginal lubricants are intended to relieve friction and dyspareunia related to vaginal dryness during intercourse, with the ultimate goal of trapping moisture and providing long-term relief of vaginal dryness.

Although data are limited on the efficacy of these products, prospective studies have demonstrated that vaginal moisturizers improve vaginal dryness, pH balance, and elasticity and reduce vaginal itching, irritation, and dyspareunia.

Data are insufficient to support the use of herbal remedies or soy products for the treatment of vaginal symptoms.

An emerging therapy: fractional CO₂ laser
In September 2014, the FDA cleared for use the SmartXide² CO₂ laser system (DEKA Medical) for “incision, excision, vaporization and coagulation of body soft tissues” in medical specialties that include gynecology and genitourinary surgery.¹⁵ The system, also marketed by Cynosure as the MonaLisa Touch treatment, was not approved specifically for treatment of GSM—and it is important to note that the path to device clearance by the FDA is much less cumbersome than the route to drug approval. As NAMS notes in an article about the fractional CO₂ laser, “Device clearance does not require the large, double-blind, randomized, placebo-controlled trials with established efficacy and safety endpoints required for the approval of new drugs.”¹⁶ Nevertheless, this laser system appears to be poised to become a new treatment for the symptoms of GSM. 

This laser supplies energy with a specific pulse to the vaginal wall to rapidly and superficially ablate the epithelial component of atrophic mucosa, which is characterized by low water content. Ablation is followed by tissue coagulation, stimulated by laser energy penetrating into deeper tissues, triggering the synthesis of new collagen and other components of the ground substance of the matrix.

The supraphysiologic level of heat generated by the CO₂ laser induces a rapid and transient heat-shock response that temporarily alters cellular metabolism and activates a small family of proteins referred to as the “heat shock proteins” (HSPs). HSP 70, which is overexpressed following laser treatment, stimulates transforming growth­factor‑beta, triggering an inflammatory response that stimulates fibroblasts, which produce new collagen and extracellular matrix.

The laser has emissions characteristics aligned for the transfer of the energy load to the mucosa while avoiding excessive localized damage. This aspect of its design allows for restoration of the permeability of the connective tissue, enabling the physiologic transfer of various nutrients from capillaries to tissues. When there is a loss of estrogen, as during menopause, vaginal atrophy develops, with the epithelium deteriorating and thinning. The fractional CO₂ laser therapy improves the state of the epithelium by restoring epithelial cell trophism.

The vaginal dryness that occurs with atrophy is due to poor blood flow, as well as reduced activity of the fibroblasts in the deeper tissue. The increased lubrication that occurs after treatment is usually a vaginal transudate from blood outflow through the capillaries that supply blood to the vaginal epithelium. The high presence of water molecules increases permeability, allowing easier transport of metabolites and nutrients from capillaries to tissue, as well as the drainage of waste products from tissues to blood and lymph vessels.

With atrophy, the glycogen in the epithelial cells decreases. Because lactobacilli need glycogen to thrive and are responsible for maintaining the acidity of the vagina, the pH level increases. With the restoration of trophism, glycogen levels increase, furthering colonization of vaginal lactobacilli as well as vaginal acidity, reducing the pH level. This effect also may protect against the development of recurrent UTIs.

A look at the data
To date, more than 2,000 women in Italy and more than 10,000 women worldwide with GSM have been treated with fractional CO₂ laser therapy, and several peer-reviewed publications have documented its efficacy and safety.^17–21

In published studies, however, the populations have been small and the investigations have been mostly short term  (12 weeks).^17–21

A pilot study reported that a treatment cycle of 3 laser applications significantly improved the most bothersome symptoms of vulvovaginal atrophy and improved scores of vaginal health at 12 weeks’ follow-up in 50 women who had not responded to or were unsatisfied with local estrogen therapy.¹⁷ This investigation was followed by 2 additional studies involving another 92 women that specifically addressed the impact of fractional CO₂ laser therapy on dyspareunia and female sexual function.^19,20 Both studies showed statistically significant improvement in dyspareunia as well as Female Sexual Function Index (FSFI) scores. All women in these studies were treated in an office setting with no pretreatment anesthesia. No adverse events were reported.

Recently published histology data highlight significant changes 1 month after fractional CO₂ laser treatment that included a much thicker epithelium with wide columns of large epithelial cells rich in glycogen.²¹ Also noted was a significant reorganization of connective tissue, both in the lamina propria and the core of the papillae (FIGURES 1 and 2).

FIGURE 1: Early-stage vaginal atrophy    This histologic preparation of vaginal mucosa sections reveals untreated early-stage vaginal atrophy (A), with thinning epithelium and the presence of papillae, and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

FIGURE 2: Atrophic vaginitis    This histologic preparation of vaginal mucosa sections shows untreated atrophic vaginitis (A) and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

Caveats
No International Classification of Diseases (ICD) 9 or 10 code has been assigned to the procedure to date, and the cost to the patient ranges from $600 to $1,000 per procedure.¹⁶

NAMS position. A review of the technology by NAMS noted the need for large, long-term, randomized, sham-controlled studies “to further evaluate the safety and efficacy of this procedure.”¹⁶

NAMS also notes that “lasers have become a very costly option for the treatment of symptomatic [GSM], without a single trial comparing active laser treatment to sham laser treatment and no information on long-term safety. In all published trials to date, only several hundred women have been studied and most studies are only 12 weeks in duration.”¹⁶

Not a new concept. The concept of treating skin with a microablative CO₂ laser is not new. This laser has been safely used on the skin of the face, neck, and chest to produce new collagen and elastin fibers with remodeling of tissue.^22,23

Preliminary data on the use of a fractionated CO₂ microablative laser to treat symptoms associated with GSM suggest that the therapy is feasible, effective, and safe in the short term. If these findings are confirmed by larger, longer-term, well-controlled studies, this laser will be an additional safe and effective treatment for this very common and distressing disorder.

Fractional CO₂ laser: A study in progress
Two authors (Mickey Karram, MD, and Eric Sokol, MD) are performing a study of the fractional CO₂ laser for treatment of genitourinary syndrome of menopause (GSM) in the United States. To date, 30 women with GSM have been treated with 3 cycles and followed for 3 months. Preliminary data show significant improvement in all symptoms, with all patients treated in an office setting with no pretreatment or posttreatment analgesia required.

The laser settings for treatment included a power of 30 W, a dwell time of 1,000 µs, spacing between 2 adjacent treated spots of 1,000 µs, and a stack parameter for pulses from 1 to 3. 

Laser energy is delivered through a specially designed scanner and a vaginal probe. The probe is slowly inserted to the top of the vaginal canal and then gradually withdrawn, treating the vaginal epithelium at increments of almost 1 cm (FIGURE 3). The laser beam projects onto a 45° mirror placed at the tip of the probe, which reflects it at 90°, thereby ensuring that only the vaginal wall is treated, and not the uterine cervix.

A treatment cycle included 3 laser treatments at 6-week intervals. Each treatment lasted 3 to 5 minutes. Initial improvement was noted in most patients, including increased lubrication within 1 week after the first treatment, with further improvement after each session. To date, the positive results have persisted, and all women in the trial now have been followed for 3 months—all have noted improvement in symptoms. They will continue periodic assessment, with a final subjective and objective evaluation 1 year after their first treatment.

Bottom line
Although preliminary studies of the fractional CO₂ laser as a treatment for GSM are promising, local estrogen is backed by a large body of reliable data. Ospemifene also has FDA approval for treatment of this disorder.

For women who cannot or will not use a hormone-based therapy, vaginal lubricants and moisturizer may offer at least some relief.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Genitourinary syndrome of menopause (GSM) is the new terminology to describe symptoms occurring secondary to vulvovaginal atrophy.¹ The recent change in terminology originated with a consensus panel comprising the board of directors of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the board of trustees of the North American Menopause Society (NAMS). At a terminology consensus conference in May 2013, these groups determined that the term GSM is medically more accurate and all encompassing than vulvovaginal atrophy. It is also more publicly acceptable.

The symptoms of GSM derive from the hypoestrogenic state most commonly associated with menopause and its effects on the genitourinary tract.² Vaginal symptoms associated with GSM include vaginal or vulvar dryness, discharge, itching, and dyspareunia.³ Histologically, a loss of superficial epithelial cells in the genitourinary tract leads to thinning of the tissue. There is then a loss of vaginal rugae and elasticity, leading to narrowing and shortening of the vagina.

In addition, the vaginal epithelium becomes much more fragile, which can lead to tears, bleeding, and fissures. There is also a loss of the subcutaneous fat of the labia majora, a change that can result in narrowing of the introitus, fusion of the labia majora, and shrinkage of the clitoral prepuce and urethra. The vaginal pH level becomes more alkaline, which may alter vaginal flora and increase the risk of urogenital infections—specifically, urinary tract infection (UTI). Vaginal secretions, largely transudate, from the vaginal vasculature also decrease over time. These changes lead to significant dyspareunia and impairment of sexual function.

In this article, we survey the therapies available for GSM, focusing first on proven treatments such as local estrogen administration and use of ospemifene (Osphena), and then describing an emerging treatment involving the use of fractional CO₂ laser.

How prevalent is GSM?
Approximately half of all postmenopausal women in the United States report atrophy-related symptoms and a significant negative effect on quality of life.^4–6 Few women with these symptoms seek medical attention.

The Vaginal Health: Insights, Views, and Attitudes (VIVA) survey found that 80% of women with genital atrophy considered its impact on their lives to be negative, 75% reported negative consequences in their sexual life, 68% reported that it made them feel less sexual, 33% reported negative effects on their marriage or relationship, and 26% reported a negative impact on their self-esteem.⁷

Another review of the impact of this condition by Nappi and Palacios estimated that, by the year 2025, there will be 1.1 billion women worldwide older than age 50 with specific needs related to GSM.⁸ Nappi and Palacios cite 4 recent surveys that suggest that health care providers need to be more proactive in helping patients disclose their symptoms. The same can be said of other symptoms of the urinary tract, such as urinary frequency, urgency, and incontinence, as well as pelvic floor relaxation.

A recently published international survey on vaginal atrophy not only depicts the extremely high prevalence of the condition but also describes fairly significant differences in attitudes toward symptoms between countries in Europe and North America.⁹ Overall, 77% of respondents, who included more than 4,000 menopausal women, believed that women were uncomfortable discussing symptoms of vaginal atrophy.⁹

Pastore and colleagues, using data from the Women’s Health Initiative (WHI), found the most prevalent urogenital symptoms to be vaginal dryness (27%), vaginal irritation or itching (18.6%), vaginal discharge (11.1%), and dysuria (5.2%).⁴ Unlike vasomotor symptoms of menopause, which tend to decrease over time, GSM does not spontaneously remit and commonly recurs when hormone therapy—the dominant treatment—is withdrawn.

What can we offer our patients?
Vaginal estrogen
The most common therapy used to manage GSM is estrogen. Most recommendations state that if the primary menopausal symptoms are related to vaginal atrophy, then local estrogen administration should be the primary mode of therapy. The Society of Gynecologic Surgeons Systematic Review Group recently concluded that all commercially available vaginal estrogens effectively can relieve common vulvovaginal atrophy−related symptoms and have additional utility in women with urinary urgency, frequency, stress incontinence, urge incontinence, and recurrent UTIs.¹⁰ Although their meta-­analysis clearly demonstrated that estrogen therapy improves the symptoms of GSM, investigators acknowledged that a clearer understanding is needed of the exact risk to the endometrium with sustained use of vaginal estrogen, as well as a more precise assessment of changes in serum estradiol levels.¹⁰

A recent Cochrane review concluded that all forms of local estrogen appear to be equally effective for symptoms of vaginal atrophy.¹¹ One trial cited in the review found significant adverse effects following administration of cream, compared with tablets, causing uterine bleeding, breast pain, and perineal pain.¹¹

Another trial cited in the Cochrane review found significant endometrial overstimulation following use of cream, compared with the vaginal ring. As a treatment of choice, women appeared to favor the estradiol-releasing vaginal ring for ease of use, comfort of product, and overall satisfaction.¹¹

After the release of the WHI data, the US Food and Drug Administration (FDA) released a “black box” warning on postmenopausal hormone use in women, which has significantly reduced the use of both local and systemic estrogen in eligible women. NAMS has recommended that the FDA revisit this warning, calling specifically for an independent commission to scrutinize every major WHI paper to determine whether the data justify the conclusions drawn.¹²

Most data back local estrogen as treatment for GSM
In 2013, the North American Menopause Society (NAMS) issued a position statement noting that the choice of therapy for genitourinary syndrome of menopause (GSM) depends on the severity of symptoms, the efficacy and safety of therapy for the individual patient, and patient preference.¹

To date, estrogen therapy is the most effective treatment for moderate to severe GSM, although a direct comparison of estrogen and ospemifene is lacking. Nonhormonal therapies available without a prescription provide sufficient relief for most women with mild symptoms. When low-dose estrogen is administered locally, a progestin is not indicated for women without a uterus—and generally is not indicated for women with an intact uterus. However, endometrial safety has not been studied in clinical trials beyond 1 year. Data are insufficient to confirm the safety of local estrogen in women with breast cancer.

Future research on the use of the fractional CO₂ laser, which seems to be a promising emerging therapy, may provide clinicians with another option to treat the common and distressing problem of GSM.

Reference
1. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause. 2013;20(9):888–902.

Ospemifene
This estrogen agonist and antagonist selectively stimulates or inhibits estrogen receptors of different target tissues, making it a selective estrogen receptor modulator (SERM). In a study involving 826 postmenopausal women randomly allocated to 30 mg or 60 mg of ospemifene, the 60-mg dose proved to be more effective for improving vulvovaginal atrophy.¹³ Long-term safety studies revealed that ospemifene 60 mg given daily for 52 weeks was well tolerated and not associated with any endometrial- or breast-related safety issues.^13,14 Common adverse effects of ospemifene reported during clinical trials included hot flashes, vaginal discharge, muscle spasms, general discharge, and excessive sweating.¹²

Vaginal lubricants and moisturizers
Nonestrogen water- or silicone-based vaginal lubricants and moisturizers may alleviate vaginal symptoms related to menopause. These products may be particularly helpful for women who do not wish to use hormone therapies.

Vaginal lubricants are intended to relieve friction and dyspareunia related to vaginal dryness during intercourse, with the ultimate goal of trapping moisture and providing long-term relief of vaginal dryness.

Although data are limited on the efficacy of these products, prospective studies have demonstrated that vaginal moisturizers improve vaginal dryness, pH balance, and elasticity and reduce vaginal itching, irritation, and dyspareunia.

Data are insufficient to support the use of herbal remedies or soy products for the treatment of vaginal symptoms.

An emerging therapy: fractional CO₂ laser
In September 2014, the FDA cleared for use the SmartXide² CO₂ laser system (DEKA Medical) for “incision, excision, vaporization and coagulation of body soft tissues” in medical specialties that include gynecology and genitourinary surgery.¹⁵ The system, also marketed by Cynosure as the MonaLisa Touch treatment, was not approved specifically for treatment of GSM—and it is important to note that the path to device clearance by the FDA is much less cumbersome than the route to drug approval. As NAMS notes in an article about the fractional CO₂ laser, “Device clearance does not require the large, double-blind, randomized, placebo-controlled trials with established efficacy and safety endpoints required for the approval of new drugs.”¹⁶ Nevertheless, this laser system appears to be poised to become a new treatment for the symptoms of GSM. 

This laser supplies energy with a specific pulse to the vaginal wall to rapidly and superficially ablate the epithelial component of atrophic mucosa, which is characterized by low water content. Ablation is followed by tissue coagulation, stimulated by laser energy penetrating into deeper tissues, triggering the synthesis of new collagen and other components of the ground substance of the matrix.

The supraphysiologic level of heat generated by the CO₂ laser induces a rapid and transient heat-shock response that temporarily alters cellular metabolism and activates a small family of proteins referred to as the “heat shock proteins” (HSPs). HSP 70, which is overexpressed following laser treatment, stimulates transforming growth­factor‑beta, triggering an inflammatory response that stimulates fibroblasts, which produce new collagen and extracellular matrix.

The laser has emissions characteristics aligned for the transfer of the energy load to the mucosa while avoiding excessive localized damage. This aspect of its design allows for restoration of the permeability of the connective tissue, enabling the physiologic transfer of various nutrients from capillaries to tissues. When there is a loss of estrogen, as during menopause, vaginal atrophy develops, with the epithelium deteriorating and thinning. The fractional CO₂ laser therapy improves the state of the epithelium by restoring epithelial cell trophism.

The vaginal dryness that occurs with atrophy is due to poor blood flow, as well as reduced activity of the fibroblasts in the deeper tissue. The increased lubrication that occurs after treatment is usually a vaginal transudate from blood outflow through the capillaries that supply blood to the vaginal epithelium. The high presence of water molecules increases permeability, allowing easier transport of metabolites and nutrients from capillaries to tissue, as well as the drainage of waste products from tissues to blood and lymph vessels.

With atrophy, the glycogen in the epithelial cells decreases. Because lactobacilli need glycogen to thrive and are responsible for maintaining the acidity of the vagina, the pH level increases. With the restoration of trophism, glycogen levels increase, furthering colonization of vaginal lactobacilli as well as vaginal acidity, reducing the pH level. This effect also may protect against the development of recurrent UTIs.

A look at the data
To date, more than 2,000 women in Italy and more than 10,000 women worldwide with GSM have been treated with fractional CO₂ laser therapy, and several peer-reviewed publications have documented its efficacy and safety.^17–21

In published studies, however, the populations have been small and the investigations have been mostly short term  (12 weeks).^17–21

A pilot study reported that a treatment cycle of 3 laser applications significantly improved the most bothersome symptoms of vulvovaginal atrophy and improved scores of vaginal health at 12 weeks’ follow-up in 50 women who had not responded to or were unsatisfied with local estrogen therapy.¹⁷ This investigation was followed by 2 additional studies involving another 92 women that specifically addressed the impact of fractional CO₂ laser therapy on dyspareunia and female sexual function.^19,20 Both studies showed statistically significant improvement in dyspareunia as well as Female Sexual Function Index (FSFI) scores. All women in these studies were treated in an office setting with no pretreatment anesthesia. No adverse events were reported.

Recently published histology data highlight significant changes 1 month after fractional CO₂ laser treatment that included a much thicker epithelium with wide columns of large epithelial cells rich in glycogen.²¹ Also noted was a significant reorganization of connective tissue, both in the lamina propria and the core of the papillae (FIGURES 1 and 2).

FIGURE 1: Early-stage vaginal atrophy    This histologic preparation of vaginal mucosa sections reveals untreated early-stage vaginal atrophy (A), with thinning epithelium and the presence of papillae, and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

FIGURE 2: Atrophic vaginitis    This histologic preparation of vaginal mucosa sections shows untreated atrophic vaginitis (A) and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

Caveats
No International Classification of Diseases (ICD) 9 or 10 code has been assigned to the procedure to date, and the cost to the patient ranges from $600 to $1,000 per procedure.¹⁶

NAMS position. A review of the technology by NAMS noted the need for large, long-term, randomized, sham-controlled studies “to further evaluate the safety and efficacy of this procedure.”¹⁶

NAMS also notes that “lasers have become a very costly option for the treatment of symptomatic [GSM], without a single trial comparing active laser treatment to sham laser treatment and no information on long-term safety. In all published trials to date, only several hundred women have been studied and most studies are only 12 weeks in duration.”¹⁶

Not a new concept. The concept of treating skin with a microablative CO₂ laser is not new. This laser has been safely used on the skin of the face, neck, and chest to produce new collagen and elastin fibers with remodeling of tissue.^22,23

Preliminary data on the use of a fractionated CO₂ microablative laser to treat symptoms associated with GSM suggest that the therapy is feasible, effective, and safe in the short term. If these findings are confirmed by larger, longer-term, well-controlled studies, this laser will be an additional safe and effective treatment for this very common and distressing disorder.

Fractional CO₂ laser: A study in progress
Two authors (Mickey Karram, MD, and Eric Sokol, MD) are performing a study of the fractional CO₂ laser for treatment of genitourinary syndrome of menopause (GSM) in the United States. To date, 30 women with GSM have been treated with 3 cycles and followed for 3 months. Preliminary data show significant improvement in all symptoms, with all patients treated in an office setting with no pretreatment or posttreatment analgesia required.

The laser settings for treatment included a power of 30 W, a dwell time of 1,000 µs, spacing between 2 adjacent treated spots of 1,000 µs, and a stack parameter for pulses from 1 to 3. 

Laser energy is delivered through a specially designed scanner and a vaginal probe. The probe is slowly inserted to the top of the vaginal canal and then gradually withdrawn, treating the vaginal epithelium at increments of almost 1 cm (FIGURE 3). The laser beam projects onto a 45° mirror placed at the tip of the probe, which reflects it at 90°, thereby ensuring that only the vaginal wall is treated, and not the uterine cervix.

A treatment cycle included 3 laser treatments at 6-week intervals. Each treatment lasted 3 to 5 minutes. Initial improvement was noted in most patients, including increased lubrication within 1 week after the first treatment, with further improvement after each session. To date, the positive results have persisted, and all women in the trial now have been followed for 3 months—all have noted improvement in symptoms. They will continue periodic assessment, with a final subjective and objective evaluation 1 year after their first treatment.

Bottom line
Although preliminary studies of the fractional CO₂ laser as a treatment for GSM are promising, local estrogen is backed by a large body of reliable data. Ospemifene also has FDA approval for treatment of this disorder.

For women who cannot or will not use a hormone-based therapy, vaginal lubricants and moisturizer may offer at least some relief.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Genitourinary syndrome of menopause (GSM) is the new terminology to describe symptoms occurring secondary to vulvovaginal atrophy.¹ The recent change in terminology originated with a consensus panel comprising the board of directors of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the board of trustees of the North American Menopause Society (NAMS). At a terminology consensus conference in May 2013, these groups determined that the term GSM is medically more accurate and all encompassing than vulvovaginal atrophy. It is also more publicly acceptable.

The symptoms of GSM derive from the hypoestrogenic state most commonly associated with menopause and its effects on the genitourinary tract.² Vaginal symptoms associated with GSM include vaginal or vulvar dryness, discharge, itching, and dyspareunia.³ Histologically, a loss of superficial epithelial cells in the genitourinary tract leads to thinning of the tissue. There is then a loss of vaginal rugae and elasticity, leading to narrowing and shortening of the vagina.

In addition, the vaginal epithelium becomes much more fragile, which can lead to tears, bleeding, and fissures. There is also a loss of the subcutaneous fat of the labia majora, a change that can result in narrowing of the introitus, fusion of the labia majora, and shrinkage of the clitoral prepuce and urethra. The vaginal pH level becomes more alkaline, which may alter vaginal flora and increase the risk of urogenital infections—specifically, urinary tract infection (UTI). Vaginal secretions, largely transudate, from the vaginal vasculature also decrease over time. These changes lead to significant dyspareunia and impairment of sexual function.

In this article, we survey the therapies available for GSM, focusing first on proven treatments such as local estrogen administration and use of ospemifene (Osphena), and then describing an emerging treatment involving the use of fractional CO₂ laser.

How prevalent is GSM?
Approximately half of all postmenopausal women in the United States report atrophy-related symptoms and a significant negative effect on quality of life.^4–6 Few women with these symptoms seek medical attention.

The Vaginal Health: Insights, Views, and Attitudes (VIVA) survey found that 80% of women with genital atrophy considered its impact on their lives to be negative, 75% reported negative consequences in their sexual life, 68% reported that it made them feel less sexual, 33% reported negative effects on their marriage or relationship, and 26% reported a negative impact on their self-esteem.⁷

Another review of the impact of this condition by Nappi and Palacios estimated that, by the year 2025, there will be 1.1 billion women worldwide older than age 50 with specific needs related to GSM.⁸ Nappi and Palacios cite 4 recent surveys that suggest that health care providers need to be more proactive in helping patients disclose their symptoms. The same can be said of other symptoms of the urinary tract, such as urinary frequency, urgency, and incontinence, as well as pelvic floor relaxation.

A recently published international survey on vaginal atrophy not only depicts the extremely high prevalence of the condition but also describes fairly significant differences in attitudes toward symptoms between countries in Europe and North America.⁹ Overall, 77% of respondents, who included more than 4,000 menopausal women, believed that women were uncomfortable discussing symptoms of vaginal atrophy.⁹

Pastore and colleagues, using data from the Women’s Health Initiative (WHI), found the most prevalent urogenital symptoms to be vaginal dryness (27%), vaginal irritation or itching (18.6%), vaginal discharge (11.1%), and dysuria (5.2%).⁴ Unlike vasomotor symptoms of menopause, which tend to decrease over time, GSM does not spontaneously remit and commonly recurs when hormone therapy—the dominant treatment—is withdrawn.

What can we offer our patients?
Vaginal estrogen
The most common therapy used to manage GSM is estrogen. Most recommendations state that if the primary menopausal symptoms are related to vaginal atrophy, then local estrogen administration should be the primary mode of therapy. The Society of Gynecologic Surgeons Systematic Review Group recently concluded that all commercially available vaginal estrogens effectively can relieve common vulvovaginal atrophy−related symptoms and have additional utility in women with urinary urgency, frequency, stress incontinence, urge incontinence, and recurrent UTIs.¹⁰ Although their meta-­analysis clearly demonstrated that estrogen therapy improves the symptoms of GSM, investigators acknowledged that a clearer understanding is needed of the exact risk to the endometrium with sustained use of vaginal estrogen, as well as a more precise assessment of changes in serum estradiol levels.¹⁰

A recent Cochrane review concluded that all forms of local estrogen appear to be equally effective for symptoms of vaginal atrophy.¹¹ One trial cited in the review found significant adverse effects following administration of cream, compared with tablets, causing uterine bleeding, breast pain, and perineal pain.¹¹

Another trial cited in the Cochrane review found significant endometrial overstimulation following use of cream, compared with the vaginal ring. As a treatment of choice, women appeared to favor the estradiol-releasing vaginal ring for ease of use, comfort of product, and overall satisfaction.¹¹

After the release of the WHI data, the US Food and Drug Administration (FDA) released a “black box” warning on postmenopausal hormone use in women, which has significantly reduced the use of both local and systemic estrogen in eligible women. NAMS has recommended that the FDA revisit this warning, calling specifically for an independent commission to scrutinize every major WHI paper to determine whether the data justify the conclusions drawn.¹²

Most data back local estrogen as treatment for GSM
In 2013, the North American Menopause Society (NAMS) issued a position statement noting that the choice of therapy for genitourinary syndrome of menopause (GSM) depends on the severity of symptoms, the efficacy and safety of therapy for the individual patient, and patient preference.¹

To date, estrogen therapy is the most effective treatment for moderate to severe GSM, although a direct comparison of estrogen and ospemifene is lacking. Nonhormonal therapies available without a prescription provide sufficient relief for most women with mild symptoms. When low-dose estrogen is administered locally, a progestin is not indicated for women without a uterus—and generally is not indicated for women with an intact uterus. However, endometrial safety has not been studied in clinical trials beyond 1 year. Data are insufficient to confirm the safety of local estrogen in women with breast cancer.

Future research on the use of the fractional CO₂ laser, which seems to be a promising emerging therapy, may provide clinicians with another option to treat the common and distressing problem of GSM.

Reference
1. Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause. 2013;20(9):888–902.

Ospemifene
This estrogen agonist and antagonist selectively stimulates or inhibits estrogen receptors of different target tissues, making it a selective estrogen receptor modulator (SERM). In a study involving 826 postmenopausal women randomly allocated to 30 mg or 60 mg of ospemifene, the 60-mg dose proved to be more effective for improving vulvovaginal atrophy.¹³ Long-term safety studies revealed that ospemifene 60 mg given daily for 52 weeks was well tolerated and not associated with any endometrial- or breast-related safety issues.^13,14 Common adverse effects of ospemifene reported during clinical trials included hot flashes, vaginal discharge, muscle spasms, general discharge, and excessive sweating.¹²

Vaginal lubricants and moisturizers
Nonestrogen water- or silicone-based vaginal lubricants and moisturizers may alleviate vaginal symptoms related to menopause. These products may be particularly helpful for women who do not wish to use hormone therapies.

Vaginal lubricants are intended to relieve friction and dyspareunia related to vaginal dryness during intercourse, with the ultimate goal of trapping moisture and providing long-term relief of vaginal dryness.

Although data are limited on the efficacy of these products, prospective studies have demonstrated that vaginal moisturizers improve vaginal dryness, pH balance, and elasticity and reduce vaginal itching, irritation, and dyspareunia.

Data are insufficient to support the use of herbal remedies or soy products for the treatment of vaginal symptoms.

An emerging therapy: fractional CO₂ laser
In September 2014, the FDA cleared for use the SmartXide² CO₂ laser system (DEKA Medical) for “incision, excision, vaporization and coagulation of body soft tissues” in medical specialties that include gynecology and genitourinary surgery.¹⁵ The system, also marketed by Cynosure as the MonaLisa Touch treatment, was not approved specifically for treatment of GSM—and it is important to note that the path to device clearance by the FDA is much less cumbersome than the route to drug approval. As NAMS notes in an article about the fractional CO₂ laser, “Device clearance does not require the large, double-blind, randomized, placebo-controlled trials with established efficacy and safety endpoints required for the approval of new drugs.”¹⁶ Nevertheless, this laser system appears to be poised to become a new treatment for the symptoms of GSM. 

This laser supplies energy with a specific pulse to the vaginal wall to rapidly and superficially ablate the epithelial component of atrophic mucosa, which is characterized by low water content. Ablation is followed by tissue coagulation, stimulated by laser energy penetrating into deeper tissues, triggering the synthesis of new collagen and other components of the ground substance of the matrix.

The supraphysiologic level of heat generated by the CO₂ laser induces a rapid and transient heat-shock response that temporarily alters cellular metabolism and activates a small family of proteins referred to as the “heat shock proteins” (HSPs). HSP 70, which is overexpressed following laser treatment, stimulates transforming growth­factor‑beta, triggering an inflammatory response that stimulates fibroblasts, which produce new collagen and extracellular matrix.

The laser has emissions characteristics aligned for the transfer of the energy load to the mucosa while avoiding excessive localized damage. This aspect of its design allows for restoration of the permeability of the connective tissue, enabling the physiologic transfer of various nutrients from capillaries to tissues. When there is a loss of estrogen, as during menopause, vaginal atrophy develops, with the epithelium deteriorating and thinning. The fractional CO₂ laser therapy improves the state of the epithelium by restoring epithelial cell trophism.

The vaginal dryness that occurs with atrophy is due to poor blood flow, as well as reduced activity of the fibroblasts in the deeper tissue. The increased lubrication that occurs after treatment is usually a vaginal transudate from blood outflow through the capillaries that supply blood to the vaginal epithelium. The high presence of water molecules increases permeability, allowing easier transport of metabolites and nutrients from capillaries to tissue, as well as the drainage of waste products from tissues to blood and lymph vessels.

With atrophy, the glycogen in the epithelial cells decreases. Because lactobacilli need glycogen to thrive and are responsible for maintaining the acidity of the vagina, the pH level increases. With the restoration of trophism, glycogen levels increase, furthering colonization of vaginal lactobacilli as well as vaginal acidity, reducing the pH level. This effect also may protect against the development of recurrent UTIs.

A look at the data
To date, more than 2,000 women in Italy and more than 10,000 women worldwide with GSM have been treated with fractional CO₂ laser therapy, and several peer-reviewed publications have documented its efficacy and safety.^17–21

In published studies, however, the populations have been small and the investigations have been mostly short term  (12 weeks).^17–21

A pilot study reported that a treatment cycle of 3 laser applications significantly improved the most bothersome symptoms of vulvovaginal atrophy and improved scores of vaginal health at 12 weeks’ follow-up in 50 women who had not responded to or were unsatisfied with local estrogen therapy.¹⁷ This investigation was followed by 2 additional studies involving another 92 women that specifically addressed the impact of fractional CO₂ laser therapy on dyspareunia and female sexual function.^19,20 Both studies showed statistically significant improvement in dyspareunia as well as Female Sexual Function Index (FSFI) scores. All women in these studies were treated in an office setting with no pretreatment anesthesia. No adverse events were reported.

Recently published histology data highlight significant changes 1 month after fractional CO₂ laser treatment that included a much thicker epithelium with wide columns of large epithelial cells rich in glycogen.²¹ Also noted was a significant reorganization of connective tissue, both in the lamina propria and the core of the papillae (FIGURES 1 and 2).

FIGURE 1: Early-stage vaginal atrophy    This histologic preparation of vaginal mucosa sections reveals untreated early-stage vaginal atrophy (A), with thinning epithelium and the presence of papillae, and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

FIGURE 2: Atrophic vaginitis    This histologic preparation of vaginal mucosa sections shows untreated atrophic vaginitis (A) and the same mucosa 1 month after treatment with fractional CO2 laser therapy (B). Reprinted with permission from DEKA M.E.L.A. Srl (Calenzano, Italy) and Professor A. Calligaro, University of Pavia, Italy.

Caveats
No International Classification of Diseases (ICD) 9 or 10 code has been assigned to the procedure to date, and the cost to the patient ranges from $600 to $1,000 per procedure.¹⁶

NAMS position. A review of the technology by NAMS noted the need for large, long-term, randomized, sham-controlled studies “to further evaluate the safety and efficacy of this procedure.”¹⁶

NAMS also notes that “lasers have become a very costly option for the treatment of symptomatic [GSM], without a single trial comparing active laser treatment to sham laser treatment and no information on long-term safety. In all published trials to date, only several hundred women have been studied and most studies are only 12 weeks in duration.”¹⁶

Not a new concept. The concept of treating skin with a microablative CO₂ laser is not new. This laser has been safely used on the skin of the face, neck, and chest to produce new collagen and elastin fibers with remodeling of tissue.^22,23

Preliminary data on the use of a fractionated CO₂ microablative laser to treat symptoms associated with GSM suggest that the therapy is feasible, effective, and safe in the short term. If these findings are confirmed by larger, longer-term, well-controlled studies, this laser will be an additional safe and effective treatment for this very common and distressing disorder.

Fractional CO₂ laser: A study in progress
Two authors (Mickey Karram, MD, and Eric Sokol, MD) are performing a study of the fractional CO₂ laser for treatment of genitourinary syndrome of menopause (GSM) in the United States. To date, 30 women with GSM have been treated with 3 cycles and followed for 3 months. Preliminary data show significant improvement in all symptoms, with all patients treated in an office setting with no pretreatment or posttreatment analgesia required.

The laser settings for treatment included a power of 30 W, a dwell time of 1,000 µs, spacing between 2 adjacent treated spots of 1,000 µs, and a stack parameter for pulses from 1 to 3. 

Laser energy is delivered through a specially designed scanner and a vaginal probe. The probe is slowly inserted to the top of the vaginal canal and then gradually withdrawn, treating the vaginal epithelium at increments of almost 1 cm (FIGURE 3). The laser beam projects onto a 45° mirror placed at the tip of the probe, which reflects it at 90°, thereby ensuring that only the vaginal wall is treated, and not the uterine cervix.

A treatment cycle included 3 laser treatments at 6-week intervals. Each treatment lasted 3 to 5 minutes. Initial improvement was noted in most patients, including increased lubrication within 1 week after the first treatment, with further improvement after each session. To date, the positive results have persisted, and all women in the trial now have been followed for 3 months—all have noted improvement in symptoms. They will continue periodic assessment, with a final subjective and objective evaluation 1 year after their first treatment.

Bottom line
Although preliminary studies of the fractional CO₂ laser as a treatment for GSM are promising, local estrogen is backed by a large body of reliable data. Ospemifene also has FDA approval for treatment of this disorder.

For women who cannot or will not use a hormone-based therapy, vaginal lubricants and moisturizer may offer at least some relief.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.

This video was awarded the Eberhard Lotze Award at the 41st Annual Scientific Meeting of the Society of Gynecologic Surgeons.

Vidyard Video

For more videos from the Society of Gynecologic Surgeons, click here

Visit the Society of Gynecologic Surgeons online: http://sgsonline.org

This video was awarded the Eberhard Lotze Award at the 41st Annual Scientific Meeting of the Society of Gynecologic Surgeons.

Vidyard Video

For more videos from the Society of Gynecologic Surgeons, click here

Visit the Society of Gynecologic Surgeons online: http://sgsonline.org

This video was awarded the Eberhard Lotze Award at the 41st Annual Scientific Meeting of the Society of Gynecologic Surgeons.

Vidyard Video

For more videos from the Society of Gynecologic Surgeons, click here

Visit the Society of Gynecologic Surgeons online: http://sgsonline.org

NEW YORK (Reuters Health) - Young adult cancer survivors will continue to have high hospitalization rates over time, a Canadian study shows.

In five-year cancer survivors diagnosed between ages 20 and 44, hospitalization rates were elevated for at least 20 years, compared to rates in age- and sex-matched controls, according to Dr. Nancy N. Baxter at St. Michael's Hospital in Toronto and colleagues.

For all malignancies except melanoma and testicular cancer, the adjusted relative rate (ARR) of hospitalizations was significantly higher among survivors than controls.

"Late effects and complications of cancer treatments are experienced by many survivors for the rest of their lives," Dr. Baxter told Reuters Health in an e-mail.

The patients in this population-based study were treated from 1992-1999.

"Therapies have changed, she said. "In some cases there may be fewer late effects, but in others, they may be worse."

The study cohort included 20,275 survivors of young adult cancers who were recurrence-free for at least five years, and 101,344 controls. The authors observed survivors for a median of 9.93 years (range 0-16 years), according to their report online July 13 in the Journal of Clinical Oncology.

During this period, 34.3% had at least one hospitalization, vs. 27.3% for controls. The rate per 100 person-years was similar between male and female survivors.

Overall, the ARR of hospitalization in survivors compared with controls was 1.51.

At all time periods, survivors were more likely to be hospitalized than controls. The rate of hospitalization (per 100-person years) among survivors was 0.22 during years 5 to 8, 9 to11, and 12 to14. It decreased significantly during years 15 to 17 and 18 to 20, falling to 0.17 and 0.15, respectively (p

Among controls, the hospitalization rate was relatively constant during all time periods, ranging from 0.13 at 5 to 8 years to 0.12 at years 18 to 20.

The ARR of hospitalizations in survivors compared with controls was also relatively constant during for the first three3 time periods: 1.67, 1.55, and 1.57 at years 5 to 8, 9 to 11, and 12 to 14, respectively. It decreased to 1.36 at 15 to 17 years and 1.22 at years 18 to 20.

Those who survived gastrointestinal, urologic, colorectal, or brain cancers, or leukemia or lymphoma, had an ARR of hospitalization at least twice that of controls.

"We only looked at hospital admissions, not visits to the family doctor or medical conditions and disabilities that didn't require inpatient care," Dr. Baxter said, explaining that this likely underestimated the long-term impact of intense treatments that include surgery, chemotherapy, radiation, and hormonal therapy.

Lillie D. Shockney, Director of Cancer Survivorship Programs at the Sidney Kimmel Cancer Center at Johns Hopkins in Baltimore, said in an e-mail to Reuters Health that physical symptoms can be "guilty by association."

"If a patient had cancer, more tests, including inpatient procedures, might be done to rule out recurrence or the presence of a new malignancy," she said.

Studies such as this one could pave the way for more detailed research on the risk of treatment-related conditions that lead to more medical care, she said.

Shockney also said the report raises awareness of the need to pay special attention to cancer survivors; to consider survivorship as we would a chronic illness.

"Understanding the late effects of cancer treatment will help us design better treatments, counsel patients, and improve symptom management," said Dr. Baxter.

NEW YORK (Reuters Health) - Young adult cancer survivors will continue to have high hospitalization rates over time, a Canadian study shows.

In five-year cancer survivors diagnosed between ages 20 and 44, hospitalization rates were elevated for at least 20 years, compared to rates in age- and sex-matched controls, according to Dr. Nancy N. Baxter at St. Michael's Hospital in Toronto and colleagues.

For all malignancies except melanoma and testicular cancer, the adjusted relative rate (ARR) of hospitalizations was significantly higher among survivors than controls.

"Late effects and complications of cancer treatments are experienced by many survivors for the rest of their lives," Dr. Baxter told Reuters Health in an e-mail.

The patients in this population-based study were treated from 1992-1999.

"Therapies have changed, she said. "In some cases there may be fewer late effects, but in others, they may be worse."

The study cohort included 20,275 survivors of young adult cancers who were recurrence-free for at least five years, and 101,344 controls. The authors observed survivors for a median of 9.93 years (range 0-16 years), according to their report online July 13 in the Journal of Clinical Oncology.

During this period, 34.3% had at least one hospitalization, vs. 27.3% for controls. The rate per 100 person-years was similar between male and female survivors.

Overall, the ARR of hospitalization in survivors compared with controls was 1.51.

At all time periods, survivors were more likely to be hospitalized than controls. The rate of hospitalization (per 100-person years) among survivors was 0.22 during years 5 to 8, 9 to11, and 12 to14. It decreased significantly during years 15 to 17 and 18 to 20, falling to 0.17 and 0.15, respectively (p

Among controls, the hospitalization rate was relatively constant during all time periods, ranging from 0.13 at 5 to 8 years to 0.12 at years 18 to 20.

The ARR of hospitalizations in survivors compared with controls was also relatively constant during for the first three3 time periods: 1.67, 1.55, and 1.57 at years 5 to 8, 9 to 11, and 12 to 14, respectively. It decreased to 1.36 at 15 to 17 years and 1.22 at years 18 to 20.

Those who survived gastrointestinal, urologic, colorectal, or brain cancers, or leukemia or lymphoma, had an ARR of hospitalization at least twice that of controls.

"We only looked at hospital admissions, not visits to the family doctor or medical conditions and disabilities that didn't require inpatient care," Dr. Baxter said, explaining that this likely underestimated the long-term impact of intense treatments that include surgery, chemotherapy, radiation, and hormonal therapy.

Lillie D. Shockney, Director of Cancer Survivorship Programs at the Sidney Kimmel Cancer Center at Johns Hopkins in Baltimore, said in an e-mail to Reuters Health that physical symptoms can be "guilty by association."

"If a patient had cancer, more tests, including inpatient procedures, might be done to rule out recurrence or the presence of a new malignancy," she said.

Studies such as this one could pave the way for more detailed research on the risk of treatment-related conditions that lead to more medical care, she said.

Shockney also said the report raises awareness of the need to pay special attention to cancer survivors; to consider survivorship as we would a chronic illness.

"Understanding the late effects of cancer treatment will help us design better treatments, counsel patients, and improve symptom management," said Dr. Baxter.

NEW YORK (Reuters Health) - Young adult cancer survivors will continue to have high hospitalization rates over time, a Canadian study shows.

In five-year cancer survivors diagnosed between ages 20 and 44, hospitalization rates were elevated for at least 20 years, compared to rates in age- and sex-matched controls, according to Dr. Nancy N. Baxter at St. Michael's Hospital in Toronto and colleagues.

For all malignancies except melanoma and testicular cancer, the adjusted relative rate (ARR) of hospitalizations was significantly higher among survivors than controls.

"Late effects and complications of cancer treatments are experienced by many survivors for the rest of their lives," Dr. Baxter told Reuters Health in an e-mail.

The patients in this population-based study were treated from 1992-1999.

"Therapies have changed, she said. "In some cases there may be fewer late effects, but in others, they may be worse."

The study cohort included 20,275 survivors of young adult cancers who were recurrence-free for at least five years, and 101,344 controls. The authors observed survivors for a median of 9.93 years (range 0-16 years), according to their report online July 13 in the Journal of Clinical Oncology.

During this period, 34.3% had at least one hospitalization, vs. 27.3% for controls. The rate per 100 person-years was similar between male and female survivors.

Overall, the ARR of hospitalization in survivors compared with controls was 1.51.

At all time periods, survivors were more likely to be hospitalized than controls. The rate of hospitalization (per 100-person years) among survivors was 0.22 during years 5 to 8, 9 to11, and 12 to14. It decreased significantly during years 15 to 17 and 18 to 20, falling to 0.17 and 0.15, respectively (p

Among controls, the hospitalization rate was relatively constant during all time periods, ranging from 0.13 at 5 to 8 years to 0.12 at years 18 to 20.

The ARR of hospitalizations in survivors compared with controls was also relatively constant during for the first three3 time periods: 1.67, 1.55, and 1.57 at years 5 to 8, 9 to 11, and 12 to 14, respectively. It decreased to 1.36 at 15 to 17 years and 1.22 at years 18 to 20.

Those who survived gastrointestinal, urologic, colorectal, or brain cancers, or leukemia or lymphoma, had an ARR of hospitalization at least twice that of controls.

"We only looked at hospital admissions, not visits to the family doctor or medical conditions and disabilities that didn't require inpatient care," Dr. Baxter said, explaining that this likely underestimated the long-term impact of intense treatments that include surgery, chemotherapy, radiation, and hormonal therapy.

Lillie D. Shockney, Director of Cancer Survivorship Programs at the Sidney Kimmel Cancer Center at Johns Hopkins in Baltimore, said in an e-mail to Reuters Health that physical symptoms can be "guilty by association."

"If a patient had cancer, more tests, including inpatient procedures, might be done to rule out recurrence or the presence of a new malignancy," she said.

Studies such as this one could pave the way for more detailed research on the risk of treatment-related conditions that lead to more medical care, she said.

Shockney also said the report raises awareness of the need to pay special attention to cancer survivors; to consider survivorship as we would a chronic illness.

"Understanding the late effects of cancer treatment will help us design better treatments, counsel patients, and improve symptom management," said Dr. Baxter.

Blood sample collection

Photo by Juan D. Alfonso

Researchers from the International Myeloma Working Group (IMWG) have proposed revising the International Staging System (ISS) used to stratify patients with newly diagnosed multiple myeloma (MM).

The group’s revised ISS (R-ISS) combines the current ISS with tests for chromosomal abnormalities (CAs) and serum lactate dehydrogenase (LDH) in an attempt to refine the system’s prognostic value.

IMWG researchers assessed the R-ISS in more than 3000 newly diagnosed MM patients and found that patients with R-ISS stage I disease had better overall survival (OS) and progression-free survival (PFS) than patients with stage I disease according to the ISS.

And patients with R-ISS stage III disease had worse survival rates than patients with stage III disease according to the ISS. But PFS and OS numbers for stage II disease were the same with both systems.

The researchers reported these results in the Journal of Clinical Oncology.

They noted that the existing ISS relies on tests for serum β₂-microglobulin and serum albumin to divide patients into 3 risk-factor stages. But the R-ISS adds interphase fluorescence in situ hybridization to check for CAs, along with separate tests for heightened LDH.

The researchers define the 3 R-ISS groups as follows:

• R-ISS I includes patients with ISS stage I disease (serum β₂-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CAs (del[17p] and/or t[4;14] and/or t[14;16]), and normal LDH levels (less than the upper limit of normal range).
• R-ISS III includes patients with ISS stage III disease (serum β₂-microglobulin level > 5.5 mg/L) and high-risk CAs or high LDH levels.
• R-ISS II includes patients with all other possible combinations.

To evaluate the prognostic value of the R-ISS, the researchers analyzed data from 4445 newly diagnosed MM patients who were enrolled in 11 completed trials. ISS, CA, and LDH data were available for 3060 patients.

At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I group (n=871), 62% in the R-ISS II group (n=1894), and 40% in the R-ISS III group (n=295). The 5-year PFS rates were 55%, 36%, and 24%, respectively.

In comparison, the 5-year OS rate was 77% for patients with ISS stage I disease (n=1615), 62% for ISS stage II (n=1630), and 47% for ISS stage III (n=987). The 5-year PFS rates were 49%, 36%, and 30%, respectively.

Based on this work, the researchers said the R-ISS is a simple but powerful prognostic staging system, and they recommend its use in future studies to stratify newly diagnosed MM patients effectively.

“The revised staging system can be used by doctors to discuss prognostic results very carefully with individual patients,” added Brian G.M. Durie, MD, chairman of the IMWG.

“It’s helpful to know the expectations and consider how treatments can be modified based on the new ISS system.”

Blood sample collection

Photo by Juan D. Alfonso

Researchers from the International Myeloma Working Group (IMWG) have proposed revising the International Staging System (ISS) used to stratify patients with newly diagnosed multiple myeloma (MM).

The group’s revised ISS (R-ISS) combines the current ISS with tests for chromosomal abnormalities (CAs) and serum lactate dehydrogenase (LDH) in an attempt to refine the system’s prognostic value.

IMWG researchers assessed the R-ISS in more than 3000 newly diagnosed MM patients and found that patients with R-ISS stage I disease had better overall survival (OS) and progression-free survival (PFS) than patients with stage I disease according to the ISS.

And patients with R-ISS stage III disease had worse survival rates than patients with stage III disease according to the ISS. But PFS and OS numbers for stage II disease were the same with both systems.

The researchers reported these results in the Journal of Clinical Oncology.

They noted that the existing ISS relies on tests for serum β₂-microglobulin and serum albumin to divide patients into 3 risk-factor stages. But the R-ISS adds interphase fluorescence in situ hybridization to check for CAs, along with separate tests for heightened LDH.

The researchers define the 3 R-ISS groups as follows:

• R-ISS I includes patients with ISS stage I disease (serum β₂-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CAs (del[17p] and/or t[4;14] and/or t[14;16]), and normal LDH levels (less than the upper limit of normal range).
• R-ISS III includes patients with ISS stage III disease (serum β₂-microglobulin level > 5.5 mg/L) and high-risk CAs or high LDH levels.
• R-ISS II includes patients with all other possible combinations.

To evaluate the prognostic value of the R-ISS, the researchers analyzed data from 4445 newly diagnosed MM patients who were enrolled in 11 completed trials. ISS, CA, and LDH data were available for 3060 patients.

At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I group (n=871), 62% in the R-ISS II group (n=1894), and 40% in the R-ISS III group (n=295). The 5-year PFS rates were 55%, 36%, and 24%, respectively.

In comparison, the 5-year OS rate was 77% for patients with ISS stage I disease (n=1615), 62% for ISS stage II (n=1630), and 47% for ISS stage III (n=987). The 5-year PFS rates were 49%, 36%, and 30%, respectively.

Based on this work, the researchers said the R-ISS is a simple but powerful prognostic staging system, and they recommend its use in future studies to stratify newly diagnosed MM patients effectively.

“The revised staging system can be used by doctors to discuss prognostic results very carefully with individual patients,” added Brian G.M. Durie, MD, chairman of the IMWG.

“It’s helpful to know the expectations and consider how treatments can be modified based on the new ISS system.”

Blood sample collection

Photo by Juan D. Alfonso

Researchers from the International Myeloma Working Group (IMWG) have proposed revising the International Staging System (ISS) used to stratify patients with newly diagnosed multiple myeloma (MM).

The group’s revised ISS (R-ISS) combines the current ISS with tests for chromosomal abnormalities (CAs) and serum lactate dehydrogenase (LDH) in an attempt to refine the system’s prognostic value.

IMWG researchers assessed the R-ISS in more than 3000 newly diagnosed MM patients and found that patients with R-ISS stage I disease had better overall survival (OS) and progression-free survival (PFS) than patients with stage I disease according to the ISS.

And patients with R-ISS stage III disease had worse survival rates than patients with stage III disease according to the ISS. But PFS and OS numbers for stage II disease were the same with both systems.

The researchers reported these results in the Journal of Clinical Oncology.

They noted that the existing ISS relies on tests for serum β₂-microglobulin and serum albumin to divide patients into 3 risk-factor stages. But the R-ISS adds interphase fluorescence in situ hybridization to check for CAs, along with separate tests for heightened LDH.

The researchers define the 3 R-ISS groups as follows:

• R-ISS I includes patients with ISS stage I disease (serum β₂-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CAs (del[17p] and/or t[4;14] and/or t[14;16]), and normal LDH levels (less than the upper limit of normal range).
• R-ISS III includes patients with ISS stage III disease (serum β₂-microglobulin level > 5.5 mg/L) and high-risk CAs or high LDH levels.
• R-ISS II includes patients with all other possible combinations.

To evaluate the prognostic value of the R-ISS, the researchers analyzed data from 4445 newly diagnosed MM patients who were enrolled in 11 completed trials. ISS, CA, and LDH data were available for 3060 patients.

At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I group (n=871), 62% in the R-ISS II group (n=1894), and 40% in the R-ISS III group (n=295). The 5-year PFS rates were 55%, 36%, and 24%, respectively.

In comparison, the 5-year OS rate was 77% for patients with ISS stage I disease (n=1615), 62% for ISS stage II (n=1630), and 47% for ISS stage III (n=987). The 5-year PFS rates were 49%, 36%, and 30%, respectively.

Based on this work, the researchers said the R-ISS is a simple but powerful prognostic staging system, and they recommend its use in future studies to stratify newly diagnosed MM patients effectively.

“The revised staging system can be used by doctors to discuss prognostic results very carefully with individual patients,” added Brian G.M. Durie, MD, chairman of the IMWG.

“It’s helpful to know the expectations and consider how treatments can be modified based on the new ISS system.”

Growing monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan designation to veltuzumab for the treatment of immune thrombocytopenia (ITP).

Veltuzumab is a 2nd-generation, humanized monoclonal antibody targeting CD20. The drug is being developed by Immunomedics as a treatment for ITP, other autoimmune diseases, and non-Hodgkin lymphoma.

Veltuzumab was considered active and well-tolerated in a phase 1 study of adults with ITP. The drug produced responses in about half of patients, with some responses lasting more than 4 years.

The study included 50 patients with primary ITP who had failed 1 or more types of standard therapy, had platelet levels of 30,000/μL or less, and did not have major bleeding. The patients’ median age was 54, and most were female (n=31). Eight patients had undergone splenectomy.

Patients were a median of 2 years from diagnosis. Fourteen had been diagnosed with ITP for a year or less and had received corticosteroids and/or immunoglobulins.

Thirty-six patients had chronic ITP and had received azathioprine or danazol (n=15), thrombopoietin-receptor agonists (n=10), rituximab (n=7), platelets (n=5), and/or chemotherapy (n=4).

The 34 patients assigned to cohort 1 received 2 doses of subcutaneous veltuzumab at 80 mg, 160 mg, or 320 mg, 2 weeks apart (total doses of 160 mg, 320 mg, and 640 mg, respectively). The 18 patients in cohort 2 (which included 2 rollovers) received once-weekly doses at 320 mg for 4 weeks (total dose of 1280 mg).

The researchers said veltuzumab was well tolerated. The only adverse events were grade 1-2, transient injection reactions.

Forty-seven patients were evaluable for response. Forty-seven percent (n=22) had objective responses (ORs), and 28% (n=13) had complete responses (CRs).

Responses did not differ much according to disease duration. Patients with chronic ITP had an OR rate of 42% and a CR rate of 27%. Patients who had ITP for a year or less had an OR rate of 51% and a CR rate of 29%.

The median time to relapse (TTR) did not differ much between patients with CRs and those with partial responses, but there was a sizable difference between patients with chronic ITP and those with newly diagnosed ITP.

The median TTR was 7.9 months for patients with a CR and 7.6 months for patients with a partial response. The median TTR was 6.9 months for patients with chronic ITP and 14.4 months for patients who had ITP for a year or less.

The phase 2 expansion trial of veltuzumab in ITP has completed accrual, and patients are being followed for up to 5 years.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. Orphan designation provides the sponsor of a drug with various development incentives.

The orphan designation for veltuzumab provides Immunomedics with opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, 7 years of US marketing exclusivity if the drug is approved, and other benefits.

Growing monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan designation to veltuzumab for the treatment of immune thrombocytopenia (ITP).

Veltuzumab is a 2nd-generation, humanized monoclonal antibody targeting CD20. The drug is being developed by Immunomedics as a treatment for ITP, other autoimmune diseases, and non-Hodgkin lymphoma.

Veltuzumab was considered active and well-tolerated in a phase 1 study of adults with ITP. The drug produced responses in about half of patients, with some responses lasting more than 4 years.

The study included 50 patients with primary ITP who had failed 1 or more types of standard therapy, had platelet levels of 30,000/μL or less, and did not have major bleeding. The patients’ median age was 54, and most were female (n=31). Eight patients had undergone splenectomy.

Patients were a median of 2 years from diagnosis. Fourteen had been diagnosed with ITP for a year or less and had received corticosteroids and/or immunoglobulins.

Thirty-six patients had chronic ITP and had received azathioprine or danazol (n=15), thrombopoietin-receptor agonists (n=10), rituximab (n=7), platelets (n=5), and/or chemotherapy (n=4).

The 34 patients assigned to cohort 1 received 2 doses of subcutaneous veltuzumab at 80 mg, 160 mg, or 320 mg, 2 weeks apart (total doses of 160 mg, 320 mg, and 640 mg, respectively). The 18 patients in cohort 2 (which included 2 rollovers) received once-weekly doses at 320 mg for 4 weeks (total dose of 1280 mg).

The researchers said veltuzumab was well tolerated. The only adverse events were grade 1-2, transient injection reactions.

Forty-seven patients were evaluable for response. Forty-seven percent (n=22) had objective responses (ORs), and 28% (n=13) had complete responses (CRs).

Responses did not differ much according to disease duration. Patients with chronic ITP had an OR rate of 42% and a CR rate of 27%. Patients who had ITP for a year or less had an OR rate of 51% and a CR rate of 29%.

The median time to relapse (TTR) did not differ much between patients with CRs and those with partial responses, but there was a sizable difference between patients with chronic ITP and those with newly diagnosed ITP.

The median TTR was 7.9 months for patients with a CR and 7.6 months for patients with a partial response. The median TTR was 6.9 months for patients with chronic ITP and 14.4 months for patients who had ITP for a year or less.

The phase 2 expansion trial of veltuzumab in ITP has completed accrual, and patients are being followed for up to 5 years.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. Orphan designation provides the sponsor of a drug with various development incentives.

The orphan designation for veltuzumab provides Immunomedics with opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, 7 years of US marketing exclusivity if the drug is approved, and other benefits.

Growing monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan designation to veltuzumab for the treatment of immune thrombocytopenia (ITP).

Veltuzumab is a 2nd-generation, humanized monoclonal antibody targeting CD20. The drug is being developed by Immunomedics as a treatment for ITP, other autoimmune diseases, and non-Hodgkin lymphoma.

Veltuzumab was considered active and well-tolerated in a phase 1 study of adults with ITP. The drug produced responses in about half of patients, with some responses lasting more than 4 years.

The study included 50 patients with primary ITP who had failed 1 or more types of standard therapy, had platelet levels of 30,000/μL or less, and did not have major bleeding. The patients’ median age was 54, and most were female (n=31). Eight patients had undergone splenectomy.

Patients were a median of 2 years from diagnosis. Fourteen had been diagnosed with ITP for a year or less and had received corticosteroids and/or immunoglobulins.

Thirty-six patients had chronic ITP and had received azathioprine or danazol (n=15), thrombopoietin-receptor agonists (n=10), rituximab (n=7), platelets (n=5), and/or chemotherapy (n=4).

The 34 patients assigned to cohort 1 received 2 doses of subcutaneous veltuzumab at 80 mg, 160 mg, or 320 mg, 2 weeks apart (total doses of 160 mg, 320 mg, and 640 mg, respectively). The 18 patients in cohort 2 (which included 2 rollovers) received once-weekly doses at 320 mg for 4 weeks (total dose of 1280 mg).

The researchers said veltuzumab was well tolerated. The only adverse events were grade 1-2, transient injection reactions.

Forty-seven patients were evaluable for response. Forty-seven percent (n=22) had objective responses (ORs), and 28% (n=13) had complete responses (CRs).

Responses did not differ much according to disease duration. Patients with chronic ITP had an OR rate of 42% and a CR rate of 27%. Patients who had ITP for a year or less had an OR rate of 51% and a CR rate of 29%.

The median time to relapse (TTR) did not differ much between patients with CRs and those with partial responses, but there was a sizable difference between patients with chronic ITP and those with newly diagnosed ITP.

The median TTR was 7.9 months for patients with a CR and 7.6 months for patients with a partial response. The median TTR was 6.9 months for patients with chronic ITP and 14.4 months for patients who had ITP for a year or less.

The phase 2 expansion trial of veltuzumab in ITP has completed accrual, and patients are being followed for up to 5 years.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. Orphan designation provides the sponsor of a drug with various development incentives.

The orphan designation for veltuzumab provides Immunomedics with opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, 7 years of US marketing exclusivity if the drug is approved, and other benefits.

Preparing pills for a clinical trial

Photo by Esther Dyson

The reporting requirements developed to increase transparency in US medical research may lead to fewer positive trial outcomes, according to a study published in PLOS ONE.

Researchers analyzed data from large-budget trials funded by the National Heart, Lung and Blood Institute (NHLBI).

And they found evidence suggesting the reporting requirements may have contributed to a significant reduction in studies with positive findings.

The reporting standards were phased in around 2000. They require researchers conducting drug or dietary supplement trials using human subjects to identify

projected outcomes and register their trials on ClinicalTrials.gov before they begin to collect data.

When entering their trial into the database, researchers are required to state the specific outcome on which they will focus. In the past, a researcher might have published an aspect of a study that was successful, even if the study overall did not produce the expected results.

But the new requirements mean researchers are less likely to change their analysis plan to consider another outcome that may have shown a positive result, said Veronica L. Irvin, PhD, of Oregon State University in Corvallis.

Dr Irvin began working on this project with the study’s lead author, Robert M. Kaplan, PhD, of the Agency for Healthcare Research and Quality in Rockville,

Maryland, while the two worked together in the National Institutes of Health’s Office of Behavior and Social Science Research.

The pair reviewed all large-budget clinical trials evaluating drugs or dietary supplements for the treatment or prevention of cardiovascular disease that had received funding from the NHLBI between 1970 and 2012.

They chose large-budget, NHLBI-funded trials in part because outcomes from the trials were more likely to be published, even if they did not produce the expected result.

Fifty-five studies were included in the research. Thirty were published prior to the reporting changes in 2000 (1970 to 1999), and 25 were published after the changes (2000 to 2012).

Of the studies published after 2000, only 2 (8%) showed positive outcomes, while 17 (57%) of the studies published before 2000 showed positive results.

Drs Kaplan and Irvin acknowledged that factors other than the reporting requirements may be contributing to the decline in positive outcomes, but they were unable to identify other compelling explanations.

For example, one suggestion was that older trials were more likely to compare new treatments to placebos, while newer trials were more likely to compare new

treatments to established treatments.

But when Drs Kaplan and Irvin examined the data, they found that 60% of trials published before 2000 used placebo comparators and nearly the same amount, 64%, of trials published after 2000 used placebos.

The researchers noted that although this work focused on clinical trials related to cardiovascular health, it would be reasonable to see similar changes in results

across other disease types.

“We don’t know if this decrease in positive outcomes also affects drug trials for prevention and treatment of cancer, diabetes, or other diseases,” Dr Irvin said. “But it would not be surprising because they have the same reporting requirements.”

Preparing pills for a clinical trial

Photo by Esther Dyson

The reporting requirements developed to increase transparency in US medical research may lead to fewer positive trial outcomes, according to a study published in PLOS ONE.

Researchers analyzed data from large-budget trials funded by the National Heart, Lung and Blood Institute (NHLBI).

And they found evidence suggesting the reporting requirements may have contributed to a significant reduction in studies with positive findings.

The reporting standards were phased in around 2000. They require researchers conducting drug or dietary supplement trials using human subjects to identify

projected outcomes and register their trials on ClinicalTrials.gov before they begin to collect data.

When entering their trial into the database, researchers are required to state the specific outcome on which they will focus. In the past, a researcher might have published an aspect of a study that was successful, even if the study overall did not produce the expected results.

But the new requirements mean researchers are less likely to change their analysis plan to consider another outcome that may have shown a positive result, said Veronica L. Irvin, PhD, of Oregon State University in Corvallis.

Dr Irvin began working on this project with the study’s lead author, Robert M. Kaplan, PhD, of the Agency for Healthcare Research and Quality in Rockville,

Maryland, while the two worked together in the National Institutes of Health’s Office of Behavior and Social Science Research.

The pair reviewed all large-budget clinical trials evaluating drugs or dietary supplements for the treatment or prevention of cardiovascular disease that had received funding from the NHLBI between 1970 and 2012.

They chose large-budget, NHLBI-funded trials in part because outcomes from the trials were more likely to be published, even if they did not produce the expected result.

Fifty-five studies were included in the research. Thirty were published prior to the reporting changes in 2000 (1970 to 1999), and 25 were published after the changes (2000 to 2012).

Of the studies published after 2000, only 2 (8%) showed positive outcomes, while 17 (57%) of the studies published before 2000 showed positive results.

Drs Kaplan and Irvin acknowledged that factors other than the reporting requirements may be contributing to the decline in positive outcomes, but they were unable to identify other compelling explanations.

For example, one suggestion was that older trials were more likely to compare new treatments to placebos, while newer trials were more likely to compare new

treatments to established treatments.

But when Drs Kaplan and Irvin examined the data, they found that 60% of trials published before 2000 used placebo comparators and nearly the same amount, 64%, of trials published after 2000 used placebos.

The researchers noted that although this work focused on clinical trials related to cardiovascular health, it would be reasonable to see similar changes in results

across other disease types.

“We don’t know if this decrease in positive outcomes also affects drug trials for prevention and treatment of cancer, diabetes, or other diseases,” Dr Irvin said. “But it would not be surprising because they have the same reporting requirements.”

Preparing pills for a clinical trial

Photo by Esther Dyson

The reporting requirements developed to increase transparency in US medical research may lead to fewer positive trial outcomes, according to a study published in PLOS ONE.

Researchers analyzed data from large-budget trials funded by the National Heart, Lung and Blood Institute (NHLBI).

And they found evidence suggesting the reporting requirements may have contributed to a significant reduction in studies with positive findings.

The reporting standards were phased in around 2000. They require researchers conducting drug or dietary supplement trials using human subjects to identify

projected outcomes and register their trials on ClinicalTrials.gov before they begin to collect data.

When entering their trial into the database, researchers are required to state the specific outcome on which they will focus. In the past, a researcher might have published an aspect of a study that was successful, even if the study overall did not produce the expected results.

But the new requirements mean researchers are less likely to change their analysis plan to consider another outcome that may have shown a positive result, said Veronica L. Irvin, PhD, of Oregon State University in Corvallis.

Dr Irvin began working on this project with the study’s lead author, Robert M. Kaplan, PhD, of the Agency for Healthcare Research and Quality in Rockville,

Maryland, while the two worked together in the National Institutes of Health’s Office of Behavior and Social Science Research.

The pair reviewed all large-budget clinical trials evaluating drugs or dietary supplements for the treatment or prevention of cardiovascular disease that had received funding from the NHLBI between 1970 and 2012.

They chose large-budget, NHLBI-funded trials in part because outcomes from the trials were more likely to be published, even if they did not produce the expected result.

Fifty-five studies were included in the research. Thirty were published prior to the reporting changes in 2000 (1970 to 1999), and 25 were published after the changes (2000 to 2012).

Of the studies published after 2000, only 2 (8%) showed positive outcomes, while 17 (57%) of the studies published before 2000 showed positive results.

Drs Kaplan and Irvin acknowledged that factors other than the reporting requirements may be contributing to the decline in positive outcomes, but they were unable to identify other compelling explanations.

For example, one suggestion was that older trials were more likely to compare new treatments to placebos, while newer trials were more likely to compare new

treatments to established treatments.

But when Drs Kaplan and Irvin examined the data, they found that 60% of trials published before 2000 used placebo comparators and nearly the same amount, 64%, of trials published after 2000 used placebos.

The researchers noted that although this work focused on clinical trials related to cardiovascular health, it would be reasonable to see similar changes in results

across other disease types.

“We don’t know if this decrease in positive outcomes also affects drug trials for prevention and treatment of cancer, diabetes, or other diseases,” Dr Irvin said. “But it would not be surprising because they have the same reporting requirements.”

Blood smear showing MDS

Treatment with lenalidomide can have a significant effect on pulmonary sarcoidosis in myelodysplastic syndrome (MDS), according to a case study.

The case was a 71-year-old woman with newly diagnosed 5q-MDS and a long-standing history of refractory pulmonary sarcoidosis.

After 2 cycles of treatment with lenalidomide, the patient had substantial improvements in lung function, fatigue, daily activity, and quality of life.

This case is the first of its kind to show the potential effects of lenalidomide as a therapeutic option in patients with pulmonary sarcoidosis.

Ali Bazargan, MD, of St. Vincent’s Hospital in Melbourne, Victoria, Australia, and his colleagues described this case in CHEST.

The patient had a 12-year history of stage IV pulmonary sarcoidosis with no extrapulmonary organ involvement. She had never smoked but had a history of hypertension that was managed with perindopril.

The patient presented with refractory and worsening dyspnea, despite receiving long-term therapy with methotrexate and inhaled and systemic corticosteroids. Before she began receiving lenalidomide, the patient was taking 15 mg of prednisolone and 400 mg of inhaled budesonide daily.

Blood tests revealed the patient had macrocytic anemia (hemoglobin level, 81 g/L; mean corpuscular volume, 114 fL).

A subsequent bone marrow biopsy revealed hypocellular marrow with trilineage dysplasia consistent with 5q-MDS but no evidence of noncaseating granulomas. So the patient began receiving lenalidomide at 10 mg daily.

While the researchers were trying to establish her diagnosis of 5q-MDS, the patient became transfusion-dependent and experienced severe dyspnea, fatigue, and a considerable decline in quality of life.

A chest CT scan revealed irregular masses in her lung, with bibasal alveolar infiltrates that had developed within a 12-month period.

However, after 2 cycles of lenalidomide, the patient had significant improvements in dyspnea, fatigue, daily activity, and quality of life. Lung function testing showed an increase in vital capacity from 1.73 L to 1.93 L.

And a chest CT scan performed 4 months after the patient began taking lenalidomide showed that the bibasal alveolar infiltrates had completely cleared.

During this period, the patient’s dose of prednisolone was reduced from 15 mg daily to 5 mg on alternate days, but she continues to receive the same dose of lenalidomide.

Blood smear showing MDS

Treatment with lenalidomide can have a significant effect on pulmonary sarcoidosis in myelodysplastic syndrome (MDS), according to a case study.

The case was a 71-year-old woman with newly diagnosed 5q-MDS and a long-standing history of refractory pulmonary sarcoidosis.

After 2 cycles of treatment with lenalidomide, the patient had substantial improvements in lung function, fatigue, daily activity, and quality of life.

This case is the first of its kind to show the potential effects of lenalidomide as a therapeutic option in patients with pulmonary sarcoidosis.

Ali Bazargan, MD, of St. Vincent’s Hospital in Melbourne, Victoria, Australia, and his colleagues described this case in CHEST.

The patient had a 12-year history of stage IV pulmonary sarcoidosis with no extrapulmonary organ involvement. She had never smoked but had a history of hypertension that was managed with perindopril.

The patient presented with refractory and worsening dyspnea, despite receiving long-term therapy with methotrexate and inhaled and systemic corticosteroids. Before she began receiving lenalidomide, the patient was taking 15 mg of prednisolone and 400 mg of inhaled budesonide daily.

Blood tests revealed the patient had macrocytic anemia (hemoglobin level, 81 g/L; mean corpuscular volume, 114 fL).

A subsequent bone marrow biopsy revealed hypocellular marrow with trilineage dysplasia consistent with 5q-MDS but no evidence of noncaseating granulomas. So the patient began receiving lenalidomide at 10 mg daily.

While the researchers were trying to establish her diagnosis of 5q-MDS, the patient became transfusion-dependent and experienced severe dyspnea, fatigue, and a considerable decline in quality of life.

A chest CT scan revealed irregular masses in her lung, with bibasal alveolar infiltrates that had developed within a 12-month period.

However, after 2 cycles of lenalidomide, the patient had significant improvements in dyspnea, fatigue, daily activity, and quality of life. Lung function testing showed an increase in vital capacity from 1.73 L to 1.93 L.

And a chest CT scan performed 4 months after the patient began taking lenalidomide showed that the bibasal alveolar infiltrates had completely cleared.

During this period, the patient’s dose of prednisolone was reduced from 15 mg daily to 5 mg on alternate days, but she continues to receive the same dose of lenalidomide.

Blood smear showing MDS

Treatment with lenalidomide can have a significant effect on pulmonary sarcoidosis in myelodysplastic syndrome (MDS), according to a case study.

The case was a 71-year-old woman with newly diagnosed 5q-MDS and a long-standing history of refractory pulmonary sarcoidosis.

After 2 cycles of treatment with lenalidomide, the patient had substantial improvements in lung function, fatigue, daily activity, and quality of life.

This case is the first of its kind to show the potential effects of lenalidomide as a therapeutic option in patients with pulmonary sarcoidosis.

Ali Bazargan, MD, of St. Vincent’s Hospital in Melbourne, Victoria, Australia, and his colleagues described this case in CHEST.

The patient had a 12-year history of stage IV pulmonary sarcoidosis with no extrapulmonary organ involvement. She had never smoked but had a history of hypertension that was managed with perindopril.

The patient presented with refractory and worsening dyspnea, despite receiving long-term therapy with methotrexate and inhaled and systemic corticosteroids. Before she began receiving lenalidomide, the patient was taking 15 mg of prednisolone and 400 mg of inhaled budesonide daily.

Blood tests revealed the patient had macrocytic anemia (hemoglobin level, 81 g/L; mean corpuscular volume, 114 fL).

A subsequent bone marrow biopsy revealed hypocellular marrow with trilineage dysplasia consistent with 5q-MDS but no evidence of noncaseating granulomas. So the patient began receiving lenalidomide at 10 mg daily.

While the researchers were trying to establish her diagnosis of 5q-MDS, the patient became transfusion-dependent and experienced severe dyspnea, fatigue, and a considerable decline in quality of life.

A chest CT scan revealed irregular masses in her lung, with bibasal alveolar infiltrates that had developed within a 12-month period.

However, after 2 cycles of lenalidomide, the patient had significant improvements in dyspnea, fatigue, daily activity, and quality of life. Lung function testing showed an increase in vital capacity from 1.73 L to 1.93 L.

And a chest CT scan performed 4 months after the patient began taking lenalidomide showed that the bibasal alveolar infiltrates had completely cleared.

During this period, the patient’s dose of prednisolone was reduced from 15 mg daily to 5 mg on alternate days, but she continues to receive the same dose of lenalidomide.

Only a minority of patients with atrial fibrillation or venous thromboembolism achieved good anticoagulation control while on warfarin, according to a population-based data analysis by Ana Filipa Macedo and her colleagues at Boehringer Ingelheim in the United Kingdom. In fact, only 44% of 140,078 AF patients and 36% of 70,371 VTE patients assessed had an optimal International Normalized Ratio (INR) time in therapeutic range (TTR) more than 70% of the time while on warfarin.

Patient characteristics associated with a significant increase in time spent above or below the recommended INR range of 2.0-3.0 were current smoking, the use of NSAIDs, age less than 45 years, and a body mass index less than 18.5 kg/m² in both AF and VTE patients, whereas patients with VTE alone had predictors of poor control that included chronic obstructive pulmonary disease or asthma, heart failure, and active cancer.

“The study provides evidence that in the first 12 months of warfarin use, there is a high amount of unpredictable variability in an individual’s TTR,” the researchers summarized. “These findings confirm the difficulty of achieving high-quality anticoagulation with warfarin in real-world clinical practice and can be used to identify patients who require closer monitoring or innovative management strategies,” the authors added.

More of the study can be read here (Thromb Res. 2015 Aug; 136(2):250-260.).

The study received funding from Boehringer Ingelheim, and the authors disclosed that they were all employees of the company, which makes a variety of cardiovascular therapies, including anticoagulants.

[email protected]

Only a minority of patients with atrial fibrillation or venous thromboembolism achieved good anticoagulation control while on warfarin, according to a population-based data analysis by Ana Filipa Macedo and her colleagues at Boehringer Ingelheim in the United Kingdom. In fact, only 44% of 140,078 AF patients and 36% of 70,371 VTE patients assessed had an optimal International Normalized Ratio (INR) time in therapeutic range (TTR) more than 70% of the time while on warfarin.

Patient characteristics associated with a significant increase in time spent above or below the recommended INR range of 2.0-3.0 were current smoking, the use of NSAIDs, age less than 45 years, and a body mass index less than 18.5 kg/m² in both AF and VTE patients, whereas patients with VTE alone had predictors of poor control that included chronic obstructive pulmonary disease or asthma, heart failure, and active cancer.

“The study provides evidence that in the first 12 months of warfarin use, there is a high amount of unpredictable variability in an individual’s TTR,” the researchers summarized. “These findings confirm the difficulty of achieving high-quality anticoagulation with warfarin in real-world clinical practice and can be used to identify patients who require closer monitoring or innovative management strategies,” the authors added.

More of the study can be read here (Thromb Res. 2015 Aug; 136(2):250-260.).

The study received funding from Boehringer Ingelheim, and the authors disclosed that they were all employees of the company, which makes a variety of cardiovascular therapies, including anticoagulants.

[email protected]

Only a minority of patients with atrial fibrillation or venous thromboembolism achieved good anticoagulation control while on warfarin, according to a population-based data analysis by Ana Filipa Macedo and her colleagues at Boehringer Ingelheim in the United Kingdom. In fact, only 44% of 140,078 AF patients and 36% of 70,371 VTE patients assessed had an optimal International Normalized Ratio (INR) time in therapeutic range (TTR) more than 70% of the time while on warfarin.

Patient characteristics associated with a significant increase in time spent above or below the recommended INR range of 2.0-3.0 were current smoking, the use of NSAIDs, age less than 45 years, and a body mass index less than 18.5 kg/m² in both AF and VTE patients, whereas patients with VTE alone had predictors of poor control that included chronic obstructive pulmonary disease or asthma, heart failure, and active cancer.

“The study provides evidence that in the first 12 months of warfarin use, there is a high amount of unpredictable variability in an individual’s TTR,” the researchers summarized. “These findings confirm the difficulty of achieving high-quality anticoagulation with warfarin in real-world clinical practice and can be used to identify patients who require closer monitoring or innovative management strategies,” the authors added.

More of the study can be read here (Thromb Res. 2015 Aug; 136(2):250-260.).

The study received funding from Boehringer Ingelheim, and the authors disclosed that they were all employees of the company, which makes a variety of cardiovascular therapies, including anticoagulants.

[email protected]