In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).

Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.

“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.

ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.

Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,

Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.

In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.

The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.

However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.

SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.

In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).

Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.

“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.

ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.

Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,

Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.

In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.

The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.

However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.

SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.

In women with HER2-positive early breast cancer, the anti-HER2 biosimilar agent ABP-980 was clinically similar in efficacy and safety to the original drug trastuzumab (Herceptin).

Although ABP 980 was associated with a higher pathologic complete response (pCR) rate in breast tissues and axillary lymph nodes compared with trastuzumab, the trial technically failed to meet its coprimary endpoints of risk ratio and risk difference because of a statistical nicety involving local lab review of tissue samples vs. centralized review, reported Gunter von Minckwitz, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, and his colleagues.

“In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study,” the researchers wrote. The report was published in The Lancet Oncology.

ABP 980 is one of several contenders for trastuzumab biosimilar making their way through clinical trials. In phase 1 studies, it was shown to be similar in its structure, pharmacodynamics, and pharmacokinetics to the reference agent trastuzumab. In the LILAC trial Dr. von Minckwitz and his associates put the biosimilar through its paces to see whether it would also be equivalent in efficacy and safety, including in patients switched from the original drug to the copy-cat agent.

Investigators for the randomized phase 3 trial, conducted in 97 centers in 20 countries in Europe, South America, and Canada, enrolled 827 women age and 18 and older with HER2-positive breast cancer, 725 of whom were randomly assigned to neoadjuvant therapy with either ABP 980 or trastuzumab plus paclitaxel after a four-cycle run-in of anthracycline-based chemotherapy,

Neoadjuvant therapy was followed 3-7 weeks later by surgery and adjuvant therapy with either of the HER2 inhibitors. At baseline, patients were randomly assigned to either continue adjuvant therapy with their original HER2 inhibitor, or to switch from trastuzumab in the neoadjuvant setting to ABP 980 in the adjuvant setting.

In all, 696 patients were evaluable for the primary endpoint, 358 of whom received the biosimilar, and 338 of whom received trastuzumab. In all, 48% of patients randomly assigned to ABP 980 had a pCR in breast and axillary lymph node tissues assessed at a local laboratory, compared with 41% assigned to trastuzumab.

The risk difference was 7.3%, (90% confidence interval [CI] 1.2-13.4), The risk ratio was 1.188 (90% CI, 1.033-1.366). Although the lower bounds of the confidence intervals showed that ABP 980 was noninferior to trastuzumab, the upper bounds exceeded the predefined equivalence margins of a 13% risk difference and 1.318 risk ratio, respectively, meaning that technically the trial did not meet its coprimary endpoints.

However, in central laboratory review pCR was seen in 48% of patients assigned to ABP 980 at baseline and 42% of those assigned to trastuzumab at baseline. The risk difference was 5.8% (90% CI, –0.5-12.0), and risk ratio was 1.142 (90% CI, 0.993-1.312), and both the lower and upper bounds of the confidence intervals fell within prespecified limits.

SOURCE: von Minckwitz G et al. Lancet Oncol 2018 Jun 4. doi: 10.1016/S1470-2045(18)30241-9.

The mSToPS study “represents an innovative example of the potential (and challenges) inherent in a pragmatic information technology trial. The trial “represents a brave new world for clinical research: an innovative, highly commendable, contemporary pragmatic health care information technology study that tested an important question and yielded significant clinical findings,” wrote two leaders in trial design in an editorial about the study.

In addition, the mHealth Screening to Prevent Strokes (mSToPS) trial tested the utility of a wearable ECG patch to detect new-onset episodes of atrial fibrillation. Thus the study also served as one of the first examples of a trial designed to examine whether a wearable, digital device can transform health care by improving clinical outcomes, an advance that crosses the current “chasm between the technology and clinical worlds,” wrote Eric D. Peterson, MD, and Robert A. Harrington, MD. Their editorial framed mSToPS as a breakthrough in a new type of information technology–based, pragmatic clinical trial (JAMA. 2018 July 10;320[2]:137-8).

Future trials with similar designs and novel health information technology methods could tap into the enormous information contained in electronic health records, wrote Dr. Peterson, a cardiologist, professor of medicine, and executive director of the Duke Clinical Research Institute at Duke University in Durham, N.C., and Dr. Harrington, a cardiologist, professor, and chairman of medicine at Stanford (Calif.) University.

Dr. Steven R. Steinhubl, lead investigator for the mSToPS trial, agreed with this assessment. Speaking in a video interview in March 2018 during the annual scientific sessions of the American College of Cardiology, where Dr. Steinhubl first reported the mSToPS results, he characterized the trial as “completely reimagining how clinical trials are done,” by making them less expensive and more convenient for participants. In this way, mSToPS is a break from the traditional randomized clinical trial format, which creates an “artificial treatment environment and artificial patient behaviors,” said Dr. Steinhubl, a cardiologist and director of digital medicine at the Scripps Translational Science Institute in La Jolla, Calif.

Dr. Peterson has received personal fees from Livogo and has received research funding from Akili, RefleXion Medical, and Verily Life Sciences. Dr. Harrington has been a consultant to Amgen, Element Science, Gilead Sciences, MyoKardia, and WebMD; has served on the board of directors of Signal Path and Scanadu; has received personal fees from Bayer; and has received research funding from Apple, AstraZeneca, Bristol-Myers Squibb, CSL, Janssen, Novartis, Portola, Sanofi, and the Medicines Company. Dr. Steinhubl has received research funding from Janssen, DynoSense, EasyG, SpryHealth, and Striiv.

mzoler@mdedge.com

SOURCE: Peterson ED et al. JAMA. 2018 July 10;320[2]:138-9.

The mSToPS study “represents an innovative example of the potential (and challenges) inherent in a pragmatic information technology trial. The trial “represents a brave new world for clinical research: an innovative, highly commendable, contemporary pragmatic health care information technology study that tested an important question and yielded significant clinical findings,” wrote two leaders in trial design in an editorial about the study.

In addition, the mHealth Screening to Prevent Strokes (mSToPS) trial tested the utility of a wearable ECG patch to detect new-onset episodes of atrial fibrillation. Thus the study also served as one of the first examples of a trial designed to examine whether a wearable, digital device can transform health care by improving clinical outcomes, an advance that crosses the current “chasm between the technology and clinical worlds,” wrote Eric D. Peterson, MD, and Robert A. Harrington, MD. Their editorial framed mSToPS as a breakthrough in a new type of information technology–based, pragmatic clinical trial (JAMA. 2018 July 10;320[2]:137-8).

Future trials with similar designs and novel health information technology methods could tap into the enormous information contained in electronic health records, wrote Dr. Peterson, a cardiologist, professor of medicine, and executive director of the Duke Clinical Research Institute at Duke University in Durham, N.C., and Dr. Harrington, a cardiologist, professor, and chairman of medicine at Stanford (Calif.) University.

Dr. Steven R. Steinhubl, lead investigator for the mSToPS trial, agreed with this assessment. Speaking in a video interview in March 2018 during the annual scientific sessions of the American College of Cardiology, where Dr. Steinhubl first reported the mSToPS results, he characterized the trial as “completely reimagining how clinical trials are done,” by making them less expensive and more convenient for participants. In this way, mSToPS is a break from the traditional randomized clinical trial format, which creates an “artificial treatment environment and artificial patient behaviors,” said Dr. Steinhubl, a cardiologist and director of digital medicine at the Scripps Translational Science Institute in La Jolla, Calif.

Dr. Peterson has received personal fees from Livogo and has received research funding from Akili, RefleXion Medical, and Verily Life Sciences. Dr. Harrington has been a consultant to Amgen, Element Science, Gilead Sciences, MyoKardia, and WebMD; has served on the board of directors of Signal Path and Scanadu; has received personal fees from Bayer; and has received research funding from Apple, AstraZeneca, Bristol-Myers Squibb, CSL, Janssen, Novartis, Portola, Sanofi, and the Medicines Company. Dr. Steinhubl has received research funding from Janssen, DynoSense, EasyG, SpryHealth, and Striiv.

mzoler@mdedge.com

SOURCE: Peterson ED et al. JAMA. 2018 July 10;320[2]:138-9.

The mSToPS study “represents an innovative example of the potential (and challenges) inherent in a pragmatic information technology trial. The trial “represents a brave new world for clinical research: an innovative, highly commendable, contemporary pragmatic health care information technology study that tested an important question and yielded significant clinical findings,” wrote two leaders in trial design in an editorial about the study.

In addition, the mHealth Screening to Prevent Strokes (mSToPS) trial tested the utility of a wearable ECG patch to detect new-onset episodes of atrial fibrillation. Thus the study also served as one of the first examples of a trial designed to examine whether a wearable, digital device can transform health care by improving clinical outcomes, an advance that crosses the current “chasm between the technology and clinical worlds,” wrote Eric D. Peterson, MD, and Robert A. Harrington, MD. Their editorial framed mSToPS as a breakthrough in a new type of information technology–based, pragmatic clinical trial (JAMA. 2018 July 10;320[2]:137-8).

Future trials with similar designs and novel health information technology methods could tap into the enormous information contained in electronic health records, wrote Dr. Peterson, a cardiologist, professor of medicine, and executive director of the Duke Clinical Research Institute at Duke University in Durham, N.C., and Dr. Harrington, a cardiologist, professor, and chairman of medicine at Stanford (Calif.) University.

Dr. Steven R. Steinhubl, lead investigator for the mSToPS trial, agreed with this assessment. Speaking in a video interview in March 2018 during the annual scientific sessions of the American College of Cardiology, where Dr. Steinhubl first reported the mSToPS results, he characterized the trial as “completely reimagining how clinical trials are done,” by making them less expensive and more convenient for participants. In this way, mSToPS is a break from the traditional randomized clinical trial format, which creates an “artificial treatment environment and artificial patient behaviors,” said Dr. Steinhubl, a cardiologist and director of digital medicine at the Scripps Translational Science Institute in La Jolla, Calif.

Dr. Peterson has received personal fees from Livogo and has received research funding from Akili, RefleXion Medical, and Verily Life Sciences. Dr. Harrington has been a consultant to Amgen, Element Science, Gilead Sciences, MyoKardia, and WebMD; has served on the board of directors of Signal Path and Scanadu; has received personal fees from Bayer; and has received research funding from Apple, AstraZeneca, Bristol-Myers Squibb, CSL, Janssen, Novartis, Portola, Sanofi, and the Medicines Company. Dr. Steinhubl has received research funding from Janssen, DynoSense, EasyG, SpryHealth, and Striiv.

mzoler@mdedge.com

SOURCE: Peterson ED et al. JAMA. 2018 July 10;320[2]:138-9.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

ABSTRACT

The traditional technique for patella fracture fixation utilizes prominent hardware. Prominent hardware use, however, results in a high rate of reoperation for symptomatic implant removal. This biomechanical study evaluates the effectiveness of a novel patella fixation technique that minimizes implant prominence.

Patellar transverse osteotomies were created in 13 pairs of cadaveric knees. Paired knees were assigned to either standard fixation (SF) using cannulated partially threaded screws and stainless steel wire tension band, or buried fixation (BF) using headless compression screws with a No. 2 FiberWire tension band and a No. 5 FiberWire cerclage suture. Quadriceps tendons were cyclically loaded to full extension followed by load to failure. The gap across the fracture site, stiffness, and load to failure were measured.

The differences in stiffness and load to failure between the 2 groups were not statistically significant. During cyclic loading, significantly greater gapping was observed across the fracture site in the BF group compared with SF group (P < .05).

Both constructs failed under loads that exceeded typical loads experienced during the postoperative rehabilitation period. Nevertheless, the BF technique demonstrated larger gap formation and a reduced load to failure than the SF technique. Further clinical studies are therefore underway to determine whether the use of constructs with decreased stability but increased patient comfort could improve clinical outcomes and reduce reoperation rates.

Continue to: Patella fractures are common...

Patella fractures are common injuries that can cause considerable disability to the knee extensor apparatus.^1-3 Transverse patella fractures are the most common fracture pattern associated with patella fractures.{Harrell, 2003 #3}² Given that the patella plays a crucial role in knee extensor biomechanics, its proper integrity is vital for physiological knee motion and ambulation.⁴ Traditionally, patella fractures with >2 mm of displacement have been managed with cannulated screws or Kirschner wires (K-wires) and a stainless-steel wire tension band.^5-9 The goal in the treatment of patellar fractures is to reduce fracture fragments accurately and to minimize additional insults to the articular cartilage.¹⁰

Despite advances in surgical protocols and acceptable radiographic outcomes, functional impairment remains common after the treatment of patella fractures. Functional impairment includes knee pain, screw head pain, implant removal, wire breakage, and patella baja.¹ The need for implant removal is one of the most common complications following the open reduction internal fixation of patella fractures.^2,11 The subcutaneous and exposed nature of the patella in conjunction with soft tissue irritation resulting from standard fixation (SF) predisposes the patient toward prominence and discomfort with the retained implant. Although nonunion rates are low, the rate of implant removal can reach as high as 52%.^2,10-12 To overcome some of these complications, we designed a novel buried fixation (BF) method for the treatment of transverse fractures. Our method minimizes the amount of exposed implant to improve patient comfort and potentially reduce the need for future implant removal. These effects are achieved by using headless compression screws and nonabsorbable sutures to attenuate the soft tissue irritation associated with traditional fixation.¹³ While our novel technique has demonstrated improved clinical results, it has not been tested biomechanically against a traditional fixation technique. Therefore, this study aims to evaluate and compare the structural integrity of our novel BF technique with that of the standard technique that uses cannulated screws and wire tension band. We hypothesized that the stability provided by our technique would be similar to that provided by SF for transverse patella fractures.

MATERIALS AND METHODS

SPECIMEN PREPARATION

Thirteen matched pairs of fresh-frozen human cadaveric knees were obtained from a Cedars-Sinai approved tissue bank. Specimens were cut midfemur and were intact to the foot. Legs with major structural bony or ligamentous abnormalities, extensor mechanism disruption, or septic knees were excluded from testing. To assess the bone quality of each specimen prior to testing, dual-energy X-ray absorptiometry was performed using a GE Lunar iDXA scanner (GE Healthcare). Specimens were stored at −30°C and thawed at room temperature for 24 hours prior to biomechanical testing.

A midline anterior approach to the patella was performed, and the extensor retinaculum, quadriceps tendon, and patellar tendon were exposed. A digital caliper was used to measure the craniocaudal and mediolateral dimensions of the patella, and a transverse osteotomy (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association [AO/OTA] type 34-C1) was created at the midway point between superior and inferior poles by using an oscillating saw. The retinaculum was then incised to the level of the midaxial line of the femur. One leg from each matched pair was allocated to the SF group, and the other was allocated to the BF group. Left and right legs were alternately assigned to each group to ensure that laterality was balanced between the 2 groups.

SURGICAL TECHNIQUE

The repair of the specimens in the SF group involved the use of 2 parallel 4.0-mm partially threaded cannulated screws (Acumed) and an 18-gauge monofilament steel wire (Ethicon) in a figure-eight tension band (Figure 1A). The repair of the specimens in the BF group involved the use of 2 parallel standard Acutrak headless compression screws (Acumed), a No. 2 FiberWire (Arthrex) in a figure-eight tension band, and a No. 5 FiberWire (Arthrex) was applied as cerclage around the patella (Figure 1B).

Continue to: Mechanical testing...

MECHANICAL TESTING

Mechanical testing was performed on a biaxial 370.02 Bionix Testing System (MTS Systems Corp.). The femur was rigidly and horizontally secured to a custom-built test frame, and the lower leg was left free to move. The quadriceps tendon was secured in a freeze clamp and was attached to the MTS actuator for loading via a pulley system such that raising the actuator was translated into a simulated quadriceps extensor force.

A differential variable reluctance transducer (DVRT) (Lord MicroStrain) was placed across the osteotomy site to measure the distraction, or gap, across the fracture line. The minimum load to full extension for each specimen was then determined under a slow, controlled increase in load until the leg was in a fully extended position. Any distraction across the fracture line during the initial loading phase was determined by using digital calipers. The specimen was then subjected to a preconditioning phase with 10 cycles from 0 N to full extension under the previously determined load, which was applied at the rate of 5 N/s. Meanwhile, displacement across the fracture site was recorded via the DVRT. Following the preconditioning phase, each specimen was then tested to failure in displacement control at the rate of 1.5 mm/s. Failure was defined as implant failure (screw pullout) or DVRT gapping across the osteotomy site >3 mm.^10,14

Outcome measures included stiffness (N/mm), which was calculated as the slope of the linear change in load from full extension to failure vs DVRT displacement during the final loading phase; failure load (N); gapping (mm) across the osteotomy site at each cycle during the preconditioning phase; and failure mode (pullout vs >3.0 mm gap).

STATISTICAL ANALYSIS

An a priori power analysis revealed that 13 knees per group would be required to obtain an α of 0.05 and a power of 0.80. This calculation was based on a 20% difference in fracture displacement calculated by using the standard deviation and mean previously reported for cannulated screws with nonabsorbable sutures.¹⁴

Means and standard deviations for all dependent outcome measures were computed and compared across the independent measure of fixation type (BF vs SF) through repeated measures Analysis of variance (ANOVA-GLM, SAS 9.3, SAS Institute, Inc.) after controlling for bone mineral density (BMD), gender, and age. Multivariate repeated-measures ANOVA with Tukey's studentized range was applied to cyclic gap data. The mode of failure was compared across fixation type (BF vs SF) for matched data using McNemar’s test. Intracorrelations were computed and examined over all data and separately on the basis of screw fixation type (BF vs SF). All tests were considered statistically significant when P < .05.

Continue to: Results...

RESULTS

Specimen donors were 46% (6/13) male with an average age of 78.5 years (±13.77; range, 56-91 years) and 54% (7/13) female with an average age of 76.57 years (±14.37; range, 59-102 years). Average BMD was significantly lower in female (0.71 ± 0.18) than in male specimens (1.15 ± 0.33) (P < .05).

The average load to full extension across all specimens was 272 N (±54; range, 160-360 N) and was well balanced across matched pairs (270 ± 56 N for BF and 273 ± 54 N for SF). Of the 13 BF specimens, 4 experienced distraction across the fracture line during the determination of the minimum load to full extension. This initial pretest gap was measured with digital calipers (average, 1.5 mm; range, 0.90-1.85 mm) and added as an offset to the respective DVRT displacement data recorded during testing.

The total number of specimens included in the displacement data calculations decreased from 13 to 11 per group because DVRT data were not recorded during cyclic loading for 1 specimen and were considered unreliable in another. The maximum displacement measured across the fracture site during cyclic loading was significantly higher in the BF (0.94 ± 1.21) group than in the SF group (0.19 ± 0.26) as shown in the Table. The average slope of the gap per cycle for each specimen was calculated and compared between the BF and SF groups. The BF group demonstrated a significantly greater increase in gap per cycle than the SF group (Figure 2). Stiffness during load to failure was calculated for all but 1 specimen that did not display any measurable displacement during the final loading cycle. The average final stiffness and failure load between the BF and SF groups were not significantly different (Table). An equal number of specimens in both groups failed through gapping (6/13) and pullout (7/13).

Table. Means and Standard Deviations of the Main Outcome Measures

^aIndicates statistical significance (P < .05).

Abbreviation: NS, not significant.

Failure load was significantly positively correlated with BMD (R = 0.62, P < .001) when all specimens were grouped together. When analyzed separately, the SF group was significantly correlated with BMD (P < .01), whereas the BF group had a marginally significant correlation (P = .06) with BMD (Figure 3). In both groups, BMD was positively correlated with stiffness and negatively correlated with gapping. Neither of these trends, however, was significant.

Continue to: Discussion...

DISCUSSION

We proposed a novel BF technique for the treatment of noncomminuted transverse patella fractures. Our technique utilizes headless cannulated compression screws and nonabsorbable suture tension bands. We then biomechanically compared our proposed technique with an established fixation technique that uses partially threaded cannulated screws and stainless steel wire tension bands. We hypothesized that the mechanical response of the BF technique to cyclic and failure loading would be similar to that of the SF technique. Our results demonstrate a significant increase in gap formation across the fracture site among knees and an overall reduced load to failure in the BF group (Figure 2). Whether these inferior results manifest clinically is not yet established. Both constructs could withstand forces that are typically experienced during the postoperative period. Given the high rate of symptomatic implant removal associated with the traditional technique, the low-profile buried technique might be an attractive alternative that provides increased patient comfort but may require an extended period of postoperative protection against bony ingrowths.

Patellar fixation constructs that use a combination of cannulated screws and a wire tension band provide the best resistance to patella fracture displacement when compared with screws or wires alone.^4,15 Although this combination is biomechanically favorable, the steel wire often causes the painful irritation of the surrounding soft tissues and can break or migrate, thus increasing the rates of implant removal surgery to as high as 52%.^4,10,12,15 We developed our novel BF technique, which uses headless compression screws and a No. 2 FiberWire tension band, to address the high rates of reoperation and patient dissatisfaction associated with the SF technique.

Headless compression screws have been successfully used in the reduction and fixation of scaphoid fractures and sesamoid fractures.^16,17 The pull-out strengths of these screws are comparable with those of other commonly used screws, such as Twinfix and Herbert-Whipple screws.¹⁶ Similarly, the strength of a No. 5 FiberWire is comparable with that of an 18-gauge stainless-steel wire.^14,18 Several studies have also obtained good outcomes with nonmetallic constructs that use nonabsorbable sutures alone.^19,20 In this study, we utilized a No. 2 FiberWire as the tension band. The use of the No. 2 FiberWire facilitated threading through headless cannulated screws and created a low-profile knot. However, the use of thin FiberWire, despite a No. 5 FiberWire cerclage, likely contributed to the increase in distraction across the fracture.

The highest patellofemoral joint reaction force during level walking is approximately 35 kg (half body weight), which is equivalent to 350 N.^15,21,22 This force is similar to the average cyclic load used in this experiment (272 ± 54 N). Gapping increased in the BF group but did not reach the defined failure value of 3 mm, and the ultimate load to failure was relatively high across both groups (SF, 1123 N; BF, 973 N). These results suggest that both fixation methods can withstand the typical patellofemoral joint forces that are experienced during the postoperative period.⁴ In addition, in a clinical setting, patients are placed in hinged knee braces for at least 2 weeks to limit their flexion angle and to allow for healing and bony ingrowth. Postoperative knee-brace protection presumably increases the overall strength of the fixation.

The number of specimens (n = 26) evaluated in this study was greater than that used in other biomechanical patella fracture studies.¹⁴ Furthermore, none of our specimens were reused. Our study design was further strengthened given that fellowship-trained trauma surgeons performed all surgical procedures. Finally, the data collection and analysis of numerous clinically relevant factors, such as BMD, age, and cyclical loading, contributed to the comprehensive description of each technique with respect to patient-specific criteria.

Similar to all cadaveric studies, our data only represent the immediate postoperative condition and does not represent any healing that would occur during postoperative rehabilitation. Postoperative knee-brace protection and bone healing across the fracture site would likely strengthen both constructs in a clinical setting. In addition, the average age of our specimens is 77.5 years, and therefore does not best represent the age range (20-50 years) of the typical adult population affected by patella fractures.^3,23,24 Finally, postsurgical reduction was confirmed through visual inspection and not through fluoroscopy as in a clinical setting. Radiographic images were obtained after each experiment only to confirm screw placement post facto (Figures 4A, 4B).

CONCLUSION

This study demonstrates the utility of a novel BF technique. Nevertheless, the proposed technique exhibited increased gapping and a lower load to failure than the current gold standard. The significance of these inferior results in clinical and functional settings has not been established. The proposed BF technique may be an appealing alternative to the SF technique given its low profile and potential to reduce the rates of future implant removal. Further studies on the long-term outcomes of patients treated through the BF technique are currently under way and will ultimately determine the utility of the proposed construct.

This paper will be judged for the Resident Writer’s Award.

ABSTRACT

The traditional technique for patella fracture fixation utilizes prominent hardware. Prominent hardware use, however, results in a high rate of reoperation for symptomatic implant removal. This biomechanical study evaluates the effectiveness of a novel patella fixation technique that minimizes implant prominence.

Patellar transverse osteotomies were created in 13 pairs of cadaveric knees. Paired knees were assigned to either standard fixation (SF) using cannulated partially threaded screws and stainless steel wire tension band, or buried fixation (BF) using headless compression screws with a No. 2 FiberWire tension band and a No. 5 FiberWire cerclage suture. Quadriceps tendons were cyclically loaded to full extension followed by load to failure. The gap across the fracture site, stiffness, and load to failure were measured.

The differences in stiffness and load to failure between the 2 groups were not statistically significant. During cyclic loading, significantly greater gapping was observed across the fracture site in the BF group compared with SF group (P < .05).

Both constructs failed under loads that exceeded typical loads experienced during the postoperative rehabilitation period. Nevertheless, the BF technique demonstrated larger gap formation and a reduced load to failure than the SF technique. Further clinical studies are therefore underway to determine whether the use of constructs with decreased stability but increased patient comfort could improve clinical outcomes and reduce reoperation rates.

Continue to: Patella fractures are common...

Patella fractures are common injuries that can cause considerable disability to the knee extensor apparatus.^1-3 Transverse patella fractures are the most common fracture pattern associated with patella fractures.{Harrell, 2003 #3}² Given that the patella plays a crucial role in knee extensor biomechanics, its proper integrity is vital for physiological knee motion and ambulation.⁴ Traditionally, patella fractures with >2 mm of displacement have been managed with cannulated screws or Kirschner wires (K-wires) and a stainless-steel wire tension band.^5-9 The goal in the treatment of patellar fractures is to reduce fracture fragments accurately and to minimize additional insults to the articular cartilage.¹⁰

Despite advances in surgical protocols and acceptable radiographic outcomes, functional impairment remains common after the treatment of patella fractures. Functional impairment includes knee pain, screw head pain, implant removal, wire breakage, and patella baja.¹ The need for implant removal is one of the most common complications following the open reduction internal fixation of patella fractures.^2,11 The subcutaneous and exposed nature of the patella in conjunction with soft tissue irritation resulting from standard fixation (SF) predisposes the patient toward prominence and discomfort with the retained implant. Although nonunion rates are low, the rate of implant removal can reach as high as 52%.^2,10-12 To overcome some of these complications, we designed a novel buried fixation (BF) method for the treatment of transverse fractures. Our method minimizes the amount of exposed implant to improve patient comfort and potentially reduce the need for future implant removal. These effects are achieved by using headless compression screws and nonabsorbable sutures to attenuate the soft tissue irritation associated with traditional fixation.¹³ While our novel technique has demonstrated improved clinical results, it has not been tested biomechanically against a traditional fixation technique. Therefore, this study aims to evaluate and compare the structural integrity of our novel BF technique with that of the standard technique that uses cannulated screws and wire tension band. We hypothesized that the stability provided by our technique would be similar to that provided by SF for transverse patella fractures.

MATERIALS AND METHODS

SPECIMEN PREPARATION

Thirteen matched pairs of fresh-frozen human cadaveric knees were obtained from a Cedars-Sinai approved tissue bank. Specimens were cut midfemur and were intact to the foot. Legs with major structural bony or ligamentous abnormalities, extensor mechanism disruption, or septic knees were excluded from testing. To assess the bone quality of each specimen prior to testing, dual-energy X-ray absorptiometry was performed using a GE Lunar iDXA scanner (GE Healthcare). Specimens were stored at −30°C and thawed at room temperature for 24 hours prior to biomechanical testing.

A midline anterior approach to the patella was performed, and the extensor retinaculum, quadriceps tendon, and patellar tendon were exposed. A digital caliper was used to measure the craniocaudal and mediolateral dimensions of the patella, and a transverse osteotomy (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association [AO/OTA] type 34-C1) was created at the midway point between superior and inferior poles by using an oscillating saw. The retinaculum was then incised to the level of the midaxial line of the femur. One leg from each matched pair was allocated to the SF group, and the other was allocated to the BF group. Left and right legs were alternately assigned to each group to ensure that laterality was balanced between the 2 groups.

SURGICAL TECHNIQUE

The repair of the specimens in the SF group involved the use of 2 parallel 4.0-mm partially threaded cannulated screws (Acumed) and an 18-gauge monofilament steel wire (Ethicon) in a figure-eight tension band (Figure 1A). The repair of the specimens in the BF group involved the use of 2 parallel standard Acutrak headless compression screws (Acumed), a No. 2 FiberWire (Arthrex) in a figure-eight tension band, and a No. 5 FiberWire (Arthrex) was applied as cerclage around the patella (Figure 1B).

Continue to: Mechanical testing...

MECHANICAL TESTING

Mechanical testing was performed on a biaxial 370.02 Bionix Testing System (MTS Systems Corp.). The femur was rigidly and horizontally secured to a custom-built test frame, and the lower leg was left free to move. The quadriceps tendon was secured in a freeze clamp and was attached to the MTS actuator for loading via a pulley system such that raising the actuator was translated into a simulated quadriceps extensor force.

A differential variable reluctance transducer (DVRT) (Lord MicroStrain) was placed across the osteotomy site to measure the distraction, or gap, across the fracture line. The minimum load to full extension for each specimen was then determined under a slow, controlled increase in load until the leg was in a fully extended position. Any distraction across the fracture line during the initial loading phase was determined by using digital calipers. The specimen was then subjected to a preconditioning phase with 10 cycles from 0 N to full extension under the previously determined load, which was applied at the rate of 5 N/s. Meanwhile, displacement across the fracture site was recorded via the DVRT. Following the preconditioning phase, each specimen was then tested to failure in displacement control at the rate of 1.5 mm/s. Failure was defined as implant failure (screw pullout) or DVRT gapping across the osteotomy site >3 mm.^10,14

Outcome measures included stiffness (N/mm), which was calculated as the slope of the linear change in load from full extension to failure vs DVRT displacement during the final loading phase; failure load (N); gapping (mm) across the osteotomy site at each cycle during the preconditioning phase; and failure mode (pullout vs >3.0 mm gap).

STATISTICAL ANALYSIS

An a priori power analysis revealed that 13 knees per group would be required to obtain an α of 0.05 and a power of 0.80. This calculation was based on a 20% difference in fracture displacement calculated by using the standard deviation and mean previously reported for cannulated screws with nonabsorbable sutures.¹⁴

Means and standard deviations for all dependent outcome measures were computed and compared across the independent measure of fixation type (BF vs SF) through repeated measures Analysis of variance (ANOVA-GLM, SAS 9.3, SAS Institute, Inc.) after controlling for bone mineral density (BMD), gender, and age. Multivariate repeated-measures ANOVA with Tukey's studentized range was applied to cyclic gap data. The mode of failure was compared across fixation type (BF vs SF) for matched data using McNemar’s test. Intracorrelations were computed and examined over all data and separately on the basis of screw fixation type (BF vs SF). All tests were considered statistically significant when P < .05.

Continue to: Results...

RESULTS

Specimen donors were 46% (6/13) male with an average age of 78.5 years (±13.77; range, 56-91 years) and 54% (7/13) female with an average age of 76.57 years (±14.37; range, 59-102 years). Average BMD was significantly lower in female (0.71 ± 0.18) than in male specimens (1.15 ± 0.33) (P < .05).

The average load to full extension across all specimens was 272 N (±54; range, 160-360 N) and was well balanced across matched pairs (270 ± 56 N for BF and 273 ± 54 N for SF). Of the 13 BF specimens, 4 experienced distraction across the fracture line during the determination of the minimum load to full extension. This initial pretest gap was measured with digital calipers (average, 1.5 mm; range, 0.90-1.85 mm) and added as an offset to the respective DVRT displacement data recorded during testing.

The total number of specimens included in the displacement data calculations decreased from 13 to 11 per group because DVRT data were not recorded during cyclic loading for 1 specimen and were considered unreliable in another. The maximum displacement measured across the fracture site during cyclic loading was significantly higher in the BF (0.94 ± 1.21) group than in the SF group (0.19 ± 0.26) as shown in the Table. The average slope of the gap per cycle for each specimen was calculated and compared between the BF and SF groups. The BF group demonstrated a significantly greater increase in gap per cycle than the SF group (Figure 2). Stiffness during load to failure was calculated for all but 1 specimen that did not display any measurable displacement during the final loading cycle. The average final stiffness and failure load between the BF and SF groups were not significantly different (Table). An equal number of specimens in both groups failed through gapping (6/13) and pullout (7/13).

Table. Means and Standard Deviations of the Main Outcome Measures

^aIndicates statistical significance (P < .05).

Abbreviation: NS, not significant.

Failure load was significantly positively correlated with BMD (R = 0.62, P < .001) when all specimens were grouped together. When analyzed separately, the SF group was significantly correlated with BMD (P < .01), whereas the BF group had a marginally significant correlation (P = .06) with BMD (Figure 3). In both groups, BMD was positively correlated with stiffness and negatively correlated with gapping. Neither of these trends, however, was significant.

Continue to: Discussion...

DISCUSSION

We proposed a novel BF technique for the treatment of noncomminuted transverse patella fractures. Our technique utilizes headless cannulated compression screws and nonabsorbable suture tension bands. We then biomechanically compared our proposed technique with an established fixation technique that uses partially threaded cannulated screws and stainless steel wire tension bands. We hypothesized that the mechanical response of the BF technique to cyclic and failure loading would be similar to that of the SF technique. Our results demonstrate a significant increase in gap formation across the fracture site among knees and an overall reduced load to failure in the BF group (Figure 2). Whether these inferior results manifest clinically is not yet established. Both constructs could withstand forces that are typically experienced during the postoperative period. Given the high rate of symptomatic implant removal associated with the traditional technique, the low-profile buried technique might be an attractive alternative that provides increased patient comfort but may require an extended period of postoperative protection against bony ingrowths.

Patellar fixation constructs that use a combination of cannulated screws and a wire tension band provide the best resistance to patella fracture displacement when compared with screws or wires alone.^4,15 Although this combination is biomechanically favorable, the steel wire often causes the painful irritation of the surrounding soft tissues and can break or migrate, thus increasing the rates of implant removal surgery to as high as 52%.^4,10,12,15 We developed our novel BF technique, which uses headless compression screws and a No. 2 FiberWire tension band, to address the high rates of reoperation and patient dissatisfaction associated with the SF technique.

Headless compression screws have been successfully used in the reduction and fixation of scaphoid fractures and sesamoid fractures.^16,17 The pull-out strengths of these screws are comparable with those of other commonly used screws, such as Twinfix and Herbert-Whipple screws.¹⁶ Similarly, the strength of a No. 5 FiberWire is comparable with that of an 18-gauge stainless-steel wire.^14,18 Several studies have also obtained good outcomes with nonmetallic constructs that use nonabsorbable sutures alone.^19,20 In this study, we utilized a No. 2 FiberWire as the tension band. The use of the No. 2 FiberWire facilitated threading through headless cannulated screws and created a low-profile knot. However, the use of thin FiberWire, despite a No. 5 FiberWire cerclage, likely contributed to the increase in distraction across the fracture.

The highest patellofemoral joint reaction force during level walking is approximately 35 kg (half body weight), which is equivalent to 350 N.^15,21,22 This force is similar to the average cyclic load used in this experiment (272 ± 54 N). Gapping increased in the BF group but did not reach the defined failure value of 3 mm, and the ultimate load to failure was relatively high across both groups (SF, 1123 N; BF, 973 N). These results suggest that both fixation methods can withstand the typical patellofemoral joint forces that are experienced during the postoperative period.⁴ In addition, in a clinical setting, patients are placed in hinged knee braces for at least 2 weeks to limit their flexion angle and to allow for healing and bony ingrowth. Postoperative knee-brace protection presumably increases the overall strength of the fixation.

The number of specimens (n = 26) evaluated in this study was greater than that used in other biomechanical patella fracture studies.¹⁴ Furthermore, none of our specimens were reused. Our study design was further strengthened given that fellowship-trained trauma surgeons performed all surgical procedures. Finally, the data collection and analysis of numerous clinically relevant factors, such as BMD, age, and cyclical loading, contributed to the comprehensive description of each technique with respect to patient-specific criteria.

Similar to all cadaveric studies, our data only represent the immediate postoperative condition and does not represent any healing that would occur during postoperative rehabilitation. Postoperative knee-brace protection and bone healing across the fracture site would likely strengthen both constructs in a clinical setting. In addition, the average age of our specimens is 77.5 years, and therefore does not best represent the age range (20-50 years) of the typical adult population affected by patella fractures.^3,23,24 Finally, postsurgical reduction was confirmed through visual inspection and not through fluoroscopy as in a clinical setting. Radiographic images were obtained after each experiment only to confirm screw placement post facto (Figures 4A, 4B).

CONCLUSION

This study demonstrates the utility of a novel BF technique. Nevertheless, the proposed technique exhibited increased gapping and a lower load to failure than the current gold standard. The significance of these inferior results in clinical and functional settings has not been established. The proposed BF technique may be an appealing alternative to the SF technique given its low profile and potential to reduce the rates of future implant removal. Further studies on the long-term outcomes of patients treated through the BF technique are currently under way and will ultimately determine the utility of the proposed construct.

This paper will be judged for the Resident Writer’s Award.

ABSTRACT

The traditional technique for patella fracture fixation utilizes prominent hardware. Prominent hardware use, however, results in a high rate of reoperation for symptomatic implant removal. This biomechanical study evaluates the effectiveness of a novel patella fixation technique that minimizes implant prominence.

Patellar transverse osteotomies were created in 13 pairs of cadaveric knees. Paired knees were assigned to either standard fixation (SF) using cannulated partially threaded screws and stainless steel wire tension band, or buried fixation (BF) using headless compression screws with a No. 2 FiberWire tension band and a No. 5 FiberWire cerclage suture. Quadriceps tendons were cyclically loaded to full extension followed by load to failure. The gap across the fracture site, stiffness, and load to failure were measured.

The differences in stiffness and load to failure between the 2 groups were not statistically significant. During cyclic loading, significantly greater gapping was observed across the fracture site in the BF group compared with SF group (P < .05).

Both constructs failed under loads that exceeded typical loads experienced during the postoperative rehabilitation period. Nevertheless, the BF technique demonstrated larger gap formation and a reduced load to failure than the SF technique. Further clinical studies are therefore underway to determine whether the use of constructs with decreased stability but increased patient comfort could improve clinical outcomes and reduce reoperation rates.

Continue to: Patella fractures are common...

Patella fractures are common injuries that can cause considerable disability to the knee extensor apparatus.^1-3 Transverse patella fractures are the most common fracture pattern associated with patella fractures.{Harrell, 2003 #3}² Given that the patella plays a crucial role in knee extensor biomechanics, its proper integrity is vital for physiological knee motion and ambulation.⁴ Traditionally, patella fractures with >2 mm of displacement have been managed with cannulated screws or Kirschner wires (K-wires) and a stainless-steel wire tension band.^5-9 The goal in the treatment of patellar fractures is to reduce fracture fragments accurately and to minimize additional insults to the articular cartilage.¹⁰

Despite advances in surgical protocols and acceptable radiographic outcomes, functional impairment remains common after the treatment of patella fractures. Functional impairment includes knee pain, screw head pain, implant removal, wire breakage, and patella baja.¹ The need for implant removal is one of the most common complications following the open reduction internal fixation of patella fractures.^2,11 The subcutaneous and exposed nature of the patella in conjunction with soft tissue irritation resulting from standard fixation (SF) predisposes the patient toward prominence and discomfort with the retained implant. Although nonunion rates are low, the rate of implant removal can reach as high as 52%.^2,10-12 To overcome some of these complications, we designed a novel buried fixation (BF) method for the treatment of transverse fractures. Our method minimizes the amount of exposed implant to improve patient comfort and potentially reduce the need for future implant removal. These effects are achieved by using headless compression screws and nonabsorbable sutures to attenuate the soft tissue irritation associated with traditional fixation.¹³ While our novel technique has demonstrated improved clinical results, it has not been tested biomechanically against a traditional fixation technique. Therefore, this study aims to evaluate and compare the structural integrity of our novel BF technique with that of the standard technique that uses cannulated screws and wire tension band. We hypothesized that the stability provided by our technique would be similar to that provided by SF for transverse patella fractures.

MATERIALS AND METHODS

SPECIMEN PREPARATION

Thirteen matched pairs of fresh-frozen human cadaveric knees were obtained from a Cedars-Sinai approved tissue bank. Specimens were cut midfemur and were intact to the foot. Legs with major structural bony or ligamentous abnormalities, extensor mechanism disruption, or septic knees were excluded from testing. To assess the bone quality of each specimen prior to testing, dual-energy X-ray absorptiometry was performed using a GE Lunar iDXA scanner (GE Healthcare). Specimens were stored at −30°C and thawed at room temperature for 24 hours prior to biomechanical testing.

A midline anterior approach to the patella was performed, and the extensor retinaculum, quadriceps tendon, and patellar tendon were exposed. A digital caliper was used to measure the craniocaudal and mediolateral dimensions of the patella, and a transverse osteotomy (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association [AO/OTA] type 34-C1) was created at the midway point between superior and inferior poles by using an oscillating saw. The retinaculum was then incised to the level of the midaxial line of the femur. One leg from each matched pair was allocated to the SF group, and the other was allocated to the BF group. Left and right legs were alternately assigned to each group to ensure that laterality was balanced between the 2 groups.

SURGICAL TECHNIQUE

The repair of the specimens in the SF group involved the use of 2 parallel 4.0-mm partially threaded cannulated screws (Acumed) and an 18-gauge monofilament steel wire (Ethicon) in a figure-eight tension band (Figure 1A). The repair of the specimens in the BF group involved the use of 2 parallel standard Acutrak headless compression screws (Acumed), a No. 2 FiberWire (Arthrex) in a figure-eight tension band, and a No. 5 FiberWire (Arthrex) was applied as cerclage around the patella (Figure 1B).

Continue to: Mechanical testing...

MECHANICAL TESTING

Mechanical testing was performed on a biaxial 370.02 Bionix Testing System (MTS Systems Corp.). The femur was rigidly and horizontally secured to a custom-built test frame, and the lower leg was left free to move. The quadriceps tendon was secured in a freeze clamp and was attached to the MTS actuator for loading via a pulley system such that raising the actuator was translated into a simulated quadriceps extensor force.

A differential variable reluctance transducer (DVRT) (Lord MicroStrain) was placed across the osteotomy site to measure the distraction, or gap, across the fracture line. The minimum load to full extension for each specimen was then determined under a slow, controlled increase in load until the leg was in a fully extended position. Any distraction across the fracture line during the initial loading phase was determined by using digital calipers. The specimen was then subjected to a preconditioning phase with 10 cycles from 0 N to full extension under the previously determined load, which was applied at the rate of 5 N/s. Meanwhile, displacement across the fracture site was recorded via the DVRT. Following the preconditioning phase, each specimen was then tested to failure in displacement control at the rate of 1.5 mm/s. Failure was defined as implant failure (screw pullout) or DVRT gapping across the osteotomy site >3 mm.^10,14

Outcome measures included stiffness (N/mm), which was calculated as the slope of the linear change in load from full extension to failure vs DVRT displacement during the final loading phase; failure load (N); gapping (mm) across the osteotomy site at each cycle during the preconditioning phase; and failure mode (pullout vs >3.0 mm gap).

STATISTICAL ANALYSIS

An a priori power analysis revealed that 13 knees per group would be required to obtain an α of 0.05 and a power of 0.80. This calculation was based on a 20% difference in fracture displacement calculated by using the standard deviation and mean previously reported for cannulated screws with nonabsorbable sutures.¹⁴

Means and standard deviations for all dependent outcome measures were computed and compared across the independent measure of fixation type (BF vs SF) through repeated measures Analysis of variance (ANOVA-GLM, SAS 9.3, SAS Institute, Inc.) after controlling for bone mineral density (BMD), gender, and age. Multivariate repeated-measures ANOVA with Tukey's studentized range was applied to cyclic gap data. The mode of failure was compared across fixation type (BF vs SF) for matched data using McNemar’s test. Intracorrelations were computed and examined over all data and separately on the basis of screw fixation type (BF vs SF). All tests were considered statistically significant when P < .05.

Continue to: Results...

RESULTS

Specimen donors were 46% (6/13) male with an average age of 78.5 years (±13.77; range, 56-91 years) and 54% (7/13) female with an average age of 76.57 years (±14.37; range, 59-102 years). Average BMD was significantly lower in female (0.71 ± 0.18) than in male specimens (1.15 ± 0.33) (P < .05).

The average load to full extension across all specimens was 272 N (±54; range, 160-360 N) and was well balanced across matched pairs (270 ± 56 N for BF and 273 ± 54 N for SF). Of the 13 BF specimens, 4 experienced distraction across the fracture line during the determination of the minimum load to full extension. This initial pretest gap was measured with digital calipers (average, 1.5 mm; range, 0.90-1.85 mm) and added as an offset to the respective DVRT displacement data recorded during testing.

The total number of specimens included in the displacement data calculations decreased from 13 to 11 per group because DVRT data were not recorded during cyclic loading for 1 specimen and were considered unreliable in another. The maximum displacement measured across the fracture site during cyclic loading was significantly higher in the BF (0.94 ± 1.21) group than in the SF group (0.19 ± 0.26) as shown in the Table. The average slope of the gap per cycle for each specimen was calculated and compared between the BF and SF groups. The BF group demonstrated a significantly greater increase in gap per cycle than the SF group (Figure 2). Stiffness during load to failure was calculated for all but 1 specimen that did not display any measurable displacement during the final loading cycle. The average final stiffness and failure load between the BF and SF groups were not significantly different (Table). An equal number of specimens in both groups failed through gapping (6/13) and pullout (7/13).

Table. Means and Standard Deviations of the Main Outcome Measures

^aIndicates statistical significance (P < .05).

Abbreviation: NS, not significant.

Failure load was significantly positively correlated with BMD (R = 0.62, P < .001) when all specimens were grouped together. When analyzed separately, the SF group was significantly correlated with BMD (P < .01), whereas the BF group had a marginally significant correlation (P = .06) with BMD (Figure 3). In both groups, BMD was positively correlated with stiffness and negatively correlated with gapping. Neither of these trends, however, was significant.

Continue to: Discussion...

DISCUSSION

We proposed a novel BF technique for the treatment of noncomminuted transverse patella fractures. Our technique utilizes headless cannulated compression screws and nonabsorbable suture tension bands. We then biomechanically compared our proposed technique with an established fixation technique that uses partially threaded cannulated screws and stainless steel wire tension bands. We hypothesized that the mechanical response of the BF technique to cyclic and failure loading would be similar to that of the SF technique. Our results demonstrate a significant increase in gap formation across the fracture site among knees and an overall reduced load to failure in the BF group (Figure 2). Whether these inferior results manifest clinically is not yet established. Both constructs could withstand forces that are typically experienced during the postoperative period. Given the high rate of symptomatic implant removal associated with the traditional technique, the low-profile buried technique might be an attractive alternative that provides increased patient comfort but may require an extended period of postoperative protection against bony ingrowths.

Patellar fixation constructs that use a combination of cannulated screws and a wire tension band provide the best resistance to patella fracture displacement when compared with screws or wires alone.^4,15 Although this combination is biomechanically favorable, the steel wire often causes the painful irritation of the surrounding soft tissues and can break or migrate, thus increasing the rates of implant removal surgery to as high as 52%.^4,10,12,15 We developed our novel BF technique, which uses headless compression screws and a No. 2 FiberWire tension band, to address the high rates of reoperation and patient dissatisfaction associated with the SF technique.

Headless compression screws have been successfully used in the reduction and fixation of scaphoid fractures and sesamoid fractures.^16,17 The pull-out strengths of these screws are comparable with those of other commonly used screws, such as Twinfix and Herbert-Whipple screws.¹⁶ Similarly, the strength of a No. 5 FiberWire is comparable with that of an 18-gauge stainless-steel wire.^14,18 Several studies have also obtained good outcomes with nonmetallic constructs that use nonabsorbable sutures alone.^19,20 In this study, we utilized a No. 2 FiberWire as the tension band. The use of the No. 2 FiberWire facilitated threading through headless cannulated screws and created a low-profile knot. However, the use of thin FiberWire, despite a No. 5 FiberWire cerclage, likely contributed to the increase in distraction across the fracture.

The highest patellofemoral joint reaction force during level walking is approximately 35 kg (half body weight), which is equivalent to 350 N.^15,21,22 This force is similar to the average cyclic load used in this experiment (272 ± 54 N). Gapping increased in the BF group but did not reach the defined failure value of 3 mm, and the ultimate load to failure was relatively high across both groups (SF, 1123 N; BF, 973 N). These results suggest that both fixation methods can withstand the typical patellofemoral joint forces that are experienced during the postoperative period.⁴ In addition, in a clinical setting, patients are placed in hinged knee braces for at least 2 weeks to limit their flexion angle and to allow for healing and bony ingrowth. Postoperative knee-brace protection presumably increases the overall strength of the fixation.

The number of specimens (n = 26) evaluated in this study was greater than that used in other biomechanical patella fracture studies.¹⁴ Furthermore, none of our specimens were reused. Our study design was further strengthened given that fellowship-trained trauma surgeons performed all surgical procedures. Finally, the data collection and analysis of numerous clinically relevant factors, such as BMD, age, and cyclical loading, contributed to the comprehensive description of each technique with respect to patient-specific criteria.

Similar to all cadaveric studies, our data only represent the immediate postoperative condition and does not represent any healing that would occur during postoperative rehabilitation. Postoperative knee-brace protection and bone healing across the fracture site would likely strengthen both constructs in a clinical setting. In addition, the average age of our specimens is 77.5 years, and therefore does not best represent the age range (20-50 years) of the typical adult population affected by patella fractures.^3,23,24 Finally, postsurgical reduction was confirmed through visual inspection and not through fluoroscopy as in a clinical setting. Radiographic images were obtained after each experiment only to confirm screw placement post facto (Figures 4A, 4B).

CONCLUSION

This study demonstrates the utility of a novel BF technique. Nevertheless, the proposed technique exhibited increased gapping and a lower load to failure than the current gold standard. The significance of these inferior results in clinical and functional settings has not been established. The proposed BF technique may be an appealing alternative to the SF technique given its low profile and potential to reduce the rates of future implant removal. Further studies on the long-term outcomes of patients treated through the BF technique are currently under way and will ultimately determine the utility of the proposed construct.

This paper will be judged for the Resident Writer’s Award.

ORLANDO – Serum uric acid lowering might help prevent kidney disease in children with type 2 diabetes mellitus, according to a 7-year investigation of 539 children.

Every 1-mg/dL climb in baseline serum uric acid increased the risk of subsequent elevated urine albumin excretion 1.23 fold, after adjustment for potential confounders (P = .02).

The finding adds to growing evidence that serum uric acid (SUA) isn’t just a marker of diabetic kidney disease, but a contributor to it. “There is definitely” cross-talk between gout and diabetes, said lead investigator Petter Bjornstad, MD, assistant professor of pediatric endocrinology at the University of Colorado, Aurora.

Elevated SUA is common in both conditions and a risk factor for kidney disease. Newer studies have linked higher levels to nephron number decline and other pathologies, perhaps through renal inflammation. Allopurinol, the traditional uric acid lowering agent in gout, is already under investigation to prevent kidney decline in adults with type 1 diabetes mellitus. There’s also evidence that the potent uric acid lowering agent, febuxostat (Uloric), attenuates hypofiltration in early diabetic kidney disease.

M. Alexander Otto/MDedge News

aotto@mdedge.com

SOURCE: Bjornstad P et al. ADA 2018, abstract 339-OR.

ORLANDO – Serum uric acid lowering might help prevent kidney disease in children with type 2 diabetes mellitus, according to a 7-year investigation of 539 children.

Every 1-mg/dL climb in baseline serum uric acid increased the risk of subsequent elevated urine albumin excretion 1.23 fold, after adjustment for potential confounders (P = .02).

The finding adds to growing evidence that serum uric acid (SUA) isn’t just a marker of diabetic kidney disease, but a contributor to it. “There is definitely” cross-talk between gout and diabetes, said lead investigator Petter Bjornstad, MD, assistant professor of pediatric endocrinology at the University of Colorado, Aurora.

Elevated SUA is common in both conditions and a risk factor for kidney disease. Newer studies have linked higher levels to nephron number decline and other pathologies, perhaps through renal inflammation. Allopurinol, the traditional uric acid lowering agent in gout, is already under investigation to prevent kidney decline in adults with type 1 diabetes mellitus. There’s also evidence that the potent uric acid lowering agent, febuxostat (Uloric), attenuates hypofiltration in early diabetic kidney disease.

M. Alexander Otto/MDedge News

aotto@mdedge.com

SOURCE: Bjornstad P et al. ADA 2018, abstract 339-OR.

ORLANDO – Serum uric acid lowering might help prevent kidney disease in children with type 2 diabetes mellitus, according to a 7-year investigation of 539 children.

Every 1-mg/dL climb in baseline serum uric acid increased the risk of subsequent elevated urine albumin excretion 1.23 fold, after adjustment for potential confounders (P = .02).

The finding adds to growing evidence that serum uric acid (SUA) isn’t just a marker of diabetic kidney disease, but a contributor to it. “There is definitely” cross-talk between gout and diabetes, said lead investigator Petter Bjornstad, MD, assistant professor of pediatric endocrinology at the University of Colorado, Aurora.

Elevated SUA is common in both conditions and a risk factor for kidney disease. Newer studies have linked higher levels to nephron number decline and other pathologies, perhaps through renal inflammation. Allopurinol, the traditional uric acid lowering agent in gout, is already under investigation to prevent kidney decline in adults with type 1 diabetes mellitus. There’s also evidence that the potent uric acid lowering agent, febuxostat (Uloric), attenuates hypofiltration in early diabetic kidney disease.

M. Alexander Otto/MDedge News

aotto@mdedge.com

SOURCE: Bjornstad P et al. ADA 2018, abstract 339-OR.

Vitamin D receptors are found in every cell of the body and have been shown to play a role in bone, neural, and cardiovascular health; immune regulation; and possibly cancer prevention via the regulation of cell differentiation, proliferation, and apoptosis.¹ Although it is controversial, vitamin D deficiency has been associated with various forms of nonscarring hair loss,^2-4 including telogen effluvium, androgenetic alopecia, and alopecia areata. We describe a notable case of nonscarring alopecia associated with vitamin D deficiency in which vitamin D replacement therapy promoted hair regrowth.

Case Report

An otherwise healthy 34-year-old black woman presented to the Hair and Nail Clinic at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) for evaluation of progressive hair loss of 4 years’ duration that began shortly after her fourth child was born. Although she denied any history of excessive shedding, she stated that she used to have shoulder-length hair and somehow it had become extremely short without shaving or cutting the hair (Figure 1). Her current medications included a progestin intrauterine device and biotin 10 mg once daily, the latter of which she had taken for several months for the hair loss without any improvement.

On physical examination, the patient was noted to have diffusely thinning, short, brittle hair. Trichoscopy was notable for hairs of varying diameters, with some fractured at the level of the follicular ostia but no yellow dots at the follicular openings or exclamation point hairs. No scarring or erythema was seen on the scalp. The patient refused several of our team’s recommendations for scalp biopsy due to needle phobia. A hair growth window was made that showed good regrowth at 2 weeks after the initial presentation. Initial blood work revealed a total serum 25-hydroxyvitamin D level of 12 ng/mL (optimal, >30 ng/mL). Complete blood cell count, hormonal panel, zinc level, iron level, and thyroid studies were all normal.

The patient was started on vitamin D₃ replacement therapy 50,000 IU once weekly for 4 weeks followed by 1000 IU once daily for 6 months. No other topical or systemic treatments were administered for the nonscarring alopecia. At a follow-up visit 6 months later, the patient’s vitamin D level was 36 ng/mL, and she had noticeable hair regrowth (Figure 2). At this time, the diagnosis of nonscarring alopecia associated with vitamin D deficiency was made.

Comment

Vitamin D is a fat-soluble vitamin that can be obtained via sun exposure, food sources (eg, fish, vitamin D–fortified foods), and direct supplementation.⁵ It has been estimated that nearly 1 billion individuals worldwide⁶ and approximately 41.6% of US adults are vitamin D deficient.⁷ Certainly not all of these individuals will present with alopecia, but in patients with hair loss, we suggest that vitamin D deficiency is an important factor to consider. Risk factors for vitamin D deficiency include older age, obesity, darker skin types, residence in northern latitudes, and malabsorption syndromes.⁷

Pathogenesis
Vitamin D is thought to play a role in the normal initiation and completion of the hair cycle as well as the differentiation of the follicular and interfollicular epidermis. The vitamin D receptor (VDR) is thought to induce the development of mature anagen hairs via the canonical WNT-β-catenin and hedgehog signaling pathways.⁸ In the absence of VDRs, the stem cells in the bulge of the hair follicle have an impaired ability to replicate, and as a result, VDR-deficient mice have shown near-total hair loss.^9-12 We propose that vitamin D deficiency can not only be a trigger for hair loss but also can perpetuate hair loss and poor regrowth.

Diagnosis and Prevention of Vitamin D Deficiency
In the skin, 7-dehydrocholesterol is converted to previtamin D₃ via UVB light, followed by subsequent conversion to vitamin D₃. Dietary sources are in the form of either vitamin D₂ or D₃, both of which are converted in the liver to 25-hydroxyvitamin D, the major circulating metabolite. In the kidneys, 25-hydroxyvitamin D is then converted to 1,25-dihydroxyvitamin D, the biologically active form. Paradoxically, serum levels of 1,25-dihydroxyvitamin D can be normal or high in the setting of vitamin D deficiency; therefore, serum total 25-hydroxyvitamin D is the best way to assess a patient’s vitamin D status.^5,13

The optimal serum 25-hydroxyvitamin D level is controversial. Recommendations range between 20 to 40 ng/mL¹⁴ and 30 to 50 ng/mL.^13,15,16 Vitamin D levels higher than 50 ng/mL have been correlated with an increased risk of bone fractures and certain cancers.^16-18 Vitamin D toxicity usually is noted in serum levels greater than 88 ng/mL; symptoms of toxicity include hypercalcemia, nausea, vomiting, and muscle weakness. For nondeficient patients, the National Academy of Medicine (formerly the Institute of Medicine) recommended an upper limit of 4000 IU daily.¹⁴ The optimal dose in preventing vitamin D deficiency ranges from 600 to 1000 IU daily.^13-15

Treatment of Vitamin D Deficiency
In the setting of vitamin D deficiency, the amount required for repletion often is dependent on each individual’s ability to absorb and convert to 25-hydroxyvitamin D. Typically every 100 IU of vitamin D correlates with a 0.7 to 1.0 ng/mL increase in serum 25-hydroxyvitamin D levels.¹⁹ There are multiple dosing regimens used to achieve the desired serum 25-hydroxyvitamin D levels in deficient patients. One recommendation from the Endocrine Society is 50,000 IU once weekly for 6 to 8 weeks (single doses >50,000 IU typically are not recommended due to increased risk for toxicity), followed by 600 to 1000 IU once daily in children and 1500 to 2000 IU once daily in adults thereafter.¹³ In patients with vitamin D deficiency, reassessment of serum 25-hydroxyvitamin D levels is recommended after 3 to 4 months of treatment, and adjustments to the repletion regimen should be made as needed.^15,16 Generally, vitamin D₃ is recommended over vitamin D₂ due to enhanced efficacy in raising serum 25-hydroxyvitamin D levels.²⁰

Vitamin D Deficiency in Alopecia
Although most recommendations are given in the interest of optimizing bone health, in the setting of alopecia, we set a similar serum 25-hydroxyvitamin D goal of greater than 30 ng/mL. We recommend treatment with vitamin D₃ and practice the following repletion protocol: 50,000 IU once weekly for 4 weeks, followed by 1000 IU once daily for at least 8 weeks for serum 25-hydroxyvitamin D levels less than 20 ng/mL. For serum hydroxyvitamin D levels between 20 and 29 ng/mL, we recommend 1000 IU once daily for at least 12 weeks. We recheck blood levels again in 3 months. If levels fail to normalize, we will refer the patient to endocrinology. If levels return to normal, we transition to a daily multivitamin with vitamin D (400–800 IU) once daily and refer the patient back to the primary care physician for long-term monitoring.

Vitamin D receptors are found in every cell of the body and have been shown to play a role in bone, neural, and cardiovascular health; immune regulation; and possibly cancer prevention via the regulation of cell differentiation, proliferation, and apoptosis.¹ Although it is controversial, vitamin D deficiency has been associated with various forms of nonscarring hair loss,^2-4 including telogen effluvium, androgenetic alopecia, and alopecia areata. We describe a notable case of nonscarring alopecia associated with vitamin D deficiency in which vitamin D replacement therapy promoted hair regrowth.

Case Report

An otherwise healthy 34-year-old black woman presented to the Hair and Nail Clinic at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) for evaluation of progressive hair loss of 4 years’ duration that began shortly after her fourth child was born. Although she denied any history of excessive shedding, she stated that she used to have shoulder-length hair and somehow it had become extremely short without shaving or cutting the hair (Figure 1). Her current medications included a progestin intrauterine device and biotin 10 mg once daily, the latter of which she had taken for several months for the hair loss without any improvement.

On physical examination, the patient was noted to have diffusely thinning, short, brittle hair. Trichoscopy was notable for hairs of varying diameters, with some fractured at the level of the follicular ostia but no yellow dots at the follicular openings or exclamation point hairs. No scarring or erythema was seen on the scalp. The patient refused several of our team’s recommendations for scalp biopsy due to needle phobia. A hair growth window was made that showed good regrowth at 2 weeks after the initial presentation. Initial blood work revealed a total serum 25-hydroxyvitamin D level of 12 ng/mL (optimal, >30 ng/mL). Complete blood cell count, hormonal panel, zinc level, iron level, and thyroid studies were all normal.

The patient was started on vitamin D₃ replacement therapy 50,000 IU once weekly for 4 weeks followed by 1000 IU once daily for 6 months. No other topical or systemic treatments were administered for the nonscarring alopecia. At a follow-up visit 6 months later, the patient’s vitamin D level was 36 ng/mL, and she had noticeable hair regrowth (Figure 2). At this time, the diagnosis of nonscarring alopecia associated with vitamin D deficiency was made.

Comment

Vitamin D is a fat-soluble vitamin that can be obtained via sun exposure, food sources (eg, fish, vitamin D–fortified foods), and direct supplementation.⁵ It has been estimated that nearly 1 billion individuals worldwide⁶ and approximately 41.6% of US adults are vitamin D deficient.⁷ Certainly not all of these individuals will present with alopecia, but in patients with hair loss, we suggest that vitamin D deficiency is an important factor to consider. Risk factors for vitamin D deficiency include older age, obesity, darker skin types, residence in northern latitudes, and malabsorption syndromes.⁷

Pathogenesis
Vitamin D is thought to play a role in the normal initiation and completion of the hair cycle as well as the differentiation of the follicular and interfollicular epidermis. The vitamin D receptor (VDR) is thought to induce the development of mature anagen hairs via the canonical WNT-β-catenin and hedgehog signaling pathways.⁸ In the absence of VDRs, the stem cells in the bulge of the hair follicle have an impaired ability to replicate, and as a result, VDR-deficient mice have shown near-total hair loss.^9-12 We propose that vitamin D deficiency can not only be a trigger for hair loss but also can perpetuate hair loss and poor regrowth.

Diagnosis and Prevention of Vitamin D Deficiency
In the skin, 7-dehydrocholesterol is converted to previtamin D₃ via UVB light, followed by subsequent conversion to vitamin D₃. Dietary sources are in the form of either vitamin D₂ or D₃, both of which are converted in the liver to 25-hydroxyvitamin D, the major circulating metabolite. In the kidneys, 25-hydroxyvitamin D is then converted to 1,25-dihydroxyvitamin D, the biologically active form. Paradoxically, serum levels of 1,25-dihydroxyvitamin D can be normal or high in the setting of vitamin D deficiency; therefore, serum total 25-hydroxyvitamin D is the best way to assess a patient’s vitamin D status.^5,13

The optimal serum 25-hydroxyvitamin D level is controversial. Recommendations range between 20 to 40 ng/mL¹⁴ and 30 to 50 ng/mL.^13,15,16 Vitamin D levels higher than 50 ng/mL have been correlated with an increased risk of bone fractures and certain cancers.^16-18 Vitamin D toxicity usually is noted in serum levels greater than 88 ng/mL; symptoms of toxicity include hypercalcemia, nausea, vomiting, and muscle weakness. For nondeficient patients, the National Academy of Medicine (formerly the Institute of Medicine) recommended an upper limit of 4000 IU daily.¹⁴ The optimal dose in preventing vitamin D deficiency ranges from 600 to 1000 IU daily.^13-15

Treatment of Vitamin D Deficiency
In the setting of vitamin D deficiency, the amount required for repletion often is dependent on each individual’s ability to absorb and convert to 25-hydroxyvitamin D. Typically every 100 IU of vitamin D correlates with a 0.7 to 1.0 ng/mL increase in serum 25-hydroxyvitamin D levels.¹⁹ There are multiple dosing regimens used to achieve the desired serum 25-hydroxyvitamin D levels in deficient patients. One recommendation from the Endocrine Society is 50,000 IU once weekly for 6 to 8 weeks (single doses >50,000 IU typically are not recommended due to increased risk for toxicity), followed by 600 to 1000 IU once daily in children and 1500 to 2000 IU once daily in adults thereafter.¹³ In patients with vitamin D deficiency, reassessment of serum 25-hydroxyvitamin D levels is recommended after 3 to 4 months of treatment, and adjustments to the repletion regimen should be made as needed.^15,16 Generally, vitamin D₃ is recommended over vitamin D₂ due to enhanced efficacy in raising serum 25-hydroxyvitamin D levels.²⁰

Vitamin D Deficiency in Alopecia
Although most recommendations are given in the interest of optimizing bone health, in the setting of alopecia, we set a similar serum 25-hydroxyvitamin D goal of greater than 30 ng/mL. We recommend treatment with vitamin D₃ and practice the following repletion protocol: 50,000 IU once weekly for 4 weeks, followed by 1000 IU once daily for at least 8 weeks for serum 25-hydroxyvitamin D levels less than 20 ng/mL. For serum hydroxyvitamin D levels between 20 and 29 ng/mL, we recommend 1000 IU once daily for at least 12 weeks. We recheck blood levels again in 3 months. If levels fail to normalize, we will refer the patient to endocrinology. If levels return to normal, we transition to a daily multivitamin with vitamin D (400–800 IU) once daily and refer the patient back to the primary care physician for long-term monitoring.

Vitamin D receptors are found in every cell of the body and have been shown to play a role in bone, neural, and cardiovascular health; immune regulation; and possibly cancer prevention via the regulation of cell differentiation, proliferation, and apoptosis.¹ Although it is controversial, vitamin D deficiency has been associated with various forms of nonscarring hair loss,^2-4 including telogen effluvium, androgenetic alopecia, and alopecia areata. We describe a notable case of nonscarring alopecia associated with vitamin D deficiency in which vitamin D replacement therapy promoted hair regrowth.

Case Report

An otherwise healthy 34-year-old black woman presented to the Hair and Nail Clinic at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) for evaluation of progressive hair loss of 4 years’ duration that began shortly after her fourth child was born. Although she denied any history of excessive shedding, she stated that she used to have shoulder-length hair and somehow it had become extremely short without shaving or cutting the hair (Figure 1). Her current medications included a progestin intrauterine device and biotin 10 mg once daily, the latter of which she had taken for several months for the hair loss without any improvement.

On physical examination, the patient was noted to have diffusely thinning, short, brittle hair. Trichoscopy was notable for hairs of varying diameters, with some fractured at the level of the follicular ostia but no yellow dots at the follicular openings or exclamation point hairs. No scarring or erythema was seen on the scalp. The patient refused several of our team’s recommendations for scalp biopsy due to needle phobia. A hair growth window was made that showed good regrowth at 2 weeks after the initial presentation. Initial blood work revealed a total serum 25-hydroxyvitamin D level of 12 ng/mL (optimal, >30 ng/mL). Complete blood cell count, hormonal panel, zinc level, iron level, and thyroid studies were all normal.

The patient was started on vitamin D₃ replacement therapy 50,000 IU once weekly for 4 weeks followed by 1000 IU once daily for 6 months. No other topical or systemic treatments were administered for the nonscarring alopecia. At a follow-up visit 6 months later, the patient’s vitamin D level was 36 ng/mL, and she had noticeable hair regrowth (Figure 2). At this time, the diagnosis of nonscarring alopecia associated with vitamin D deficiency was made.

Comment

Vitamin D is a fat-soluble vitamin that can be obtained via sun exposure, food sources (eg, fish, vitamin D–fortified foods), and direct supplementation.⁵ It has been estimated that nearly 1 billion individuals worldwide⁶ and approximately 41.6% of US adults are vitamin D deficient.⁷ Certainly not all of these individuals will present with alopecia, but in patients with hair loss, we suggest that vitamin D deficiency is an important factor to consider. Risk factors for vitamin D deficiency include older age, obesity, darker skin types, residence in northern latitudes, and malabsorption syndromes.⁷

Pathogenesis
Vitamin D is thought to play a role in the normal initiation and completion of the hair cycle as well as the differentiation of the follicular and interfollicular epidermis. The vitamin D receptor (VDR) is thought to induce the development of mature anagen hairs via the canonical WNT-β-catenin and hedgehog signaling pathways.⁸ In the absence of VDRs, the stem cells in the bulge of the hair follicle have an impaired ability to replicate, and as a result, VDR-deficient mice have shown near-total hair loss.^9-12 We propose that vitamin D deficiency can not only be a trigger for hair loss but also can perpetuate hair loss and poor regrowth.

Diagnosis and Prevention of Vitamin D Deficiency
In the skin, 7-dehydrocholesterol is converted to previtamin D₃ via UVB light, followed by subsequent conversion to vitamin D₃. Dietary sources are in the form of either vitamin D₂ or D₃, both of which are converted in the liver to 25-hydroxyvitamin D, the major circulating metabolite. In the kidneys, 25-hydroxyvitamin D is then converted to 1,25-dihydroxyvitamin D, the biologically active form. Paradoxically, serum levels of 1,25-dihydroxyvitamin D can be normal or high in the setting of vitamin D deficiency; therefore, serum total 25-hydroxyvitamin D is the best way to assess a patient’s vitamin D status.^5,13

The optimal serum 25-hydroxyvitamin D level is controversial. Recommendations range between 20 to 40 ng/mL¹⁴ and 30 to 50 ng/mL.^13,15,16 Vitamin D levels higher than 50 ng/mL have been correlated with an increased risk of bone fractures and certain cancers.^16-18 Vitamin D toxicity usually is noted in serum levels greater than 88 ng/mL; symptoms of toxicity include hypercalcemia, nausea, vomiting, and muscle weakness. For nondeficient patients, the National Academy of Medicine (formerly the Institute of Medicine) recommended an upper limit of 4000 IU daily.¹⁴ The optimal dose in preventing vitamin D deficiency ranges from 600 to 1000 IU daily.^13-15

Treatment of Vitamin D Deficiency
In the setting of vitamin D deficiency, the amount required for repletion often is dependent on each individual’s ability to absorb and convert to 25-hydroxyvitamin D. Typically every 100 IU of vitamin D correlates with a 0.7 to 1.0 ng/mL increase in serum 25-hydroxyvitamin D levels.¹⁹ There are multiple dosing regimens used to achieve the desired serum 25-hydroxyvitamin D levels in deficient patients. One recommendation from the Endocrine Society is 50,000 IU once weekly for 6 to 8 weeks (single doses >50,000 IU typically are not recommended due to increased risk for toxicity), followed by 600 to 1000 IU once daily in children and 1500 to 2000 IU once daily in adults thereafter.¹³ In patients with vitamin D deficiency, reassessment of serum 25-hydroxyvitamin D levels is recommended after 3 to 4 months of treatment, and adjustments to the repletion regimen should be made as needed.^15,16 Generally, vitamin D₃ is recommended over vitamin D₂ due to enhanced efficacy in raising serum 25-hydroxyvitamin D levels.²⁰

Vitamin D Deficiency in Alopecia
Although most recommendations are given in the interest of optimizing bone health, in the setting of alopecia, we set a similar serum 25-hydroxyvitamin D goal of greater than 30 ng/mL. We recommend treatment with vitamin D₃ and practice the following repletion protocol: 50,000 IU once weekly for 4 weeks, followed by 1000 IU once daily for at least 8 weeks for serum 25-hydroxyvitamin D levels less than 20 ng/mL. For serum hydroxyvitamin D levels between 20 and 29 ng/mL, we recommend 1000 IU once daily for at least 12 weeks. We recheck blood levels again in 3 months. If levels fail to normalize, we will refer the patient to endocrinology. If levels return to normal, we transition to a daily multivitamin with vitamin D (400–800 IU) once daily and refer the patient back to the primary care physician for long-term monitoring.

Social media has become a prominent source of medical information for patients, including those with dermatologic conditions.^1,2 Physicians, patients, and pharmaceutical companies can use social media platforms to communicate with each other and share knowledge and advertisements related to conditions. Social media can influence patients’ perceptions of their disease and serve as a modality to acquire medical treatments.³ Furthermore, social media posts from illicit pharmacies can result in patients buying harmful medications without physician oversight.^4,5 Examination of the content and sources of social media posts related to acne may be useful in determining those who are primarily utilizing social media and for what purpose. The goal of this systematic review was to identify sources of acne-related social media posts to determine communication trends to gain a better understanding of the potential impact social media may have on patient care.

Methods

Social media posts were identified (May 2008 to May 2016) using the search terms acne and treatment across all social media platforms available through a commercial social media data aggregating software (Crimson Hexagon). Information from relevant posts was extracted and compiled into a spreadsheet that included the content, post date, social media platform, and hyperlink. To further analyze the data, the first 100 posts on acne treatment from May 2008 to May 2016 were selected and manually classified by the following types of communication: (1) patient-to-patient (eg, testimonies of patients’ medical experiences); (2) professional-to-patient (eg, clinical knowledge or experience provided by a medical provider and/or cited article in reference to relevant treatments); (3) pharmaceutical company–to-patient (eg, information from reputable drug manufacturers regarding drug activity and adverse effects); (4) illicit pharmacy–to-patient (eg, pharmacies with advertisements calling patients to buy a drug online or offering discrete shipping without a prescription)^4,5; or (5) other-to-patient (eg, posts that did not contain enough detail to be classified).

Results

Hundreds of thousands of social media posts discussing acne treatment were identified over the 8-year study period (Figure 1). The social media data aggregator extracted posts from various blogs, website comment sections, and online forums, as well as major social media platforms (ie, Facebook, Twitter, Google+, Tumblr). The first 100 posts selected for further analysis included 0 from 2008, 6 from 2009, 36 from 2010, 15 from 2011, 7 from 2012, 8 from 2013, 12 from 2014, 11 from 2015, and 5 from 2016. From this sample, 65 posts were considered to have an illicit source; conversely, 18 posts were from patients and 7 posts were from pharmaceutical companies (Figure 2).

Comment

This study demonstrated that discussion of acne treatment is prevalent in social media. Although our research underrepresents the social media interest in specific acne treatments, as only posts mentioning the terms acne and treatment were evaluated to gain insights into how social media platforms are being used by individuals with cutaneous disease. As such, even with this potential underrepresentation, our study demonstrated a high incidence of illicit marketing of prescription acne medications across multiple social media platforms (Figure 2). The sale of dermatologic pharmaceuticals (eg, isotretinoin) without a prescription is recognized by the US Government as a problem that is rapidly growing.^4,5 Illicit pharmacies pose as legitimate pharmacies that can provide prescription medications to consumers without a prescription.^5,6 The fact that these illicit pharmacy–to-patient posts were the most abundant in our study may speak to their relative success on social media platforms in encouraging patients to purchase prescription medications without physician oversight. These findings should concern health care providers, as the procurement of prescription medications without a prescription may put patients at risk.

Social media has become a prominent source of medical information for patients, including those with dermatologic conditions.^1,2 Physicians, patients, and pharmaceutical companies can use social media platforms to communicate with each other and share knowledge and advertisements related to conditions. Social media can influence patients’ perceptions of their disease and serve as a modality to acquire medical treatments.³ Furthermore, social media posts from illicit pharmacies can result in patients buying harmful medications without physician oversight.^4,5 Examination of the content and sources of social media posts related to acne may be useful in determining those who are primarily utilizing social media and for what purpose. The goal of this systematic review was to identify sources of acne-related social media posts to determine communication trends to gain a better understanding of the potential impact social media may have on patient care.

Methods

Social media posts were identified (May 2008 to May 2016) using the search terms acne and treatment across all social media platforms available through a commercial social media data aggregating software (Crimson Hexagon). Information from relevant posts was extracted and compiled into a spreadsheet that included the content, post date, social media platform, and hyperlink. To further analyze the data, the first 100 posts on acne treatment from May 2008 to May 2016 were selected and manually classified by the following types of communication: (1) patient-to-patient (eg, testimonies of patients’ medical experiences); (2) professional-to-patient (eg, clinical knowledge or experience provided by a medical provider and/or cited article in reference to relevant treatments); (3) pharmaceutical company–to-patient (eg, information from reputable drug manufacturers regarding drug activity and adverse effects); (4) illicit pharmacy–to-patient (eg, pharmacies with advertisements calling patients to buy a drug online or offering discrete shipping without a prescription)^4,5; or (5) other-to-patient (eg, posts that did not contain enough detail to be classified).

Results

Hundreds of thousands of social media posts discussing acne treatment were identified over the 8-year study period (Figure 1). The social media data aggregator extracted posts from various blogs, website comment sections, and online forums, as well as major social media platforms (ie, Facebook, Twitter, Google+, Tumblr). The first 100 posts selected for further analysis included 0 from 2008, 6 from 2009, 36 from 2010, 15 from 2011, 7 from 2012, 8 from 2013, 12 from 2014, 11 from 2015, and 5 from 2016. From this sample, 65 posts were considered to have an illicit source; conversely, 18 posts were from patients and 7 posts were from pharmaceutical companies (Figure 2).

Comment

This study demonstrated that discussion of acne treatment is prevalent in social media. Although our research underrepresents the social media interest in specific acne treatments, as only posts mentioning the terms acne and treatment were evaluated to gain insights into how social media platforms are being used by individuals with cutaneous disease. As such, even with this potential underrepresentation, our study demonstrated a high incidence of illicit marketing of prescription acne medications across multiple social media platforms (Figure 2). The sale of dermatologic pharmaceuticals (eg, isotretinoin) without a prescription is recognized by the US Government as a problem that is rapidly growing.^4,5 Illicit pharmacies pose as legitimate pharmacies that can provide prescription medications to consumers without a prescription.^5,6 The fact that these illicit pharmacy–to-patient posts were the most abundant in our study may speak to their relative success on social media platforms in encouraging patients to purchase prescription medications without physician oversight. These findings should concern health care providers, as the procurement of prescription medications without a prescription may put patients at risk.

Social media has become a prominent source of medical information for patients, including those with dermatologic conditions.^1,2 Physicians, patients, and pharmaceutical companies can use social media platforms to communicate with each other and share knowledge and advertisements related to conditions. Social media can influence patients’ perceptions of their disease and serve as a modality to acquire medical treatments.³ Furthermore, social media posts from illicit pharmacies can result in patients buying harmful medications without physician oversight.^4,5 Examination of the content and sources of social media posts related to acne may be useful in determining those who are primarily utilizing social media and for what purpose. The goal of this systematic review was to identify sources of acne-related social media posts to determine communication trends to gain a better understanding of the potential impact social media may have on patient care.

Methods

Social media posts were identified (May 2008 to May 2016) using the search terms acne and treatment across all social media platforms available through a commercial social media data aggregating software (Crimson Hexagon). Information from relevant posts was extracted and compiled into a spreadsheet that included the content, post date, social media platform, and hyperlink. To further analyze the data, the first 100 posts on acne treatment from May 2008 to May 2016 were selected and manually classified by the following types of communication: (1) patient-to-patient (eg, testimonies of patients’ medical experiences); (2) professional-to-patient (eg, clinical knowledge or experience provided by a medical provider and/or cited article in reference to relevant treatments); (3) pharmaceutical company–to-patient (eg, information from reputable drug manufacturers regarding drug activity and adverse effects); (4) illicit pharmacy–to-patient (eg, pharmacies with advertisements calling patients to buy a drug online or offering discrete shipping without a prescription)^4,5; or (5) other-to-patient (eg, posts that did not contain enough detail to be classified).

Results

Hundreds of thousands of social media posts discussing acne treatment were identified over the 8-year study period (Figure 1). The social media data aggregator extracted posts from various blogs, website comment sections, and online forums, as well as major social media platforms (ie, Facebook, Twitter, Google+, Tumblr). The first 100 posts selected for further analysis included 0 from 2008, 6 from 2009, 36 from 2010, 15 from 2011, 7 from 2012, 8 from 2013, 12 from 2014, 11 from 2015, and 5 from 2016. From this sample, 65 posts were considered to have an illicit source; conversely, 18 posts were from patients and 7 posts were from pharmaceutical companies (Figure 2).

Comment

This study demonstrated that discussion of acne treatment is prevalent in social media. Although our research underrepresents the social media interest in specific acne treatments, as only posts mentioning the terms acne and treatment were evaluated to gain insights into how social media platforms are being used by individuals with cutaneous disease. As such, even with this potential underrepresentation, our study demonstrated a high incidence of illicit marketing of prescription acne medications across multiple social media platforms (Figure 2). The sale of dermatologic pharmaceuticals (eg, isotretinoin) without a prescription is recognized by the US Government as a problem that is rapidly growing.^4,5 Illicit pharmacies pose as legitimate pharmacies that can provide prescription medications to consumers without a prescription.^5,6 The fact that these illicit pharmacy–to-patient posts were the most abundant in our study may speak to their relative success on social media platforms in encouraging patients to purchase prescription medications without physician oversight. These findings should concern health care providers, as the procurement of prescription medications without a prescription may put patients at risk.

The Centers for Medicare & Medicaid Services announced July 7 that it will no longer make adjustment payments to insurers until litigation regarding them is resolved, further destabilizing the individual and small group markets created by the Affordable Care Act.

The risk adjustment payment uses statewide average premiums to draw money from health insurance plans within a state that have low levels of high-need patients and funnels that money to plans in that state with high amounts of high-need patients, as a way to minimize adverse selection and to spread risk.

The government was set to make a budget neutral payment of $10.4 billion for the 2017 plan year. But in a rare Saturday announcement, the agency said July 7 that the reason for putting the risk adjustment payments on hold was differing legal opinions on the validity of the payments.

designer491/Thinkstock

gtwachtman@mdedge.com

The Centers for Medicare & Medicaid Services announced July 7 that it will no longer make adjustment payments to insurers until litigation regarding them is resolved, further destabilizing the individual and small group markets created by the Affordable Care Act.

The risk adjustment payment uses statewide average premiums to draw money from health insurance plans within a state that have low levels of high-need patients and funnels that money to plans in that state with high amounts of high-need patients, as a way to minimize adverse selection and to spread risk.

The government was set to make a budget neutral payment of $10.4 billion for the 2017 plan year. But in a rare Saturday announcement, the agency said July 7 that the reason for putting the risk adjustment payments on hold was differing legal opinions on the validity of the payments.

designer491/Thinkstock

gtwachtman@mdedge.com

The Centers for Medicare & Medicaid Services announced July 7 that it will no longer make adjustment payments to insurers until litigation regarding them is resolved, further destabilizing the individual and small group markets created by the Affordable Care Act.

The risk adjustment payment uses statewide average premiums to draw money from health insurance plans within a state that have low levels of high-need patients and funnels that money to plans in that state with high amounts of high-need patients, as a way to minimize adverse selection and to spread risk.

The government was set to make a budget neutral payment of $10.4 billion for the 2017 plan year. But in a rare Saturday announcement, the agency said July 7 that the reason for putting the risk adjustment payments on hold was differing legal opinions on the validity of the payments.

designer491/Thinkstock

gtwachtman@mdedge.com

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.