The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.

Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.

[email protected]

On Twitter @karioakes

The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.

Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.

[email protected]

On Twitter @karioakes

The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.

Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.

[email protected]

On Twitter @karioakes

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

SALT LAKE CITY – Low serum levels of anti-Müllerian hormone predicted miscarriage after in vitro fertilization and embryo transfer, according to a single-center prospective study of more than 2,000 women.

This relationship remained statistically significant after the study controlled for age and response to controlled ovarian hyperstimulation, which suggests that AMH is a marker of the reproductive potential of oocytes, not just of oocyte quantity, Bruno Tarasconi, MD, said at the annual meeting of the American Society for Reproductive Medicine.

“Low” serum AMH was defined as less than 1.61 ng per mL, but specific levels vary by test type, so “this is not a definite cutoff,” Dr. Tarasconi emphasized. “What we need to know is that patients with low AMH are probably experiencing some problems in the ovary that affect oocyte quality.”

iStock

SALT LAKE CITY – Low serum levels of anti-Müllerian hormone predicted miscarriage after in vitro fertilization and embryo transfer, according to a single-center prospective study of more than 2,000 women.

This relationship remained statistically significant after the study controlled for age and response to controlled ovarian hyperstimulation, which suggests that AMH is a marker of the reproductive potential of oocytes, not just of oocyte quantity, Bruno Tarasconi, MD, said at the annual meeting of the American Society for Reproductive Medicine.

“Low” serum AMH was defined as less than 1.61 ng per mL, but specific levels vary by test type, so “this is not a definite cutoff,” Dr. Tarasconi emphasized. “What we need to know is that patients with low AMH are probably experiencing some problems in the ovary that affect oocyte quality.”

iStock

SALT LAKE CITY – Low serum levels of anti-Müllerian hormone predicted miscarriage after in vitro fertilization and embryo transfer, according to a single-center prospective study of more than 2,000 women.

This relationship remained statistically significant after the study controlled for age and response to controlled ovarian hyperstimulation, which suggests that AMH is a marker of the reproductive potential of oocytes, not just of oocyte quantity, Bruno Tarasconi, MD, said at the annual meeting of the American Society for Reproductive Medicine.

“Low” serum AMH was defined as less than 1.61 ng per mL, but specific levels vary by test type, so “this is not a definite cutoff,” Dr. Tarasconi emphasized. “What we need to know is that patients with low AMH are probably experiencing some problems in the ovary that affect oocyte quality.”

iStock

VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.

It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.

Bruce Jancin/Frontline Medical News

[email protected]

VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.

It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.

Bruce Jancin/Frontline Medical News

[email protected]

VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.

It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.

Bruce Jancin/Frontline Medical News

[email protected]

Given the copious amount of printed and blog space that has been devoted in recent months to MACRA – the Medicare Access and CHIP Reauthorization Act of 2015 – I felt no particular obligation to add to the din. Then I was startled to read a recent poll from Deloitte that found that half of all private-practice physicians had never heard of MACRA. Furthermore, only 21% of solo or small-group physicians, and 9% of those employed by hospitals or larger groups, were even somewhat familiar with its financial implications.

Since yet another significant percentage of your Medicare reimbursements will be at risk under this new bureaucracy, an introduction is in order.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected] .

Given the copious amount of printed and blog space that has been devoted in recent months to MACRA – the Medicare Access and CHIP Reauthorization Act of 2015 – I felt no particular obligation to add to the din. Then I was startled to read a recent poll from Deloitte that found that half of all private-practice physicians had never heard of MACRA. Furthermore, only 21% of solo or small-group physicians, and 9% of those employed by hospitals or larger groups, were even somewhat familiar with its financial implications.

Since yet another significant percentage of your Medicare reimbursements will be at risk under this new bureaucracy, an introduction is in order.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected] .

Given the copious amount of printed and blog space that has been devoted in recent months to MACRA – the Medicare Access and CHIP Reauthorization Act of 2015 – I felt no particular obligation to add to the din. Then I was startled to read a recent poll from Deloitte that found that half of all private-practice physicians had never heard of MACRA. Furthermore, only 21% of solo or small-group physicians, and 9% of those employed by hospitals or larger groups, were even somewhat familiar with its financial implications.

Since yet another significant percentage of your Medicare reimbursements will be at risk under this new bureaucracy, an introduction is in order.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected] .

In fact, according to the 2015 Palliative Care Report Card from the Center to Advance Palliative Care (CAPC), 67 percent of hospitals with 50 or more beds had a designated palliative care program.1

While core palliative care skills can be performed by frontline clinicians including hospitalists, specialty palliative care consults are the ones who are called in for complicated cases. The Hospitalist asked several palliative care experts for advice on how to clarify definitions, distinctions, and roles. This is what they told us:

Palliative care is not synonymous with end-of-life care.

Palliative care advocates call this the biggest misconception they struggle to overcome, with the potential to inhibit its contributions to patient care in the hospital. Palliative care, they say, is for any patient with a serious illness who is struggling to cope with the fallout from that illness in their lives.

“Our biggest impact can come earlier in the illness,” says Jeanie Youngwerth, MD, director of the University of Colorado Hospital’s Palliative Care Consult Service in Aurora. “We help people do the best they can for as long as they can. If you’re even considering a palliative-care consult, then do it sooner rather than later.”

Palliative care can offer more than just help with difficult conversations, adds Daniel Fischberg, MD, PhD, FAAHPM, medical director of the Pain and Palliative Care Department at The Queen’s Medical Center in Honolulu. For example, the palliative-care team can work with patients to clarify their expectations and goals for care, plan for what comes next, and address troubling symptoms—whether physical or emotional, Dr. Fischberg says.

“We can really help patients and families who are facing unique and challenging needs,” he says.

The experts also say that palliative care is not synonymous with hospice care, which is a comprehensive service that provides specialized terminal care for patients with a prognosis of six months or fewer to live. Both, however, share many of the same principles and techniques of symptom management and psycho-social-spiritual support. But some patients and families may associate a palliative-care referral with hospice care or have other misconceptions and fears about it. Hospitalists are challenged to provide a consistent message clarifying that palliative care can be helpful for seriously ill patients regardless of prognosis or other medical treatments they’re receiving.

“It’s human nature not to want to deal with our mortality, and any word that gets associated with death and dying can turn people off,” says Joseph Rotella, MD, chief medical officer of the American Academy of Hospice and Palliative Medicine (AAHPM). “The best way to prevent this is to define it in terms of patient and family needs: ‘Let’s bring in our comfort specialists.’ Doctors should not apologize when referring to a service that has proven its value. We should be happy to recommend it often and early.”

Patients with serious illness can benefit from palliative care.

CAPC defines palliative care as “specialized medical care for people with serious illnesses.” It focuses on providing patients with relief from the symptoms and stress of a serious illness, regardless of their diagnosis, at any age and at any stage of a serious illness. This service is provided by a specially trained interdisciplinary palliative-care team of doctors, nurses, and other specialists who work together with patients’ other doctors. Their goal is to improve quality of life for both patients and their families with an extra layer of support.

Palliative care is also a medical specialty that involves specialty training, including year-long hospice and palliative medicine (HPM) fellowships now offered at 112 sites accredited by the Accreditation Council for Graduate Medical Education. Subspecialty board certification is also available through 10 collaborating medical specialty boards within the American Board of Medical Specialties as well as by the American Osteopathic Association. Palliative-care programs are now certified by The Joint Commission, with similar recognition under development by the Community Health Accreditation Partner.

Palliative care is intended for patients facing challenges.

Palliative care is intended for patients who might be expected to face stresses and challenges in any area of their lives as a result of serious illness. This may include, for example, patients who experience frequent emergency department visits, hospital readmissions, or prolonged ICU stays, as well as cancer patients who are admitted to the hospital solely to address out-of-control symptoms resulting from their disease and its treatment.

“We can help with the burdens of any challenging symptoms,” Dr. Fischberg says.

Other examples of appropriate palliative-care referrals are when next steps for patients’ treatment are not clear, when there are questions about patients’ real goals of care, and when unmet needs such as unrelieved symptoms have put their families in a state of distress, whether physical, emotional, social, or spiritual. Patients may need guidance about weighing their care options.

Palliative care is also available for children and their families.

The philosophy and organization of palliative care for delivering compassionate care for children with chronic, complex, or life-threatening conditions are much the same as for adults. In 2013, the American Academy of Pediatrics issued a Pediatric Palliative Care and Hospice Care policy statement,2 which outlined core commitments in such areas as respecting and partnering with patients and families and pursuing care that is high-quality, readily accessible, and equitable.

As with adults, a referral for palliative care typically is most helpful for the more complex cases, says Joanne Wolfe, MD, MPH, director of Pediatric Palliative Care at Boston Children’s Hospital. The palliative care team can offer emotional support to the parents of children with complex illnesses and help them understand confusing treatment options. The children, too, need a sounding board.

“If I were teaching a group of hospitalists, I would emphasize foundational principles of palliative care, starting with relationship and understanding patients’ and families’ goals of care,” Dr. Wolfe says. If the family is struggling to cope with the illness and the hospitalist doesn’t have good answers, that’s when to call palliative care, she adds.

Palliative care’s role is not to talk patients and their families out of treatments.

The palliative-care team tries to enter cases without an agenda, Dr. Fischberg says, rather than aiming to get patients to stop treatments or agree to a do-not-resuscitate (DNR) order.

“We’re interested in what the hospitalist thinks about what best care for this patient looks like but also in eliciting the patient’s values and preferences,” he says.

Palliative-care professionals are skilled at delicately communicating bad news and helping patients and families clarify what their goals of care really are, says Robert Crook, MD, FACP, associate medical director of Mount Carmel Hospice and Palliative Care in Columbus, Ohio.

“It’s more about helping to improve communication between the primary-care team and the patient and family—not talking somebody out of something but helping them understand each other better,” Dr. Crook says.

Palliative care can reduce costs of care on average, but it does not achieve this by rationing care or denying treatments.

“We’re not there to cut costs or to get patients discharged sooner or to steer them away from costly treatments,” explains Dr. Rotella. “The last thing a palliative-care team wants is to be viewed as a care rationer. But if the patient understands what’s really going on, they often won’t want treatments that don’t help. So, in that way, we are part of the solution.”

Dr. Rotella calls this cost-effectiveness a side effect of palliative care, when patients are empowered to make decisions about their own care. “That’s where you achieve the triple aim,” he says. “They feel better about it because they are in the driver’s seat. If a patient wants a treatment consistent with their values, we will advocate for it.”

One study found that patients at eight U.S. hospitals who received palliative care incurred significantly lower hospital costs than a matched group receiving usual care, with an average reduction in direct hospital costs of almost $1,700 for patients discharged alive and almost $5,000 per admission for patients who died in the hospital.3 Another study found that early palliative care interventions for cancer patients led to significant improvements in both quality of life and mood compared with patients receiving standard care, with less cost and fewer aggressive treatments at the end of life but longer survival.4

One of the main tools of the palliative care team is the family meeting.

Family meetings are scheduled to allow as many family members as possible to attend, and the primary-care team and relevant specialists typically are also invited. Many palliative-care teams use a standardized format that involves introductions, clarification of each participant’s understanding of the patient’s prognosis, and an effort to reconcile the patient’s hopes and values with medical realities and possibilities, Dr. Fischberg explains.

“That is such a critical component of our care, where we make sure the patient and family are fully informed and foster shared decision making that results in patients being more comfortable with care that better matches what they want,” says Dr. Rotella.

The palliative-care team typically becomes involved via a consultation request from a patient’s attending physician.

“A big part of our job is doing our homework,” Dr. Youngwerth says. “We’ll talk to the team about what’s going on. We want to get as much information as possible about the patient, about prognosis, about the perspectives of people caring for them. Don’t be surprised if the palliative-care team contacts you to get your input on the prognosis and other medical details in order to best inform their discussion with the patient and family.”

Then the palliative-care team will follow consult protocol in reporting back to the primary medical team.

Palliative-care teams can assist busy hospitalists with difficult patient conversations.

“When I’m on the hospitalist service, I’ll pull in the palliative-care team,” Dr. Youngwerth explains. “It’s not that I don’t have the skills; I don’t have the time.”

Conversations aimed at clarifying goals of care can take 90 minutes or more, but the palliative-care team will take as much time as needed to achieve clarification.

It’s important that hospitalists remain involved in these cases, says Christian Sinclair, MD, assistant professor in the division of palliative medicine at the University of Kansas Medical Center in Kansas City and president-elect of AAHPM.

“Just because you have access to palliative-care services, don’t miss the chance to enhance your own communication skills and your ability to address these issues head on,” Dr. Sinclair says.

American Academy of Hospice and Palliative Medicine is a participant in Choosing Wisely.

The Choosing Wisely program, initiated by the American Board of Internal Medicine Foundation, invites medical societies to identify five treatments that should be questioned by physicians and patients based on lack of supporting evidence in the research base. The Society of Hospital Medicine is also a participant in this initiative.

For AAHPM, one of its recommendations was: “Don’t delay palliative care for a patient with serious illness who has a physical, psychological, social, or spiritual distress because they are pursuing disease-directed treatment.” Other Choosing Wisely suggestions include not recommending feeding tubes for patients with advanced dementia, not leaving implantable cardioverter defibrillators (ICDs) activated when these are not consistent with patient/family goals of care, and not recommending more than a single fraction of palliative radiation for an uncomplicated painful bone metastasis.

Different palliative-care programs provide different services.

It is important for hospitalists to learn their local palliative-care programs and what they emphasize and are able to offer—or not, says Dr. Sinclair.

“There are so many different models,” he says. “Spend some time reaching out to them, outside of actual consults, and find out what their comfort level is on various issues. Hospitalists and palliative-care teams should get to know each other better.”

Access to palliative care and the comprehensiveness of the team and services can vary between hospitals, while access to community-based palliative care outside of the hospital is even more variable.

“Palliative-care teams often have a better sense of our partners in the community and access to community-based palliative care,” Dr. Fischberg says.

References

1. Morrison RS, Meier DE. America’s Care of Serious Illness: 2015 State-by-State Report Card on Access to Palliative Care in Our Nation’s Hospitals. New York, NY: Center to Advance Palliative Care; 2015.
2. American Academy of Pediatrics. Policy statement: pediatric palliative care and hospice care commitments, guidelines, and recommendations. Pediatr. 2013;132(5):966-972.
3. Morrison RS, Penrod JD, Cassel JB, et al. Cost savings associated with US hospital palliative care consultation programs. Arch Intern Med. 2008;168(16):1783-1790.
4. Temel JS, Greer JA, Muzikansky et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742.

In fact, according to the 2015 Palliative Care Report Card from the Center to Advance Palliative Care (CAPC), 67 percent of hospitals with 50 or more beds had a designated palliative care program.1

While core palliative care skills can be performed by frontline clinicians including hospitalists, specialty palliative care consults are the ones who are called in for complicated cases. The Hospitalist asked several palliative care experts for advice on how to clarify definitions, distinctions, and roles. This is what they told us:

Palliative care is not synonymous with end-of-life care.

Palliative care advocates call this the biggest misconception they struggle to overcome, with the potential to inhibit its contributions to patient care in the hospital. Palliative care, they say, is for any patient with a serious illness who is struggling to cope with the fallout from that illness in their lives.

“Our biggest impact can come earlier in the illness,” says Jeanie Youngwerth, MD, director of the University of Colorado Hospital’s Palliative Care Consult Service in Aurora. “We help people do the best they can for as long as they can. If you’re even considering a palliative-care consult, then do it sooner rather than later.”

Palliative care can offer more than just help with difficult conversations, adds Daniel Fischberg, MD, PhD, FAAHPM, medical director of the Pain and Palliative Care Department at The Queen’s Medical Center in Honolulu. For example, the palliative-care team can work with patients to clarify their expectations and goals for care, plan for what comes next, and address troubling symptoms—whether physical or emotional, Dr. Fischberg says.

“We can really help patients and families who are facing unique and challenging needs,” he says.

The experts also say that palliative care is not synonymous with hospice care, which is a comprehensive service that provides specialized terminal care for patients with a prognosis of six months or fewer to live. Both, however, share many of the same principles and techniques of symptom management and psycho-social-spiritual support. But some patients and families may associate a palliative-care referral with hospice care or have other misconceptions and fears about it. Hospitalists are challenged to provide a consistent message clarifying that palliative care can be helpful for seriously ill patients regardless of prognosis or other medical treatments they’re receiving.

“It’s human nature not to want to deal with our mortality, and any word that gets associated with death and dying can turn people off,” says Joseph Rotella, MD, chief medical officer of the American Academy of Hospice and Palliative Medicine (AAHPM). “The best way to prevent this is to define it in terms of patient and family needs: ‘Let’s bring in our comfort specialists.’ Doctors should not apologize when referring to a service that has proven its value. We should be happy to recommend it often and early.”

Patients with serious illness can benefit from palliative care.

CAPC defines palliative care as “specialized medical care for people with serious illnesses.” It focuses on providing patients with relief from the symptoms and stress of a serious illness, regardless of their diagnosis, at any age and at any stage of a serious illness. This service is provided by a specially trained interdisciplinary palliative-care team of doctors, nurses, and other specialists who work together with patients’ other doctors. Their goal is to improve quality of life for both patients and their families with an extra layer of support.

Palliative care is also a medical specialty that involves specialty training, including year-long hospice and palliative medicine (HPM) fellowships now offered at 112 sites accredited by the Accreditation Council for Graduate Medical Education. Subspecialty board certification is also available through 10 collaborating medical specialty boards within the American Board of Medical Specialties as well as by the American Osteopathic Association. Palliative-care programs are now certified by The Joint Commission, with similar recognition under development by the Community Health Accreditation Partner.

Palliative care is intended for patients facing challenges.

Palliative care is intended for patients who might be expected to face stresses and challenges in any area of their lives as a result of serious illness. This may include, for example, patients who experience frequent emergency department visits, hospital readmissions, or prolonged ICU stays, as well as cancer patients who are admitted to the hospital solely to address out-of-control symptoms resulting from their disease and its treatment.

“We can help with the burdens of any challenging symptoms,” Dr. Fischberg says.

Other examples of appropriate palliative-care referrals are when next steps for patients’ treatment are not clear, when there are questions about patients’ real goals of care, and when unmet needs such as unrelieved symptoms have put their families in a state of distress, whether physical, emotional, social, or spiritual. Patients may need guidance about weighing their care options.

Palliative care is also available for children and their families.

The philosophy and organization of palliative care for delivering compassionate care for children with chronic, complex, or life-threatening conditions are much the same as for adults. In 2013, the American Academy of Pediatrics issued a Pediatric Palliative Care and Hospice Care policy statement,2 which outlined core commitments in such areas as respecting and partnering with patients and families and pursuing care that is high-quality, readily accessible, and equitable.

As with adults, a referral for palliative care typically is most helpful for the more complex cases, says Joanne Wolfe, MD, MPH, director of Pediatric Palliative Care at Boston Children’s Hospital. The palliative care team can offer emotional support to the parents of children with complex illnesses and help them understand confusing treatment options. The children, too, need a sounding board.

“If I were teaching a group of hospitalists, I would emphasize foundational principles of palliative care, starting with relationship and understanding patients’ and families’ goals of care,” Dr. Wolfe says. If the family is struggling to cope with the illness and the hospitalist doesn’t have good answers, that’s when to call palliative care, she adds.

Palliative care’s role is not to talk patients and their families out of treatments.

The palliative-care team tries to enter cases without an agenda, Dr. Fischberg says, rather than aiming to get patients to stop treatments or agree to a do-not-resuscitate (DNR) order.

“We’re interested in what the hospitalist thinks about what best care for this patient looks like but also in eliciting the patient’s values and preferences,” he says.

Palliative-care professionals are skilled at delicately communicating bad news and helping patients and families clarify what their goals of care really are, says Robert Crook, MD, FACP, associate medical director of Mount Carmel Hospice and Palliative Care in Columbus, Ohio.

“It’s more about helping to improve communication between the primary-care team and the patient and family—not talking somebody out of something but helping them understand each other better,” Dr. Crook says.

Palliative care can reduce costs of care on average, but it does not achieve this by rationing care or denying treatments.

“We’re not there to cut costs or to get patients discharged sooner or to steer them away from costly treatments,” explains Dr. Rotella. “The last thing a palliative-care team wants is to be viewed as a care rationer. But if the patient understands what’s really going on, they often won’t want treatments that don’t help. So, in that way, we are part of the solution.”

Dr. Rotella calls this cost-effectiveness a side effect of palliative care, when patients are empowered to make decisions about their own care. “That’s where you achieve the triple aim,” he says. “They feel better about it because they are in the driver’s seat. If a patient wants a treatment consistent with their values, we will advocate for it.”

One study found that patients at eight U.S. hospitals who received palliative care incurred significantly lower hospital costs than a matched group receiving usual care, with an average reduction in direct hospital costs of almost $1,700 for patients discharged alive and almost $5,000 per admission for patients who died in the hospital.3 Another study found that early palliative care interventions for cancer patients led to significant improvements in both quality of life and mood compared with patients receiving standard care, with less cost and fewer aggressive treatments at the end of life but longer survival.4

One of the main tools of the palliative care team is the family meeting.

Family meetings are scheduled to allow as many family members as possible to attend, and the primary-care team and relevant specialists typically are also invited. Many palliative-care teams use a standardized format that involves introductions, clarification of each participant’s understanding of the patient’s prognosis, and an effort to reconcile the patient’s hopes and values with medical realities and possibilities, Dr. Fischberg explains.

“That is such a critical component of our care, where we make sure the patient and family are fully informed and foster shared decision making that results in patients being more comfortable with care that better matches what they want,” says Dr. Rotella.

The palliative-care team typically becomes involved via a consultation request from a patient’s attending physician.

“A big part of our job is doing our homework,” Dr. Youngwerth says. “We’ll talk to the team about what’s going on. We want to get as much information as possible about the patient, about prognosis, about the perspectives of people caring for them. Don’t be surprised if the palliative-care team contacts you to get your input on the prognosis and other medical details in order to best inform their discussion with the patient and family.”

Then the palliative-care team will follow consult protocol in reporting back to the primary medical team.

Palliative-care teams can assist busy hospitalists with difficult patient conversations.

“When I’m on the hospitalist service, I’ll pull in the palliative-care team,” Dr. Youngwerth explains. “It’s not that I don’t have the skills; I don’t have the time.”

Conversations aimed at clarifying goals of care can take 90 minutes or more, but the palliative-care team will take as much time as needed to achieve clarification.

It’s important that hospitalists remain involved in these cases, says Christian Sinclair, MD, assistant professor in the division of palliative medicine at the University of Kansas Medical Center in Kansas City and president-elect of AAHPM.

“Just because you have access to palliative-care services, don’t miss the chance to enhance your own communication skills and your ability to address these issues head on,” Dr. Sinclair says.

American Academy of Hospice and Palliative Medicine is a participant in Choosing Wisely.

The Choosing Wisely program, initiated by the American Board of Internal Medicine Foundation, invites medical societies to identify five treatments that should be questioned by physicians and patients based on lack of supporting evidence in the research base. The Society of Hospital Medicine is also a participant in this initiative.

For AAHPM, one of its recommendations was: “Don’t delay palliative care for a patient with serious illness who has a physical, psychological, social, or spiritual distress because they are pursuing disease-directed treatment.” Other Choosing Wisely suggestions include not recommending feeding tubes for patients with advanced dementia, not leaving implantable cardioverter defibrillators (ICDs) activated when these are not consistent with patient/family goals of care, and not recommending more than a single fraction of palliative radiation for an uncomplicated painful bone metastasis.

Different palliative-care programs provide different services.

It is important for hospitalists to learn their local palliative-care programs and what they emphasize and are able to offer—or not, says Dr. Sinclair.

“There are so many different models,” he says. “Spend some time reaching out to them, outside of actual consults, and find out what their comfort level is on various issues. Hospitalists and palliative-care teams should get to know each other better.”

Access to palliative care and the comprehensiveness of the team and services can vary between hospitals, while access to community-based palliative care outside of the hospital is even more variable.

“Palliative-care teams often have a better sense of our partners in the community and access to community-based palliative care,” Dr. Fischberg says.

References

1. Morrison RS, Meier DE. America’s Care of Serious Illness: 2015 State-by-State Report Card on Access to Palliative Care in Our Nation’s Hospitals. New York, NY: Center to Advance Palliative Care; 2015.
2. American Academy of Pediatrics. Policy statement: pediatric palliative care and hospice care commitments, guidelines, and recommendations. Pediatr. 2013;132(5):966-972.
3. Morrison RS, Penrod JD, Cassel JB, et al. Cost savings associated with US hospital palliative care consultation programs. Arch Intern Med. 2008;168(16):1783-1790.
4. Temel JS, Greer JA, Muzikansky et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742.

In fact, according to the 2015 Palliative Care Report Card from the Center to Advance Palliative Care (CAPC), 67 percent of hospitals with 50 or more beds had a designated palliative care program.1

While core palliative care skills can be performed by frontline clinicians including hospitalists, specialty palliative care consults are the ones who are called in for complicated cases. The Hospitalist asked several palliative care experts for advice on how to clarify definitions, distinctions, and roles. This is what they told us:

Palliative care is not synonymous with end-of-life care.

Palliative care advocates call this the biggest misconception they struggle to overcome, with the potential to inhibit its contributions to patient care in the hospital. Palliative care, they say, is for any patient with a serious illness who is struggling to cope with the fallout from that illness in their lives.

“Our biggest impact can come earlier in the illness,” says Jeanie Youngwerth, MD, director of the University of Colorado Hospital’s Palliative Care Consult Service in Aurora. “We help people do the best they can for as long as they can. If you’re even considering a palliative-care consult, then do it sooner rather than later.”

Palliative care can offer more than just help with difficult conversations, adds Daniel Fischberg, MD, PhD, FAAHPM, medical director of the Pain and Palliative Care Department at The Queen’s Medical Center in Honolulu. For example, the palliative-care team can work with patients to clarify their expectations and goals for care, plan for what comes next, and address troubling symptoms—whether physical or emotional, Dr. Fischberg says.

“We can really help patients and families who are facing unique and challenging needs,” he says.

The experts also say that palliative care is not synonymous with hospice care, which is a comprehensive service that provides specialized terminal care for patients with a prognosis of six months or fewer to live. Both, however, share many of the same principles and techniques of symptom management and psycho-social-spiritual support. But some patients and families may associate a palliative-care referral with hospice care or have other misconceptions and fears about it. Hospitalists are challenged to provide a consistent message clarifying that palliative care can be helpful for seriously ill patients regardless of prognosis or other medical treatments they’re receiving.

“It’s human nature not to want to deal with our mortality, and any word that gets associated with death and dying can turn people off,” says Joseph Rotella, MD, chief medical officer of the American Academy of Hospice and Palliative Medicine (AAHPM). “The best way to prevent this is to define it in terms of patient and family needs: ‘Let’s bring in our comfort specialists.’ Doctors should not apologize when referring to a service that has proven its value. We should be happy to recommend it often and early.”

Patients with serious illness can benefit from palliative care.

CAPC defines palliative care as “specialized medical care for people with serious illnesses.” It focuses on providing patients with relief from the symptoms and stress of a serious illness, regardless of their diagnosis, at any age and at any stage of a serious illness. This service is provided by a specially trained interdisciplinary palliative-care team of doctors, nurses, and other specialists who work together with patients’ other doctors. Their goal is to improve quality of life for both patients and their families with an extra layer of support.

Palliative care is also a medical specialty that involves specialty training, including year-long hospice and palliative medicine (HPM) fellowships now offered at 112 sites accredited by the Accreditation Council for Graduate Medical Education. Subspecialty board certification is also available through 10 collaborating medical specialty boards within the American Board of Medical Specialties as well as by the American Osteopathic Association. Palliative-care programs are now certified by The Joint Commission, with similar recognition under development by the Community Health Accreditation Partner.

Palliative care is intended for patients facing challenges.

Palliative care is intended for patients who might be expected to face stresses and challenges in any area of their lives as a result of serious illness. This may include, for example, patients who experience frequent emergency department visits, hospital readmissions, or prolonged ICU stays, as well as cancer patients who are admitted to the hospital solely to address out-of-control symptoms resulting from their disease and its treatment.

“We can help with the burdens of any challenging symptoms,” Dr. Fischberg says.

Other examples of appropriate palliative-care referrals are when next steps for patients’ treatment are not clear, when there are questions about patients’ real goals of care, and when unmet needs such as unrelieved symptoms have put their families in a state of distress, whether physical, emotional, social, or spiritual. Patients may need guidance about weighing their care options.

Palliative care is also available for children and their families.

The philosophy and organization of palliative care for delivering compassionate care for children with chronic, complex, or life-threatening conditions are much the same as for adults. In 2013, the American Academy of Pediatrics issued a Pediatric Palliative Care and Hospice Care policy statement,2 which outlined core commitments in such areas as respecting and partnering with patients and families and pursuing care that is high-quality, readily accessible, and equitable.

As with adults, a referral for palliative care typically is most helpful for the more complex cases, says Joanne Wolfe, MD, MPH, director of Pediatric Palliative Care at Boston Children’s Hospital. The palliative care team can offer emotional support to the parents of children with complex illnesses and help them understand confusing treatment options. The children, too, need a sounding board.

“If I were teaching a group of hospitalists, I would emphasize foundational principles of palliative care, starting with relationship and understanding patients’ and families’ goals of care,” Dr. Wolfe says. If the family is struggling to cope with the illness and the hospitalist doesn’t have good answers, that’s when to call palliative care, she adds.

Palliative care’s role is not to talk patients and their families out of treatments.

The palliative-care team tries to enter cases without an agenda, Dr. Fischberg says, rather than aiming to get patients to stop treatments or agree to a do-not-resuscitate (DNR) order.

“We’re interested in what the hospitalist thinks about what best care for this patient looks like but also in eliciting the patient’s values and preferences,” he says.

Palliative-care professionals are skilled at delicately communicating bad news and helping patients and families clarify what their goals of care really are, says Robert Crook, MD, FACP, associate medical director of Mount Carmel Hospice and Palliative Care in Columbus, Ohio.

“It’s more about helping to improve communication between the primary-care team and the patient and family—not talking somebody out of something but helping them understand each other better,” Dr. Crook says.

Palliative care can reduce costs of care on average, but it does not achieve this by rationing care or denying treatments.

“We’re not there to cut costs or to get patients discharged sooner or to steer them away from costly treatments,” explains Dr. Rotella. “The last thing a palliative-care team wants is to be viewed as a care rationer. But if the patient understands what’s really going on, they often won’t want treatments that don’t help. So, in that way, we are part of the solution.”

Dr. Rotella calls this cost-effectiveness a side effect of palliative care, when patients are empowered to make decisions about their own care. “That’s where you achieve the triple aim,” he says. “They feel better about it because they are in the driver’s seat. If a patient wants a treatment consistent with their values, we will advocate for it.”

One study found that patients at eight U.S. hospitals who received palliative care incurred significantly lower hospital costs than a matched group receiving usual care, with an average reduction in direct hospital costs of almost $1,700 for patients discharged alive and almost $5,000 per admission for patients who died in the hospital.3 Another study found that early palliative care interventions for cancer patients led to significant improvements in both quality of life and mood compared with patients receiving standard care, with less cost and fewer aggressive treatments at the end of life but longer survival.4

One of the main tools of the palliative care team is the family meeting.

Family meetings are scheduled to allow as many family members as possible to attend, and the primary-care team and relevant specialists typically are also invited. Many palliative-care teams use a standardized format that involves introductions, clarification of each participant’s understanding of the patient’s prognosis, and an effort to reconcile the patient’s hopes and values with medical realities and possibilities, Dr. Fischberg explains.

“That is such a critical component of our care, where we make sure the patient and family are fully informed and foster shared decision making that results in patients being more comfortable with care that better matches what they want,” says Dr. Rotella.

The palliative-care team typically becomes involved via a consultation request from a patient’s attending physician.

“A big part of our job is doing our homework,” Dr. Youngwerth says. “We’ll talk to the team about what’s going on. We want to get as much information as possible about the patient, about prognosis, about the perspectives of people caring for them. Don’t be surprised if the palliative-care team contacts you to get your input on the prognosis and other medical details in order to best inform their discussion with the patient and family.”

Then the palliative-care team will follow consult protocol in reporting back to the primary medical team.

Palliative-care teams can assist busy hospitalists with difficult patient conversations.

“When I’m on the hospitalist service, I’ll pull in the palliative-care team,” Dr. Youngwerth explains. “It’s not that I don’t have the skills; I don’t have the time.”

Conversations aimed at clarifying goals of care can take 90 minutes or more, but the palliative-care team will take as much time as needed to achieve clarification.

It’s important that hospitalists remain involved in these cases, says Christian Sinclair, MD, assistant professor in the division of palliative medicine at the University of Kansas Medical Center in Kansas City and president-elect of AAHPM.

“Just because you have access to palliative-care services, don’t miss the chance to enhance your own communication skills and your ability to address these issues head on,” Dr. Sinclair says.

American Academy of Hospice and Palliative Medicine is a participant in Choosing Wisely.

The Choosing Wisely program, initiated by the American Board of Internal Medicine Foundation, invites medical societies to identify five treatments that should be questioned by physicians and patients based on lack of supporting evidence in the research base. The Society of Hospital Medicine is also a participant in this initiative.

For AAHPM, one of its recommendations was: “Don’t delay palliative care for a patient with serious illness who has a physical, psychological, social, or spiritual distress because they are pursuing disease-directed treatment.” Other Choosing Wisely suggestions include not recommending feeding tubes for patients with advanced dementia, not leaving implantable cardioverter defibrillators (ICDs) activated when these are not consistent with patient/family goals of care, and not recommending more than a single fraction of palliative radiation for an uncomplicated painful bone metastasis.

Different palliative-care programs provide different services.

It is important for hospitalists to learn their local palliative-care programs and what they emphasize and are able to offer—or not, says Dr. Sinclair.

“There are so many different models,” he says. “Spend some time reaching out to them, outside of actual consults, and find out what their comfort level is on various issues. Hospitalists and palliative-care teams should get to know each other better.”

Access to palliative care and the comprehensiveness of the team and services can vary between hospitals, while access to community-based palliative care outside of the hospital is even more variable.

“Palliative-care teams often have a better sense of our partners in the community and access to community-based palliative care,” Dr. Fischberg says.

References

1. Morrison RS, Meier DE. America’s Care of Serious Illness: 2015 State-by-State Report Card on Access to Palliative Care in Our Nation’s Hospitals. New York, NY: Center to Advance Palliative Care; 2015.
2. American Academy of Pediatrics. Policy statement: pediatric palliative care and hospice care commitments, guidelines, and recommendations. Pediatr. 2013;132(5):966-972.
3. Morrison RS, Penrod JD, Cassel JB, et al. Cost savings associated with US hospital palliative care consultation programs. Arch Intern Med. 2008;168(16):1783-1790.
4. Temel JS, Greer JA, Muzikansky et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742.

The CAR T-cell therapy CTL019

Photo from Penn Medicine

NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.

Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.

“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.

He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.

Pilot study of CTL019 in CLL

CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.

The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.

Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.

Two patients in this trial are still in CR beyond 5 years.

When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.

First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.

Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.

“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”

Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.

“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”

“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”

Dose-finding trial of CTL019 in CLL

The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.

The high-dose arm (5x10⁸ CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x10⁷ CTL019).

Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.

Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.

Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.

With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.

“Toxicities were identical in each group,” Dr Schuster said.

He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.

There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.

So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.

Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.

“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”

Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”

Toxicity of CTL019 in CLL

“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”

Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.

B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.

“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”

In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.

Other CAR T-cell trials in CLL

Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.

“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.

Combination trials with ibrutinib

Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”

So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.

A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.

“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”

The CAR T-cell therapy CTL019

Photo from Penn Medicine

NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.

Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.

“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.

He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.

Pilot study of CTL019 in CLL

CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.

The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.

Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.

Two patients in this trial are still in CR beyond 5 years.

When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.

First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.

Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.

“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”

Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.

“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”

“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”

Dose-finding trial of CTL019 in CLL

The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.

The high-dose arm (5x10⁸ CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x10⁷ CTL019).

Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.

Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.

Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.

With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.

“Toxicities were identical in each group,” Dr Schuster said.

He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.

There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.

So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.

Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.

“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”

Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”

Toxicity of CTL019 in CLL

“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”

Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.

B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.

“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”

In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.

Other CAR T-cell trials in CLL

Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.

“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.

Combination trials with ibrutinib

Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”

So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.

A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.

“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”

The CAR T-cell therapy CTL019

Photo from Penn Medicine

NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.

Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.

“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.

He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.

Pilot study of CTL019 in CLL

CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.

The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.

Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.

Two patients in this trial are still in CR beyond 5 years.

When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.

First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.

Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.

“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”

Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.

“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”

“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”

Dose-finding trial of CTL019 in CLL

The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.

The high-dose arm (5x10⁸ CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x10⁷ CTL019).

Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.

Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.

Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.

With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.

“Toxicities were identical in each group,” Dr Schuster said.

He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.

There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.

So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.

Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.

“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”

Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”

Toxicity of CTL019 in CLL

“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”

Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.

B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.

“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”

In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.

Other CAR T-cell trials in CLL

Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.

“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.

Combination trials with ibrutinib

Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”

So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.

A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.

“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”

Golden retriever

A new discovery contradicts prevailing assumptions about hemophilia and could change the treatment of hemophilia A, according to researchers.

The team discovered that the protein furin, which is required in factor IX (FIX) replacement, is not required in factor VIII (FVIII) replacement.

In fact, furin impairs clotting in hemophilia A, so gene therapy that can avoid furin processing may provide more effective treatment of hemophilia A.

Experiments in mice and dogs with severe hemophilia A supported this idea. Researchers described the experiments in JCI Insight.

“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Arruda and his colleagues noted that biological differences between FVIII and FIX mean there are obstacles to effective gene therapy in hemophilia A that are not an issue in hemophilia B.

Specifically, the gene encoding FIX is much smaller than the gene for FVIII. So the gene encoding FIX is easier to fit into a vector designed to deliver the therapy to a patient.

“In gene therapy, size matters,” Dr Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”

He added that, according to his group’s research, deleting the furin-recognition components both decreases the size of the gene therapy payload and strengthens its benefits for treating hemophilia A.

Dr Arruda and his colleagues bioengineered a new variant protein, FVIII-ΔF, which avoids interacting with furin. The team then used that variant in gene therapy experiments in animals with severe hemophilia A.

In mice, FVIII-ΔF gene therapy increased recombinant protein yields, enhanced clotting activity, and produced higher circulating FVIII levels when compared to B-domain-deleted FVIII.

In lab dogs with naturally occurring severe hemophilia A, FVIII-ΔF gene therapy decreased bleeding without triggering a higher level of unwanted immune reactions.

“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Dr Arruda said.

“Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”

Golden retriever

A new discovery contradicts prevailing assumptions about hemophilia and could change the treatment of hemophilia A, according to researchers.

The team discovered that the protein furin, which is required in factor IX (FIX) replacement, is not required in factor VIII (FVIII) replacement.

In fact, furin impairs clotting in hemophilia A, so gene therapy that can avoid furin processing may provide more effective treatment of hemophilia A.

Experiments in mice and dogs with severe hemophilia A supported this idea. Researchers described the experiments in JCI Insight.

“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Arruda and his colleagues noted that biological differences between FVIII and FIX mean there are obstacles to effective gene therapy in hemophilia A that are not an issue in hemophilia B.

Specifically, the gene encoding FIX is much smaller than the gene for FVIII. So the gene encoding FIX is easier to fit into a vector designed to deliver the therapy to a patient.

“In gene therapy, size matters,” Dr Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”

He added that, according to his group’s research, deleting the furin-recognition components both decreases the size of the gene therapy payload and strengthens its benefits for treating hemophilia A.

Dr Arruda and his colleagues bioengineered a new variant protein, FVIII-ΔF, which avoids interacting with furin. The team then used that variant in gene therapy experiments in animals with severe hemophilia A.

In mice, FVIII-ΔF gene therapy increased recombinant protein yields, enhanced clotting activity, and produced higher circulating FVIII levels when compared to B-domain-deleted FVIII.

In lab dogs with naturally occurring severe hemophilia A, FVIII-ΔF gene therapy decreased bleeding without triggering a higher level of unwanted immune reactions.

“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Dr Arruda said.

“Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”

Golden retriever

A new discovery contradicts prevailing assumptions about hemophilia and could change the treatment of hemophilia A, according to researchers.

The team discovered that the protein furin, which is required in factor IX (FIX) replacement, is not required in factor VIII (FVIII) replacement.

In fact, furin impairs clotting in hemophilia A, so gene therapy that can avoid furin processing may provide more effective treatment of hemophilia A.

Experiments in mice and dogs with severe hemophilia A supported this idea. Researchers described the experiments in JCI Insight.

“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Arruda and his colleagues noted that biological differences between FVIII and FIX mean there are obstacles to effective gene therapy in hemophilia A that are not an issue in hemophilia B.

Specifically, the gene encoding FIX is much smaller than the gene for FVIII. So the gene encoding FIX is easier to fit into a vector designed to deliver the therapy to a patient.

“In gene therapy, size matters,” Dr Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”

He added that, according to his group’s research, deleting the furin-recognition components both decreases the size of the gene therapy payload and strengthens its benefits for treating hemophilia A.

Dr Arruda and his colleagues bioengineered a new variant protein, FVIII-ΔF, which avoids interacting with furin. The team then used that variant in gene therapy experiments in animals with severe hemophilia A.

In mice, FVIII-ΔF gene therapy increased recombinant protein yields, enhanced clotting activity, and produced higher circulating FVIII levels when compared to B-domain-deleted FVIII.

In lab dogs with naturally occurring severe hemophilia A, FVIII-ΔF gene therapy decreased bleeding without triggering a higher level of unwanted immune reactions.

“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Dr Arruda said.

“Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”

AML cells in the bone marrow

By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).

The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.

Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.

This research was published in Cell Reports.

For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.

This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.

“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.

“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”

In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.

The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.

The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.

KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.

The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.

“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.

“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”

The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.

“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.

“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”

AML cells in the bone marrow

By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).

The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.

Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.

This research was published in Cell Reports.

For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.

This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.

“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.

“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”

In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.

The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.

The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.

KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.

The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.

“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.

“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”

The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.

“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.

“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”

AML cells in the bone marrow

By adapting CRISPR-Cas9 technology and using it to screen the leukemia genome, researchers have identified hundreds of potential therapeutic targets for acute myeloid leukemia (AML).

The group’s work revealed nearly 500 genes, many of which had not been identified previously, that might serve as targets for AML treatment.

Subsequent experiments showed that targeting one of the genes, KAT2A, can destroy AML cells without harming normal blood cells.

This research was published in Cell Reports.

For this study, the researchers used CRISPR-Cas9 gene-editing technology to screen leukemia cells for vulnerable points. The team said they refined the technology so they could disrupt all genes in the leukemia cell genome individually.

This allowed the researchers to identify those genes whose disruption was detrimental to the growth and survival of AML cells, particularly the AML cell lines MOLM-13, HL-60, OCI-AML2, OCI-AML3, and MV4-11.

“Previous studies showed proof of principle, but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML,” said study author Kosuke Yusa, PhD, of Wellcome Trust Sanger Institute in Hinxton, Cambridge, UK.

“We have improved and applied CRISPR-Cas9 technology to look at what actually kills cells.”

In this way, the researchers identified 492 genes that are essential for AML cell survival, including 227 genes that are druggable.

The team noted that a handful of the genes they identified—including DOT1L, BCL2, and MEN1—are already established therapeutic targets, but most of them are not.

The researchers chose to perform additional experiments with one of the genes they identified, KAT2A, to demonstrate the validity of their findings.

KAT2A was one of 66 genes that were essential to 3 or more of the AML cell lines studied. KAT2A was essential for survival in MOLM-13, OCI-AML2, and OCI-AML3.

The team inhibited KAT2A in vitro using genetic and drug-based techniques. Results showed that disrupting KAT2A inhibited the growth and survival of AML cells but did not affect normal blood cells.

“This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes,” said study author Konstantinos Tzelepis, a PhD student at Wellcome Trust Sanger Institute.

“Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.”

The researchers also targeted KAT2A in transgenic mice. The team observed a significant reduction in AML cell expansion and a significant improvement in survival when KAT2A was disrupted.

“This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore,” said study author George Vassiliou, PhD, of Wellcome Trust Sanger Institute.

“Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukemia, there are many more candidates to pursue by the leukemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”

Drug release in a cancer cell

Image from PNAS

A new type of nanoparticle can deliver chemotherapy directly and efficiently to individual cells, according to research published in the Journal of the American Chemical Society.

These nanoparticles, known as connectosomes, are equipped with gap junctions—a pathway that allows for the rapid movement of molecules between 2 cells.

The gap junctions allow the connectosomes to create a direct channel to deliver drugs to each individual cell.

“Gap junctions are the cells’ mechanism for sharing small molecules between neighboring cells,” said study author Jeanne Stachowiak, PhD, of The University of Texas at Austin.

“We believed that there must be a way to utilize them for better drug delivery. The big challenge was in making the materials efficiently and showing that the drugs are delivered through the gap junctions and not some other component.”

To create the connectosomes, the researchers used a chemical process to derive liposomes from donor cells that were engineered to over-produce gap junctions, which are made of proteins.

The team then loaded the connectosomes with the chemotherapy drug doxorubicin.

In in vitro tests with human cells, the researchers found that doxorubicin delivered through connectosomes was 10 times as efficient at killing cancer cells as freely delivered doxorubicin.

Connectosomes were also 100 to 100,000 times as efficient as conventional nanoparticles in delivering doxorubicin, because a drug can diffuse more efficiently through a gap junction than across the oily lipid membrane.

“Connectosomes could open doors for the improved utilization of nanoparticles to deliver other types of therapies,” said Avinash Gadok, a doctoral student at The University of Texas at Austin.

“A huge advantage of nanoparticles is that they can target cells, which helps protect off-target tissues.”

Now, the researchers are investigating whether connectosomes can biochemically target tumor cells and whether they could be useful in inhibiting the migration of tumor cells.

Gap junctions are known to suppress cell migration, creating the potential for connectosomes to help control the movement of tumor cells out of the tumor and into the bloodstream.

“We would like to see whether this approach could delay metastasis while treating the tumor,” Dr Stachowiak said.

“It would be nice to have a multi-pronged approach where you have a particle that slows down metastasis, rapidly delivers drugs, and turns off expression of genes that are promoting the migration of tumor cells.”

Drug release in a cancer cell

Image from PNAS

A new type of nanoparticle can deliver chemotherapy directly and efficiently to individual cells, according to research published in the Journal of the American Chemical Society.

These nanoparticles, known as connectosomes, are equipped with gap junctions—a pathway that allows for the rapid movement of molecules between 2 cells.

The gap junctions allow the connectosomes to create a direct channel to deliver drugs to each individual cell.

“Gap junctions are the cells’ mechanism for sharing small molecules between neighboring cells,” said study author Jeanne Stachowiak, PhD, of The University of Texas at Austin.

“We believed that there must be a way to utilize them for better drug delivery. The big challenge was in making the materials efficiently and showing that the drugs are delivered through the gap junctions and not some other component.”

To create the connectosomes, the researchers used a chemical process to derive liposomes from donor cells that were engineered to over-produce gap junctions, which are made of proteins.

The team then loaded the connectosomes with the chemotherapy drug doxorubicin.

In in vitro tests with human cells, the researchers found that doxorubicin delivered through connectosomes was 10 times as efficient at killing cancer cells as freely delivered doxorubicin.

Connectosomes were also 100 to 100,000 times as efficient as conventional nanoparticles in delivering doxorubicin, because a drug can diffuse more efficiently through a gap junction than across the oily lipid membrane.

“Connectosomes could open doors for the improved utilization of nanoparticles to deliver other types of therapies,” said Avinash Gadok, a doctoral student at The University of Texas at Austin.

“A huge advantage of nanoparticles is that they can target cells, which helps protect off-target tissues.”

Now, the researchers are investigating whether connectosomes can biochemically target tumor cells and whether they could be useful in inhibiting the migration of tumor cells.

Gap junctions are known to suppress cell migration, creating the potential for connectosomes to help control the movement of tumor cells out of the tumor and into the bloodstream.

“We would like to see whether this approach could delay metastasis while treating the tumor,” Dr Stachowiak said.

“It would be nice to have a multi-pronged approach where you have a particle that slows down metastasis, rapidly delivers drugs, and turns off expression of genes that are promoting the migration of tumor cells.”

Drug release in a cancer cell

Image from PNAS

A new type of nanoparticle can deliver chemotherapy directly and efficiently to individual cells, according to research published in the Journal of the American Chemical Society.

These nanoparticles, known as connectosomes, are equipped with gap junctions—a pathway that allows for the rapid movement of molecules between 2 cells.

The gap junctions allow the connectosomes to create a direct channel to deliver drugs to each individual cell.

“Gap junctions are the cells’ mechanism for sharing small molecules between neighboring cells,” said study author Jeanne Stachowiak, PhD, of The University of Texas at Austin.

“We believed that there must be a way to utilize them for better drug delivery. The big challenge was in making the materials efficiently and showing that the drugs are delivered through the gap junctions and not some other component.”

To create the connectosomes, the researchers used a chemical process to derive liposomes from donor cells that were engineered to over-produce gap junctions, which are made of proteins.

The team then loaded the connectosomes with the chemotherapy drug doxorubicin.

In in vitro tests with human cells, the researchers found that doxorubicin delivered through connectosomes was 10 times as efficient at killing cancer cells as freely delivered doxorubicin.

Connectosomes were also 100 to 100,000 times as efficient as conventional nanoparticles in delivering doxorubicin, because a drug can diffuse more efficiently through a gap junction than across the oily lipid membrane.

“Connectosomes could open doors for the improved utilization of nanoparticles to deliver other types of therapies,” said Avinash Gadok, a doctoral student at The University of Texas at Austin.

“A huge advantage of nanoparticles is that they can target cells, which helps protect off-target tissues.”

Now, the researchers are investigating whether connectosomes can biochemically target tumor cells and whether they could be useful in inhibiting the migration of tumor cells.

Gap junctions are known to suppress cell migration, creating the potential for connectosomes to help control the movement of tumor cells out of the tumor and into the bloodstream.

“We would like to see whether this approach could delay metastasis while treating the tumor,” Dr Stachowiak said.

“It would be nice to have a multi-pronged approach where you have a particle that slows down metastasis, rapidly delivers drugs, and turns off expression of genes that are promoting the migration of tumor cells.”