CHICAGO – Rapid deployment sutureless valves can be a good option for some patients, providing a highly functional and nearly leakproof valve with less cardiopulmonary bypass and aortic cross-clamp times than those of conventional procedures.

“Why use a sutureless valve?” asked Vinod H. Thourani, MD, speaking at Heart Valve Summit 2016. He said that for many patients, there are abundant good reasons for the choice. The rapidity of the implantation procedure is a huge plus, he said. Cardiopulmonary bypass times are reduced when sutureless valve replacement is a stand-alone procedure, added Dr. Thourani, chief of cardiovascular surgery at Emory Hospital Midtown and codirector of the Structural Heart and Valve Center at Emory University, Atlanta.

Dr. Thourani reported multiple financial relationships with medical device companies.

[email protected]

On Twitter @karioakes

CHICAGO – Rapid deployment sutureless valves can be a good option for some patients, providing a highly functional and nearly leakproof valve with less cardiopulmonary bypass and aortic cross-clamp times than those of conventional procedures.

“Why use a sutureless valve?” asked Vinod H. Thourani, MD, speaking at Heart Valve Summit 2016. He said that for many patients, there are abundant good reasons for the choice. The rapidity of the implantation procedure is a huge plus, he said. Cardiopulmonary bypass times are reduced when sutureless valve replacement is a stand-alone procedure, added Dr. Thourani, chief of cardiovascular surgery at Emory Hospital Midtown and codirector of the Structural Heart and Valve Center at Emory University, Atlanta.

Dr. Thourani reported multiple financial relationships with medical device companies.

[email protected]

On Twitter @karioakes

CHICAGO – Rapid deployment sutureless valves can be a good option for some patients, providing a highly functional and nearly leakproof valve with less cardiopulmonary bypass and aortic cross-clamp times than those of conventional procedures.

“Why use a sutureless valve?” asked Vinod H. Thourani, MD, speaking at Heart Valve Summit 2016. He said that for many patients, there are abundant good reasons for the choice. The rapidity of the implantation procedure is a huge plus, he said. Cardiopulmonary bypass times are reduced when sutureless valve replacement is a stand-alone procedure, added Dr. Thourani, chief of cardiovascular surgery at Emory Hospital Midtown and codirector of the Structural Heart and Valve Center at Emory University, Atlanta.

Dr. Thourani reported multiple financial relationships with medical device companies.

[email protected]

On Twitter @karioakes

Infantile hemangiomas of the nose develop more complications than those at all other body sites combined, according to a report published in Pediatric Dermatology.

In what they described as the largest study to date to assess nasal infantile hemangiomas, researchers assessed which traits are associated with complications and predict residual skin changes at the age of 5 years. “Nasal infantile hemangiomas pose an immediate risk of airway obstruction because infants are obligate nasal breathers, and may have long-term functional and psychosocial consequences if involution is incomplete or development of surrounding structures, such as nasal cartilage, is compromised,” said Maria S. Kryatova of the departments of pediatrics and dermatology, Johns Hopkins University, Baltimore, and her associates.

The investigators identified all patients younger than 18 years who had been treated at their academic referral center for nasal infantile hemangiomas between 2001 and 2014. They performed retrospective chart reviews, which included photographs, for 89 participants. The parents of 63 of these children were interviewed when the participants reached a median age of 5 years and provided comparison photographs taken at their entry into kindergarten.

Thirty-five children (39%) developed one or more complications at some time during follow-up, including airway compromise, compression, or functional impairment; ulceration; visual obstruction or ocular compression; and infection. In comparison, the Hemangioma Investigator Group has previously reported a 24% overall rate of complications at all body sites. Similarly, the proportion of study participants who received at least one type of treatment (propranolol, oral steroids, pulsed dye laser, surgery, topical timolol, intralesional corticosteroids, yttrium-aluminum-garnet laser, carbon dioxide laser, or fraxel laser) was markedly higher (80%) than that reported previously by the Hemangioma Investigator Group for all body sites (38%).

“Our study is the first to report a significant association between [the hemangioma’s location on the nose] and depth. Lesions on the nasal dorsum are unlikely to be deep, whereas nasal tip lesions are unlikely to be superficial. Deep vertical growth may be limited by underlying nasal bone in the dorsum but less so by the soft tissue of the nasal tip.” Alternatively, as suggested by other investigators, an embryologic explanation is also possible – “the fusion lines between neural crest–derived mesenchyme and ectoderm-derived nasal placodes may have different properties in the vicinity of the nasal dorsum and nasal tip that predispose them to the development of superficial and deep hemangiomas, respectively,” Ms. Kryatova and her associates reported (Ped Dermatol. 2016;33[6]:652-8).

Segmental- and indeterminate-type lesions were more likely than focal-type lesions to develop ulceration, compression, or functional obstruction, and mixed-depth hemangiomas were more likely than deep or superficial hemangiomas to ulcerate. Overall, the lesions had involuted by kindergarten age in 70% of the study participants but persisted in 30%, and most of the children with involution showed residual skin changes such as telangiectasia (14 children), fibrofatty tissue (11 children), and scarring (9 children).

These findings show that a multicenter study to expand on these conclusions and to determine the best treatment algorithm for nasal infantile hemangiomas is warranted, the investigators added.

[email protected]

Infantile hemangiomas of the nose develop more complications than those at all other body sites combined, according to a report published in Pediatric Dermatology.

In what they described as the largest study to date to assess nasal infantile hemangiomas, researchers assessed which traits are associated with complications and predict residual skin changes at the age of 5 years. “Nasal infantile hemangiomas pose an immediate risk of airway obstruction because infants are obligate nasal breathers, and may have long-term functional and psychosocial consequences if involution is incomplete or development of surrounding structures, such as nasal cartilage, is compromised,” said Maria S. Kryatova of the departments of pediatrics and dermatology, Johns Hopkins University, Baltimore, and her associates.

The investigators identified all patients younger than 18 years who had been treated at their academic referral center for nasal infantile hemangiomas between 2001 and 2014. They performed retrospective chart reviews, which included photographs, for 89 participants. The parents of 63 of these children were interviewed when the participants reached a median age of 5 years and provided comparison photographs taken at their entry into kindergarten.

Thirty-five children (39%) developed one or more complications at some time during follow-up, including airway compromise, compression, or functional impairment; ulceration; visual obstruction or ocular compression; and infection. In comparison, the Hemangioma Investigator Group has previously reported a 24% overall rate of complications at all body sites. Similarly, the proportion of study participants who received at least one type of treatment (propranolol, oral steroids, pulsed dye laser, surgery, topical timolol, intralesional corticosteroids, yttrium-aluminum-garnet laser, carbon dioxide laser, or fraxel laser) was markedly higher (80%) than that reported previously by the Hemangioma Investigator Group for all body sites (38%).

“Our study is the first to report a significant association between [the hemangioma’s location on the nose] and depth. Lesions on the nasal dorsum are unlikely to be deep, whereas nasal tip lesions are unlikely to be superficial. Deep vertical growth may be limited by underlying nasal bone in the dorsum but less so by the soft tissue of the nasal tip.” Alternatively, as suggested by other investigators, an embryologic explanation is also possible – “the fusion lines between neural crest–derived mesenchyme and ectoderm-derived nasal placodes may have different properties in the vicinity of the nasal dorsum and nasal tip that predispose them to the development of superficial and deep hemangiomas, respectively,” Ms. Kryatova and her associates reported (Ped Dermatol. 2016;33[6]:652-8).

Segmental- and indeterminate-type lesions were more likely than focal-type lesions to develop ulceration, compression, or functional obstruction, and mixed-depth hemangiomas were more likely than deep or superficial hemangiomas to ulcerate. Overall, the lesions had involuted by kindergarten age in 70% of the study participants but persisted in 30%, and most of the children with involution showed residual skin changes such as telangiectasia (14 children), fibrofatty tissue (11 children), and scarring (9 children).

These findings show that a multicenter study to expand on these conclusions and to determine the best treatment algorithm for nasal infantile hemangiomas is warranted, the investigators added.

[email protected]

Infantile hemangiomas of the nose develop more complications than those at all other body sites combined, according to a report published in Pediatric Dermatology.

In what they described as the largest study to date to assess nasal infantile hemangiomas, researchers assessed which traits are associated with complications and predict residual skin changes at the age of 5 years. “Nasal infantile hemangiomas pose an immediate risk of airway obstruction because infants are obligate nasal breathers, and may have long-term functional and psychosocial consequences if involution is incomplete or development of surrounding structures, such as nasal cartilage, is compromised,” said Maria S. Kryatova of the departments of pediatrics and dermatology, Johns Hopkins University, Baltimore, and her associates.

The investigators identified all patients younger than 18 years who had been treated at their academic referral center for nasal infantile hemangiomas between 2001 and 2014. They performed retrospective chart reviews, which included photographs, for 89 participants. The parents of 63 of these children were interviewed when the participants reached a median age of 5 years and provided comparison photographs taken at their entry into kindergarten.

Thirty-five children (39%) developed one or more complications at some time during follow-up, including airway compromise, compression, or functional impairment; ulceration; visual obstruction or ocular compression; and infection. In comparison, the Hemangioma Investigator Group has previously reported a 24% overall rate of complications at all body sites. Similarly, the proportion of study participants who received at least one type of treatment (propranolol, oral steroids, pulsed dye laser, surgery, topical timolol, intralesional corticosteroids, yttrium-aluminum-garnet laser, carbon dioxide laser, or fraxel laser) was markedly higher (80%) than that reported previously by the Hemangioma Investigator Group for all body sites (38%).

“Our study is the first to report a significant association between [the hemangioma’s location on the nose] and depth. Lesions on the nasal dorsum are unlikely to be deep, whereas nasal tip lesions are unlikely to be superficial. Deep vertical growth may be limited by underlying nasal bone in the dorsum but less so by the soft tissue of the nasal tip.” Alternatively, as suggested by other investigators, an embryologic explanation is also possible – “the fusion lines between neural crest–derived mesenchyme and ectoderm-derived nasal placodes may have different properties in the vicinity of the nasal dorsum and nasal tip that predispose them to the development of superficial and deep hemangiomas, respectively,” Ms. Kryatova and her associates reported (Ped Dermatol. 2016;33[6]:652-8).

Segmental- and indeterminate-type lesions were more likely than focal-type lesions to develop ulceration, compression, or functional obstruction, and mixed-depth hemangiomas were more likely than deep or superficial hemangiomas to ulcerate. Overall, the lesions had involuted by kindergarten age in 70% of the study participants but persisted in 30%, and most of the children with involution showed residual skin changes such as telangiectasia (14 children), fibrofatty tissue (11 children), and scarring (9 children).

These findings show that a multicenter study to expand on these conclusions and to determine the best treatment algorithm for nasal infantile hemangiomas is warranted, the investigators added.

[email protected]

Fractional microneedling radiofrequency (FMR) therapy resulted in modest but clinically significant improvements in the appearance and inflammation of rosacea in a small study of patients with mild to moderate rosacea.

The treatment delivers bipolar radiofrequency energy to the dermis via an array of microneedles, without damaging the epidermis, noted Seon Yong Park, MD, and colleagues from the department of dermatology at Seoul (South Korea) National University. It has previously been associated with clinical and histological improvements in acne-associated postinflammatory erythema and is used in the treatment of cutaneous wrinkles. The authors said that, as far as they know, this is the first study to evaluate the use of FMR in patients with rosacea.

In the prospective, single-blind, randomized, split-face clinical study, 21 patients (20 females, 1 male) with mild to moderate rosacea were treated with two FMR sessions, 4 weeks apart, then assessed 4, 8, and 12 weeks after the second session. The mean age of the patients was 43 years; they had Fitzpatrick skin type III (13 patients) or IV (8 patients), and rosacea was considered mild in 12 patients and moderate in 9 patients at baseline.

Researchers saw clinical improvements in 17 (81%) of the patients on the treated side; these patients had a mean improvement in the Investigator’s Global Assessment (IGA) score of 2.47 by week 12, representing about a 20% improvement (Dermatol Surg. 2016 Dec;42[12]:1362-9).

In the group overall, mean IGA scores at weeks 4, 8, and 12 were 1.05, 1.57, and 2.00 for the treated side, compared with 0.29, 0.38, and 0.38, respectively, for the untreated side, which, the authors wrote, indicated that “there was modest but statistically significant improvements in the treated side.”

Photometric measurements of redness showed significant reductions on the treated side, compared with the untreated side and baseline, with reductions in the erythema index of 11.9%, 10.7%, and 13.6% at week 4, 8, and 12, respectively.

Histological assessment showed reduced dermal inflammation, significant reductions in average mast cell count, and an overall decrease in immunohistochemical intensity in the treated skin 8 weeks after treatment. Similarly, there were significant decreases in markers of angiogenesis, inflammation, innate immunity, and neuroimmunity on the treated side, compared with baseline.

“Fractional microneedling radiofrequency was slightly more effective in reducing erythema in patients with PPR [papulopustular rosacea] than in those with ETR [erythematotelangiectatic rosacea], suggesting that inflammatory lesions, such as papules and pustules, could be more effectively treated with this device,” the authors wrote. “This result agreed with reports showing that FMR is effective in treating inflammatory acne.”

No serious adverse effects were reported, although 19 patients (90.5%) experienced mild pain during the procedure and 17 (81%) had mild erythema that lasted for up to 5 days. Patients also reported less itching, heat, burning, or pricking on the treated side, which showed that the treatment was effective in controlling the symptoms of rosacea, Dr. Park and associates said.

The study was supported by the SNUH Research Fund and National Research Foundation of Korea. The authors, who are also in the acne and rosacea research laboratory, Seoul National University Hospital, had no conflicts to disclose.

Fractional microneedling radiofrequency (FMR) therapy resulted in modest but clinically significant improvements in the appearance and inflammation of rosacea in a small study of patients with mild to moderate rosacea.

The treatment delivers bipolar radiofrequency energy to the dermis via an array of microneedles, without damaging the epidermis, noted Seon Yong Park, MD, and colleagues from the department of dermatology at Seoul (South Korea) National University. It has previously been associated with clinical and histological improvements in acne-associated postinflammatory erythema and is used in the treatment of cutaneous wrinkles. The authors said that, as far as they know, this is the first study to evaluate the use of FMR in patients with rosacea.

In the prospective, single-blind, randomized, split-face clinical study, 21 patients (20 females, 1 male) with mild to moderate rosacea were treated with two FMR sessions, 4 weeks apart, then assessed 4, 8, and 12 weeks after the second session. The mean age of the patients was 43 years; they had Fitzpatrick skin type III (13 patients) or IV (8 patients), and rosacea was considered mild in 12 patients and moderate in 9 patients at baseline.

Researchers saw clinical improvements in 17 (81%) of the patients on the treated side; these patients had a mean improvement in the Investigator’s Global Assessment (IGA) score of 2.47 by week 12, representing about a 20% improvement (Dermatol Surg. 2016 Dec;42[12]:1362-9).

In the group overall, mean IGA scores at weeks 4, 8, and 12 were 1.05, 1.57, and 2.00 for the treated side, compared with 0.29, 0.38, and 0.38, respectively, for the untreated side, which, the authors wrote, indicated that “there was modest but statistically significant improvements in the treated side.”

Photometric measurements of redness showed significant reductions on the treated side, compared with the untreated side and baseline, with reductions in the erythema index of 11.9%, 10.7%, and 13.6% at week 4, 8, and 12, respectively.

Histological assessment showed reduced dermal inflammation, significant reductions in average mast cell count, and an overall decrease in immunohistochemical intensity in the treated skin 8 weeks after treatment. Similarly, there were significant decreases in markers of angiogenesis, inflammation, innate immunity, and neuroimmunity on the treated side, compared with baseline.

“Fractional microneedling radiofrequency was slightly more effective in reducing erythema in patients with PPR [papulopustular rosacea] than in those with ETR [erythematotelangiectatic rosacea], suggesting that inflammatory lesions, such as papules and pustules, could be more effectively treated with this device,” the authors wrote. “This result agreed with reports showing that FMR is effective in treating inflammatory acne.”

No serious adverse effects were reported, although 19 patients (90.5%) experienced mild pain during the procedure and 17 (81%) had mild erythema that lasted for up to 5 days. Patients also reported less itching, heat, burning, or pricking on the treated side, which showed that the treatment was effective in controlling the symptoms of rosacea, Dr. Park and associates said.

The study was supported by the SNUH Research Fund and National Research Foundation of Korea. The authors, who are also in the acne and rosacea research laboratory, Seoul National University Hospital, had no conflicts to disclose.

Fractional microneedling radiofrequency (FMR) therapy resulted in modest but clinically significant improvements in the appearance and inflammation of rosacea in a small study of patients with mild to moderate rosacea.

The treatment delivers bipolar radiofrequency energy to the dermis via an array of microneedles, without damaging the epidermis, noted Seon Yong Park, MD, and colleagues from the department of dermatology at Seoul (South Korea) National University. It has previously been associated with clinical and histological improvements in acne-associated postinflammatory erythema and is used in the treatment of cutaneous wrinkles. The authors said that, as far as they know, this is the first study to evaluate the use of FMR in patients with rosacea.

In the prospective, single-blind, randomized, split-face clinical study, 21 patients (20 females, 1 male) with mild to moderate rosacea were treated with two FMR sessions, 4 weeks apart, then assessed 4, 8, and 12 weeks after the second session. The mean age of the patients was 43 years; they had Fitzpatrick skin type III (13 patients) or IV (8 patients), and rosacea was considered mild in 12 patients and moderate in 9 patients at baseline.

Researchers saw clinical improvements in 17 (81%) of the patients on the treated side; these patients had a mean improvement in the Investigator’s Global Assessment (IGA) score of 2.47 by week 12, representing about a 20% improvement (Dermatol Surg. 2016 Dec;42[12]:1362-9).

In the group overall, mean IGA scores at weeks 4, 8, and 12 were 1.05, 1.57, and 2.00 for the treated side, compared with 0.29, 0.38, and 0.38, respectively, for the untreated side, which, the authors wrote, indicated that “there was modest but statistically significant improvements in the treated side.”

Photometric measurements of redness showed significant reductions on the treated side, compared with the untreated side and baseline, with reductions in the erythema index of 11.9%, 10.7%, and 13.6% at week 4, 8, and 12, respectively.

Histological assessment showed reduced dermal inflammation, significant reductions in average mast cell count, and an overall decrease in immunohistochemical intensity in the treated skin 8 weeks after treatment. Similarly, there were significant decreases in markers of angiogenesis, inflammation, innate immunity, and neuroimmunity on the treated side, compared with baseline.

“Fractional microneedling radiofrequency was slightly more effective in reducing erythema in patients with PPR [papulopustular rosacea] than in those with ETR [erythematotelangiectatic rosacea], suggesting that inflammatory lesions, such as papules and pustules, could be more effectively treated with this device,” the authors wrote. “This result agreed with reports showing that FMR is effective in treating inflammatory acne.”

No serious adverse effects were reported, although 19 patients (90.5%) experienced mild pain during the procedure and 17 (81%) had mild erythema that lasted for up to 5 days. Patients also reported less itching, heat, burning, or pricking on the treated side, which showed that the treatment was effective in controlling the symptoms of rosacea, Dr. Park and associates said.

The study was supported by the SNUH Research Fund and National Research Foundation of Korea. The authors, who are also in the acne and rosacea research laboratory, Seoul National University Hospital, had no conflicts to disclose.

Fat embolism syndrome (FES) occurs in long-bone fractures and classically presents with the triad of hypoxia, petechia, and altered mental status, or the criteria of Gurd and Wilson.¹ The Lindeque criteria (femur fracture, pH <7.3, increased work of breathing) are also used.^1,2 FES is a potentially fatal complication, with mortality rates ranging from 10% to 36%.^1,3 FES typically occurs within 24 to 72 hours after initial insult, with one study finding an average of 48.5 hours after injury and an incidence of 0.15% to 2.4%.⁴ The overall FES rate is <1% in retrospective reviews and 11% to 29% in prospective studies.⁵ FES may present without one or all of the Gurd and Wilson criteria,⁶ and cerebral fat embolism (CFE) can be even more difficult to diagnose. Patients with CFE typically present with a wide array of postoperative neurologic deficits, commonly in the 24- to 72-hour window in which FES typically occurs. Correct diagnosis and management of CFE require a high index of suspicion and knowledge of the diagnostic work-up. In the postoperative setting, it can be difficult to distinguish CFE-related neurologic deficits from the normal sequelae of anesthesia, pain medications, and other factors.

In this article, we report the case of a 42-year-old woman who developed CFE after reamed intramedullary nail fixation of femoral and tibial shaft fractures. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 42-year-old woman with no past medical history was injured when a horse reared and fell on her. Initial emergent computed tomography (CT) was negative for intracranial hemorrhage, and injury radiographs were obtained (Figures 1A, 1B).

About 9 hours after surgery and 36 hours after injury, the patient was unresponsive. Vital signs, including oxygen saturation, were within normal limits, but she was unable to verbalize. Physical examination revealed symmetric facial musculature but also generalized weakness and diffuse hypertonicity and hyperreflexia. Initial laboratory results, including complete blood cell count, electrolyte panel, and troponin levels, were unremarkable. Naloxone was administered to rule out opioid overdose. An immediate code stroke and neurology consultation was requested. An emergent CT scan of the brain was negative; an urgent magnetic resonance imaging (MRI) scan showed multiple punctate T2/FLAIR (fluid attenuated inversion recovery) hyperintensities with restricted diffusion, predominantly in a parasagittal white matter distribution (Figure 2).

Discussion

Postoperative Acute Mental Status Change

There are many causes of postoperative mental status change after intramedullary nailing. Change may be cardiogenic, infectious, pharmacologic, or neurologic in origin. Age should be considered in the work-up of postoperative mental status change, as common complications differ between older and younger patients, with geriatric patients at particularly high risk for delirium.

Next to be evaluated are vital signs—particularly hypoxia, as isolated tachycardia may simply be a manifestation of pain. The cardiac system is then assessed with EKG and cardiac-specific laboratory tests, including a troponin level test if there is suspicion of myocardial infarction. PE and FES are complications with a higher prevalence in intramedullary nailing, and pulmonary involvement can be ruled out with the CT with PE protocol. Skin examination is important as well, as FES presents with petechial rash in 60% of patients⁸ (rash was absent in our patient’s case). Narcotic overdose is easily ruled out with administration of naloxone. Infection and sepsis can cause mental changes, though more commonly in the elderly and seldom so soon after surgery. Evaluation for infection and sepsis involves urinalysis and culturing of blood, urine, and other bodily fluids. If there is concern about surgical site infection, the postoperative dressing should be immediately removed and the wound examined. Last, neurologic and embolic phenomena can be initially investigated with CT to rule out hemorrhagic stroke. If CT of the brain is negative, MRI should be performed. MRI is the gold standard for diagnosing ischemic stroke and CFE caused by FES.⁹

Prevalence of Fat Embolism Syndrome

Development of intramedullary fat release in patients with long-bone injuries is common. A prospective study found circulating fat globules in 95% of 43 patients with femur fractures.¹⁰ In another study, transesophageal EKG showed cardiac embolism in 62% of patients who had undergone intramedullary nail fixation.¹¹ Despite this high rate, only 0.9% to 2.2% of patients developed symptomatic FES. Risk factors for FES include younger age, multiple fractures, closed fractures, and nonoperative or delayed management of long-bone fractures.² As already mentioned, average time to FES presentation after long-bone fracture is about 48 hours. One study found that FES typically occurs within 24 to 72 hours after initial insult (average, 48.5 hours) and that the incidence of FES is 0.15% in tibia fractures, 0.78% in femur fractures, and 2.4% in multiple long-bone fractures.⁴ The timeline is consistent with the present case—our patient developed symptoms about 36 hours after injury. In addition, other studies have found a higher mortality rate (5%-15%) for patients with bilateral femur fractures than for patients with only one fracture.^7,12,13 Patients with a floating knee injury (ipsilateral tibia and femur fractures) are at higher risk for FES and have higher overall morbidity and mortality rates in comparison with patients with an isolated femur or tibia fracture, though the increased risk has not been quantified.

Review of Case Literature: FES With CFE

Few cases of FES with symptomatic CFE in the setting of long-bone fracture or long-bone surgery have been reported in the literature. There is wide variation in the development of FES with respect to preoperative or postoperative status and mechanism of injury. Duran and colleagues¹⁴ described a 20-year-old man with ipsilateral tibia and femur fractures caused by gunshots. Twenty-four hours after presentation, he developed tonic-clonic seizures and the classic triad of rash, hypoxia, and altered mental status. MRI confirmed CFE secondary to FES. The patient was optimized neurologically before definitive fixation and was discharged with minimal neurologic deficits on POD-27. Chang and colleagues¹⁵ and Yeo and colleagues¹⁶ described CFE in patients who underwent bilateral total knee arthroplasty. Symptoms developed 9 hours and 2 days after surgery, respectively. Both patients had fat emboli in the lungs and brain, underwent intensive care treatment, and recovered from the initial insult. After discharge at 44 days and 2 weeks, respectively, they fully recovered.

Other patients with CFE have had less favorable outcomes. Chen and colleagues⁶ reported the case of a 31-year-old man who sustained closed femur and tibia fractures in an automobile collision and experienced an acute decline in neurologic status 1 hour after arrival in the emergency department. The patient was intubated, CFE was diagnosed on the basis of MRI findings, and the orthopedic injuries were treated with external fixation. After 2 weeks, the patient was discharged with persistent neurologic deficits and the need for long-term tube feeding. Walshe and colleagues¹⁷ reported the case of a 19-year-old woman who sustained multiple long-bone injuries and traumatic brain injury and showed fat emboli on MRI. The patient experienced brain herniation while in the intensive care unit and later was declared brain-dead. According to the literature, it is important to maintain high suspicion for FES and possible CFE in the setting of high-energy fracture but also to be aware that FES may develop even with nondisplaced fracture or with reaming of the intramedullary canal in elective total joint arthroplasty.¹⁸

Pathophysiology of Fat Embolism Syndrome

The pathophysiology of FES and specifically of CFE is not widely understood. Two main theories on the development of FES have been advanced.

The mechanical theory suggests that exposing intramedullary long-bone contents allows fat to mobilize into the bloodstream.¹⁹ This occurs in the setting of long-bone fracture and in canal preparation during joint replacement surgery. More fat extravasates into the venous system after femur fracture than after tibia fracture, which accounts for the higher risk for FES in femoral shaft fractures and the even higher risk in concomitant femur and tibia fractures.⁴ In addition to there being a risk of fat embolism from the fracture itself, placing the patient in traction or reaming the intramedullary canal may exacerbate this effect by increased extravasation of fat from the medullary canal. With extravasation of fatty bone marrow into the venous system, fat emboli are free to travel back to the lungs, where they can cause infarcts within the lung parenchyma.

In the mechanical theory, presence of PFO may allow fat globules to pass into the systemic circulation and cause end-organ emboli. In the event of cerebral emboli, neurologic symptoms may vary widely and may include diffuse encephalopathy and global deficits.²⁰ Dog studies have found a possible mechanism for CFE in the absence of PFO. One such study, which used femoral pressurization to replicate cemented femoral arthroplasty, found that many fat globules had traversed the lungs after release into bone marrow,²¹ supporting the theory that fat droplets can traverse the pulmonary system without sequestration in the lung parenchyma. Riding and colleagues²² reported finding pulmonary arteriovenous shunts, which are thought to allow CFE to occur in the absence of PFO. More studies are needed to determine the prevalence of shunts and their overall contribution to CFE development in patients with long-bone fracture.

The biochemical theory holds that bodily trauma induces the release of free fatty acids (FFAs) from the capillaries into the bloodstream.²³ This stress response is mediated by catecholamines, which activate the adenyl cyclase pathway, which activates lipase, which hydrolyzes stored triglycerides to FFAs and glycerol. The concentration of circulating FFA was increased in 9 of 10 patients in one study.²³ Increased FFAs in the bloodstream can accelerate local and end-organ clotting, leading to thrombocytopenia and endothelial injury. In addition, patients with hypercoagulable diseases are at higher risk for postoperative thromboembolism.²⁴ However, with a negative hypercoagulable work-up and with negative chest helical CT and EKG, which did not demonstrate PFO, the explanation for CFE in our patient may more likely reside with the arteriovenous shunt theory proposed by Riding and colleagues.²²

Diagnosis and Treatment

Proper care of orthopedic patients who potentially have FES/CFE involves prompt diagnosis, immediate symptomatic care, and early coordination with neurology and medical services to rule out other causes of symptoms. Obtaining advanced imaging to rule out other potential causes and to confirm the diagnosis is crucial. The patient in this case report did not exhibit any focal neurologic deficits, but emergent CT of the brain was indicated to rule out a hemorrhagic event. If a stroke secondary to FES is clinically suspected, MRI should be obtained as soon as possible. Multiple studies have found that the “starfield” pattern, which is best seen as multiple punctate hyperintensities on T2 imaging, is the typical radiographic manifestation of CFE.⁹ This applies to patients who are in the 24- to 72-hour window after long-bone fracture or fixation and who fit Gurd and Wilson¹ criteria or Lindeque^1,2criteria, or who exhibit a change in mental status but have a negative CT scan of the brain, as was the case with our patient. Once the diagnosis is made, treatment involves addressing the symptoms (Figure 4).

Fat Embolism Syndrome in Reamed and Unreamed Nailing

Over the past several decades, the number of long bones fixed with intramedullary nails has increased significantly.²⁶ There is debate regarding whether use of reamed intramedullary nails increases the risk of fat emboli relative to use of unreamed nails, but multiple studies have found no significant difference.^26,27 Pulmonary shunting occurs in both reamed and unreamed nailing; neither technique has an advantage in terms of cardiopulmonary complications. In multiple studies, reamed nails have the advantage of improved healing rates.²⁷ A sheep study compared reamed and unreamed femoral nailing.²⁸ After nailing, sheep lungs were examined histologically for the presence of bone marrow fat embolism. The embolism rate was higher with unreamed nailing (10.25%) than with reamed nailing (6.66%). One large study of the adverse effects of reamed and unreamed nailing in 1226 patients with tibial shaft fracture found that those with open fractures had higher rates of a negative event (nonunion, infection, fasciotomy, hardware failure, need for dynamization) after reamed nailing.²⁹ Patients with closed fractures had fewer events after reamed nailing. The authors concluded there is a potential benefit in outcome with reamed intramedullary nailing in patients with closed tibial shaft fractures, but they did not comment on development of FES. In a study of the effect of subject position on intramedullary pressure and fat embolism release, dogs were positioned either supine or lateral for tibial and femoral reaming.³⁰ The authors measured various physiologic parameters, including cardiac output, pulmonary arterial wedge pressure, arterial and venous blood gas, and blood cell counts. There were no statistically significant differences in values between the 2 groups in any variable, indicating that position does not affect FES development in the orthopedic trauma setting.

Conclusion

FES and CFE are potential devastating sequelae of both long-bone fracture and long-bone instrumentation. It is important to recognize these entities in the acute setting and to consider them in the differential diagnosis of a trauma or postoperative patient who experiences sudden onset of altered mental status with or without dyspnea or a petechial rash. If CFE is suspected, early advanced imaging (including urgent MRI) should be obtained with rapid involvement of a multidisciplinary team that can optimize the chance for successful recovery of both neurologic and physical function. The best treatment, early prevention and diagnosis, maximizes care of symptoms. As is evidenced in this case report, rapid diagnosis and treatment often result in recovery from a majority of the symptoms of FES and CFE.

Am J Orthop. 2016;45(7):E515-E521. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Fat embolism syndrome (FES) occurs in long-bone fractures and classically presents with the triad of hypoxia, petechia, and altered mental status, or the criteria of Gurd and Wilson.¹ The Lindeque criteria (femur fracture, pH <7.3, increased work of breathing) are also used.^1,2 FES is a potentially fatal complication, with mortality rates ranging from 10% to 36%.^1,3 FES typically occurs within 24 to 72 hours after initial insult, with one study finding an average of 48.5 hours after injury and an incidence of 0.15% to 2.4%.⁴ The overall FES rate is <1% in retrospective reviews and 11% to 29% in prospective studies.⁵ FES may present without one or all of the Gurd and Wilson criteria,⁶ and cerebral fat embolism (CFE) can be even more difficult to diagnose. Patients with CFE typically present with a wide array of postoperative neurologic deficits, commonly in the 24- to 72-hour window in which FES typically occurs. Correct diagnosis and management of CFE require a high index of suspicion and knowledge of the diagnostic work-up. In the postoperative setting, it can be difficult to distinguish CFE-related neurologic deficits from the normal sequelae of anesthesia, pain medications, and other factors.

In this article, we report the case of a 42-year-old woman who developed CFE after reamed intramedullary nail fixation of femoral and tibial shaft fractures. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 42-year-old woman with no past medical history was injured when a horse reared and fell on her. Initial emergent computed tomography (CT) was negative for intracranial hemorrhage, and injury radiographs were obtained (Figures 1A, 1B).

About 9 hours after surgery and 36 hours after injury, the patient was unresponsive. Vital signs, including oxygen saturation, were within normal limits, but she was unable to verbalize. Physical examination revealed symmetric facial musculature but also generalized weakness and diffuse hypertonicity and hyperreflexia. Initial laboratory results, including complete blood cell count, electrolyte panel, and troponin levels, were unremarkable. Naloxone was administered to rule out opioid overdose. An immediate code stroke and neurology consultation was requested. An emergent CT scan of the brain was negative; an urgent magnetic resonance imaging (MRI) scan showed multiple punctate T2/FLAIR (fluid attenuated inversion recovery) hyperintensities with restricted diffusion, predominantly in a parasagittal white matter distribution (Figure 2).

Discussion

Postoperative Acute Mental Status Change

There are many causes of postoperative mental status change after intramedullary nailing. Change may be cardiogenic, infectious, pharmacologic, or neurologic in origin. Age should be considered in the work-up of postoperative mental status change, as common complications differ between older and younger patients, with geriatric patients at particularly high risk for delirium.

Next to be evaluated are vital signs—particularly hypoxia, as isolated tachycardia may simply be a manifestation of pain. The cardiac system is then assessed with EKG and cardiac-specific laboratory tests, including a troponin level test if there is suspicion of myocardial infarction. PE and FES are complications with a higher prevalence in intramedullary nailing, and pulmonary involvement can be ruled out with the CT with PE protocol. Skin examination is important as well, as FES presents with petechial rash in 60% of patients⁸ (rash was absent in our patient’s case). Narcotic overdose is easily ruled out with administration of naloxone. Infection and sepsis can cause mental changes, though more commonly in the elderly and seldom so soon after surgery. Evaluation for infection and sepsis involves urinalysis and culturing of blood, urine, and other bodily fluids. If there is concern about surgical site infection, the postoperative dressing should be immediately removed and the wound examined. Last, neurologic and embolic phenomena can be initially investigated with CT to rule out hemorrhagic stroke. If CT of the brain is negative, MRI should be performed. MRI is the gold standard for diagnosing ischemic stroke and CFE caused by FES.⁹

Prevalence of Fat Embolism Syndrome

Development of intramedullary fat release in patients with long-bone injuries is common. A prospective study found circulating fat globules in 95% of 43 patients with femur fractures.¹⁰ In another study, transesophageal EKG showed cardiac embolism in 62% of patients who had undergone intramedullary nail fixation.¹¹ Despite this high rate, only 0.9% to 2.2% of patients developed symptomatic FES. Risk factors for FES include younger age, multiple fractures, closed fractures, and nonoperative or delayed management of long-bone fractures.² As already mentioned, average time to FES presentation after long-bone fracture is about 48 hours. One study found that FES typically occurs within 24 to 72 hours after initial insult (average, 48.5 hours) and that the incidence of FES is 0.15% in tibia fractures, 0.78% in femur fractures, and 2.4% in multiple long-bone fractures.⁴ The timeline is consistent with the present case—our patient developed symptoms about 36 hours after injury. In addition, other studies have found a higher mortality rate (5%-15%) for patients with bilateral femur fractures than for patients with only one fracture.^7,12,13 Patients with a floating knee injury (ipsilateral tibia and femur fractures) are at higher risk for FES and have higher overall morbidity and mortality rates in comparison with patients with an isolated femur or tibia fracture, though the increased risk has not been quantified.

Review of Case Literature: FES With CFE

Few cases of FES with symptomatic CFE in the setting of long-bone fracture or long-bone surgery have been reported in the literature. There is wide variation in the development of FES with respect to preoperative or postoperative status and mechanism of injury. Duran and colleagues¹⁴ described a 20-year-old man with ipsilateral tibia and femur fractures caused by gunshots. Twenty-four hours after presentation, he developed tonic-clonic seizures and the classic triad of rash, hypoxia, and altered mental status. MRI confirmed CFE secondary to FES. The patient was optimized neurologically before definitive fixation and was discharged with minimal neurologic deficits on POD-27. Chang and colleagues¹⁵ and Yeo and colleagues¹⁶ described CFE in patients who underwent bilateral total knee arthroplasty. Symptoms developed 9 hours and 2 days after surgery, respectively. Both patients had fat emboli in the lungs and brain, underwent intensive care treatment, and recovered from the initial insult. After discharge at 44 days and 2 weeks, respectively, they fully recovered.

Other patients with CFE have had less favorable outcomes. Chen and colleagues⁶ reported the case of a 31-year-old man who sustained closed femur and tibia fractures in an automobile collision and experienced an acute decline in neurologic status 1 hour after arrival in the emergency department. The patient was intubated, CFE was diagnosed on the basis of MRI findings, and the orthopedic injuries were treated with external fixation. After 2 weeks, the patient was discharged with persistent neurologic deficits and the need for long-term tube feeding. Walshe and colleagues¹⁷ reported the case of a 19-year-old woman who sustained multiple long-bone injuries and traumatic brain injury and showed fat emboli on MRI. The patient experienced brain herniation while in the intensive care unit and later was declared brain-dead. According to the literature, it is important to maintain high suspicion for FES and possible CFE in the setting of high-energy fracture but also to be aware that FES may develop even with nondisplaced fracture or with reaming of the intramedullary canal in elective total joint arthroplasty.¹⁸

Pathophysiology of Fat Embolism Syndrome

The pathophysiology of FES and specifically of CFE is not widely understood. Two main theories on the development of FES have been advanced.

The mechanical theory suggests that exposing intramedullary long-bone contents allows fat to mobilize into the bloodstream.¹⁹ This occurs in the setting of long-bone fracture and in canal preparation during joint replacement surgery. More fat extravasates into the venous system after femur fracture than after tibia fracture, which accounts for the higher risk for FES in femoral shaft fractures and the even higher risk in concomitant femur and tibia fractures.⁴ In addition to there being a risk of fat embolism from the fracture itself, placing the patient in traction or reaming the intramedullary canal may exacerbate this effect by increased extravasation of fat from the medullary canal. With extravasation of fatty bone marrow into the venous system, fat emboli are free to travel back to the lungs, where they can cause infarcts within the lung parenchyma.

In the mechanical theory, presence of PFO may allow fat globules to pass into the systemic circulation and cause end-organ emboli. In the event of cerebral emboli, neurologic symptoms may vary widely and may include diffuse encephalopathy and global deficits.²⁰ Dog studies have found a possible mechanism for CFE in the absence of PFO. One such study, which used femoral pressurization to replicate cemented femoral arthroplasty, found that many fat globules had traversed the lungs after release into bone marrow,²¹ supporting the theory that fat droplets can traverse the pulmonary system without sequestration in the lung parenchyma. Riding and colleagues²² reported finding pulmonary arteriovenous shunts, which are thought to allow CFE to occur in the absence of PFO. More studies are needed to determine the prevalence of shunts and their overall contribution to CFE development in patients with long-bone fracture.

The biochemical theory holds that bodily trauma induces the release of free fatty acids (FFAs) from the capillaries into the bloodstream.²³ This stress response is mediated by catecholamines, which activate the adenyl cyclase pathway, which activates lipase, which hydrolyzes stored triglycerides to FFAs and glycerol. The concentration of circulating FFA was increased in 9 of 10 patients in one study.²³ Increased FFAs in the bloodstream can accelerate local and end-organ clotting, leading to thrombocytopenia and endothelial injury. In addition, patients with hypercoagulable diseases are at higher risk for postoperative thromboembolism.²⁴ However, with a negative hypercoagulable work-up and with negative chest helical CT and EKG, which did not demonstrate PFO, the explanation for CFE in our patient may more likely reside with the arteriovenous shunt theory proposed by Riding and colleagues.²²

Diagnosis and Treatment

Proper care of orthopedic patients who potentially have FES/CFE involves prompt diagnosis, immediate symptomatic care, and early coordination with neurology and medical services to rule out other causes of symptoms. Obtaining advanced imaging to rule out other potential causes and to confirm the diagnosis is crucial. The patient in this case report did not exhibit any focal neurologic deficits, but emergent CT of the brain was indicated to rule out a hemorrhagic event. If a stroke secondary to FES is clinically suspected, MRI should be obtained as soon as possible. Multiple studies have found that the “starfield” pattern, which is best seen as multiple punctate hyperintensities on T2 imaging, is the typical radiographic manifestation of CFE.⁹ This applies to patients who are in the 24- to 72-hour window after long-bone fracture or fixation and who fit Gurd and Wilson¹ criteria or Lindeque^1,2criteria, or who exhibit a change in mental status but have a negative CT scan of the brain, as was the case with our patient. Once the diagnosis is made, treatment involves addressing the symptoms (Figure 4).

Fat Embolism Syndrome in Reamed and Unreamed Nailing

Over the past several decades, the number of long bones fixed with intramedullary nails has increased significantly.²⁶ There is debate regarding whether use of reamed intramedullary nails increases the risk of fat emboli relative to use of unreamed nails, but multiple studies have found no significant difference.^26,27 Pulmonary shunting occurs in both reamed and unreamed nailing; neither technique has an advantage in terms of cardiopulmonary complications. In multiple studies, reamed nails have the advantage of improved healing rates.²⁷ A sheep study compared reamed and unreamed femoral nailing.²⁸ After nailing, sheep lungs were examined histologically for the presence of bone marrow fat embolism. The embolism rate was higher with unreamed nailing (10.25%) than with reamed nailing (6.66%). One large study of the adverse effects of reamed and unreamed nailing in 1226 patients with tibial shaft fracture found that those with open fractures had higher rates of a negative event (nonunion, infection, fasciotomy, hardware failure, need for dynamization) after reamed nailing.²⁹ Patients with closed fractures had fewer events after reamed nailing. The authors concluded there is a potential benefit in outcome with reamed intramedullary nailing in patients with closed tibial shaft fractures, but they did not comment on development of FES. In a study of the effect of subject position on intramedullary pressure and fat embolism release, dogs were positioned either supine or lateral for tibial and femoral reaming.³⁰ The authors measured various physiologic parameters, including cardiac output, pulmonary arterial wedge pressure, arterial and venous blood gas, and blood cell counts. There were no statistically significant differences in values between the 2 groups in any variable, indicating that position does not affect FES development in the orthopedic trauma setting.

Conclusion

FES and CFE are potential devastating sequelae of both long-bone fracture and long-bone instrumentation. It is important to recognize these entities in the acute setting and to consider them in the differential diagnosis of a trauma or postoperative patient who experiences sudden onset of altered mental status with or without dyspnea or a petechial rash. If CFE is suspected, early advanced imaging (including urgent MRI) should be obtained with rapid involvement of a multidisciplinary team that can optimize the chance for successful recovery of both neurologic and physical function. The best treatment, early prevention and diagnosis, maximizes care of symptoms. As is evidenced in this case report, rapid diagnosis and treatment often result in recovery from a majority of the symptoms of FES and CFE.

Am J Orthop. 2016;45(7):E515-E521. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Fat embolism syndrome (FES) occurs in long-bone fractures and classically presents with the triad of hypoxia, petechia, and altered mental status, or the criteria of Gurd and Wilson.¹ The Lindeque criteria (femur fracture, pH <7.3, increased work of breathing) are also used.^1,2 FES is a potentially fatal complication, with mortality rates ranging from 10% to 36%.^1,3 FES typically occurs within 24 to 72 hours after initial insult, with one study finding an average of 48.5 hours after injury and an incidence of 0.15% to 2.4%.⁴ The overall FES rate is <1% in retrospective reviews and 11% to 29% in prospective studies.⁵ FES may present without one or all of the Gurd and Wilson criteria,⁶ and cerebral fat embolism (CFE) can be even more difficult to diagnose. Patients with CFE typically present with a wide array of postoperative neurologic deficits, commonly in the 24- to 72-hour window in which FES typically occurs. Correct diagnosis and management of CFE require a high index of suspicion and knowledge of the diagnostic work-up. In the postoperative setting, it can be difficult to distinguish CFE-related neurologic deficits from the normal sequelae of anesthesia, pain medications, and other factors.

In this article, we report the case of a 42-year-old woman who developed CFE after reamed intramedullary nail fixation of femoral and tibial shaft fractures. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 42-year-old woman with no past medical history was injured when a horse reared and fell on her. Initial emergent computed tomography (CT) was negative for intracranial hemorrhage, and injury radiographs were obtained (Figures 1A, 1B).

About 9 hours after surgery and 36 hours after injury, the patient was unresponsive. Vital signs, including oxygen saturation, were within normal limits, but she was unable to verbalize. Physical examination revealed symmetric facial musculature but also generalized weakness and diffuse hypertonicity and hyperreflexia. Initial laboratory results, including complete blood cell count, electrolyte panel, and troponin levels, were unremarkable. Naloxone was administered to rule out opioid overdose. An immediate code stroke and neurology consultation was requested. An emergent CT scan of the brain was negative; an urgent magnetic resonance imaging (MRI) scan showed multiple punctate T2/FLAIR (fluid attenuated inversion recovery) hyperintensities with restricted diffusion, predominantly in a parasagittal white matter distribution (Figure 2).

Discussion

Postoperative Acute Mental Status Change

There are many causes of postoperative mental status change after intramedullary nailing. Change may be cardiogenic, infectious, pharmacologic, or neurologic in origin. Age should be considered in the work-up of postoperative mental status change, as common complications differ between older and younger patients, with geriatric patients at particularly high risk for delirium.

Next to be evaluated are vital signs—particularly hypoxia, as isolated tachycardia may simply be a manifestation of pain. The cardiac system is then assessed with EKG and cardiac-specific laboratory tests, including a troponin level test if there is suspicion of myocardial infarction. PE and FES are complications with a higher prevalence in intramedullary nailing, and pulmonary involvement can be ruled out with the CT with PE protocol. Skin examination is important as well, as FES presents with petechial rash in 60% of patients⁸ (rash was absent in our patient’s case). Narcotic overdose is easily ruled out with administration of naloxone. Infection and sepsis can cause mental changes, though more commonly in the elderly and seldom so soon after surgery. Evaluation for infection and sepsis involves urinalysis and culturing of blood, urine, and other bodily fluids. If there is concern about surgical site infection, the postoperative dressing should be immediately removed and the wound examined. Last, neurologic and embolic phenomena can be initially investigated with CT to rule out hemorrhagic stroke. If CT of the brain is negative, MRI should be performed. MRI is the gold standard for diagnosing ischemic stroke and CFE caused by FES.⁹

Prevalence of Fat Embolism Syndrome

Development of intramedullary fat release in patients with long-bone injuries is common. A prospective study found circulating fat globules in 95% of 43 patients with femur fractures.¹⁰ In another study, transesophageal EKG showed cardiac embolism in 62% of patients who had undergone intramedullary nail fixation.¹¹ Despite this high rate, only 0.9% to 2.2% of patients developed symptomatic FES. Risk factors for FES include younger age, multiple fractures, closed fractures, and nonoperative or delayed management of long-bone fractures.² As already mentioned, average time to FES presentation after long-bone fracture is about 48 hours. One study found that FES typically occurs within 24 to 72 hours after initial insult (average, 48.5 hours) and that the incidence of FES is 0.15% in tibia fractures, 0.78% in femur fractures, and 2.4% in multiple long-bone fractures.⁴ The timeline is consistent with the present case—our patient developed symptoms about 36 hours after injury. In addition, other studies have found a higher mortality rate (5%-15%) for patients with bilateral femur fractures than for patients with only one fracture.^7,12,13 Patients with a floating knee injury (ipsilateral tibia and femur fractures) are at higher risk for FES and have higher overall morbidity and mortality rates in comparison with patients with an isolated femur or tibia fracture, though the increased risk has not been quantified.

Review of Case Literature: FES With CFE

Few cases of FES with symptomatic CFE in the setting of long-bone fracture or long-bone surgery have been reported in the literature. There is wide variation in the development of FES with respect to preoperative or postoperative status and mechanism of injury. Duran and colleagues¹⁴ described a 20-year-old man with ipsilateral tibia and femur fractures caused by gunshots. Twenty-four hours after presentation, he developed tonic-clonic seizures and the classic triad of rash, hypoxia, and altered mental status. MRI confirmed CFE secondary to FES. The patient was optimized neurologically before definitive fixation and was discharged with minimal neurologic deficits on POD-27. Chang and colleagues¹⁵ and Yeo and colleagues¹⁶ described CFE in patients who underwent bilateral total knee arthroplasty. Symptoms developed 9 hours and 2 days after surgery, respectively. Both patients had fat emboli in the lungs and brain, underwent intensive care treatment, and recovered from the initial insult. After discharge at 44 days and 2 weeks, respectively, they fully recovered.

Other patients with CFE have had less favorable outcomes. Chen and colleagues⁶ reported the case of a 31-year-old man who sustained closed femur and tibia fractures in an automobile collision and experienced an acute decline in neurologic status 1 hour after arrival in the emergency department. The patient was intubated, CFE was diagnosed on the basis of MRI findings, and the orthopedic injuries were treated with external fixation. After 2 weeks, the patient was discharged with persistent neurologic deficits and the need for long-term tube feeding. Walshe and colleagues¹⁷ reported the case of a 19-year-old woman who sustained multiple long-bone injuries and traumatic brain injury and showed fat emboli on MRI. The patient experienced brain herniation while in the intensive care unit and later was declared brain-dead. According to the literature, it is important to maintain high suspicion for FES and possible CFE in the setting of high-energy fracture but also to be aware that FES may develop even with nondisplaced fracture or with reaming of the intramedullary canal in elective total joint arthroplasty.¹⁸

Pathophysiology of Fat Embolism Syndrome

The pathophysiology of FES and specifically of CFE is not widely understood. Two main theories on the development of FES have been advanced.

The mechanical theory suggests that exposing intramedullary long-bone contents allows fat to mobilize into the bloodstream.¹⁹ This occurs in the setting of long-bone fracture and in canal preparation during joint replacement surgery. More fat extravasates into the venous system after femur fracture than after tibia fracture, which accounts for the higher risk for FES in femoral shaft fractures and the even higher risk in concomitant femur and tibia fractures.⁴ In addition to there being a risk of fat embolism from the fracture itself, placing the patient in traction or reaming the intramedullary canal may exacerbate this effect by increased extravasation of fat from the medullary canal. With extravasation of fatty bone marrow into the venous system, fat emboli are free to travel back to the lungs, where they can cause infarcts within the lung parenchyma.

In the mechanical theory, presence of PFO may allow fat globules to pass into the systemic circulation and cause end-organ emboli. In the event of cerebral emboli, neurologic symptoms may vary widely and may include diffuse encephalopathy and global deficits.²⁰ Dog studies have found a possible mechanism for CFE in the absence of PFO. One such study, which used femoral pressurization to replicate cemented femoral arthroplasty, found that many fat globules had traversed the lungs after release into bone marrow,²¹ supporting the theory that fat droplets can traverse the pulmonary system without sequestration in the lung parenchyma. Riding and colleagues²² reported finding pulmonary arteriovenous shunts, which are thought to allow CFE to occur in the absence of PFO. More studies are needed to determine the prevalence of shunts and their overall contribution to CFE development in patients with long-bone fracture.

The biochemical theory holds that bodily trauma induces the release of free fatty acids (FFAs) from the capillaries into the bloodstream.²³ This stress response is mediated by catecholamines, which activate the adenyl cyclase pathway, which activates lipase, which hydrolyzes stored triglycerides to FFAs and glycerol. The concentration of circulating FFA was increased in 9 of 10 patients in one study.²³ Increased FFAs in the bloodstream can accelerate local and end-organ clotting, leading to thrombocytopenia and endothelial injury. In addition, patients with hypercoagulable diseases are at higher risk for postoperative thromboembolism.²⁴ However, with a negative hypercoagulable work-up and with negative chest helical CT and EKG, which did not demonstrate PFO, the explanation for CFE in our patient may more likely reside with the arteriovenous shunt theory proposed by Riding and colleagues.²²

Diagnosis and Treatment

Proper care of orthopedic patients who potentially have FES/CFE involves prompt diagnosis, immediate symptomatic care, and early coordination with neurology and medical services to rule out other causes of symptoms. Obtaining advanced imaging to rule out other potential causes and to confirm the diagnosis is crucial. The patient in this case report did not exhibit any focal neurologic deficits, but emergent CT of the brain was indicated to rule out a hemorrhagic event. If a stroke secondary to FES is clinically suspected, MRI should be obtained as soon as possible. Multiple studies have found that the “starfield” pattern, which is best seen as multiple punctate hyperintensities on T2 imaging, is the typical radiographic manifestation of CFE.⁹ This applies to patients who are in the 24- to 72-hour window after long-bone fracture or fixation and who fit Gurd and Wilson¹ criteria or Lindeque^1,2criteria, or who exhibit a change in mental status but have a negative CT scan of the brain, as was the case with our patient. Once the diagnosis is made, treatment involves addressing the symptoms (Figure 4).

Fat Embolism Syndrome in Reamed and Unreamed Nailing

Over the past several decades, the number of long bones fixed with intramedullary nails has increased significantly.²⁶ There is debate regarding whether use of reamed intramedullary nails increases the risk of fat emboli relative to use of unreamed nails, but multiple studies have found no significant difference.^26,27 Pulmonary shunting occurs in both reamed and unreamed nailing; neither technique has an advantage in terms of cardiopulmonary complications. In multiple studies, reamed nails have the advantage of improved healing rates.²⁷ A sheep study compared reamed and unreamed femoral nailing.²⁸ After nailing, sheep lungs were examined histologically for the presence of bone marrow fat embolism. The embolism rate was higher with unreamed nailing (10.25%) than with reamed nailing (6.66%). One large study of the adverse effects of reamed and unreamed nailing in 1226 patients with tibial shaft fracture found that those with open fractures had higher rates of a negative event (nonunion, infection, fasciotomy, hardware failure, need for dynamization) after reamed nailing.²⁹ Patients with closed fractures had fewer events after reamed nailing. The authors concluded there is a potential benefit in outcome with reamed intramedullary nailing in patients with closed tibial shaft fractures, but they did not comment on development of FES. In a study of the effect of subject position on intramedullary pressure and fat embolism release, dogs were positioned either supine or lateral for tibial and femoral reaming.³⁰ The authors measured various physiologic parameters, including cardiac output, pulmonary arterial wedge pressure, arterial and venous blood gas, and blood cell counts. There were no statistically significant differences in values between the 2 groups in any variable, indicating that position does not affect FES development in the orthopedic trauma setting.

Conclusion

FES and CFE are potential devastating sequelae of both long-bone fracture and long-bone instrumentation. It is important to recognize these entities in the acute setting and to consider them in the differential diagnosis of a trauma or postoperative patient who experiences sudden onset of altered mental status with or without dyspnea or a petechial rash. If CFE is suspected, early advanced imaging (including urgent MRI) should be obtained with rapid involvement of a multidisciplinary team that can optimize the chance for successful recovery of both neurologic and physical function. The best treatment, early prevention and diagnosis, maximizes care of symptoms. As is evidenced in this case report, rapid diagnosis and treatment often result in recovery from a majority of the symptoms of FES and CFE.

Am J Orthop. 2016;45(7):E515-E521. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

While in medical school, I learned about what was then called GRID (gay-related immune deficiency) and we now know as HIV/AIDS. I thought this condition would become so central to practice in nearly any specialty that I decided to try to keep up with all of the literature on it. It wasn’t yet in textbooks, so I thought it would be very important to keep up with all the new research studies and review articles about it.

I kept in my apartment a growing file of articles photocopied and torn out of journals. But I had badly misjudged the enormity of the task, and within a few years, there were far too many articles for me to read or keep up with in any fashion. Before long, HIV medicine became its own specialty, and while it has always been something I, like any hospitalist, need to know something about, I’ve left it to others to be the real HIV experts.

I was naive to have embarked on the quest. What seemed manageable at first became overwhelming very quickly. The same could be said for trying to keep up with new payment models.

New Professional Fee Reimbursement Models

For decades, most physicians could understand the general concept of how their professional activities generated revenue. But it’s gotten a lot more complicated lately.

The growing prevalence of capitation and other managed-care reimbursement models in the ’80s and ’90s might have been when reimbursement complexity began to increase significantly. But while nearly every doctor in the country heard about managed care, for many, it was something happening elsewhere that never made its way to them.

But for hospitalists, I think the arrival of the Physician Quality Reporting System (PQRS, originally Physician Quality Reporting Initiative, or PQRI) marks the swerve in reimbursement complexity. Some years ago I wrote in these pages about the importance of hospitalists understanding PQRS and described key features of the program.

Like HIV/AIDS medicine literature, the breadth and complexity of reimbursement programs from the Centers for Medicare & Medicaid Services (and other payors) seem to have grown logarithmically since PQRS. The still relatively new bundled payment and MACRA-related models are far more complicated than PQRS. And they change often. Calendar milestones come and go with changes in relevant metrics and performance thresholds, etc. Even the terminology changes frequently. Did you know, for example, that under MIPSi “Advancing Care Information” is essentially a new name for EHR Meaningful Use?

Bundled payments and MACRA are only a small portion of new models implemented over the last few years. There are many others, and dedicated effort is required just to keep track of whether each model influences only physicians (and other providers), only hospitals, or both.

Clinicians’ Responsibility for Keeping Up

My thinking about most hospitalists, or doctors in any specialty, keeping up with all of these models has evolved the same way it did with HIV/AIDS. I think it’s pretty clear that it’s folly to expect most clinicians to know more than the broad outlines of these programs.

Payment models are important. Someone needs to know them in detail, but clinicians should reserve brain cells for clinical knowledge base and focus only on the big picture of payment models. Think how well you’ve done learning and keeping up with CPT coding, observation versus inpatient status determinations, and clinical documentation. You probably still aren’t an expert at these things, so is it wise to set about becoming an expert in new payment models?

Instead, most hospitalists should rely on others to keep up with the precise details of these programs. Most commonly that will mean our employer will appoint or hire one or more people, or engage an outside party, to do this.

Don’t Feel Guilty

It’s common to leave a presentation or doctor’s lounge conversation on payment models feeling like you need to study up on the details of this or that payment model since good performance under that model will be important for your paycheck and to remain a viable “player.” And speakers sometimes intentionally or unintentionally enhance your anxiety about this. Maybe they love to show off what they know, and it’s easy for them to think only about their topic and not keep in mind all of the other stuff you need to know.

It’s terrific if someone in your practice is particularly interested in payment models and chooses to stay on top of them. Just make sure that doesn’t come at the expense of keeping up with changes in clinical practice. Most groups won’t have such a person and should rely on others, including SHM, without feeling the smallest bit of guilt.

SHM is advocating on behalf of hospitalists and working diligently to distill the impact MACRA and its various alternative payment frameworks will have on hospital medicine. With webinars, Q&As, and additional online and print resources, SHM will continue to provide digestible updates for hospitalists and their practices.

The End of Small-Group Physician Practice?

While the intent of these programs is to encourage and reward improvements in clinical practice, keeping up with and managing them is a tax that takes resources away from clinical practice. This is an especially difficult burden for small private practices and may prove to be a significant factor in nearly extinguishing them. There are relatively few small private hospitalist groups,ii but all of them should carefully consider how they will keep up with new reimbursement models.

While in medical school, I learned about what was then called GRID (gay-related immune deficiency) and we now know as HIV/AIDS. I thought this condition would become so central to practice in nearly any specialty that I decided to try to keep up with all of the literature on it. It wasn’t yet in textbooks, so I thought it would be very important to keep up with all the new research studies and review articles about it.

I kept in my apartment a growing file of articles photocopied and torn out of journals. But I had badly misjudged the enormity of the task, and within a few years, there were far too many articles for me to read or keep up with in any fashion. Before long, HIV medicine became its own specialty, and while it has always been something I, like any hospitalist, need to know something about, I’ve left it to others to be the real HIV experts.

I was naive to have embarked on the quest. What seemed manageable at first became overwhelming very quickly. The same could be said for trying to keep up with new payment models.

New Professional Fee Reimbursement Models

For decades, most physicians could understand the general concept of how their professional activities generated revenue. But it’s gotten a lot more complicated lately.

The growing prevalence of capitation and other managed-care reimbursement models in the ’80s and ’90s might have been when reimbursement complexity began to increase significantly. But while nearly every doctor in the country heard about managed care, for many, it was something happening elsewhere that never made its way to them.

But for hospitalists, I think the arrival of the Physician Quality Reporting System (PQRS, originally Physician Quality Reporting Initiative, or PQRI) marks the swerve in reimbursement complexity. Some years ago I wrote in these pages about the importance of hospitalists understanding PQRS and described key features of the program.

Like HIV/AIDS medicine literature, the breadth and complexity of reimbursement programs from the Centers for Medicare & Medicaid Services (and other payors) seem to have grown logarithmically since PQRS. The still relatively new bundled payment and MACRA-related models are far more complicated than PQRS. And they change often. Calendar milestones come and go with changes in relevant metrics and performance thresholds, etc. Even the terminology changes frequently. Did you know, for example, that under MIPSi “Advancing Care Information” is essentially a new name for EHR Meaningful Use?

Bundled payments and MACRA are only a small portion of new models implemented over the last few years. There are many others, and dedicated effort is required just to keep track of whether each model influences only physicians (and other providers), only hospitals, or both.

Clinicians’ Responsibility for Keeping Up

My thinking about most hospitalists, or doctors in any specialty, keeping up with all of these models has evolved the same way it did with HIV/AIDS. I think it’s pretty clear that it’s folly to expect most clinicians to know more than the broad outlines of these programs.

Payment models are important. Someone needs to know them in detail, but clinicians should reserve brain cells for clinical knowledge base and focus only on the big picture of payment models. Think how well you’ve done learning and keeping up with CPT coding, observation versus inpatient status determinations, and clinical documentation. You probably still aren’t an expert at these things, so is it wise to set about becoming an expert in new payment models?

Instead, most hospitalists should rely on others to keep up with the precise details of these programs. Most commonly that will mean our employer will appoint or hire one or more people, or engage an outside party, to do this.

Don’t Feel Guilty

It’s common to leave a presentation or doctor’s lounge conversation on payment models feeling like you need to study up on the details of this or that payment model since good performance under that model will be important for your paycheck and to remain a viable “player.” And speakers sometimes intentionally or unintentionally enhance your anxiety about this. Maybe they love to show off what they know, and it’s easy for them to think only about their topic and not keep in mind all of the other stuff you need to know.

It’s terrific if someone in your practice is particularly interested in payment models and chooses to stay on top of them. Just make sure that doesn’t come at the expense of keeping up with changes in clinical practice. Most groups won’t have such a person and should rely on others, including SHM, without feeling the smallest bit of guilt.

SHM is advocating on behalf of hospitalists and working diligently to distill the impact MACRA and its various alternative payment frameworks will have on hospital medicine. With webinars, Q&As, and additional online and print resources, SHM will continue to provide digestible updates for hospitalists and their practices.

The End of Small-Group Physician Practice?

While the intent of these programs is to encourage and reward improvements in clinical practice, keeping up with and managing them is a tax that takes resources away from clinical practice. This is an especially difficult burden for small private practices and may prove to be a significant factor in nearly extinguishing them. There are relatively few small private hospitalist groups,ii but all of them should carefully consider how they will keep up with new reimbursement models.

While in medical school, I learned about what was then called GRID (gay-related immune deficiency) and we now know as HIV/AIDS. I thought this condition would become so central to practice in nearly any specialty that I decided to try to keep up with all of the literature on it. It wasn’t yet in textbooks, so I thought it would be very important to keep up with all the new research studies and review articles about it.

I kept in my apartment a growing file of articles photocopied and torn out of journals. But I had badly misjudged the enormity of the task, and within a few years, there were far too many articles for me to read or keep up with in any fashion. Before long, HIV medicine became its own specialty, and while it has always been something I, like any hospitalist, need to know something about, I’ve left it to others to be the real HIV experts.

I was naive to have embarked on the quest. What seemed manageable at first became overwhelming very quickly. The same could be said for trying to keep up with new payment models.

New Professional Fee Reimbursement Models

For decades, most physicians could understand the general concept of how their professional activities generated revenue. But it’s gotten a lot more complicated lately.

The growing prevalence of capitation and other managed-care reimbursement models in the ’80s and ’90s might have been when reimbursement complexity began to increase significantly. But while nearly every doctor in the country heard about managed care, for many, it was something happening elsewhere that never made its way to them.

But for hospitalists, I think the arrival of the Physician Quality Reporting System (PQRS, originally Physician Quality Reporting Initiative, or PQRI) marks the swerve in reimbursement complexity. Some years ago I wrote in these pages about the importance of hospitalists understanding PQRS and described key features of the program.

Like HIV/AIDS medicine literature, the breadth and complexity of reimbursement programs from the Centers for Medicare & Medicaid Services (and other payors) seem to have grown logarithmically since PQRS. The still relatively new bundled payment and MACRA-related models are far more complicated than PQRS. And they change often. Calendar milestones come and go with changes in relevant metrics and performance thresholds, etc. Even the terminology changes frequently. Did you know, for example, that under MIPSi “Advancing Care Information” is essentially a new name for EHR Meaningful Use?

Bundled payments and MACRA are only a small portion of new models implemented over the last few years. There are many others, and dedicated effort is required just to keep track of whether each model influences only physicians (and other providers), only hospitals, or both.

Clinicians’ Responsibility for Keeping Up

My thinking about most hospitalists, or doctors in any specialty, keeping up with all of these models has evolved the same way it did with HIV/AIDS. I think it’s pretty clear that it’s folly to expect most clinicians to know more than the broad outlines of these programs.

Payment models are important. Someone needs to know them in detail, but clinicians should reserve brain cells for clinical knowledge base and focus only on the big picture of payment models. Think how well you’ve done learning and keeping up with CPT coding, observation versus inpatient status determinations, and clinical documentation. You probably still aren’t an expert at these things, so is it wise to set about becoming an expert in new payment models?

Instead, most hospitalists should rely on others to keep up with the precise details of these programs. Most commonly that will mean our employer will appoint or hire one or more people, or engage an outside party, to do this.

Don’t Feel Guilty

It’s common to leave a presentation or doctor’s lounge conversation on payment models feeling like you need to study up on the details of this or that payment model since good performance under that model will be important for your paycheck and to remain a viable “player.” And speakers sometimes intentionally or unintentionally enhance your anxiety about this. Maybe they love to show off what they know, and it’s easy for them to think only about their topic and not keep in mind all of the other stuff you need to know.

It’s terrific if someone in your practice is particularly interested in payment models and chooses to stay on top of them. Just make sure that doesn’t come at the expense of keeping up with changes in clinical practice. Most groups won’t have such a person and should rely on others, including SHM, without feeling the smallest bit of guilt.

SHM is advocating on behalf of hospitalists and working diligently to distill the impact MACRA and its various alternative payment frameworks will have on hospital medicine. With webinars, Q&As, and additional online and print resources, SHM will continue to provide digestible updates for hospitalists and their practices.

The End of Small-Group Physician Practice?

While the intent of these programs is to encourage and reward improvements in clinical practice, keeping up with and managing them is a tax that takes resources away from clinical practice. This is an especially difficult burden for small private practices and may prove to be a significant factor in nearly extinguishing them. There are relatively few small private hospitalist groups,ii but all of them should carefully consider how they will keep up with new reimbursement models.

TORONTO – Nonalcoholic fatty liver disease seems to accelerate physical brain aging by up to 7 years, according to a new subanalysis of the ongoing Framingham Heart Study.

However, while finding that the liver disorder directly endangers brains, the study also offers hope, Galit Weinstein, PhD, said at the Alzheimer’s Association International Conference 2016. “If indeed nonalcoholic fatty liver disease is a risk factor for brain aging and subsequent dementia, then it is a modifiable one,” said Dr. Weinstein of Boston University. “We have reason to hope that NAFLD remission could possibly improve cognitive outcomes” as patients age.

Courtesy of Wikimedia / Nephron / Creative Commons License

For this study, the researchers assessed the presence of NAFLD by abdominal CT scans and white-matter hyperintensities and brain volume (total, frontal, and hippocampal) by MRI. The resulting associations were then adjusted for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, current smoking, diabetes, history of cardiovascular disease, physical activity, insulin resistance, and C-reactive protein.

There were no significant associations with white-matter hyperintensities or with hippocampal volume, but the researches did find a significant association with total brain volume: Even after adjustment for all of the covariates, patients with NAFLD had smaller-than-normal brains for their age. This can be seen as a pathologic acceleration of the brain aging process, Dr. Weinstein said.

The finding was most striking among the youngest subjects, she said, accounting for about a 7-year advance in brain aging for those younger than 60 years. Older patients with NAFLD showed about a 2-year advance in brain aging.

The effect is probably mediated by the liver’s complex interplay in metabolism and vascular functions, Dr. Weinstein said.

She had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

TORONTO – Nonalcoholic fatty liver disease seems to accelerate physical brain aging by up to 7 years, according to a new subanalysis of the ongoing Framingham Heart Study.

However, while finding that the liver disorder directly endangers brains, the study also offers hope, Galit Weinstein, PhD, said at the Alzheimer’s Association International Conference 2016. “If indeed nonalcoholic fatty liver disease is a risk factor for brain aging and subsequent dementia, then it is a modifiable one,” said Dr. Weinstein of Boston University. “We have reason to hope that NAFLD remission could possibly improve cognitive outcomes” as patients age.

Courtesy of Wikimedia / Nephron / Creative Commons License

For this study, the researchers assessed the presence of NAFLD by abdominal CT scans and white-matter hyperintensities and brain volume (total, frontal, and hippocampal) by MRI. The resulting associations were then adjusted for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, current smoking, diabetes, history of cardiovascular disease, physical activity, insulin resistance, and C-reactive protein.

There were no significant associations with white-matter hyperintensities or with hippocampal volume, but the researches did find a significant association with total brain volume: Even after adjustment for all of the covariates, patients with NAFLD had smaller-than-normal brains for their age. This can be seen as a pathologic acceleration of the brain aging process, Dr. Weinstein said.

The finding was most striking among the youngest subjects, she said, accounting for about a 7-year advance in brain aging for those younger than 60 years. Older patients with NAFLD showed about a 2-year advance in brain aging.

The effect is probably mediated by the liver’s complex interplay in metabolism and vascular functions, Dr. Weinstein said.

She had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

TORONTO – Nonalcoholic fatty liver disease seems to accelerate physical brain aging by up to 7 years, according to a new subanalysis of the ongoing Framingham Heart Study.

However, while finding that the liver disorder directly endangers brains, the study also offers hope, Galit Weinstein, PhD, said at the Alzheimer’s Association International Conference 2016. “If indeed nonalcoholic fatty liver disease is a risk factor for brain aging and subsequent dementia, then it is a modifiable one,” said Dr. Weinstein of Boston University. “We have reason to hope that NAFLD remission could possibly improve cognitive outcomes” as patients age.

Courtesy of Wikimedia / Nephron / Creative Commons License

For this study, the researchers assessed the presence of NAFLD by abdominal CT scans and white-matter hyperintensities and brain volume (total, frontal, and hippocampal) by MRI. The resulting associations were then adjusted for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, current smoking, diabetes, history of cardiovascular disease, physical activity, insulin resistance, and C-reactive protein.

There were no significant associations with white-matter hyperintensities or with hippocampal volume, but the researches did find a significant association with total brain volume: Even after adjustment for all of the covariates, patients with NAFLD had smaller-than-normal brains for their age. This can be seen as a pathologic acceleration of the brain aging process, Dr. Weinstein said.

The finding was most striking among the youngest subjects, she said, accounting for about a 7-year advance in brain aging for those younger than 60 years. Older patients with NAFLD showed about a 2-year advance in brain aging.

The effect is probably mediated by the liver’s complex interplay in metabolism and vascular functions, Dr. Weinstein said.

She had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

VIENNA – Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that received U.S. marketing approval in November 2015 as second-line treatment for selected patients with non–small-cell lung cancer based on phase II trial data, now has the pivotal-trial results that completely justify that action.

During a median follow-up of just over 8 months, patients who had progressed on their first-line EGFR tyrosine kinase inhibitor (TKI) and carried the T790M mutation and switched to osimertinib (Tagrisso) had “overwhelmingly” better response rates and progression-free survival, compared with patients put on standard-of-care chemotherapy in a multicenter randomized trial involving 419 patients, Vassiliki A. Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

VIENNA – Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that received U.S. marketing approval in November 2015 as second-line treatment for selected patients with non–small-cell lung cancer based on phase II trial data, now has the pivotal-trial results that completely justify that action.

During a median follow-up of just over 8 months, patients who had progressed on their first-line EGFR tyrosine kinase inhibitor (TKI) and carried the T790M mutation and switched to osimertinib (Tagrisso) had “overwhelmingly” better response rates and progression-free survival, compared with patients put on standard-of-care chemotherapy in a multicenter randomized trial involving 419 patients, Vassiliki A. Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

VIENNA – Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that received U.S. marketing approval in November 2015 as second-line treatment for selected patients with non–small-cell lung cancer based on phase II trial data, now has the pivotal-trial results that completely justify that action.

During a median follow-up of just over 8 months, patients who had progressed on their first-line EGFR tyrosine kinase inhibitor (TKI) and carried the T790M mutation and switched to osimertinib (Tagrisso) had “overwhelmingly” better response rates and progression-free survival, compared with patients put on standard-of-care chemotherapy in a multicenter randomized trial involving 419 patients, Vassiliki A. Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Patients whose Crohn’s disease fully remits after resection should not wait for endoscopic recurrence to start tumor-necrosis-factor inhibitors or thiopurines, according to a new guideline from the American Gastroenterological Association.

Patients who are low risk or worried about side effects, however, “may reasonably select endoscopy-guided pharmacological treatment,” the guidelines state (doi: 10.1053/j.gastro.2016.10.038).

The AGA made a conditional recommendation against the prophylactic use of budesonide, probiotics, and 5-aminosalicylates such as mesalamine. Only low-quality evidence supports their efficacy after resection, and by using these agents, clinicians may inadvertently boost the risk of recurrence by forgoing better therapies, the guideline states.

The initial endoscopy should be timed for 6-12 months after resection, regardless of whether patients are receiving pharmacologic prophylaxis, the guideline states. If there is endoscopic recurrence, then anti-TNF or thiopurine therapy should be started or optimized.

In the Postoperative Crohn’s Endoscopic Recurrence (POCER) trial, endoscopic monitoring and treatment escalation in the face of endoscopic recurrence cut the risk of subsequent clinical and endoscopic recurrence by about 18% and 27%, respectively, compared with continuing the original treatment regimen. Most patients received azathioprine or adalimumab with 3 months of metronidazole postoperatively, so “even [those] who were already on postoperative prophylaxis benefited from endoscopic monitoring with colonoscopy at 6-12 months,” the guideline notes. However, patients who elect early prophylaxis after resection can reasonably forego colonoscopy if endoscopic recurrence is unlikely to affect their treatment plan, the AGA states. The guideline strongly recommends ongoing surveillance endoscopies if patients decide against early postresection prophylaxis, but notes a lack of evidence on how far to space out these procedures.

None of the authors had relevant financial disclosures.

Patients whose Crohn’s disease fully remits after resection should not wait for endoscopic recurrence to start tumor-necrosis-factor inhibitors or thiopurines, according to a new guideline from the American Gastroenterological Association.

Patients who are low risk or worried about side effects, however, “may reasonably select endoscopy-guided pharmacological treatment,” the guidelines state (doi: 10.1053/j.gastro.2016.10.038).

The AGA made a conditional recommendation against the prophylactic use of budesonide, probiotics, and 5-aminosalicylates such as mesalamine. Only low-quality evidence supports their efficacy after resection, and by using these agents, clinicians may inadvertently boost the risk of recurrence by forgoing better therapies, the guideline states.

The initial endoscopy should be timed for 6-12 months after resection, regardless of whether patients are receiving pharmacologic prophylaxis, the guideline states. If there is endoscopic recurrence, then anti-TNF or thiopurine therapy should be started or optimized.

In the Postoperative Crohn’s Endoscopic Recurrence (POCER) trial, endoscopic monitoring and treatment escalation in the face of endoscopic recurrence cut the risk of subsequent clinical and endoscopic recurrence by about 18% and 27%, respectively, compared with continuing the original treatment regimen. Most patients received azathioprine or adalimumab with 3 months of metronidazole postoperatively, so “even [those] who were already on postoperative prophylaxis benefited from endoscopic monitoring with colonoscopy at 6-12 months,” the guideline notes. However, patients who elect early prophylaxis after resection can reasonably forego colonoscopy if endoscopic recurrence is unlikely to affect their treatment plan, the AGA states. The guideline strongly recommends ongoing surveillance endoscopies if patients decide against early postresection prophylaxis, but notes a lack of evidence on how far to space out these procedures.

None of the authors had relevant financial disclosures.

Patients whose Crohn’s disease fully remits after resection should not wait for endoscopic recurrence to start tumor-necrosis-factor inhibitors or thiopurines, according to a new guideline from the American Gastroenterological Association.

Patients who are low risk or worried about side effects, however, “may reasonably select endoscopy-guided pharmacological treatment,” the guidelines state (doi: 10.1053/j.gastro.2016.10.038).

The AGA made a conditional recommendation against the prophylactic use of budesonide, probiotics, and 5-aminosalicylates such as mesalamine. Only low-quality evidence supports their efficacy after resection, and by using these agents, clinicians may inadvertently boost the risk of recurrence by forgoing better therapies, the guideline states.

The initial endoscopy should be timed for 6-12 months after resection, regardless of whether patients are receiving pharmacologic prophylaxis, the guideline states. If there is endoscopic recurrence, then anti-TNF or thiopurine therapy should be started or optimized.

In the Postoperative Crohn’s Endoscopic Recurrence (POCER) trial, endoscopic monitoring and treatment escalation in the face of endoscopic recurrence cut the risk of subsequent clinical and endoscopic recurrence by about 18% and 27%, respectively, compared with continuing the original treatment regimen. Most patients received azathioprine or adalimumab with 3 months of metronidazole postoperatively, so “even [those] who were already on postoperative prophylaxis benefited from endoscopic monitoring with colonoscopy at 6-12 months,” the guideline notes. However, patients who elect early prophylaxis after resection can reasonably forego colonoscopy if endoscopic recurrence is unlikely to affect their treatment plan, the AGA states. The guideline strongly recommends ongoing surveillance endoscopies if patients decide against early postresection prophylaxis, but notes a lack of evidence on how far to space out these procedures.

None of the authors had relevant financial disclosures.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.