In this DocThoughts interview, The American Journal of Orthopedics' associate editor, Dr. Cole, delves into the mind of a surgeon and gives insight into the surgical decision making process for his athletes. 

In this DocThoughts interview, The American Journal of Orthopedics' associate editor, Dr. Cole, delves into the mind of a surgeon and gives insight into the surgical decision making process for his athletes. 

In this DocThoughts interview, The American Journal of Orthopedics' associate editor, Dr. Cole, delves into the mind of a surgeon and gives insight into the surgical decision making process for his athletes. 

AMSTERDAM – Analyses of patient-reported outcomes in the UK START A and B trials show that radiation doses greater than 2 Gy to the supraclavicular fossa or axilla are safe and are associated with acceptable near- and late-term toxicities, trial investigators reported.

The START trials compared standard adjuvant radiation doses and schedules with accelerated, hypofractionated doses in women with early breast cancer.

At the annual San Antonio Breast Cancer Symposium in 2012, lead investigator John Yarnold, MD, professor of clinical oncology at the Institute of Cancer Research in London, reported that a 40-Gy, 15-fraction regimen was associated with fewer adverse events over 10 years of follow-up compared with a 50-Gy, 25-fraction regimen that was at the time the standard in the United States and the United Kingdom.

Here at an annual congress sponsored by the European Cancer Organisation, Dr. Yarnold reported that among 479 patients in the two trials who had lymphatic radiation, there were no significant differences in arm or shoulder pain, swelling, motion problems, or shoulder stiffness between patients who received conventional 2-Gy fractions for a total of 50 Gy, or lower total doses of radiation divided into fractions larger than 2 Gy.

“A post hoc analysis of outcomes in 479 patients treated with radiotherapy fractions larger than 2 Gy to the supraclavicular fossa and/or the axilla raise no concerns in terms of safety or patient acceptability, and it was for this reason that this schedule has been the standard for locoregional radiotherapy in the UK for some years now,” he said.

START (Standardization of Breast Radiotherapy) A enrolled 2,236 patients from 35 UK centers with breast cancer stages T 1-3, nodal stage N0-1, and no distant metastases (M0) and randomly assigned them to 50 Gy in 25 fractions of 2 Gy each over 5 weeks, 39.0 Gy in 13 fractions of 3.0 Gy over 5 weeks, and 41.6 Gy in 13 fractions of 3.2 Gy over 5 weeks.

In START B, 2,215 women were randomly assigned to the 50 Gy or 40 Gy regimens.

As reported in 2012, over a median follow-up of 9.3 years in START A, the 41.6-Gy regimen was similar in its adverse events profile compared with the 50-Gy dose (hazard ratio [HR] 0.94, and the lower-dose regimen also was comparable in efficacy, as measured by the rate of locoregional tumor relapse.

There were numerically but not significantly more relapses in the 39-Gy dose, however.

In START B, the 40-Gy dose was associated with significantly fewer adverse events over a median of 9.9 years of follow-up (HR 0.77). Efficacy was similar, although there was a nonsignificant trend toward superiority for the hypofractionated regimen.

In the post hoc analysis, the investigators looked at adverse events in 479 total patients in START A and B, 365 of whom had completed patient-reported outcome measures on the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer–Specific Quality of Life Questionnaire (QLQ-BR23).

A total of 262 patients in START A, and 103 in START B completed the questionnaires at 0, 6, 12, 24, and 60 months. Of these patients. The majority in each arm had radiation to the supraclavicular fossa only, and a minority had axilla radiation alone or in addition to supraclavicular fossa radiation.

In START B, 5-year patient reported outcomes of severity of 3 or 4 on a 4-point scale were low in each treatment arm, with arm or hand swelling reported in 10% of patients on 50 Gy, and 6% of patients on 40 Gy, and shoulder stiffness reported in 12% on the 50-Gy dose, vs. 15% on the 40-Gy dose.

Among all 479 patients with clinical assessments at 10 years, there were also no significant differences in either arm edema or shoulder stiffness between patients who received 50 Gy and those who received other, hypofractionated in each of the two trials.

The findings lend support to the Danish Breast Cancer Cooperative Group’s SKAGEN Trial 1, which is evaluating moderately hypofractionated locoregional adjuvant radiation therapy of early breast cancer combined with a simultaneous integrated boost in patients with an indication for boost, Dr. Yarnold said.

The UK START trials were supported by Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no conflicts of interest.

AMSTERDAM – Analyses of patient-reported outcomes in the UK START A and B trials show that radiation doses greater than 2 Gy to the supraclavicular fossa or axilla are safe and are associated with acceptable near- and late-term toxicities, trial investigators reported.

The START trials compared standard adjuvant radiation doses and schedules with accelerated, hypofractionated doses in women with early breast cancer.

At the annual San Antonio Breast Cancer Symposium in 2012, lead investigator John Yarnold, MD, professor of clinical oncology at the Institute of Cancer Research in London, reported that a 40-Gy, 15-fraction regimen was associated with fewer adverse events over 10 years of follow-up compared with a 50-Gy, 25-fraction regimen that was at the time the standard in the United States and the United Kingdom.

Here at an annual congress sponsored by the European Cancer Organisation, Dr. Yarnold reported that among 479 patients in the two trials who had lymphatic radiation, there were no significant differences in arm or shoulder pain, swelling, motion problems, or shoulder stiffness between patients who received conventional 2-Gy fractions for a total of 50 Gy, or lower total doses of radiation divided into fractions larger than 2 Gy.

“A post hoc analysis of outcomes in 479 patients treated with radiotherapy fractions larger than 2 Gy to the supraclavicular fossa and/or the axilla raise no concerns in terms of safety or patient acceptability, and it was for this reason that this schedule has been the standard for locoregional radiotherapy in the UK for some years now,” he said.

START (Standardization of Breast Radiotherapy) A enrolled 2,236 patients from 35 UK centers with breast cancer stages T 1-3, nodal stage N0-1, and no distant metastases (M0) and randomly assigned them to 50 Gy in 25 fractions of 2 Gy each over 5 weeks, 39.0 Gy in 13 fractions of 3.0 Gy over 5 weeks, and 41.6 Gy in 13 fractions of 3.2 Gy over 5 weeks.

In START B, 2,215 women were randomly assigned to the 50 Gy or 40 Gy regimens.

As reported in 2012, over a median follow-up of 9.3 years in START A, the 41.6-Gy regimen was similar in its adverse events profile compared with the 50-Gy dose (hazard ratio [HR] 0.94, and the lower-dose regimen also was comparable in efficacy, as measured by the rate of locoregional tumor relapse.

There were numerically but not significantly more relapses in the 39-Gy dose, however.

In START B, the 40-Gy dose was associated with significantly fewer adverse events over a median of 9.9 years of follow-up (HR 0.77). Efficacy was similar, although there was a nonsignificant trend toward superiority for the hypofractionated regimen.

In the post hoc analysis, the investigators looked at adverse events in 479 total patients in START A and B, 365 of whom had completed patient-reported outcome measures on the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer–Specific Quality of Life Questionnaire (QLQ-BR23).

A total of 262 patients in START A, and 103 in START B completed the questionnaires at 0, 6, 12, 24, and 60 months. Of these patients. The majority in each arm had radiation to the supraclavicular fossa only, and a minority had axilla radiation alone or in addition to supraclavicular fossa radiation.

In START B, 5-year patient reported outcomes of severity of 3 or 4 on a 4-point scale were low in each treatment arm, with arm or hand swelling reported in 10% of patients on 50 Gy, and 6% of patients on 40 Gy, and shoulder stiffness reported in 12% on the 50-Gy dose, vs. 15% on the 40-Gy dose.

Among all 479 patients with clinical assessments at 10 years, there were also no significant differences in either arm edema or shoulder stiffness between patients who received 50 Gy and those who received other, hypofractionated in each of the two trials.

The findings lend support to the Danish Breast Cancer Cooperative Group’s SKAGEN Trial 1, which is evaluating moderately hypofractionated locoregional adjuvant radiation therapy of early breast cancer combined with a simultaneous integrated boost in patients with an indication for boost, Dr. Yarnold said.

The UK START trials were supported by Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no conflicts of interest.

AMSTERDAM – Analyses of patient-reported outcomes in the UK START A and B trials show that radiation doses greater than 2 Gy to the supraclavicular fossa or axilla are safe and are associated with acceptable near- and late-term toxicities, trial investigators reported.

The START trials compared standard adjuvant radiation doses and schedules with accelerated, hypofractionated doses in women with early breast cancer.

At the annual San Antonio Breast Cancer Symposium in 2012, lead investigator John Yarnold, MD, professor of clinical oncology at the Institute of Cancer Research in London, reported that a 40-Gy, 15-fraction regimen was associated with fewer adverse events over 10 years of follow-up compared with a 50-Gy, 25-fraction regimen that was at the time the standard in the United States and the United Kingdom.

Here at an annual congress sponsored by the European Cancer Organisation, Dr. Yarnold reported that among 479 patients in the two trials who had lymphatic radiation, there were no significant differences in arm or shoulder pain, swelling, motion problems, or shoulder stiffness between patients who received conventional 2-Gy fractions for a total of 50 Gy, or lower total doses of radiation divided into fractions larger than 2 Gy.

“A post hoc analysis of outcomes in 479 patients treated with radiotherapy fractions larger than 2 Gy to the supraclavicular fossa and/or the axilla raise no concerns in terms of safety or patient acceptability, and it was for this reason that this schedule has been the standard for locoregional radiotherapy in the UK for some years now,” he said.

START (Standardization of Breast Radiotherapy) A enrolled 2,236 patients from 35 UK centers with breast cancer stages T 1-3, nodal stage N0-1, and no distant metastases (M0) and randomly assigned them to 50 Gy in 25 fractions of 2 Gy each over 5 weeks, 39.0 Gy in 13 fractions of 3.0 Gy over 5 weeks, and 41.6 Gy in 13 fractions of 3.2 Gy over 5 weeks.

In START B, 2,215 women were randomly assigned to the 50 Gy or 40 Gy regimens.

As reported in 2012, over a median follow-up of 9.3 years in START A, the 41.6-Gy regimen was similar in its adverse events profile compared with the 50-Gy dose (hazard ratio [HR] 0.94, and the lower-dose regimen also was comparable in efficacy, as measured by the rate of locoregional tumor relapse.

There were numerically but not significantly more relapses in the 39-Gy dose, however.

In START B, the 40-Gy dose was associated with significantly fewer adverse events over a median of 9.9 years of follow-up (HR 0.77). Efficacy was similar, although there was a nonsignificant trend toward superiority for the hypofractionated regimen.

In the post hoc analysis, the investigators looked at adverse events in 479 total patients in START A and B, 365 of whom had completed patient-reported outcome measures on the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer–Specific Quality of Life Questionnaire (QLQ-BR23).

A total of 262 patients in START A, and 103 in START B completed the questionnaires at 0, 6, 12, 24, and 60 months. Of these patients. The majority in each arm had radiation to the supraclavicular fossa only, and a minority had axilla radiation alone or in addition to supraclavicular fossa radiation.

In START B, 5-year patient reported outcomes of severity of 3 or 4 on a 4-point scale were low in each treatment arm, with arm or hand swelling reported in 10% of patients on 50 Gy, and 6% of patients on 40 Gy, and shoulder stiffness reported in 12% on the 50-Gy dose, vs. 15% on the 40-Gy dose.

Among all 479 patients with clinical assessments at 10 years, there were also no significant differences in either arm edema or shoulder stiffness between patients who received 50 Gy and those who received other, hypofractionated in each of the two trials.

The findings lend support to the Danish Breast Cancer Cooperative Group’s SKAGEN Trial 1, which is evaluating moderately hypofractionated locoregional adjuvant radiation therapy of early breast cancer combined with a simultaneous integrated boost in patients with an indication for boost, Dr. Yarnold said.

The UK START trials were supported by Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no conflicts of interest.

WAILEA, HAWAII – Plaque type psoriasis continues to be the most common type of psoriasis in children, but there are other presentations that should be considered, said Wynnis Tom, MD, a pediatric dermatologist at the University of California, San Diego, and Rady Children’s Hospital, San Diego.

“We certainly see a form of what some people would call napkin dermatitis,” or “diaper psoriasis,” affecting the diaper area in young infants, Dr. Tom said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

So when a child has a more refractory diaper rash, “look around to see if there are other lesions in the surrounding area that might be more typical for psoriasis,” she noted.

“We also see a lot more guttate disease” in children with psoriasis, which is more likely to be related to infections and triggers, Dr. Tom said. The face and scalp are often affected in children, and it is important to attend to these areas early to help avoid social stigma, she added.

Dr. Tom disclosed financial relationships with companies including Celgene, Janssen, and Promius. SDEF and this news organization are owned by the same parent company.

WAILEA, HAWAII – Plaque type psoriasis continues to be the most common type of psoriasis in children, but there are other presentations that should be considered, said Wynnis Tom, MD, a pediatric dermatologist at the University of California, San Diego, and Rady Children’s Hospital, San Diego.

“We certainly see a form of what some people would call napkin dermatitis,” or “diaper psoriasis,” affecting the diaper area in young infants, Dr. Tom said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

So when a child has a more refractory diaper rash, “look around to see if there are other lesions in the surrounding area that might be more typical for psoriasis,” she noted.

“We also see a lot more guttate disease” in children with psoriasis, which is more likely to be related to infections and triggers, Dr. Tom said. The face and scalp are often affected in children, and it is important to attend to these areas early to help avoid social stigma, she added.

Dr. Tom disclosed financial relationships with companies including Celgene, Janssen, and Promius. SDEF and this news organization are owned by the same parent company.

WAILEA, HAWAII – Plaque type psoriasis continues to be the most common type of psoriasis in children, but there are other presentations that should be considered, said Wynnis Tom, MD, a pediatric dermatologist at the University of California, San Diego, and Rady Children’s Hospital, San Diego.

“We certainly see a form of what some people would call napkin dermatitis,” or “diaper psoriasis,” affecting the diaper area in young infants, Dr. Tom said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

So when a child has a more refractory diaper rash, “look around to see if there are other lesions in the surrounding area that might be more typical for psoriasis,” she noted.

“We also see a lot more guttate disease” in children with psoriasis, which is more likely to be related to infections and triggers, Dr. Tom said. The face and scalp are often affected in children, and it is important to attend to these areas early to help avoid social stigma, she added.

Dr. Tom disclosed financial relationships with companies including Celgene, Janssen, and Promius. SDEF and this news organization are owned by the same parent company.

The Diagnosis: Xanthoma Disseminatum

Genital examination revealed approximately 1.5×3-cm soft, yellow-pink plaques extending from the bilateral inguinal folds to the proximal medial thighs (Figure 1). There was no mucosal, axillary, extensor extremity, or palmoplantar involvement. Histopathologic examination of a biopsy from a plaque on the left side of the lower abdomen revealed sheets of foamy histiocytes distributed throughout a fibrotic dermis. Both mononucleated and multinucleated histiocytes were present, including many Touton giant cells (Figure 2). A patchy infiltrate of lymphocytes and rare eosinophils also was noted. The histiocytes labeled with factor XIIIa but not with S-100. Laboratory tests were performed with the following pertinent findings: low-density lipoprotein, 150 mg/dL (reference range, <130 mg/dL); high-density lipoprotein, 30 mg/dL (reference range, >40 mg/dL). Total cholesterol and triglyceride levels were within reference range, and complete blood cell count and basic metabolic panel were normal.

Xanthoma disseminatum (XD)(also known as Montgomery syndrome) is a rare, nonfamilial, normolipemic non-Langerhans cell histiocytosis characterized by extensive lipid deposition in the skin, mucous membranes, and internal organs. The pathogenesis of XD is poorly understood, but it may represent a macrophage-mediated reactive process triggered by superantigens.¹

Xanthoma disseminatum most commonly affects males aged 5 to 25 years.² Clinically, it is characterized by red-brown to yellowish papules and plaques symmetrically distributed over the eyelids, trunk, face, and proximal extremities. There is a predilection for involvement of flexural and intertriginous surfaces and tendency for extension along Langer lines. Extracutaneous involvement can be a notable cause of morbidity and mortality, underscoring the importance of distinguishing XD from other clinically similar xanthomatoses. Mucous membrane involvement occurs in 40% to 60% of patients.³ The oropharynx, larynx, and corneal and conjunctival membranes are most commonly affected, resulting in dysphagia, dysphonia or dyspnea, and visual impairment, respectively. Symptoms of internal organ involvement can be manifold, including pain or limited mobility secondary to osteolytic bone lesions or muscle or synovial membrane involvement, as well as seizures, strabismus, and cerebellar ataxia due to central nervous system lesions.^2-4 Approximately 40% of patients develop diabetes insipidus secondary to involvement of the pituitary meninges.³

The differential diagnosis of XD includes juvenile xanthogranuloma, papular xanthomas, eruptive xanthomas, generalized eruptive histiocytosis, progressive nodular histiocytosis, multicentric reticulohistiocytosis, eruptive syringomas, sarcoidosis, and Langerhans cell histiocytosis; the latter should be considered, especially when there is concomitant diabetes insipidus.⁵ Laboratory studies typically are unremarkable. Although the majority of patients are normolipemic, rates of hyperlipemia within this group are comparable to the general population, occasionally rendering it difficult for the clinician to distinguish XD from hyperlipemic xanthomatoses. As such, diagnosis and differentiation from other xanthomatous processes rests on clinicopathological correlation. Histopathology reveals dermal collections of histiocytes, some with foamy cytoplasm, that range in appearance from spindled to scalloped to Touton-like. Early histopathology demonstrates scalloped macrophages with few foamy cells; a mixture of foamy cells, scalloped cells, inflammatory cells, and Touton and foreign body giant cells is characteristic of late lesions. Immunohistochemistry stains positive for non-Langerhans cell surface markers CD68 and factor XIIIa. Electron microscopy demonstrates dense and myeloid bodies, cholesterol crystals, and lipid vacuoles.⁵

Three subtypes of XD have been described based on the distinct clinical courses that have been observed in patients: a common, persistent, cutaneous form; a self-limited form with spontaneous resolution; and a progressive subtype with internal organ involvement. No consistently efficacious therapies have been identified, but isolated case reports attest to the efficacy of various agents, including azathioprine, clofibrate, cyclophosphamide, glucocorticoids, chlorambucil, and combination or monotherapy with lipid-lowering agents.^3,5,6 Surgical resection, cryotherapy, radiotherapy, and CO2 laser therapy may offer some temporary benefit but do not alter the typically relapsing course of the disease.^7,8 Remission and long-term control of lesions was reported with use of 2-chlorodeoxyadenosine, a purine nucleoside analogue, for 5 of 8 patients in a case series.³

The Diagnosis: Xanthoma Disseminatum

Genital examination revealed approximately 1.5×3-cm soft, yellow-pink plaques extending from the bilateral inguinal folds to the proximal medial thighs (Figure 1). There was no mucosal, axillary, extensor extremity, or palmoplantar involvement. Histopathologic examination of a biopsy from a plaque on the left side of the lower abdomen revealed sheets of foamy histiocytes distributed throughout a fibrotic dermis. Both mononucleated and multinucleated histiocytes were present, including many Touton giant cells (Figure 2). A patchy infiltrate of lymphocytes and rare eosinophils also was noted. The histiocytes labeled with factor XIIIa but not with S-100. Laboratory tests were performed with the following pertinent findings: low-density lipoprotein, 150 mg/dL (reference range, <130 mg/dL); high-density lipoprotein, 30 mg/dL (reference range, >40 mg/dL). Total cholesterol and triglyceride levels were within reference range, and complete blood cell count and basic metabolic panel were normal.

Xanthoma disseminatum (XD)(also known as Montgomery syndrome) is a rare, nonfamilial, normolipemic non-Langerhans cell histiocytosis characterized by extensive lipid deposition in the skin, mucous membranes, and internal organs. The pathogenesis of XD is poorly understood, but it may represent a macrophage-mediated reactive process triggered by superantigens.¹

Xanthoma disseminatum most commonly affects males aged 5 to 25 years.² Clinically, it is characterized by red-brown to yellowish papules and plaques symmetrically distributed over the eyelids, trunk, face, and proximal extremities. There is a predilection for involvement of flexural and intertriginous surfaces and tendency for extension along Langer lines. Extracutaneous involvement can be a notable cause of morbidity and mortality, underscoring the importance of distinguishing XD from other clinically similar xanthomatoses. Mucous membrane involvement occurs in 40% to 60% of patients.³ The oropharynx, larynx, and corneal and conjunctival membranes are most commonly affected, resulting in dysphagia, dysphonia or dyspnea, and visual impairment, respectively. Symptoms of internal organ involvement can be manifold, including pain or limited mobility secondary to osteolytic bone lesions or muscle or synovial membrane involvement, as well as seizures, strabismus, and cerebellar ataxia due to central nervous system lesions.^2-4 Approximately 40% of patients develop diabetes insipidus secondary to involvement of the pituitary meninges.³

The differential diagnosis of XD includes juvenile xanthogranuloma, papular xanthomas, eruptive xanthomas, generalized eruptive histiocytosis, progressive nodular histiocytosis, multicentric reticulohistiocytosis, eruptive syringomas, sarcoidosis, and Langerhans cell histiocytosis; the latter should be considered, especially when there is concomitant diabetes insipidus.⁵ Laboratory studies typically are unremarkable. Although the majority of patients are normolipemic, rates of hyperlipemia within this group are comparable to the general population, occasionally rendering it difficult for the clinician to distinguish XD from hyperlipemic xanthomatoses. As such, diagnosis and differentiation from other xanthomatous processes rests on clinicopathological correlation. Histopathology reveals dermal collections of histiocytes, some with foamy cytoplasm, that range in appearance from spindled to scalloped to Touton-like. Early histopathology demonstrates scalloped macrophages with few foamy cells; a mixture of foamy cells, scalloped cells, inflammatory cells, and Touton and foreign body giant cells is characteristic of late lesions. Immunohistochemistry stains positive for non-Langerhans cell surface markers CD68 and factor XIIIa. Electron microscopy demonstrates dense and myeloid bodies, cholesterol crystals, and lipid vacuoles.⁵

Three subtypes of XD have been described based on the distinct clinical courses that have been observed in patients: a common, persistent, cutaneous form; a self-limited form with spontaneous resolution; and a progressive subtype with internal organ involvement. No consistently efficacious therapies have been identified, but isolated case reports attest to the efficacy of various agents, including azathioprine, clofibrate, cyclophosphamide, glucocorticoids, chlorambucil, and combination or monotherapy with lipid-lowering agents.^3,5,6 Surgical resection, cryotherapy, radiotherapy, and CO2 laser therapy may offer some temporary benefit but do not alter the typically relapsing course of the disease.^7,8 Remission and long-term control of lesions was reported with use of 2-chlorodeoxyadenosine, a purine nucleoside analogue, for 5 of 8 patients in a case series.³

The Diagnosis: Xanthoma Disseminatum

Genital examination revealed approximately 1.5×3-cm soft, yellow-pink plaques extending from the bilateral inguinal folds to the proximal medial thighs (Figure 1). There was no mucosal, axillary, extensor extremity, or palmoplantar involvement. Histopathologic examination of a biopsy from a plaque on the left side of the lower abdomen revealed sheets of foamy histiocytes distributed throughout a fibrotic dermis. Both mononucleated and multinucleated histiocytes were present, including many Touton giant cells (Figure 2). A patchy infiltrate of lymphocytes and rare eosinophils also was noted. The histiocytes labeled with factor XIIIa but not with S-100. Laboratory tests were performed with the following pertinent findings: low-density lipoprotein, 150 mg/dL (reference range, <130 mg/dL); high-density lipoprotein, 30 mg/dL (reference range, >40 mg/dL). Total cholesterol and triglyceride levels were within reference range, and complete blood cell count and basic metabolic panel were normal.

Xanthoma disseminatum (XD)(also known as Montgomery syndrome) is a rare, nonfamilial, normolipemic non-Langerhans cell histiocytosis characterized by extensive lipid deposition in the skin, mucous membranes, and internal organs. The pathogenesis of XD is poorly understood, but it may represent a macrophage-mediated reactive process triggered by superantigens.¹

Xanthoma disseminatum most commonly affects males aged 5 to 25 years.² Clinically, it is characterized by red-brown to yellowish papules and plaques symmetrically distributed over the eyelids, trunk, face, and proximal extremities. There is a predilection for involvement of flexural and intertriginous surfaces and tendency for extension along Langer lines. Extracutaneous involvement can be a notable cause of morbidity and mortality, underscoring the importance of distinguishing XD from other clinically similar xanthomatoses. Mucous membrane involvement occurs in 40% to 60% of patients.³ The oropharynx, larynx, and corneal and conjunctival membranes are most commonly affected, resulting in dysphagia, dysphonia or dyspnea, and visual impairment, respectively. Symptoms of internal organ involvement can be manifold, including pain or limited mobility secondary to osteolytic bone lesions or muscle or synovial membrane involvement, as well as seizures, strabismus, and cerebellar ataxia due to central nervous system lesions.^2-4 Approximately 40% of patients develop diabetes insipidus secondary to involvement of the pituitary meninges.³

The differential diagnosis of XD includes juvenile xanthogranuloma, papular xanthomas, eruptive xanthomas, generalized eruptive histiocytosis, progressive nodular histiocytosis, multicentric reticulohistiocytosis, eruptive syringomas, sarcoidosis, and Langerhans cell histiocytosis; the latter should be considered, especially when there is concomitant diabetes insipidus.⁵ Laboratory studies typically are unremarkable. Although the majority of patients are normolipemic, rates of hyperlipemia within this group are comparable to the general population, occasionally rendering it difficult for the clinician to distinguish XD from hyperlipemic xanthomatoses. As such, diagnosis and differentiation from other xanthomatous processes rests on clinicopathological correlation. Histopathology reveals dermal collections of histiocytes, some with foamy cytoplasm, that range in appearance from spindled to scalloped to Touton-like. Early histopathology demonstrates scalloped macrophages with few foamy cells; a mixture of foamy cells, scalloped cells, inflammatory cells, and Touton and foreign body giant cells is characteristic of late lesions. Immunohistochemistry stains positive for non-Langerhans cell surface markers CD68 and factor XIIIa. Electron microscopy demonstrates dense and myeloid bodies, cholesterol crystals, and lipid vacuoles.⁵

Three subtypes of XD have been described based on the distinct clinical courses that have been observed in patients: a common, persistent, cutaneous form; a self-limited form with spontaneous resolution; and a progressive subtype with internal organ involvement. No consistently efficacious therapies have been identified, but isolated case reports attest to the efficacy of various agents, including azathioprine, clofibrate, cyclophosphamide, glucocorticoids, chlorambucil, and combination or monotherapy with lipid-lowering agents.^3,5,6 Surgical resection, cryotherapy, radiotherapy, and CO2 laser therapy may offer some temporary benefit but do not alter the typically relapsing course of the disease.^7,8 Remission and long-term control of lesions was reported with use of 2-chlorodeoxyadenosine, a purine nucleoside analogue, for 5 of 8 patients in a case series.³

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

The Diagnosis: Persistent Still Disease

At the time of presentation, the patient had not taken systemic medications for a year. Laboratory studies revealed leukocytosis with neutrophilia and a serum ferritin level of 5493 ng/mL (reference range, 15-200 ng/mL). Rheumatoid factor and antinuclear antibody serologies were within reference range. Microbiologic workup was negative. Lymph node and bone marrow biopsies were negative for a lymphoproliferative disorder. Skin biopsies were performed on the back and forearm. Histologic evaluation revealed orthokeratosis, slight acanthosis, and dyskeratosis confined to the upper layers of the epidermis without evidence of interface dermatitis. There was a mixed perivascular infiltrate composed of lymphocytes and neutrophils with no attendant vasculitic change (Figure).

The patient was discharged on prednisone and seen for outpatient follow-up weeks later. Six weeks later, the cutaneous eruption remained unchanged. The patient was unable to start other systemic medications due to lack of insurance and ineligibility for the local patient-assistance program; he was subsequently lost to follow-up. 

Adult-onset Still disease is a rare, systemic, inflammatory condition with a broad spectrum of clinical presentations.^1-3 Still disease affects all age groups, and children with Still disease (<16 years) usually have a concurrent diagnosis of juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis).^1,2,4 Still disease preferentially affects adolescents and adults aged 16 to 35 years, with more than 75% of new cases occurring in this age range.¹ Worldwide, the incidence and prevalence of Still disease is disputed with no conclusive rates established.^1,3

Still disease is characterized by 4 cardinal signs: high spiking fevers (temperature, ≥39°C); leukocytosis with a predominance of neutrophils (≥10,000 cells/mm³ with ≥80% neutrophils); arthralgia or arthritis; and an evanescent, nonpruritic, salmon-colored morbilliform eruption of the skin, typically on the trunk or extremities.² Histologic evaluation of the classic Still disease eruption displays perivascular inflammation of the superficial dermis with infiltration by lymphocytes and histiocytes.³

In 1992, major and minor diagnostic criteria were established for adult-onset Still disease. For diagnosis, patients must meet 5 criteria, including 2 major criteria.⁵ Major criteria include arthralgia or arthritis present for more than 2 weeks, fever (temperature, >39°C) for at least 1 week, the classic Still disease morbilliform eruption (ie, salmon colored, evanescent, morbilliform), and leukocytosis with more than 80% neutrophils. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, negative rheumatoid factor and antinuclear antibody serologies, and abnormal liver function (defined as elevated transaminases).⁵ Although not included in the diagnostic criteria, there have been reports of elevated serum ferritin levels in patients with Still disease, a finding that potentially is useful in distinguishing between active and inactive rheumatic conditions.^6,7

Several case reports have described persistent Still disease, a subtype of Still disease in which patients present with brown-red, persistent, pruritic macules, papules, and plaques that are widespread and oddly shaped.^8,9 Histologically, this subtype is characterized by necrotic keratinocytes in the epidermis and dermal perivascular inflammation composed of neutrophils and lymphocytes.¹⁰ This histology differs from classic Still disease in that the latter typically does not have superficial epidermal dyskeratosis. Our case is consistent with reports of persistent Still disease.

Although the etiology of Still disease remains to be elucidated, HLA-B17, -B18, -B35, and -DR2 have been associated with the disease.³ Furthermore, helper T cell T_H1, IL-2, IFN-γ, and tumor necrosis factor α have been implicated in disease pathology, enabling the use of newer targeted pharmacologic therapies. Canakinumab, an IL-1β inhibitor, has been found to improve arthritis, fever, and rash in patients with Still disease.¹¹ These findings are particularly encouraging for patients who have not experienced improvement with traditional antirheumatic drugs, such as our patient who was not steroid responsive.³

Although a salmon-colored, evanescent, morbilliform eruption in the context of other systemic signs and symptoms readily evokes consideration of Still disease, the less common fixed cutaneous eruption seen in our case may evade accurate diagnosis. Our case aims to increase awareness of this unusual and rare subtype of the cutaneous eruption of Still disease, as a timely diagnosis may prevent potentially life-threatening sequelae including cardiopulmonary disease and respiratory failure.^3,5,9

LAS VEGAS – Closer adherence by U.S. physicians to the “39-week rule” for elective deliveries appears to have cut net neonatal mortality in an analysis of more than 14 million deliveries during 2008-2012.

This net drop in mortality occurred despite a concurrent rise in stillbirths, Rachel A. Pilliod, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine. The increase in stillbirths was more than counterbalanced by a larger drop in infant deaths during the same period.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

LAS VEGAS – Closer adherence by U.S. physicians to the “39-week rule” for elective deliveries appears to have cut net neonatal mortality in an analysis of more than 14 million deliveries during 2008-2012.

This net drop in mortality occurred despite a concurrent rise in stillbirths, Rachel A. Pilliod, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine. The increase in stillbirths was more than counterbalanced by a larger drop in infant deaths during the same period.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

LAS VEGAS – Closer adherence by U.S. physicians to the “39-week rule” for elective deliveries appears to have cut net neonatal mortality in an analysis of more than 14 million deliveries during 2008-2012.

This net drop in mortality occurred despite a concurrent rise in stillbirths, Rachel A. Pilliod, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine. The increase in stillbirths was more than counterbalanced by a larger drop in infant deaths during the same period.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

About 10% of patients with colorectal cancer had at least one germline mutation known to increase the risk of cancer, according to results from a large single-center retrospective cohort study published in Journal of Clinical Oncology.

The findings “raise the provocative question of whether all patients with colorectal cancer (CRC) should undergo multigene germline testing for inherited cancer susceptibility,” especially because the results have implications for both patients and family members, said Matthew B. Yurgelun, MD, of Dana-Farber Cancer Institute in Boston, and his associates.

Hereditary factors long have been known to play a role in CRC, but clinicians have routinely limited genetic testing to phenotypically high-risk patients and to specific syndromes. For example, all patients with CRC are now typically tested for microsatellite instability (MSI) and mismatch repair deficiency (MRD) to identify the 2%-4% with Lynch syndrome. Likewise, patients with colorectal polyposis are routinely tested for familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), the researchers noted.

copyright Gio_tto/Thinkstock

About 10% of patients with colorectal cancer had at least one germline mutation known to increase the risk of cancer, according to results from a large single-center retrospective cohort study published in Journal of Clinical Oncology.

The findings “raise the provocative question of whether all patients with colorectal cancer (CRC) should undergo multigene germline testing for inherited cancer susceptibility,” especially because the results have implications for both patients and family members, said Matthew B. Yurgelun, MD, of Dana-Farber Cancer Institute in Boston, and his associates.

Hereditary factors long have been known to play a role in CRC, but clinicians have routinely limited genetic testing to phenotypically high-risk patients and to specific syndromes. For example, all patients with CRC are now typically tested for microsatellite instability (MSI) and mismatch repair deficiency (MRD) to identify the 2%-4% with Lynch syndrome. Likewise, patients with colorectal polyposis are routinely tested for familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), the researchers noted.

copyright Gio_tto/Thinkstock

About 10% of patients with colorectal cancer had at least one germline mutation known to increase the risk of cancer, according to results from a large single-center retrospective cohort study published in Journal of Clinical Oncology.

The findings “raise the provocative question of whether all patients with colorectal cancer (CRC) should undergo multigene germline testing for inherited cancer susceptibility,” especially because the results have implications for both patients and family members, said Matthew B. Yurgelun, MD, of Dana-Farber Cancer Institute in Boston, and his associates.

Hereditary factors long have been known to play a role in CRC, but clinicians have routinely limited genetic testing to phenotypically high-risk patients and to specific syndromes. For example, all patients with CRC are now typically tested for microsatellite instability (MSI) and mismatch repair deficiency (MRD) to identify the 2%-4% with Lynch syndrome. Likewise, patients with colorectal polyposis are routinely tested for familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), the researchers noted.

copyright Gio_tto/Thinkstock

To the Editor:

A 43-year-old woman with recently diagnosed diabetes mellitus and a history of thrombotic thrombocytopenic purpura on chronic oral steroids presented with a several-year history of small bumps and bilateral hyperpigmentation on the feet. On physical examination 2- to 3-mm dark brown, hyperkeratotic, firm papules were present on the medial aspects of the feet as well as the dorsal and medial aspects of the thumbs (Figure 1). There also were brown thickened firm plaques on the heels and soles of the feet. 

A punch biopsy of the medial aspect of the right foot was performed (Figure 2). Microscopic examination revealed acral skin with hyperkeratosis, parakeratosis, mild hypergranulosis, mild basilar pigmentation, and mild dermal fibrosis (Figure 2A). A periodic acid–Schiff stain for fungus was negative. An elastic van Gieson stain showed fragmentation of the dermal elastic fibers (Figure 2B). The patient was diagnosed with acrokeratoelastoidosis (AKE).

Acrokeratoelastoidosis is a rare autosomal-dominant genodermatosis characterized by firm yellow papules and plaques that appear along the margins of the hands and feet and increase in number over time.¹ Histopathologically, hyperkeratosis with hypergranulosis and acanthosis can be seen. Elastorrhexis, resulting in fragmentation of elastic fibers within the dermis, typically is present, a feature that distinguishes AKE from focal acral hyperkeratosis.² Also, the dermis may be normal with hematoxylin and eosin stain or slightly thickened with mild depression and thin elastic fibers. There is no reported racial or sex predilection, but rapid progression of the disease during pregnancy has been observed.³

The pathogenesis of AKE is not completely understood. However, it has been implicated that abnormalities in the secretion of elastic fibers from fibroblasts may be involved in disease pathogenesis.^4,5 Electron microscopy has demonstrated fibroblasts with dense granules at the periphery of their cytoplasm and an absence of surrounding elastic fibers. Genetic studies have linked underlying mutations in chromosome 2 to the disease.⁶ Defects in keratinization and overproduction of filaggrin also may be involved in the disease process.⁷

Most therapies generally are ineffective but have included urea, salicylic acid, prednisone, and tretinoin.⁸ Six-month treatment with etretinate 25 to 50 mg has shown promising results, though recurrences occurred with dosage reduction or discontinuation.⁹ Our patient demonstrated mild improvement with urea cream 30%.

To the Editor:

A 43-year-old woman with recently diagnosed diabetes mellitus and a history of thrombotic thrombocytopenic purpura on chronic oral steroids presented with a several-year history of small bumps and bilateral hyperpigmentation on the feet. On physical examination 2- to 3-mm dark brown, hyperkeratotic, firm papules were present on the medial aspects of the feet as well as the dorsal and medial aspects of the thumbs (Figure 1). There also were brown thickened firm plaques on the heels and soles of the feet. 

A punch biopsy of the medial aspect of the right foot was performed (Figure 2). Microscopic examination revealed acral skin with hyperkeratosis, parakeratosis, mild hypergranulosis, mild basilar pigmentation, and mild dermal fibrosis (Figure 2A). A periodic acid–Schiff stain for fungus was negative. An elastic van Gieson stain showed fragmentation of the dermal elastic fibers (Figure 2B). The patient was diagnosed with acrokeratoelastoidosis (AKE).

Acrokeratoelastoidosis is a rare autosomal-dominant genodermatosis characterized by firm yellow papules and plaques that appear along the margins of the hands and feet and increase in number over time.¹ Histopathologically, hyperkeratosis with hypergranulosis and acanthosis can be seen. Elastorrhexis, resulting in fragmentation of elastic fibers within the dermis, typically is present, a feature that distinguishes AKE from focal acral hyperkeratosis.² Also, the dermis may be normal with hematoxylin and eosin stain or slightly thickened with mild depression and thin elastic fibers. There is no reported racial or sex predilection, but rapid progression of the disease during pregnancy has been observed.³

The pathogenesis of AKE is not completely understood. However, it has been implicated that abnormalities in the secretion of elastic fibers from fibroblasts may be involved in disease pathogenesis.^4,5 Electron microscopy has demonstrated fibroblasts with dense granules at the periphery of their cytoplasm and an absence of surrounding elastic fibers. Genetic studies have linked underlying mutations in chromosome 2 to the disease.⁶ Defects in keratinization and overproduction of filaggrin also may be involved in the disease process.⁷

Most therapies generally are ineffective but have included urea, salicylic acid, prednisone, and tretinoin.⁸ Six-month treatment with etretinate 25 to 50 mg has shown promising results, though recurrences occurred with dosage reduction or discontinuation.⁹ Our patient demonstrated mild improvement with urea cream 30%.

To the Editor:

A 43-year-old woman with recently diagnosed diabetes mellitus and a history of thrombotic thrombocytopenic purpura on chronic oral steroids presented with a several-year history of small bumps and bilateral hyperpigmentation on the feet. On physical examination 2- to 3-mm dark brown, hyperkeratotic, firm papules were present on the medial aspects of the feet as well as the dorsal and medial aspects of the thumbs (Figure 1). There also were brown thickened firm plaques on the heels and soles of the feet. 

A punch biopsy of the medial aspect of the right foot was performed (Figure 2). Microscopic examination revealed acral skin with hyperkeratosis, parakeratosis, mild hypergranulosis, mild basilar pigmentation, and mild dermal fibrosis (Figure 2A). A periodic acid–Schiff stain for fungus was negative. An elastic van Gieson stain showed fragmentation of the dermal elastic fibers (Figure 2B). The patient was diagnosed with acrokeratoelastoidosis (AKE).

Acrokeratoelastoidosis is a rare autosomal-dominant genodermatosis characterized by firm yellow papules and plaques that appear along the margins of the hands and feet and increase in number over time.¹ Histopathologically, hyperkeratosis with hypergranulosis and acanthosis can be seen. Elastorrhexis, resulting in fragmentation of elastic fibers within the dermis, typically is present, a feature that distinguishes AKE from focal acral hyperkeratosis.² Also, the dermis may be normal with hematoxylin and eosin stain or slightly thickened with mild depression and thin elastic fibers. There is no reported racial or sex predilection, but rapid progression of the disease during pregnancy has been observed.³

The pathogenesis of AKE is not completely understood. However, it has been implicated that abnormalities in the secretion of elastic fibers from fibroblasts may be involved in disease pathogenesis.^4,5 Electron microscopy has demonstrated fibroblasts with dense granules at the periphery of their cytoplasm and an absence of surrounding elastic fibers. Genetic studies have linked underlying mutations in chromosome 2 to the disease.⁶ Defects in keratinization and overproduction of filaggrin also may be involved in the disease process.⁷

Most therapies generally are ineffective but have included urea, salicylic acid, prednisone, and tretinoin.⁸ Six-month treatment with etretinate 25 to 50 mg has shown promising results, though recurrences occurred with dosage reduction or discontinuation.⁹ Our patient demonstrated mild improvement with urea cream 30%.

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique treatments.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference product is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such biosimilars have come on the market, at an average price of about 30% less than the reference product. Prices have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive treatments. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer treatments (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those products to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive treatments, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

[email protected]

On Twitter @alz_gal

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique treatments.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference product is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such biosimilars have come on the market, at an average price of about 30% less than the reference product. Prices have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive treatments. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer treatments (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those products to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive treatments, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

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On Twitter @alz_gal

The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique treatments.

But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.

The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.

The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.

Interchangeables jump a higher regulatory bar

An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.

Like biosimilars, interchangeable products need not be tested in every disease for which the reference product is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.

The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:

• Sandoz’ filgrastim-sndz (Zarxio).

• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).

• Sandoz’ etanercept-szzs (Erelzi).

• Amgen’s adalimumab-atto (Amjevita).

Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.

But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.

Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.

The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.

Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.

“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.

The E.U. vs. U.S. experience

The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such biosimilars have come on the market, at an average price of about 30% less than the reference product. Prices have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.

“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.

It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive treatments. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.

There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.

In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer treatments (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those products to make up for the money they were losing on the Russian market.

Nonmedical switching raises concerns

Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive treatments, they uniformly insist that patient safety – not economic pressure – should be the driving force here.

“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”

He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.

“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).

[email protected]

On Twitter @alz_gal

Clinical question: Does the increasing number of ICU beds in the U.S. affect the use of mechanical ventilation in nursing home patients with advanced dementia?

Background: Some physicians are concerned that increases in ICU beds in the U.S. will translate to increased treatment of advanced dementia in the ICU, which might not line up with their preferences, nor improve mortality.

Study design: Retrospective cohort study.

Setting: Hospitals that completed the American Hospital Association (AHA) annual survey.

Synopsis: From 2000 to 2013, there were 635,008 hospitalizations of 380,060 Medicare patients with advanced dementia who had been in a nursing home in the 120 days prior to hospital admission. ICU admissions increased to 38.5% from 16.9% during the same period. The rate of mechanical ventilation per 1,000 hospital admissions increased to 78 from 39, and 1-year mortality for ventilation was unchanged.

For each increase in 10 ICU beds within a hospital, the adjusted odds ratio for receiving mechanical ventilation was 1.06 (95% CI, 1.05-1.07).

Limitations of the study include that only hospitals completing the AHA annual survey were studied, and also lacked information on individual patients.

Bottom line: The use of mechanical ventilation increased in hospitalized nursing home patients with advanced dementia, correlating with increased ICU bed capacity, yet with no changes in survival.

Citation: Teno JM, Gozalo P, Khandelwal N, et al. Association of increasing use of mechanical ventilation among nursing home residents with advanced dementia and intensive care unit beds [published online ahead of print, Oct. 10, 2016]. JAMA Int Med. 2016;176(12):1809-16.

Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.

Clinical question: Does the increasing number of ICU beds in the U.S. affect the use of mechanical ventilation in nursing home patients with advanced dementia?

Background: Some physicians are concerned that increases in ICU beds in the U.S. will translate to increased treatment of advanced dementia in the ICU, which might not line up with their preferences, nor improve mortality.

Study design: Retrospective cohort study.

Setting: Hospitals that completed the American Hospital Association (AHA) annual survey.

Synopsis: From 2000 to 2013, there were 635,008 hospitalizations of 380,060 Medicare patients with advanced dementia who had been in a nursing home in the 120 days prior to hospital admission. ICU admissions increased to 38.5% from 16.9% during the same period. The rate of mechanical ventilation per 1,000 hospital admissions increased to 78 from 39, and 1-year mortality for ventilation was unchanged.

For each increase in 10 ICU beds within a hospital, the adjusted odds ratio for receiving mechanical ventilation was 1.06 (95% CI, 1.05-1.07).

Limitations of the study include that only hospitals completing the AHA annual survey were studied, and also lacked information on individual patients.

Bottom line: The use of mechanical ventilation increased in hospitalized nursing home patients with advanced dementia, correlating with increased ICU bed capacity, yet with no changes in survival.

Citation: Teno JM, Gozalo P, Khandelwal N, et al. Association of increasing use of mechanical ventilation among nursing home residents with advanced dementia and intensive care unit beds [published online ahead of print, Oct. 10, 2016]. JAMA Int Med. 2016;176(12):1809-16.

Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.

Clinical question: Does the increasing number of ICU beds in the U.S. affect the use of mechanical ventilation in nursing home patients with advanced dementia?

Background: Some physicians are concerned that increases in ICU beds in the U.S. will translate to increased treatment of advanced dementia in the ICU, which might not line up with their preferences, nor improve mortality.

Study design: Retrospective cohort study.

Setting: Hospitals that completed the American Hospital Association (AHA) annual survey.

Synopsis: From 2000 to 2013, there were 635,008 hospitalizations of 380,060 Medicare patients with advanced dementia who had been in a nursing home in the 120 days prior to hospital admission. ICU admissions increased to 38.5% from 16.9% during the same period. The rate of mechanical ventilation per 1,000 hospital admissions increased to 78 from 39, and 1-year mortality for ventilation was unchanged.

For each increase in 10 ICU beds within a hospital, the adjusted odds ratio for receiving mechanical ventilation was 1.06 (95% CI, 1.05-1.07).

Limitations of the study include that only hospitals completing the AHA annual survey were studied, and also lacked information on individual patients.

Bottom line: The use of mechanical ventilation increased in hospitalized nursing home patients with advanced dementia, correlating with increased ICU bed capacity, yet with no changes in survival.

Citation: Teno JM, Gozalo P, Khandelwal N, et al. Association of increasing use of mechanical ventilation among nursing home residents with advanced dementia and intensive care unit beds [published online ahead of print, Oct. 10, 2016]. JAMA Int Med. 2016;176(12):1809-16.

Dr. Balch is a clinical instructor at the University of Utah School of Medicine and an academic hospitalist at the University of Utah Hospital.