Alstonia scholaris, a tree that grows 50-80 feet high and belongs to the Apocynaceae family, has a long history of use in traditional and homeopathic medicine, including Ayurvedic medicine in India, where it is known as sapthaparna (Integr. Cancer Ther. 2009;8:273-9), in traditional Chinese medicine (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81), and in traditional medicine in Africa and Australia (Integr. Cancer Ther. 2010;9:261-9). The bark contains the alkaloids ditamine, echitamine (or ditaine), and echitanines; and decoctions or other preparations of the bark have been used to treat gastrointestinal conditions (Grieve M. A Modern Herbal (Vol. 1). New York, Dover Publications, 1971, p. 29). Often called the devil’s tree, the bark of A. scholaris also has been used to treat malaria, cutaneous diseases, tumors, ulcers, chronic respiratory conditions (such as asthma and bronchitis), helminthiasis, and agalactia (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]).

In the study of A. scholaris most directly pertinent to potential dermatologic treatment, Lee et al. found that ethanolic bark extracts of A. scholaris significantly suppressed retinoid-induced skin irritation in vitro and in vivo, in human HaCat keratinocytes. The investigators identified echitamine and loganin as the primary components likely responsible for the anti-inflammatory effects.

Courtesy Wikimedia Commons/Binh Giang/Public Domain

Data showed that A. scholaris dose-dependently inhibited the all-trans retinoic acid–induced releases of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in vitro. Also in vitro, A. scholaris extract potently suppressed radiation-induced increases in matrix metalloproteinase-1 (MMP-1). Importantly, in a cumulative irritation patch test, the botanical extract diminished retinol-induced skin irritation while enhancing retinoid activity in blocking MMP-1 expression, which is linked closely to cutaneous aging. The authors concluded that A. scholaris appears to have the dual benefits of decreasing irritation associated with retinoids while augmenting their antiaging impact (Evid. Based Complement. Alternat. Med. 2012;2012:190370).

The leaf extract of A. scholaris has been used to treat cold symptoms and tracheitis, and it has been prescribed in hospitals and approved for commercial over-the-counter sale by the State Food and Drugs Administration of China (SFDA) (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81). The broad range of biological properties associated with A. scholaris has been ascribed to particular constituent categories, including alkaloids, flavonoids, and terpenoids (specifically, phenolic acids) (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). These properties include, but are reportedly not limited to, antioxidant, anticancer, anti-inflammatory, antistress, analgesic, antimutagenic, hepatoprotective, immunomodulatory, and chemopreventive activity (Integr. Cancer Ther. 2010;9:261-9; Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). Antineoplastic effects have been linked directly to phytochemical constituents including echitamine, alstonine, pleiocarpamine, O-methylmacralstonine, macralstonine, and lupeol (Integr. Cancer Ther. 2010;9:261-9).

In 2006, Jagetia and Baliga investigated the anticancer activity of A. scholaris alkaloid fractions in vitro in cultured human neoplastic cell lines. They also conducted in vivo studies in tumor-bearing mice. The in vitro data in HeLa cells revealed a time-dependent rise in antineoplastic activity after 24 hours of exposure (25 mcg/mL). Further, once-daily administration of A. scholaris (240 mg/kg) to tumor-bearing mice yielded dose-dependent remissions, although there were toxic presentations at this dosage. The next-lower dose of 210 mg/kg was found to be most effective, with 20% of the mice surviving for as long as 120 days after tumor cell inoculation, compared with none of the control animals treated with saline (Phytother. Res. 2006;20:103-9).

Using an acute-restraint stress model in mice in 2009, Kulkarni and Juvekar evaluated the effects of stress and the impact of a methanolic extract of A. scholaris bark. Pretreatments with the extract of 100, 250, and 500 mg/kg for 7 days were found to exert significant antistress effects. In addition, nootropic activities were observed, with memory functions clearly enhanced in learning tasks. A. scholaris also was associated with significant antioxidant properties. The extract at 200 mcg/mL exhibited maximum scavenging of the stable radical 1,1-diphenyl-2-picrylhydrazyl at 90.11% and the nitric oxide radical at 62.77% (Indian J. Exp. Biol. 2009;47:47-52).

Later in 2009, Jahan et al. reported on their investigation of potential antioxidant and chemopreventive activity displayed by A. scholaris in a two-stage murine model. Skin carcinogenesis development was initiated in Swiss albino mice through one application of 7, 12-dimethyabenz(a)anthrecene (DMBA) and then promoted two weeks later by repeated application of croton oil three times per week through 16 weeks. The investigators found a lower incidence of tumors, tumor yield, tumor burden, and number of papillomas in mice treated with A. scholaris extract as compared to untreated controls (Integr. Cancer Ther. 2009;8:273-9).

In 2010, Shang et al. conducted multiple studies using A. scholaris. In the first published report, they assessed the anti-inflammatory and analgesic properties of the ethanolic leaf extract to validate its use in traditional Chinese medicine and modern clinical medicine. The investigators first determined that analgesic activity was conferred as the ethyl acetate and alkaloid fractions significantly diminished acetic acid-induced reactions in mice and, along with the ethanolic extract, reduced xylene-induced ear edema.

The researchers also performed in vivo and in vitro assessments of anti-inflammatory activity again on xylene-induced ear edema and carrageenan-induced air pouch formation in mice, as well as cyclooxygenase (COX)-1, -2 and 5-LOX inhibition.

In the air pouch model, A. scholaris alkaloids were found to have significantly spurred superoxide dismutase activity while lowering nitric oxide, prostaglandin E2, and malondialdehyde levels. In vitro tests, supporting evidence from animal models, showed that the three primary alkaloids isolated from A. scholaris leaves (picrinine, vallesamine, and scholaricine) inhibited the inflammatory mediators COX-1, COX-2, and 5-LOX. The researchers also noted that the in vitro anti-inflammatory assay results reinforced the notion of these alkaloids as the bioactive fraction of the plant (J. Ethnopharmacol. 2010;129:174-81).

In their second published report that year, Shang et al. investigated the antitussive and anti-asthmatic activities of the ethanolic extract, fractions, and chief alkaloids of A. scholaris leaf.

The researchers tested for antitussive effects using ammonia-induced or sulfur dioxide-induced coughing in mice and citric acid-induced coughing in guinea pigs. They evaluated anti-asthmatic activity via histamine-induced bronchoconstriction in guinea pigs. They also measured phenol red volume in murine tracheas to assess expectorant activity.

The data indicated antitussive activity, with significant alkaloid suppression of ammonia-induced coughing frequency in mice. Latency periods of sulfur dioxide-induced cough in mice and citric acid-induced cough in guinea pigs increased, and cough frequency in guinea pigs decreased.

Anti-asthmatic effects, such as suppression of convulsion, were observed in guinea pigs. In the expectorant assessment, tracheal phenol red production was increased. The researchers identified picrinine as the primary alkaloid responsible for these activities (J. Ethnopharmacol. 2010;129:293-8).

In addition, Jahan and Goyal showed that pretreatment with A. scholaris bark extract protected the bone marrow of mice against radiation-induced chromosomal damage and micronuclei induction (J Environ. Pathol. Toxicol. Oncol. 2010;29:101-11).

Conclusion

Despite the dearth of research on A. scholaris, the existing data are intriguing, particularly the findings that A. scholaris may have the capacity to amplify the anti-aging activity of retinoids while blunting their irritating effects. Although more research is needed to determine the dermatologic value of A. scholaris, the pursuit may potentially prove fruitful.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at [email protected].

Alstonia scholaris, a tree that grows 50-80 feet high and belongs to the Apocynaceae family, has a long history of use in traditional and homeopathic medicine, including Ayurvedic medicine in India, where it is known as sapthaparna (Integr. Cancer Ther. 2009;8:273-9), in traditional Chinese medicine (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81), and in traditional medicine in Africa and Australia (Integr. Cancer Ther. 2010;9:261-9). The bark contains the alkaloids ditamine, echitamine (or ditaine), and echitanines; and decoctions or other preparations of the bark have been used to treat gastrointestinal conditions (Grieve M. A Modern Herbal (Vol. 1). New York, Dover Publications, 1971, p. 29). Often called the devil’s tree, the bark of A. scholaris also has been used to treat malaria, cutaneous diseases, tumors, ulcers, chronic respiratory conditions (such as asthma and bronchitis), helminthiasis, and agalactia (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]).

In the study of A. scholaris most directly pertinent to potential dermatologic treatment, Lee et al. found that ethanolic bark extracts of A. scholaris significantly suppressed retinoid-induced skin irritation in vitro and in vivo, in human HaCat keratinocytes. The investigators identified echitamine and loganin as the primary components likely responsible for the anti-inflammatory effects.

Courtesy Wikimedia Commons/Binh Giang/Public Domain

Data showed that A. scholaris dose-dependently inhibited the all-trans retinoic acid–induced releases of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in vitro. Also in vitro, A. scholaris extract potently suppressed radiation-induced increases in matrix metalloproteinase-1 (MMP-1). Importantly, in a cumulative irritation patch test, the botanical extract diminished retinol-induced skin irritation while enhancing retinoid activity in blocking MMP-1 expression, which is linked closely to cutaneous aging. The authors concluded that A. scholaris appears to have the dual benefits of decreasing irritation associated with retinoids while augmenting their antiaging impact (Evid. Based Complement. Alternat. Med. 2012;2012:190370).

The leaf extract of A. scholaris has been used to treat cold symptoms and tracheitis, and it has been prescribed in hospitals and approved for commercial over-the-counter sale by the State Food and Drugs Administration of China (SFDA) (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81). The broad range of biological properties associated with A. scholaris has been ascribed to particular constituent categories, including alkaloids, flavonoids, and terpenoids (specifically, phenolic acids) (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). These properties include, but are reportedly not limited to, antioxidant, anticancer, anti-inflammatory, antistress, analgesic, antimutagenic, hepatoprotective, immunomodulatory, and chemopreventive activity (Integr. Cancer Ther. 2010;9:261-9; Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). Antineoplastic effects have been linked directly to phytochemical constituents including echitamine, alstonine, pleiocarpamine, O-methylmacralstonine, macralstonine, and lupeol (Integr. Cancer Ther. 2010;9:261-9).

In 2006, Jagetia and Baliga investigated the anticancer activity of A. scholaris alkaloid fractions in vitro in cultured human neoplastic cell lines. They also conducted in vivo studies in tumor-bearing mice. The in vitro data in HeLa cells revealed a time-dependent rise in antineoplastic activity after 24 hours of exposure (25 mcg/mL). Further, once-daily administration of A. scholaris (240 mg/kg) to tumor-bearing mice yielded dose-dependent remissions, although there were toxic presentations at this dosage. The next-lower dose of 210 mg/kg was found to be most effective, with 20% of the mice surviving for as long as 120 days after tumor cell inoculation, compared with none of the control animals treated with saline (Phytother. Res. 2006;20:103-9).

Using an acute-restraint stress model in mice in 2009, Kulkarni and Juvekar evaluated the effects of stress and the impact of a methanolic extract of A. scholaris bark. Pretreatments with the extract of 100, 250, and 500 mg/kg for 7 days were found to exert significant antistress effects. In addition, nootropic activities were observed, with memory functions clearly enhanced in learning tasks. A. scholaris also was associated with significant antioxidant properties. The extract at 200 mcg/mL exhibited maximum scavenging of the stable radical 1,1-diphenyl-2-picrylhydrazyl at 90.11% and the nitric oxide radical at 62.77% (Indian J. Exp. Biol. 2009;47:47-52).

Later in 2009, Jahan et al. reported on their investigation of potential antioxidant and chemopreventive activity displayed by A. scholaris in a two-stage murine model. Skin carcinogenesis development was initiated in Swiss albino mice through one application of 7, 12-dimethyabenz(a)anthrecene (DMBA) and then promoted two weeks later by repeated application of croton oil three times per week through 16 weeks. The investigators found a lower incidence of tumors, tumor yield, tumor burden, and number of papillomas in mice treated with A. scholaris extract as compared to untreated controls (Integr. Cancer Ther. 2009;8:273-9).

In 2010, Shang et al. conducted multiple studies using A. scholaris. In the first published report, they assessed the anti-inflammatory and analgesic properties of the ethanolic leaf extract to validate its use in traditional Chinese medicine and modern clinical medicine. The investigators first determined that analgesic activity was conferred as the ethyl acetate and alkaloid fractions significantly diminished acetic acid-induced reactions in mice and, along with the ethanolic extract, reduced xylene-induced ear edema.

The researchers also performed in vivo and in vitro assessments of anti-inflammatory activity again on xylene-induced ear edema and carrageenan-induced air pouch formation in mice, as well as cyclooxygenase (COX)-1, -2 and 5-LOX inhibition.

In the air pouch model, A. scholaris alkaloids were found to have significantly spurred superoxide dismutase activity while lowering nitric oxide, prostaglandin E2, and malondialdehyde levels. In vitro tests, supporting evidence from animal models, showed that the three primary alkaloids isolated from A. scholaris leaves (picrinine, vallesamine, and scholaricine) inhibited the inflammatory mediators COX-1, COX-2, and 5-LOX. The researchers also noted that the in vitro anti-inflammatory assay results reinforced the notion of these alkaloids as the bioactive fraction of the plant (J. Ethnopharmacol. 2010;129:174-81).

In their second published report that year, Shang et al. investigated the antitussive and anti-asthmatic activities of the ethanolic extract, fractions, and chief alkaloids of A. scholaris leaf.

The researchers tested for antitussive effects using ammonia-induced or sulfur dioxide-induced coughing in mice and citric acid-induced coughing in guinea pigs. They evaluated anti-asthmatic activity via histamine-induced bronchoconstriction in guinea pigs. They also measured phenol red volume in murine tracheas to assess expectorant activity.

The data indicated antitussive activity, with significant alkaloid suppression of ammonia-induced coughing frequency in mice. Latency periods of sulfur dioxide-induced cough in mice and citric acid-induced cough in guinea pigs increased, and cough frequency in guinea pigs decreased.

Anti-asthmatic effects, such as suppression of convulsion, were observed in guinea pigs. In the expectorant assessment, tracheal phenol red production was increased. The researchers identified picrinine as the primary alkaloid responsible for these activities (J. Ethnopharmacol. 2010;129:293-8).

In addition, Jahan and Goyal showed that pretreatment with A. scholaris bark extract protected the bone marrow of mice against radiation-induced chromosomal damage and micronuclei induction (J Environ. Pathol. Toxicol. Oncol. 2010;29:101-11).

Conclusion

Despite the dearth of research on A. scholaris, the existing data are intriguing, particularly the findings that A. scholaris may have the capacity to amplify the anti-aging activity of retinoids while blunting their irritating effects. Although more research is needed to determine the dermatologic value of A. scholaris, the pursuit may potentially prove fruitful.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at [email protected].

Alstonia scholaris, a tree that grows 50-80 feet high and belongs to the Apocynaceae family, has a long history of use in traditional and homeopathic medicine, including Ayurvedic medicine in India, where it is known as sapthaparna (Integr. Cancer Ther. 2009;8:273-9), in traditional Chinese medicine (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81), and in traditional medicine in Africa and Australia (Integr. Cancer Ther. 2010;9:261-9). The bark contains the alkaloids ditamine, echitamine (or ditaine), and echitanines; and decoctions or other preparations of the bark have been used to treat gastrointestinal conditions (Grieve M. A Modern Herbal (Vol. 1). New York, Dover Publications, 1971, p. 29). Often called the devil’s tree, the bark of A. scholaris also has been used to treat malaria, cutaneous diseases, tumors, ulcers, chronic respiratory conditions (such as asthma and bronchitis), helminthiasis, and agalactia (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]).

In the study of A. scholaris most directly pertinent to potential dermatologic treatment, Lee et al. found that ethanolic bark extracts of A. scholaris significantly suppressed retinoid-induced skin irritation in vitro and in vivo, in human HaCat keratinocytes. The investigators identified echitamine and loganin as the primary components likely responsible for the anti-inflammatory effects.

Courtesy Wikimedia Commons/Binh Giang/Public Domain

Data showed that A. scholaris dose-dependently inhibited the all-trans retinoic acid–induced releases of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in vitro. Also in vitro, A. scholaris extract potently suppressed radiation-induced increases in matrix metalloproteinase-1 (MMP-1). Importantly, in a cumulative irritation patch test, the botanical extract diminished retinol-induced skin irritation while enhancing retinoid activity in blocking MMP-1 expression, which is linked closely to cutaneous aging. The authors concluded that A. scholaris appears to have the dual benefits of decreasing irritation associated with retinoids while augmenting their antiaging impact (Evid. Based Complement. Alternat. Med. 2012;2012:190370).

The leaf extract of A. scholaris has been used to treat cold symptoms and tracheitis, and it has been prescribed in hospitals and approved for commercial over-the-counter sale by the State Food and Drugs Administration of China (SFDA) (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81). The broad range of biological properties associated with A. scholaris has been ascribed to particular constituent categories, including alkaloids, flavonoids, and terpenoids (specifically, phenolic acids) (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). These properties include, but are reportedly not limited to, antioxidant, anticancer, anti-inflammatory, antistress, analgesic, antimutagenic, hepatoprotective, immunomodulatory, and chemopreventive activity (Integr. Cancer Ther. 2010;9:261-9; Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). Antineoplastic effects have been linked directly to phytochemical constituents including echitamine, alstonine, pleiocarpamine, O-methylmacralstonine, macralstonine, and lupeol (Integr. Cancer Ther. 2010;9:261-9).

In 2006, Jagetia and Baliga investigated the anticancer activity of A. scholaris alkaloid fractions in vitro in cultured human neoplastic cell lines. They also conducted in vivo studies in tumor-bearing mice. The in vitro data in HeLa cells revealed a time-dependent rise in antineoplastic activity after 24 hours of exposure (25 mcg/mL). Further, once-daily administration of A. scholaris (240 mg/kg) to tumor-bearing mice yielded dose-dependent remissions, although there were toxic presentations at this dosage. The next-lower dose of 210 mg/kg was found to be most effective, with 20% of the mice surviving for as long as 120 days after tumor cell inoculation, compared with none of the control animals treated with saline (Phytother. Res. 2006;20:103-9).

Using an acute-restraint stress model in mice in 2009, Kulkarni and Juvekar evaluated the effects of stress and the impact of a methanolic extract of A. scholaris bark. Pretreatments with the extract of 100, 250, and 500 mg/kg for 7 days were found to exert significant antistress effects. In addition, nootropic activities were observed, with memory functions clearly enhanced in learning tasks. A. scholaris also was associated with significant antioxidant properties. The extract at 200 mcg/mL exhibited maximum scavenging of the stable radical 1,1-diphenyl-2-picrylhydrazyl at 90.11% and the nitric oxide radical at 62.77% (Indian J. Exp. Biol. 2009;47:47-52).

Later in 2009, Jahan et al. reported on their investigation of potential antioxidant and chemopreventive activity displayed by A. scholaris in a two-stage murine model. Skin carcinogenesis development was initiated in Swiss albino mice through one application of 7, 12-dimethyabenz(a)anthrecene (DMBA) and then promoted two weeks later by repeated application of croton oil three times per week through 16 weeks. The investigators found a lower incidence of tumors, tumor yield, tumor burden, and number of papillomas in mice treated with A. scholaris extract as compared to untreated controls (Integr. Cancer Ther. 2009;8:273-9).

In 2010, Shang et al. conducted multiple studies using A. scholaris. In the first published report, they assessed the anti-inflammatory and analgesic properties of the ethanolic leaf extract to validate its use in traditional Chinese medicine and modern clinical medicine. The investigators first determined that analgesic activity was conferred as the ethyl acetate and alkaloid fractions significantly diminished acetic acid-induced reactions in mice and, along with the ethanolic extract, reduced xylene-induced ear edema.

The researchers also performed in vivo and in vitro assessments of anti-inflammatory activity again on xylene-induced ear edema and carrageenan-induced air pouch formation in mice, as well as cyclooxygenase (COX)-1, -2 and 5-LOX inhibition.

In the air pouch model, A. scholaris alkaloids were found to have significantly spurred superoxide dismutase activity while lowering nitric oxide, prostaglandin E2, and malondialdehyde levels. In vitro tests, supporting evidence from animal models, showed that the three primary alkaloids isolated from A. scholaris leaves (picrinine, vallesamine, and scholaricine) inhibited the inflammatory mediators COX-1, COX-2, and 5-LOX. The researchers also noted that the in vitro anti-inflammatory assay results reinforced the notion of these alkaloids as the bioactive fraction of the plant (J. Ethnopharmacol. 2010;129:174-81).

In their second published report that year, Shang et al. investigated the antitussive and anti-asthmatic activities of the ethanolic extract, fractions, and chief alkaloids of A. scholaris leaf.

The researchers tested for antitussive effects using ammonia-induced or sulfur dioxide-induced coughing in mice and citric acid-induced coughing in guinea pigs. They evaluated anti-asthmatic activity via histamine-induced bronchoconstriction in guinea pigs. They also measured phenol red volume in murine tracheas to assess expectorant activity.

The data indicated antitussive activity, with significant alkaloid suppression of ammonia-induced coughing frequency in mice. Latency periods of sulfur dioxide-induced cough in mice and citric acid-induced cough in guinea pigs increased, and cough frequency in guinea pigs decreased.

Anti-asthmatic effects, such as suppression of convulsion, were observed in guinea pigs. In the expectorant assessment, tracheal phenol red production was increased. The researchers identified picrinine as the primary alkaloid responsible for these activities (J. Ethnopharmacol. 2010;129:293-8).

In addition, Jahan and Goyal showed that pretreatment with A. scholaris bark extract protected the bone marrow of mice against radiation-induced chromosomal damage and micronuclei induction (J Environ. Pathol. Toxicol. Oncol. 2010;29:101-11).

Conclusion

Despite the dearth of research on A. scholaris, the existing data are intriguing, particularly the findings that A. scholaris may have the capacity to amplify the anti-aging activity of retinoids while blunting their irritating effects. Although more research is needed to determine the dermatologic value of A. scholaris, the pursuit may potentially prove fruitful.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at [email protected].

Neil Fishman, MD, associate chief medical officer at the University of Pennsylvania Health System in Philadelphia, sounds like a football coach when he says the best way to fight carbapenem-resistant Enterobacteriaceae (CRE) infections is with a good defense. Hospitalists and others should focus on contact precautions, hand hygiene, removing gowns and gloves before entering new rooms, and even suggest better room cleanings when trying to prevent the spread of CRE, he says. In fact, he has worked with SHM leadership for years to engage hospitalists about the “critical necessity of antimicrobial stewardship.”

“They’re all critical to prevent transmission,” says Dr. Fishman, who chairs the CDC’s Health Infection Control Practices Advisory Committee. “That’s part of the things that can be done in the here and now to try to prevent people from getting infected with these organisms. It’s what the CDC calls ‘detect and prevent.’”

Dr. Fishman’s suggestions echo findings in a new CDC report that shows a threefold increase in the proportion of Enterobacteriaceae bugs that proved resistant to carbapenem in the past decade. The data, in the CDC’s Morbidity and Mortality Weekly Report, showed the proportion of reported Enterobacteriacae that were CRE infections jumped to 4.2% in 2011 from 1.2% in

“It is a very serious public health threat,” says co-author Alex Kallen, MD, MPH, a medical epidemiologist and outbreak response coordinator in the CDC’s Division of Healthcare Quality Promotion. “Maybe it’s not that common now, but with no action, it has the potential to become much more common—like a lot of the other MDROs [multidrug-resistant organisms] that hospitalists see regularly. [Hospitalists] have a lot of control over some of the things that could potentially lead to increased transmission.”

Part of the problem, Dr. Fishman says, is a lack of antibiotic options. Polymyxins briefly showed success against the bacteria, but performance is waning. Dr. Fishman estimates it will be up to eight years before a new antibiotic to combat the infection is in widespread use.

Listen to Dr. Fishman discuss the history of treating CRE infections and importance of antimicrobial stewardship.

Both he and Dr. Kallen say hospitalists can help reduce the spread of CRE through antibiotic stewardship, review of detailed patient histories to ferret out risk factors, and dedication to contact precautions and hand hygiene.

Dr. Kallen notes hospitalists also can play a leadership role in coordinating efforts for patients transferring between hospitals and other institutions (i.e. skilled nursing or assisted-living facilities). Part of being that leader is refusing to dismiss possible CRE cases.

“If you’re a place that doesn’t see this very often, and you see one, that’s a big deal,” Dr. Kallen says. “It needs to be acted on aggressively. Being proactive is much more effective than waiting until it’s common and then trying to intervene.” TH

Richard Quinn is a freelance writer in New Jersey.

Neil Fishman, MD, associate chief medical officer at the University of Pennsylvania Health System in Philadelphia, sounds like a football coach when he says the best way to fight carbapenem-resistant Enterobacteriaceae (CRE) infections is with a good defense. Hospitalists and others should focus on contact precautions, hand hygiene, removing gowns and gloves before entering new rooms, and even suggest better room cleanings when trying to prevent the spread of CRE, he says. In fact, he has worked with SHM leadership for years to engage hospitalists about the “critical necessity of antimicrobial stewardship.”

“They’re all critical to prevent transmission,” says Dr. Fishman, who chairs the CDC’s Health Infection Control Practices Advisory Committee. “That’s part of the things that can be done in the here and now to try to prevent people from getting infected with these organisms. It’s what the CDC calls ‘detect and prevent.’”

Dr. Fishman’s suggestions echo findings in a new CDC report that shows a threefold increase in the proportion of Enterobacteriaceae bugs that proved resistant to carbapenem in the past decade. The data, in the CDC’s Morbidity and Mortality Weekly Report, showed the proportion of reported Enterobacteriacae that were CRE infections jumped to 4.2% in 2011 from 1.2% in

“It is a very serious public health threat,” says co-author Alex Kallen, MD, MPH, a medical epidemiologist and outbreak response coordinator in the CDC’s Division of Healthcare Quality Promotion. “Maybe it’s not that common now, but with no action, it has the potential to become much more common—like a lot of the other MDROs [multidrug-resistant organisms] that hospitalists see regularly. [Hospitalists] have a lot of control over some of the things that could potentially lead to increased transmission.”

Part of the problem, Dr. Fishman says, is a lack of antibiotic options. Polymyxins briefly showed success against the bacteria, but performance is waning. Dr. Fishman estimates it will be up to eight years before a new antibiotic to combat the infection is in widespread use.

Listen to Dr. Fishman discuss the history of treating CRE infections and importance of antimicrobial stewardship.

Both he and Dr. Kallen say hospitalists can help reduce the spread of CRE through antibiotic stewardship, review of detailed patient histories to ferret out risk factors, and dedication to contact precautions and hand hygiene.

Dr. Kallen notes hospitalists also can play a leadership role in coordinating efforts for patients transferring between hospitals and other institutions (i.e. skilled nursing or assisted-living facilities). Part of being that leader is refusing to dismiss possible CRE cases.

“If you’re a place that doesn’t see this very often, and you see one, that’s a big deal,” Dr. Kallen says. “It needs to be acted on aggressively. Being proactive is much more effective than waiting until it’s common and then trying to intervene.” TH

Richard Quinn is a freelance writer in New Jersey.

Neil Fishman, MD, associate chief medical officer at the University of Pennsylvania Health System in Philadelphia, sounds like a football coach when he says the best way to fight carbapenem-resistant Enterobacteriaceae (CRE) infections is with a good defense. Hospitalists and others should focus on contact precautions, hand hygiene, removing gowns and gloves before entering new rooms, and even suggest better room cleanings when trying to prevent the spread of CRE, he says. In fact, he has worked with SHM leadership for years to engage hospitalists about the “critical necessity of antimicrobial stewardship.”

“They’re all critical to prevent transmission,” says Dr. Fishman, who chairs the CDC’s Health Infection Control Practices Advisory Committee. “That’s part of the things that can be done in the here and now to try to prevent people from getting infected with these organisms. It’s what the CDC calls ‘detect and prevent.’”

Dr. Fishman’s suggestions echo findings in a new CDC report that shows a threefold increase in the proportion of Enterobacteriaceae bugs that proved resistant to carbapenem in the past decade. The data, in the CDC’s Morbidity and Mortality Weekly Report, showed the proportion of reported Enterobacteriacae that were CRE infections jumped to 4.2% in 2011 from 1.2% in

“It is a very serious public health threat,” says co-author Alex Kallen, MD, MPH, a medical epidemiologist and outbreak response coordinator in the CDC’s Division of Healthcare Quality Promotion. “Maybe it’s not that common now, but with no action, it has the potential to become much more common—like a lot of the other MDROs [multidrug-resistant organisms] that hospitalists see regularly. [Hospitalists] have a lot of control over some of the things that could potentially lead to increased transmission.”

Part of the problem, Dr. Fishman says, is a lack of antibiotic options. Polymyxins briefly showed success against the bacteria, but performance is waning. Dr. Fishman estimates it will be up to eight years before a new antibiotic to combat the infection is in widespread use.

Listen to Dr. Fishman discuss the history of treating CRE infections and importance of antimicrobial stewardship.

Both he and Dr. Kallen say hospitalists can help reduce the spread of CRE through antibiotic stewardship, review of detailed patient histories to ferret out risk factors, and dedication to contact precautions and hand hygiene.

Dr. Kallen notes hospitalists also can play a leadership role in coordinating efforts for patients transferring between hospitals and other institutions (i.e. skilled nursing or assisted-living facilities). Part of being that leader is refusing to dismiss possible CRE cases.

“If you’re a place that doesn’t see this very often, and you see one, that’s a big deal,” Dr. Kallen says. “It needs to be acted on aggressively. Being proactive is much more effective than waiting until it’s common and then trying to intervene.” TH

Richard Quinn is a freelance writer in New Jersey.

Thirty years ago, many college patients I saw were covered by a school health policy written by a company I will call James S. Fred Insurance. Because this happened long before electronic claims submissions, we knew that ours were handled by someone named Lucille.

For reasons I no longer recall, I found myself strolling in downtown Boston one afternoon, when I saw a large office building that listed none other than James S. Fred Insurance as a major tenant. I took the elevator to the 17th floor, went in, and asked for Lucille.

Sure enough, sitting in a quiet cubicle, there she was: a pleasant older woman who did the college accounts, a small cog in a massive wheel. When I introduced myself, Lucille recognized my name and greeted me warmly.

"I never expected to meet you in person," I said, "But since I have, perhaps I can tell you about a problem we’re having with reimbursement. I described the issue. Lucille took out a large manual, listing the terms of the company’s college coverage. "Here it is," she said, showing me the relevant paragraph.

I thanked her and took the book. But when I read the paragraph, I saw that it didn’t say what she said it said. I pointed this out.

"My goodness," said Lucille. "You’re right. We should be reimbursing you for that, shouldn’t we?"

So that was it. The massive insurance giant in the glass-and-steel skyscraper turned out to be a little old lady in a cubicle who couldn’t read the manual. It was like pulling back the curtain and finding out that the Wizard of Oz was a geezer with a wind machine.

I thought of this last week when I had a talk about my own personal coverage with a Midwest insurer. The issue turned on their responsibility for covering a service provided by a physician who does not participate in Medicare at all. (Yes, I am on Medicare now.)

Last year, I spoke with a human at the company who explained that all I needed to do was confirm that the provider was not Medicare affiliated. This year, after paying a few claims, they apparently changed their mind and sent letters demanding payback and saying they would only pay what Medicare would have, even if Medicare actually didn’t.

I appealed. The appeal was denied. I could not reach a human. I gave up.

Then last week, Jeanette called from Chicago. She described herself as Head of the Appeals Division, in a voice that sounded like Marian, the no-nonsense librarian from "The Music Man."

"Our policy is based on what’s in the manual," she said. "Let me see if I can find it. Oh, here it is." Then she read a passage about doctors who don’t accept Medicare assignments. "We ask them to submit claims anyway," she explained.

"Forgive me," I said, "but a doctor who doesn’t accept assignment is a Medicare provider, just one who won’t accept as full payment what Medicare allows. My doctor is not a Medicare provider at all. He can’t submit a claim, because he doesn’t have a Medicare provider number."

"My goodness," said Jeanette. "I think you may be right. Have you documented this for us?"

"With every claim," I said. "I followed your company’s instructions, and attached to every claim my doctor’s letter saying he doesn’t participate in Medicare. You should have a dozen or so copies of this letter. If you can’t find any, I’ll be happy to send another."

"Oh, here it is!" said Jeanette. "Yes, I see. We need to rectify this."

I danced a mental jig around the room. Lucille must be long retired, but I’d love to invite her and Jeanette for tea.

"I’m really grateful to have the chance to speak to person," I told Jeanette. "Thanks so much for listening."

You could hear Jeanette glow right through the phone. "Why, you’re welcome," she said. "You’ve made my whole day!"

Faceless bureaucracies can seem intimidating, impersonal, malevolent, diabolical, Kafkaesque.

But sometimes, they’re just little old ladies who have trouble reading manuals. To find out, just follow the yellow brick road.

Dr. Rockoff practices dermatology in Brookline, Mass.

Thirty years ago, many college patients I saw were covered by a school health policy written by a company I will call James S. Fred Insurance. Because this happened long before electronic claims submissions, we knew that ours were handled by someone named Lucille.

For reasons I no longer recall, I found myself strolling in downtown Boston one afternoon, when I saw a large office building that listed none other than James S. Fred Insurance as a major tenant. I took the elevator to the 17th floor, went in, and asked for Lucille.

Sure enough, sitting in a quiet cubicle, there she was: a pleasant older woman who did the college accounts, a small cog in a massive wheel. When I introduced myself, Lucille recognized my name and greeted me warmly.

"I never expected to meet you in person," I said, "But since I have, perhaps I can tell you about a problem we’re having with reimbursement. I described the issue. Lucille took out a large manual, listing the terms of the company’s college coverage. "Here it is," she said, showing me the relevant paragraph.

I thanked her and took the book. But when I read the paragraph, I saw that it didn’t say what she said it said. I pointed this out.

"My goodness," said Lucille. "You’re right. We should be reimbursing you for that, shouldn’t we?"

So that was it. The massive insurance giant in the glass-and-steel skyscraper turned out to be a little old lady in a cubicle who couldn’t read the manual. It was like pulling back the curtain and finding out that the Wizard of Oz was a geezer with a wind machine.

I thought of this last week when I had a talk about my own personal coverage with a Midwest insurer. The issue turned on their responsibility for covering a service provided by a physician who does not participate in Medicare at all. (Yes, I am on Medicare now.)

Last year, I spoke with a human at the company who explained that all I needed to do was confirm that the provider was not Medicare affiliated. This year, after paying a few claims, they apparently changed their mind and sent letters demanding payback and saying they would only pay what Medicare would have, even if Medicare actually didn’t.

I appealed. The appeal was denied. I could not reach a human. I gave up.

Then last week, Jeanette called from Chicago. She described herself as Head of the Appeals Division, in a voice that sounded like Marian, the no-nonsense librarian from "The Music Man."

"Our policy is based on what’s in the manual," she said. "Let me see if I can find it. Oh, here it is." Then she read a passage about doctors who don’t accept Medicare assignments. "We ask them to submit claims anyway," she explained.

"Forgive me," I said, "but a doctor who doesn’t accept assignment is a Medicare provider, just one who won’t accept as full payment what Medicare allows. My doctor is not a Medicare provider at all. He can’t submit a claim, because he doesn’t have a Medicare provider number."

"My goodness," said Jeanette. "I think you may be right. Have you documented this for us?"

"With every claim," I said. "I followed your company’s instructions, and attached to every claim my doctor’s letter saying he doesn’t participate in Medicare. You should have a dozen or so copies of this letter. If you can’t find any, I’ll be happy to send another."

"Oh, here it is!" said Jeanette. "Yes, I see. We need to rectify this."

I danced a mental jig around the room. Lucille must be long retired, but I’d love to invite her and Jeanette for tea.

"I’m really grateful to have the chance to speak to person," I told Jeanette. "Thanks so much for listening."

You could hear Jeanette glow right through the phone. "Why, you’re welcome," she said. "You’ve made my whole day!"

Faceless bureaucracies can seem intimidating, impersonal, malevolent, diabolical, Kafkaesque.

But sometimes, they’re just little old ladies who have trouble reading manuals. To find out, just follow the yellow brick road.

Dr. Rockoff practices dermatology in Brookline, Mass.

Thirty years ago, many college patients I saw were covered by a school health policy written by a company I will call James S. Fred Insurance. Because this happened long before electronic claims submissions, we knew that ours were handled by someone named Lucille.

For reasons I no longer recall, I found myself strolling in downtown Boston one afternoon, when I saw a large office building that listed none other than James S. Fred Insurance as a major tenant. I took the elevator to the 17th floor, went in, and asked for Lucille.

Sure enough, sitting in a quiet cubicle, there she was: a pleasant older woman who did the college accounts, a small cog in a massive wheel. When I introduced myself, Lucille recognized my name and greeted me warmly.

"I never expected to meet you in person," I said, "But since I have, perhaps I can tell you about a problem we’re having with reimbursement. I described the issue. Lucille took out a large manual, listing the terms of the company’s college coverage. "Here it is," she said, showing me the relevant paragraph.

I thanked her and took the book. But when I read the paragraph, I saw that it didn’t say what she said it said. I pointed this out.

"My goodness," said Lucille. "You’re right. We should be reimbursing you for that, shouldn’t we?"

So that was it. The massive insurance giant in the glass-and-steel skyscraper turned out to be a little old lady in a cubicle who couldn’t read the manual. It was like pulling back the curtain and finding out that the Wizard of Oz was a geezer with a wind machine.

I thought of this last week when I had a talk about my own personal coverage with a Midwest insurer. The issue turned on their responsibility for covering a service provided by a physician who does not participate in Medicare at all. (Yes, I am on Medicare now.)

Last year, I spoke with a human at the company who explained that all I needed to do was confirm that the provider was not Medicare affiliated. This year, after paying a few claims, they apparently changed their mind and sent letters demanding payback and saying they would only pay what Medicare would have, even if Medicare actually didn’t.

I appealed. The appeal was denied. I could not reach a human. I gave up.

Then last week, Jeanette called from Chicago. She described herself as Head of the Appeals Division, in a voice that sounded like Marian, the no-nonsense librarian from "The Music Man."

"Our policy is based on what’s in the manual," she said. "Let me see if I can find it. Oh, here it is." Then she read a passage about doctors who don’t accept Medicare assignments. "We ask them to submit claims anyway," she explained.

"Forgive me," I said, "but a doctor who doesn’t accept assignment is a Medicare provider, just one who won’t accept as full payment what Medicare allows. My doctor is not a Medicare provider at all. He can’t submit a claim, because he doesn’t have a Medicare provider number."

"My goodness," said Jeanette. "I think you may be right. Have you documented this for us?"

"With every claim," I said. "I followed your company’s instructions, and attached to every claim my doctor’s letter saying he doesn’t participate in Medicare. You should have a dozen or so copies of this letter. If you can’t find any, I’ll be happy to send another."

"Oh, here it is!" said Jeanette. "Yes, I see. We need to rectify this."

I danced a mental jig around the room. Lucille must be long retired, but I’d love to invite her and Jeanette for tea.

"I’m really grateful to have the chance to speak to person," I told Jeanette. "Thanks so much for listening."

You could hear Jeanette glow right through the phone. "Why, you’re welcome," she said. "You’ve made my whole day!"

Faceless bureaucracies can seem intimidating, impersonal, malevolent, diabolical, Kafkaesque.

But sometimes, they’re just little old ladies who have trouble reading manuals. To find out, just follow the yellow brick road.

Dr. Rockoff practices dermatology in Brookline, Mass.

SAN DIEGO – Magnetic resonance-guided stereotactic laser ablation is a safe and effective option in the treatment of hypothalamic hamartoma, results from a multicenter pilot study showed.

At the annual meeting of the American Academy of Neurology, Dr. Daniel J. Curry reported results from 20 patients who have undergone treatment with a Food and Drug Administration–cleared neurosurgical tissue coagulation system called Visualase. Hypothalamic hamartoma (HH) is a rare disorder of pediatric epilepsy with an estimated prevalence of 1:50,000-100,000, said Dr. Curry, director of pediatric surgical epilepsy and functional neurosurgery at Texas Children’s Hospital, Houston.

"The main presentation is the mirthless laughter of gelastic seizures, but patients can have other seizure types," he said. "The diagnosis is frequently delayed, and high seizure burden in the brain can lead to epileptic encephalopathy. Seizures are notoriously resistant to medical managements necessitating surgical intervention ... open, endoscopic, or ablative."

To date, surgical intervention has been limited due to modest outcomes, with 37%-50% achieving seizure freedom. The location of HH tumors makes surgical intervention difficult, and as a result 7%-10% of patients have permanent surgical morbidity.

For the technique using the Visualase, Dr. Curry and his associates at four other medical centers in the United States performed the surgical technique through a single 4-mm incision, a 3.2-mm burr hole, and a 1.65-mm cannula trajectory with Visualase under real-time MR thermography, first with a confirmation test at about 3 W, followed by higher doses of 6-10 W for 50-120 seconds. Temperature limits were set to protect the hypothalamus and basilar artery and optic tract. The surgery had an immediate effect, and patients stayed in the hospital for a mean of 2 days.

The primary measure was seizure frequency at 1 year while the secondary measure was the complication profile of stereotactic laser ablation in epilepsy.

Of the 20 patients, 5 were adults, and the entire study population ranged in age from 22 months to 34 years. A total of 21 ablations were performed in the 20 patients. Dr. Curry reported that all but four patients were seizure free after the procedure. However, the rate of seizures diminished among the four who were not seizure free.

Seizures recurred in one of the pediatric patients. "We re-ablated him and he is now seizure free," Dr. Curry said.

Complications to date have included two missed targets, one case of IV phenytoin toxicity, one case of transient diabetes insipidus, two cases of transient hemiparesis, and one subarachnoid hemorrhage. Perioperative, temporary weight gain was detected in most patients. "With lack of hormonal disturbance, this is thought to be due to the perioperative, high-dose steroid use," Dr. Curry explained.

Postoperative interviews with parents of study participants "have revealed significant improvements in intellectual development, concentration, and interactiveness," he said. "Most families report improvement of mood, decreased behavioral disorders, and rage attacks."

To date, only two patients have completed formal postoperative neuropsychological testing. "There were no significant declines in memory in either patient," Dr. Curry said. One had improved math skills and reading comprehension while the other complained of memory dysfunction but was not below normal on testing.

"We have learned that laser ablation of hypothalamic hamartoma can be accomplished safely," Dr. Curry concluded. "More studies are needed to explain the antiepileptic effect in settings of incomplete radiologic destruction of the target and to advance thermal planning."

Dr. Curry said that he had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Magnetic resonance-guided stereotactic laser ablation is a safe and effective option in the treatment of hypothalamic hamartoma, results from a multicenter pilot study showed.

At the annual meeting of the American Academy of Neurology, Dr. Daniel J. Curry reported results from 20 patients who have undergone treatment with a Food and Drug Administration–cleared neurosurgical tissue coagulation system called Visualase. Hypothalamic hamartoma (HH) is a rare disorder of pediatric epilepsy with an estimated prevalence of 1:50,000-100,000, said Dr. Curry, director of pediatric surgical epilepsy and functional neurosurgery at Texas Children’s Hospital, Houston.

"The main presentation is the mirthless laughter of gelastic seizures, but patients can have other seizure types," he said. "The diagnosis is frequently delayed, and high seizure burden in the brain can lead to epileptic encephalopathy. Seizures are notoriously resistant to medical managements necessitating surgical intervention ... open, endoscopic, or ablative."

To date, surgical intervention has been limited due to modest outcomes, with 37%-50% achieving seizure freedom. The location of HH tumors makes surgical intervention difficult, and as a result 7%-10% of patients have permanent surgical morbidity.

For the technique using the Visualase, Dr. Curry and his associates at four other medical centers in the United States performed the surgical technique through a single 4-mm incision, a 3.2-mm burr hole, and a 1.65-mm cannula trajectory with Visualase under real-time MR thermography, first with a confirmation test at about 3 W, followed by higher doses of 6-10 W for 50-120 seconds. Temperature limits were set to protect the hypothalamus and basilar artery and optic tract. The surgery had an immediate effect, and patients stayed in the hospital for a mean of 2 days.

The primary measure was seizure frequency at 1 year while the secondary measure was the complication profile of stereotactic laser ablation in epilepsy.

Of the 20 patients, 5 were adults, and the entire study population ranged in age from 22 months to 34 years. A total of 21 ablations were performed in the 20 patients. Dr. Curry reported that all but four patients were seizure free after the procedure. However, the rate of seizures diminished among the four who were not seizure free.

Seizures recurred in one of the pediatric patients. "We re-ablated him and he is now seizure free," Dr. Curry said.

Complications to date have included two missed targets, one case of IV phenytoin toxicity, one case of transient diabetes insipidus, two cases of transient hemiparesis, and one subarachnoid hemorrhage. Perioperative, temporary weight gain was detected in most patients. "With lack of hormonal disturbance, this is thought to be due to the perioperative, high-dose steroid use," Dr. Curry explained.

Postoperative interviews with parents of study participants "have revealed significant improvements in intellectual development, concentration, and interactiveness," he said. "Most families report improvement of mood, decreased behavioral disorders, and rage attacks."

To date, only two patients have completed formal postoperative neuropsychological testing. "There were no significant declines in memory in either patient," Dr. Curry said. One had improved math skills and reading comprehension while the other complained of memory dysfunction but was not below normal on testing.

"We have learned that laser ablation of hypothalamic hamartoma can be accomplished safely," Dr. Curry concluded. "More studies are needed to explain the antiepileptic effect in settings of incomplete radiologic destruction of the target and to advance thermal planning."

Dr. Curry said that he had no relevant financial conflicts to disclose.

[email protected]

SAN DIEGO – Magnetic resonance-guided stereotactic laser ablation is a safe and effective option in the treatment of hypothalamic hamartoma, results from a multicenter pilot study showed.

At the annual meeting of the American Academy of Neurology, Dr. Daniel J. Curry reported results from 20 patients who have undergone treatment with a Food and Drug Administration–cleared neurosurgical tissue coagulation system called Visualase. Hypothalamic hamartoma (HH) is a rare disorder of pediatric epilepsy with an estimated prevalence of 1:50,000-100,000, said Dr. Curry, director of pediatric surgical epilepsy and functional neurosurgery at Texas Children’s Hospital, Houston.

"The main presentation is the mirthless laughter of gelastic seizures, but patients can have other seizure types," he said. "The diagnosis is frequently delayed, and high seizure burden in the brain can lead to epileptic encephalopathy. Seizures are notoriously resistant to medical managements necessitating surgical intervention ... open, endoscopic, or ablative."

To date, surgical intervention has been limited due to modest outcomes, with 37%-50% achieving seizure freedom. The location of HH tumors makes surgical intervention difficult, and as a result 7%-10% of patients have permanent surgical morbidity.

For the technique using the Visualase, Dr. Curry and his associates at four other medical centers in the United States performed the surgical technique through a single 4-mm incision, a 3.2-mm burr hole, and a 1.65-mm cannula trajectory with Visualase under real-time MR thermography, first with a confirmation test at about 3 W, followed by higher doses of 6-10 W for 50-120 seconds. Temperature limits were set to protect the hypothalamus and basilar artery and optic tract. The surgery had an immediate effect, and patients stayed in the hospital for a mean of 2 days.

The primary measure was seizure frequency at 1 year while the secondary measure was the complication profile of stereotactic laser ablation in epilepsy.

Of the 20 patients, 5 were adults, and the entire study population ranged in age from 22 months to 34 years. A total of 21 ablations were performed in the 20 patients. Dr. Curry reported that all but four patients were seizure free after the procedure. However, the rate of seizures diminished among the four who were not seizure free.

Seizures recurred in one of the pediatric patients. "We re-ablated him and he is now seizure free," Dr. Curry said.

Complications to date have included two missed targets, one case of IV phenytoin toxicity, one case of transient diabetes insipidus, two cases of transient hemiparesis, and one subarachnoid hemorrhage. Perioperative, temporary weight gain was detected in most patients. "With lack of hormonal disturbance, this is thought to be due to the perioperative, high-dose steroid use," Dr. Curry explained.

Postoperative interviews with parents of study participants "have revealed significant improvements in intellectual development, concentration, and interactiveness," he said. "Most families report improvement of mood, decreased behavioral disorders, and rage attacks."

To date, only two patients have completed formal postoperative neuropsychological testing. "There were no significant declines in memory in either patient," Dr. Curry said. One had improved math skills and reading comprehension while the other complained of memory dysfunction but was not below normal on testing.

"We have learned that laser ablation of hypothalamic hamartoma can be accomplished safely," Dr. Curry concluded. "More studies are needed to explain the antiepileptic effect in settings of incomplete radiologic destruction of the target and to advance thermal planning."

Dr. Curry said that he had no relevant financial conflicts to disclose.

[email protected]

Drug therapy of chronic myeloid leukemia (CML) used to be simple. Or rather, it was narrow and not very effective. For a long time all we had was interferon alpha (IFN-alpha) and hydoxyurea, which failed to protect most patients from progression to the blastic phase. As a result, allotransplant, although associated with high mortality, was the treatment of choice for all eligible patients. Then imatinib came along and replaced a simple but poor choice with a simple but good choice for drug therapy. Now, 12 years later, the drug therapy space for CML is populated by 5 different tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) and omacetaxine (previously known as homoharringtonine) in addition to IFN-alpha and hydoxyurea. Navigating this space is a challenge, especially for hematologists and oncologists who don’t have the privilege of specializing. The drug at issue is bosutinib, which has been approved for treating adults “with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph
) CML with resistance or intolerance to prior therapy,” but it has not received approval for frontline therapy. A combined phase 1/2 study demonstrated a 41% cumulative rate of complete cytogenetic response (CCyR) in patients with chronic phase CML with resistance to or intolerance of imatinib who were treated with bosutinib; progressionfree and overall survival at 2 years were 79% and 92%, respectively, with better results for patients with intolerance compared with patients with resistance. The results are quite comparable with those of nilotinib or dasatinib in the same setting.1-3 In contrast, only 24% of patients on bosutinib achieved CCyR if they had prior exposure to dasatinib or nilotinib in addition to imatinib, which is also similar to the results with dasatinib or nilotinib in the third line,4 although follow-up is shorter. Only 2 BCRABL1 kinase mutations confer resistance to bosutinib: the multiresistant T315I mutations and V299L.5

Drug therapy of chronic myeloid leukemia (CML) used to be simple. Or rather, it was narrow and not very effective. For a long time all we had was interferon alpha (IFN-alpha) and hydoxyurea, which failed to protect most patients from progression to the blastic phase. As a result, allotransplant, although associated with high mortality, was the treatment of choice for all eligible patients. Then imatinib came along and replaced a simple but poor choice with a simple but good choice for drug therapy. Now, 12 years later, the drug therapy space for CML is populated by 5 different tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) and omacetaxine (previously known as homoharringtonine) in addition to IFN-alpha and hydoxyurea. Navigating this space is a challenge, especially for hematologists and oncologists who don’t have the privilege of specializing. The drug at issue is bosutinib, which has been approved for treating adults “with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph
) CML with resistance or intolerance to prior therapy,” but it has not received approval for frontline therapy. A combined phase 1/2 study demonstrated a 41% cumulative rate of complete cytogenetic response (CCyR) in patients with chronic phase CML with resistance to or intolerance of imatinib who were treated with bosutinib; progressionfree and overall survival at 2 years were 79% and 92%, respectively, with better results for patients with intolerance compared with patients with resistance. The results are quite comparable with those of nilotinib or dasatinib in the same setting.1-3 In contrast, only 24% of patients on bosutinib achieved CCyR if they had prior exposure to dasatinib or nilotinib in addition to imatinib, which is also similar to the results with dasatinib or nilotinib in the third line,4 although follow-up is shorter. Only 2 BCRABL1 kinase mutations confer resistance to bosutinib: the multiresistant T315I mutations and V299L.5

Drug therapy of chronic myeloid leukemia (CML) used to be simple. Or rather, it was narrow and not very effective. For a long time all we had was interferon alpha (IFN-alpha) and hydoxyurea, which failed to protect most patients from progression to the blastic phase. As a result, allotransplant, although associated with high mortality, was the treatment of choice for all eligible patients. Then imatinib came along and replaced a simple but poor choice with a simple but good choice for drug therapy. Now, 12 years later, the drug therapy space for CML is populated by 5 different tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) and omacetaxine (previously known as homoharringtonine) in addition to IFN-alpha and hydoxyurea. Navigating this space is a challenge, especially for hematologists and oncologists who don’t have the privilege of specializing. The drug at issue is bosutinib, which has been approved for treating adults “with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph
) CML with resistance or intolerance to prior therapy,” but it has not received approval for frontline therapy. A combined phase 1/2 study demonstrated a 41% cumulative rate of complete cytogenetic response (CCyR) in patients with chronic phase CML with resistance to or intolerance of imatinib who were treated with bosutinib; progressionfree and overall survival at 2 years were 79% and 92%, respectively, with better results for patients with intolerance compared with patients with resistance. The results are quite comparable with those of nilotinib or dasatinib in the same setting.1-3 In contrast, only 24% of patients on bosutinib achieved CCyR if they had prior exposure to dasatinib or nilotinib in addition to imatinib, which is also similar to the results with dasatinib or nilotinib in the third line,4 although follow-up is shorter. Only 2 BCRABL1 kinase mutations confer resistance to bosutinib: the multiresistant T315I mutations and V299L.5

I have just returned from the Oncology Practice Summit, the annual conference for practice-based oncologists and midlevels, which was hosted by COMMUNITY ONCOLOGY and its sister publications, THE JOURNAL OF SUPPORTIVE ONCOLOGY (JSO) and THE ONCOLOGY REPORT, in Las Vegas. During my flight to the conference, I noticed that there was a certain buzz among the passengers, which I naturally assumed was about our oncology meeting. But as I looked around, I realized that not only was I the only passenger who was wearing a tie, I was also the only one who had knocked back less than one drink. The frenzy was about the first weekend of the NCAA’s March Madness, and the pervasive enthusiasm among the passengers revolved around the wellknown “science” of bracketology, in which basketball enthusiasts take all 64 teams in the tournament and try to predict which team will win each match as the teams work their way down to the Final Four and ultimately, to the winner. President Obama had already said that his pick was Indiana (we know now how that turned out — sorry Indiana), but the amateur handicappers on the plane were still sifting through the teams’ records and the coaches’ and individual players’ strengths and weakness to bet (upon their arrival in Las Vegas) on which team would ultimately prevail. Once in Las Vegas, we managed to have our conference despite the March Madness mayhem, and in the course of the meeting, the term bracketology took on an oncology-tinged relevance for me. Bear with me.

I have just returned from the Oncology Practice Summit, the annual conference for practice-based oncologists and midlevels, which was hosted by COMMUNITY ONCOLOGY and its sister publications, THE JOURNAL OF SUPPORTIVE ONCOLOGY (JSO) and THE ONCOLOGY REPORT, in Las Vegas. During my flight to the conference, I noticed that there was a certain buzz among the passengers, which I naturally assumed was about our oncology meeting. But as I looked around, I realized that not only was I the only passenger who was wearing a tie, I was also the only one who had knocked back less than one drink. The frenzy was about the first weekend of the NCAA’s March Madness, and the pervasive enthusiasm among the passengers revolved around the wellknown “science” of bracketology, in which basketball enthusiasts take all 64 teams in the tournament and try to predict which team will win each match as the teams work their way down to the Final Four and ultimately, to the winner. President Obama had already said that his pick was Indiana (we know now how that turned out — sorry Indiana), but the amateur handicappers on the plane were still sifting through the teams’ records and the coaches’ and individual players’ strengths and weakness to bet (upon their arrival in Las Vegas) on which team would ultimately prevail. Once in Las Vegas, we managed to have our conference despite the March Madness mayhem, and in the course of the meeting, the term bracketology took on an oncology-tinged relevance for me. Bear with me.

I have just returned from the Oncology Practice Summit, the annual conference for practice-based oncologists and midlevels, which was hosted by COMMUNITY ONCOLOGY and its sister publications, THE JOURNAL OF SUPPORTIVE ONCOLOGY (JSO) and THE ONCOLOGY REPORT, in Las Vegas. During my flight to the conference, I noticed that there was a certain buzz among the passengers, which I naturally assumed was about our oncology meeting. But as I looked around, I realized that not only was I the only passenger who was wearing a tie, I was also the only one who had knocked back less than one drink. The frenzy was about the first weekend of the NCAA’s March Madness, and the pervasive enthusiasm among the passengers revolved around the wellknown “science” of bracketology, in which basketball enthusiasts take all 64 teams in the tournament and try to predict which team will win each match as the teams work their way down to the Final Four and ultimately, to the winner. President Obama had already said that his pick was Indiana (we know now how that turned out — sorry Indiana), but the amateur handicappers on the plane were still sifting through the teams’ records and the coaches’ and individual players’ strengths and weakness to bet (upon their arrival in Las Vegas) on which team would ultimately prevail. Once in Las Vegas, we managed to have our conference despite the March Madness mayhem, and in the course of the meeting, the term bracketology took on an oncology-tinged relevance for me. Bear with me.

The Centers for Medicare and Medicaid Services has just announced key dates for the 2014 Medicare Shared Savings Program application cycle – and although the upcoming Jan. 1, 2014, start date for the MSSP seems far off, physicians should start organizing now.

Physician interest in participating is mounting, as physician-led accountable care organizations are emerging as leaders in improving quality while eradicating waste. In fact, there are now more physician-run ACOs than any other model (see chart below).

Physicians see opportunity

The MSSP has embraced the accountable care concept to improve the quality of care for Medicare fee-for-service beneficiaries. Eligible providers and suppliers may participate in the MSSP by creating or participating in an ACO. The MSSP rewards ACOs that lower their rate of growth in health care costs while meeting quality performance standards.

On Jan. 10, 2013, the Centers for Medicare and Medicaid Services (CMS) announced that 106 new organizations were selected to participate in the program. That’s in addition to the 87 ACOs approved in July 2012 and the 27 selected in April 2012 – bringing the total to 220 ACOs selected to participate in the MSSP. Early evidence indicates that these ACOs are decreasing costs while improving clinical outcomes.

For many of those ACOs, Medicare will be just the beginning. Private insurers such as Aetna, UnitedHealth Group, Humana, Cigna, and most Blue Cross plans are contracting with ACOs to care for more patients. Many state Medicaid programs have moved or are considering moving to accountable care.

These multiple streams of shared savings will be generated through the same ACO infrastructure needed for the MSSP, encouraging more physician-owned ACOs to form.

With the rise of ACOs, "providers are doing things in a positive way rather than a reactive way. We are seeing the beginnings of a tsunami," noted Dr. Michael Cryer, national medical director at employee benefits consultancy Aon Hewitt, in a New York Times article ("Small-picture approach flips medical economics," March 12, 2012).

According to a recent study by consulting firm Oliver Wyman entitled "The ACO Surprise," roughly 10% of the U.S. population, or from 25 million to 31 million patients, are being served by ACOs. "Successful ACOs won’t just siphon patients away from traditional providers. They will change the rules of the game," the report’s authors conclude.

Don’t miss these 2013 deadlines

CMS has just released its 2013 application cycle for 2014 (see table). The time to act is now. It will take time to understand ACOs and enlist a critical mass of informed and committed primary care providers. Though the notice of intent ("NOI") is not binding, failure to file in May is binding – you are barred from applying. Likewise, you must obtain your user ID by May 31.

The application is not hard, but it basically reflects your ACO game plan. You must be organized, have a focused care plan, and complete the application by the end of July – much earlier than last year’s deadline.

Bottom line: Do not let the start date lull you into procrastination.

Let’s have a closer look at some of the things that must be covered in the application. In addition to a culture of teamwork, patient engagement, and alignment of financial incentives, which are chief among the eight essential elements necessary for a successful ACO ("The essential elements of an ACO," Internal Medicine News, Oct. 1, 2012, p. 38), the MSSP application requires:

• Compliance with the required definitions of "ACO applicant" and "participant."

• A certification that the ACO, its ACO-provider participants, and its ACO providers/suppliers have agreed to become accountable for the quality, cost, and overall care of the Medicare fee-for-service beneficiaries assigned to the ACO.

• Establishment of a governing body.

• Implementation of a comprehensive compliance plan.

• Execution of an ACO Participation Agreement.

In addition, certain organizational milestones should be reached in advance of the application. In particular, planning for a successful ACO requires identification of a physician-champion, completion of a feasibility analysis, implementation of sufficient information technology, and internal reporting on quality and cost metrics. As in any entrepreneurial pursuit, timing is critical, and delay equates to lost potential.

Given that primary care providers are the only providers mandated for inclusion in the MSSP, it is apparent that CMS expects primary care to drive ACO value via prevention and wellness; chronic disease management; care transitions and navigation; reduced hospitalizations; and multispecialty care coordination of complex patients.

ACOs, in one form or another, are sure to be permanent fixtures in American health care, as the nation’s economy and its residents eagerly await the benefits stemming from primary care–driven innovation.

Opportunity knocks – get going!

For more information about the Medicare Shared Savings Program, click here.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, North Carolina. He has many years’ experience assisting physicians in forming integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author ([email protected] or 919-821-6612). Mr. McNeill is a practicing attorney pursuing his LLM at Duke University, currently focusing on accountable care.

Medicare Shared Savings Program deadlines
Key dates for Jan. 1, 2014, start:

Source: Centers for Medicare and Medicaid Services

The Centers for Medicare and Medicaid Services has just announced key dates for the 2014 Medicare Shared Savings Program application cycle – and although the upcoming Jan. 1, 2014, start date for the MSSP seems far off, physicians should start organizing now.

Physician interest in participating is mounting, as physician-led accountable care organizations are emerging as leaders in improving quality while eradicating waste. In fact, there are now more physician-run ACOs than any other model (see chart below).

Physicians see opportunity

The MSSP has embraced the accountable care concept to improve the quality of care for Medicare fee-for-service beneficiaries. Eligible providers and suppliers may participate in the MSSP by creating or participating in an ACO. The MSSP rewards ACOs that lower their rate of growth in health care costs while meeting quality performance standards.

On Jan. 10, 2013, the Centers for Medicare and Medicaid Services (CMS) announced that 106 new organizations were selected to participate in the program. That’s in addition to the 87 ACOs approved in July 2012 and the 27 selected in April 2012 – bringing the total to 220 ACOs selected to participate in the MSSP. Early evidence indicates that these ACOs are decreasing costs while improving clinical outcomes.

For many of those ACOs, Medicare will be just the beginning. Private insurers such as Aetna, UnitedHealth Group, Humana, Cigna, and most Blue Cross plans are contracting with ACOs to care for more patients. Many state Medicaid programs have moved or are considering moving to accountable care.

These multiple streams of shared savings will be generated through the same ACO infrastructure needed for the MSSP, encouraging more physician-owned ACOs to form.

With the rise of ACOs, "providers are doing things in a positive way rather than a reactive way. We are seeing the beginnings of a tsunami," noted Dr. Michael Cryer, national medical director at employee benefits consultancy Aon Hewitt, in a New York Times article ("Small-picture approach flips medical economics," March 12, 2012).

According to a recent study by consulting firm Oliver Wyman entitled "The ACO Surprise," roughly 10% of the U.S. population, or from 25 million to 31 million patients, are being served by ACOs. "Successful ACOs won’t just siphon patients away from traditional providers. They will change the rules of the game," the report’s authors conclude.

Don’t miss these 2013 deadlines

CMS has just released its 2013 application cycle for 2014 (see table). The time to act is now. It will take time to understand ACOs and enlist a critical mass of informed and committed primary care providers. Though the notice of intent ("NOI") is not binding, failure to file in May is binding – you are barred from applying. Likewise, you must obtain your user ID by May 31.

The application is not hard, but it basically reflects your ACO game plan. You must be organized, have a focused care plan, and complete the application by the end of July – much earlier than last year’s deadline.

Bottom line: Do not let the start date lull you into procrastination.

Let’s have a closer look at some of the things that must be covered in the application. In addition to a culture of teamwork, patient engagement, and alignment of financial incentives, which are chief among the eight essential elements necessary for a successful ACO ("The essential elements of an ACO," Internal Medicine News, Oct. 1, 2012, p. 38), the MSSP application requires:

• Compliance with the required definitions of "ACO applicant" and "participant."

• A certification that the ACO, its ACO-provider participants, and its ACO providers/suppliers have agreed to become accountable for the quality, cost, and overall care of the Medicare fee-for-service beneficiaries assigned to the ACO.

• Establishment of a governing body.

• Implementation of a comprehensive compliance plan.

• Execution of an ACO Participation Agreement.

In addition, certain organizational milestones should be reached in advance of the application. In particular, planning for a successful ACO requires identification of a physician-champion, completion of a feasibility analysis, implementation of sufficient information technology, and internal reporting on quality and cost metrics. As in any entrepreneurial pursuit, timing is critical, and delay equates to lost potential.

Given that primary care providers are the only providers mandated for inclusion in the MSSP, it is apparent that CMS expects primary care to drive ACO value via prevention and wellness; chronic disease management; care transitions and navigation; reduced hospitalizations; and multispecialty care coordination of complex patients.

ACOs, in one form or another, are sure to be permanent fixtures in American health care, as the nation’s economy and its residents eagerly await the benefits stemming from primary care–driven innovation.

Opportunity knocks – get going!

For more information about the Medicare Shared Savings Program, click here.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, North Carolina. He has many years’ experience assisting physicians in forming integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author ([email protected] or 919-821-6612). Mr. McNeill is a practicing attorney pursuing his LLM at Duke University, currently focusing on accountable care.

Medicare Shared Savings Program deadlines
Key dates for Jan. 1, 2014, start:

Source: Centers for Medicare and Medicaid Services

The Centers for Medicare and Medicaid Services has just announced key dates for the 2014 Medicare Shared Savings Program application cycle – and although the upcoming Jan. 1, 2014, start date for the MSSP seems far off, physicians should start organizing now.

Physician interest in participating is mounting, as physician-led accountable care organizations are emerging as leaders in improving quality while eradicating waste. In fact, there are now more physician-run ACOs than any other model (see chart below).

Physicians see opportunity

The MSSP has embraced the accountable care concept to improve the quality of care for Medicare fee-for-service beneficiaries. Eligible providers and suppliers may participate in the MSSP by creating or participating in an ACO. The MSSP rewards ACOs that lower their rate of growth in health care costs while meeting quality performance standards.

On Jan. 10, 2013, the Centers for Medicare and Medicaid Services (CMS) announced that 106 new organizations were selected to participate in the program. That’s in addition to the 87 ACOs approved in July 2012 and the 27 selected in April 2012 – bringing the total to 220 ACOs selected to participate in the MSSP. Early evidence indicates that these ACOs are decreasing costs while improving clinical outcomes.

For many of those ACOs, Medicare will be just the beginning. Private insurers such as Aetna, UnitedHealth Group, Humana, Cigna, and most Blue Cross plans are contracting with ACOs to care for more patients. Many state Medicaid programs have moved or are considering moving to accountable care.

These multiple streams of shared savings will be generated through the same ACO infrastructure needed for the MSSP, encouraging more physician-owned ACOs to form.

With the rise of ACOs, "providers are doing things in a positive way rather than a reactive way. We are seeing the beginnings of a tsunami," noted Dr. Michael Cryer, national medical director at employee benefits consultancy Aon Hewitt, in a New York Times article ("Small-picture approach flips medical economics," March 12, 2012).

According to a recent study by consulting firm Oliver Wyman entitled "The ACO Surprise," roughly 10% of the U.S. population, or from 25 million to 31 million patients, are being served by ACOs. "Successful ACOs won’t just siphon patients away from traditional providers. They will change the rules of the game," the report’s authors conclude.

Don’t miss these 2013 deadlines

CMS has just released its 2013 application cycle for 2014 (see table). The time to act is now. It will take time to understand ACOs and enlist a critical mass of informed and committed primary care providers. Though the notice of intent ("NOI") is not binding, failure to file in May is binding – you are barred from applying. Likewise, you must obtain your user ID by May 31.

The application is not hard, but it basically reflects your ACO game plan. You must be organized, have a focused care plan, and complete the application by the end of July – much earlier than last year’s deadline.

Bottom line: Do not let the start date lull you into procrastination.

Let’s have a closer look at some of the things that must be covered in the application. In addition to a culture of teamwork, patient engagement, and alignment of financial incentives, which are chief among the eight essential elements necessary for a successful ACO ("The essential elements of an ACO," Internal Medicine News, Oct. 1, 2012, p. 38), the MSSP application requires:

• Compliance with the required definitions of "ACO applicant" and "participant."

• A certification that the ACO, its ACO-provider participants, and its ACO providers/suppliers have agreed to become accountable for the quality, cost, and overall care of the Medicare fee-for-service beneficiaries assigned to the ACO.

• Establishment of a governing body.

• Implementation of a comprehensive compliance plan.

• Execution of an ACO Participation Agreement.

In addition, certain organizational milestones should be reached in advance of the application. In particular, planning for a successful ACO requires identification of a physician-champion, completion of a feasibility analysis, implementation of sufficient information technology, and internal reporting on quality and cost metrics. As in any entrepreneurial pursuit, timing is critical, and delay equates to lost potential.

Given that primary care providers are the only providers mandated for inclusion in the MSSP, it is apparent that CMS expects primary care to drive ACO value via prevention and wellness; chronic disease management; care transitions and navigation; reduced hospitalizations; and multispecialty care coordination of complex patients.

ACOs, in one form or another, are sure to be permanent fixtures in American health care, as the nation’s economy and its residents eagerly await the benefits stemming from primary care–driven innovation.

Opportunity knocks – get going!

For more information about the Medicare Shared Savings Program, click here.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, North Carolina. He has many years’ experience assisting physicians in forming integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author ([email protected] or 919-821-6612). Mr. McNeill is a practicing attorney pursuing his LLM at Duke University, currently focusing on accountable care.

Medicare Shared Savings Program deadlines
Key dates for Jan. 1, 2014, start:

Source: Centers for Medicare and Medicaid Services

A recent spate of observational or registry analyses have challenged conventional wisdom derived from randomized clinical trials (RCTs). Both RCTs and registries have inherent flaws, but both provide important information in regard to drug efficacy in the search for "truth."

RCTs examine therapeutic effects in highly selected patient populations by focusing on one clinical entity, thereby excluding many patients with comorbidities that could influence or blunt the effect of the intervention. In a sense, RCTs do not represent the real-world expression of disease, since diseases rarely exists in isolation.

Registry trials collect large numbers of patients with a particular diagnosis within a large database. They include unselected patients and examine the effect of therapy in one disease regardless of comorbidities and are subject to both doctor and patient bias and confounding by comorbidities like chronic renal and pulmonary disease and, above all, are not randomized. Using a contemporary analogy, RCTs are a rifle shot whereas registries are more of a shotgun blast.

There have been two recent important targets for clinical research in heart failure. One is the search for better therapy for heart failure patients with preserved ejection fraction (HFPEF). The other is a search for drugs or devices that can provide added benefit to contemporary therapy for heart failure with reduced ejection fraction (HFREF)

The observation that many HFPEF patients develop heart failure despite current therapy with renin angiotensin aldosterone system (RAAS) antagonists and beta-blockers has led to a search for better therapy. RCTs with newer agents. including focused therapy with new RAAS antagonists, have failed to affect mortality in HFPEF (Lancet 2003;362:759-66). In contrast, a recent publication using the Swedish Heart Failure Registry (JAMA 2012;308:2108-17) found that patients treated with RAAS antagonists benefited compared with patients not taking them. The failure of the newer drugs to reach significance was attributed to flawed patient selection in RCTs that led to lower mortality rates and rendered the trials underpowered.

Similar discordance was observed between RCT and registry data in patients with HFREF who were treated with aldosterone antagonist (AA) in addition to contemporary RAAS antagonists and beta-blocker therapy. Using the Medicare database (JAMA 2012;308:2097-107), the investigators failed to observe any treatment benefit of AA on mortality that had previously been reported (N. Engl. J. Med. 1999;341:709-17). They did observe a decrease in rehospitalization for heart failure associated with an increase in rehospitalization for hyperkalemia. The authors attributed the reported benefit in the RCT to the exclusion of older and diabetic patients in addition to those with renal impairment, who were included in the registry analysis and reflected the real world of HFREF.

One registry study examining the benefit of ICDs in heart failure patients (JAMA 2013;309:55-62) from the analysis by the National Cardiovascular Registry did support the mortality benefit observed in the RCT (N. Engl. J. Med. 2002; 346:877-83).

As RCTs have developed over the last half-century, they have changed from investigations of therapeutic concepts to assessments of the efficacy of new and, often, expensive drugs. Much of this search has been supported by the pharmaceutical and device industries, which are intent on more focused research because of their concern about the "noise" generated by comorbidities that could obscure the benefit of their product. As a result, RCTs have identified lower-risk, homogeneous patient populations that may not reflect the real-world experience. Nevertheless, registry studies suffer from the major effect of bias, which is influenced by the physicians’ therapeutic choices and can distort the observed outcome. Unfortunately, the search for "truth" in clinical research remains often out of our reach.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

A recent spate of observational or registry analyses have challenged conventional wisdom derived from randomized clinical trials (RCTs). Both RCTs and registries have inherent flaws, but both provide important information in regard to drug efficacy in the search for "truth."

RCTs examine therapeutic effects in highly selected patient populations by focusing on one clinical entity, thereby excluding many patients with comorbidities that could influence or blunt the effect of the intervention. In a sense, RCTs do not represent the real-world expression of disease, since diseases rarely exists in isolation.

Registry trials collect large numbers of patients with a particular diagnosis within a large database. They include unselected patients and examine the effect of therapy in one disease regardless of comorbidities and are subject to both doctor and patient bias and confounding by comorbidities like chronic renal and pulmonary disease and, above all, are not randomized. Using a contemporary analogy, RCTs are a rifle shot whereas registries are more of a shotgun blast.

There have been two recent important targets for clinical research in heart failure. One is the search for better therapy for heart failure patients with preserved ejection fraction (HFPEF). The other is a search for drugs or devices that can provide added benefit to contemporary therapy for heart failure with reduced ejection fraction (HFREF)

The observation that many HFPEF patients develop heart failure despite current therapy with renin angiotensin aldosterone system (RAAS) antagonists and beta-blockers has led to a search for better therapy. RCTs with newer agents. including focused therapy with new RAAS antagonists, have failed to affect mortality in HFPEF (Lancet 2003;362:759-66). In contrast, a recent publication using the Swedish Heart Failure Registry (JAMA 2012;308:2108-17) found that patients treated with RAAS antagonists benefited compared with patients not taking them. The failure of the newer drugs to reach significance was attributed to flawed patient selection in RCTs that led to lower mortality rates and rendered the trials underpowered.

Similar discordance was observed between RCT and registry data in patients with HFREF who were treated with aldosterone antagonist (AA) in addition to contemporary RAAS antagonists and beta-blocker therapy. Using the Medicare database (JAMA 2012;308:2097-107), the investigators failed to observe any treatment benefit of AA on mortality that had previously been reported (N. Engl. J. Med. 1999;341:709-17). They did observe a decrease in rehospitalization for heart failure associated with an increase in rehospitalization for hyperkalemia. The authors attributed the reported benefit in the RCT to the exclusion of older and diabetic patients in addition to those with renal impairment, who were included in the registry analysis and reflected the real world of HFREF.

One registry study examining the benefit of ICDs in heart failure patients (JAMA 2013;309:55-62) from the analysis by the National Cardiovascular Registry did support the mortality benefit observed in the RCT (N. Engl. J. Med. 2002; 346:877-83).

As RCTs have developed over the last half-century, they have changed from investigations of therapeutic concepts to assessments of the efficacy of new and, often, expensive drugs. Much of this search has been supported by the pharmaceutical and device industries, which are intent on more focused research because of their concern about the "noise" generated by comorbidities that could obscure the benefit of their product. As a result, RCTs have identified lower-risk, homogeneous patient populations that may not reflect the real-world experience. Nevertheless, registry studies suffer from the major effect of bias, which is influenced by the physicians’ therapeutic choices and can distort the observed outcome. Unfortunately, the search for "truth" in clinical research remains often out of our reach.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

A recent spate of observational or registry analyses have challenged conventional wisdom derived from randomized clinical trials (RCTs). Both RCTs and registries have inherent flaws, but both provide important information in regard to drug efficacy in the search for "truth."

RCTs examine therapeutic effects in highly selected patient populations by focusing on one clinical entity, thereby excluding many patients with comorbidities that could influence or blunt the effect of the intervention. In a sense, RCTs do not represent the real-world expression of disease, since diseases rarely exists in isolation.

Registry trials collect large numbers of patients with a particular diagnosis within a large database. They include unselected patients and examine the effect of therapy in one disease regardless of comorbidities and are subject to both doctor and patient bias and confounding by comorbidities like chronic renal and pulmonary disease and, above all, are not randomized. Using a contemporary analogy, RCTs are a rifle shot whereas registries are more of a shotgun blast.

There have been two recent important targets for clinical research in heart failure. One is the search for better therapy for heart failure patients with preserved ejection fraction (HFPEF). The other is a search for drugs or devices that can provide added benefit to contemporary therapy for heart failure with reduced ejection fraction (HFREF)

The observation that many HFPEF patients develop heart failure despite current therapy with renin angiotensin aldosterone system (RAAS) antagonists and beta-blockers has led to a search for better therapy. RCTs with newer agents. including focused therapy with new RAAS antagonists, have failed to affect mortality in HFPEF (Lancet 2003;362:759-66). In contrast, a recent publication using the Swedish Heart Failure Registry (JAMA 2012;308:2108-17) found that patients treated with RAAS antagonists benefited compared with patients not taking them. The failure of the newer drugs to reach significance was attributed to flawed patient selection in RCTs that led to lower mortality rates and rendered the trials underpowered.

Similar discordance was observed between RCT and registry data in patients with HFREF who were treated with aldosterone antagonist (AA) in addition to contemporary RAAS antagonists and beta-blocker therapy. Using the Medicare database (JAMA 2012;308:2097-107), the investigators failed to observe any treatment benefit of AA on mortality that had previously been reported (N. Engl. J. Med. 1999;341:709-17). They did observe a decrease in rehospitalization for heart failure associated with an increase in rehospitalization for hyperkalemia. The authors attributed the reported benefit in the RCT to the exclusion of older and diabetic patients in addition to those with renal impairment, who were included in the registry analysis and reflected the real world of HFREF.

One registry study examining the benefit of ICDs in heart failure patients (JAMA 2013;309:55-62) from the analysis by the National Cardiovascular Registry did support the mortality benefit observed in the RCT (N. Engl. J. Med. 2002; 346:877-83).

As RCTs have developed over the last half-century, they have changed from investigations of therapeutic concepts to assessments of the efficacy of new and, often, expensive drugs. Much of this search has been supported by the pharmaceutical and device industries, which are intent on more focused research because of their concern about the "noise" generated by comorbidities that could obscure the benefit of their product. As a result, RCTs have identified lower-risk, homogeneous patient populations that may not reflect the real-world experience. Nevertheless, registry studies suffer from the major effect of bias, which is influenced by the physicians’ therapeutic choices and can distort the observed outcome. Unfortunately, the search for "truth" in clinical research remains often out of our reach.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.