SHM Public Policy Committee Chair Ron Greeno, MD, MHM, talks about policy issues facing hospitalist, and how "Hill Day 2015" works as an advocacy tool.

SHM Public Policy Committee Chair Ron Greeno, MD, MHM, talks about policy issues facing hospitalist, and how "Hill Day 2015" works as an advocacy tool.

SHM Public Policy Committee Chair Ron Greeno, MD, MHM, talks about policy issues facing hospitalist, and how "Hill Day 2015" works as an advocacy tool.

HM15 Course Director Efren Manjarrez, MD, SFHM, talks about getting new and younger hospitalists involved in the annual meeting, as well as how to get the most out of the largest hospitalist-focused confab in the nation.

HM15 Course Director Efren Manjarrez, MD, SFHM, talks about getting new and younger hospitalists involved in the annual meeting, as well as how to get the most out of the largest hospitalist-focused confab in the nation.

HM15 Course Director Efren Manjarrez, MD, SFHM, talks about getting new and younger hospitalists involved in the annual meeting, as well as how to get the most out of the largest hospitalist-focused confab in the nation.

After the school shooting in Newtown, Conn., in December 2012, we saw an unprecedented amount of proposed legislation at both the state and national levels. The legislation was aimed at fixing whatever it is that is broken in our country that either causes or allows a young man to kill more than two dozen innocent people. Some legislators focused on gun control, while others focused on changing the mental health system, with the idea that the shooter’s actions were caused by his untreated mental illness.

Rep. Tim Murphy, Ph.D., has the distinction of being the only clinical psychologist in Congress, so it’s certainly understandable that he would focus on making long-overdue changes to our troubled mental health system. In addition, Rep. Murphy, a Republican from Pennsylvania, has a strong history of voting against legislation that would curb gun rights, and he carries an “A” grade from the National Rifle Association. When Rep. Murphy publicly promised the families of the Newtown victims that he would enact change, it was clear that his passion was for changing the mental health system. In 2013, Rep. Murphy, with bipartisan support, proposed The Helping Families in Mental Health Crisis Act.

The Murphy bill proposed sweeping and complex changes, and the text was 135 pages long. A major component of the bill was to create a position for an assistant secretary for mental health and substance use disorders within the Department of Health & Human Services to coordinate federal programs and ensure that evidence-based treatments were being used.

The bill also called for shifting money from the Substance Abuse and Mental Health Services Administration (SAMHSA) to the National Institute of Mental Health in the wake of recent thought that SAMHSA has become insensitive to severe mental illness and too oriented toward a recovery model that carries a vague antipsychiatry sentiment.

From there, the issues of patients’ rights versus a doctor-knows-best sentiment have influenced the act, as though one can’t be in favor of both. Perhaps the most controversial requirements include a provision that mandates all states to have outpatient civil commitment programs and a provision that says that health care providers may release information to caretakers of patients with psychiatric disorders without the patient’s consent if the information is felt to be necessary for the patient’s safety or welfare.

This last point is likely to be interpreted as suggesting that psychiatric patients don’t have the same right to confidentiality that other patients have, which would be true. It has the potential to be stigmatizing and infantilizing, and there are people who will not seek care because of the perception this creates. In addition, it may create tension between family members who feel the law now entitles them to information and psychiatrists who don’t see this is as necessary or who fear that releasing information will damage the therapeutic relationship.

Many components of the Helping Families in Mental Health Crisis Act have been applauded universally, but the American Psychiatric Association did not formally support the bill, and an opposing bill was proposed in Congress by Rep. Ron Barber, a Democrat from Arizona who took Gabrielle Giffords’ seat after an assassination attempt by a mentally ill man left her unable to serve. Both bills died when the congressional session ended in December, and Mr. Barber lost a re-election bid and has not returned to Congress.

A new Congress has convened, and Rep. Murphy will be re-introducing the Helping Families in Mental Health Crisis Act with numerous changes. Although the APA did not endorse the previous legislation, the association last week announced, with unanimous backing by the Board of Trustees, its support for the Murphy bill.

“We are pleased that Chairman Murphy is refining and reintroducing his comprehensive mental health reform bill, the Helping Families in Mental Health Crisis Act,” APA President Paul Summergrad said in the last week of January. At an event in early February, he said that he intends to add reforms that align well with APA priorities, including boosting the psychiatric workforce and monitoring and enforcement of mental health parity.

“In December the APA Board of Trustees carefully reviewed its strategy, principles and options for reform and unanimously voted to fully support the efforts of Chairman Murphy and his lead Democratic cosponsor, Rep. Eddie Bernice Johnson. Their efforts are historic in scope, and we are hopeful that Congress will through the legislative process act to pass comprehensive mental health reform with the bipartisan support it deserves.”

Still, I heard the news and was terribly disappointed in the APA. The decision to support this sweeping legislation was made without a vote by the Assembly, with the knowledge that some of these issues are quite polarizing. In addition to the HIPAA disqualification, the issue of outpatient civil commitment, in particular, is controversial. Although proponents are quick to point to research that show its benefits – the research has been done specifically on Kendra’s Law in New York, where $125 million was placed into that state’s mental health system to shore up services – we don’t have the research to know if what helps is providing more services or strong-armed coercion. The text of the bill will be released in the coming weeks. At the very least, couldn’t the APA have waited to see exactly what it is we endorsed?

 

Dr. Miller is writing a book on involuntary psychiatric care.

After the school shooting in Newtown, Conn., in December 2012, we saw an unprecedented amount of proposed legislation at both the state and national levels. The legislation was aimed at fixing whatever it is that is broken in our country that either causes or allows a young man to kill more than two dozen innocent people. Some legislators focused on gun control, while others focused on changing the mental health system, with the idea that the shooter’s actions were caused by his untreated mental illness.

Rep. Tim Murphy, Ph.D., has the distinction of being the only clinical psychologist in Congress, so it’s certainly understandable that he would focus on making long-overdue changes to our troubled mental health system. In addition, Rep. Murphy, a Republican from Pennsylvania, has a strong history of voting against legislation that would curb gun rights, and he carries an “A” grade from the National Rifle Association. When Rep. Murphy publicly promised the families of the Newtown victims that he would enact change, it was clear that his passion was for changing the mental health system. In 2013, Rep. Murphy, with bipartisan support, proposed The Helping Families in Mental Health Crisis Act.

The Murphy bill proposed sweeping and complex changes, and the text was 135 pages long. A major component of the bill was to create a position for an assistant secretary for mental health and substance use disorders within the Department of Health & Human Services to coordinate federal programs and ensure that evidence-based treatments were being used.

The bill also called for shifting money from the Substance Abuse and Mental Health Services Administration (SAMHSA) to the National Institute of Mental Health in the wake of recent thought that SAMHSA has become insensitive to severe mental illness and too oriented toward a recovery model that carries a vague antipsychiatry sentiment.

From there, the issues of patients’ rights versus a doctor-knows-best sentiment have influenced the act, as though one can’t be in favor of both. Perhaps the most controversial requirements include a provision that mandates all states to have outpatient civil commitment programs and a provision that says that health care providers may release information to caretakers of patients with psychiatric disorders without the patient’s consent if the information is felt to be necessary for the patient’s safety or welfare.

This last point is likely to be interpreted as suggesting that psychiatric patients don’t have the same right to confidentiality that other patients have, which would be true. It has the potential to be stigmatizing and infantilizing, and there are people who will not seek care because of the perception this creates. In addition, it may create tension between family members who feel the law now entitles them to information and psychiatrists who don’t see this is as necessary or who fear that releasing information will damage the therapeutic relationship.

Many components of the Helping Families in Mental Health Crisis Act have been applauded universally, but the American Psychiatric Association did not formally support the bill, and an opposing bill was proposed in Congress by Rep. Ron Barber, a Democrat from Arizona who took Gabrielle Giffords’ seat after an assassination attempt by a mentally ill man left her unable to serve. Both bills died when the congressional session ended in December, and Mr. Barber lost a re-election bid and has not returned to Congress.

A new Congress has convened, and Rep. Murphy will be re-introducing the Helping Families in Mental Health Crisis Act with numerous changes. Although the APA did not endorse the previous legislation, the association last week announced, with unanimous backing by the Board of Trustees, its support for the Murphy bill.

“We are pleased that Chairman Murphy is refining and reintroducing his comprehensive mental health reform bill, the Helping Families in Mental Health Crisis Act,” APA President Paul Summergrad said in the last week of January. At an event in early February, he said that he intends to add reforms that align well with APA priorities, including boosting the psychiatric workforce and monitoring and enforcement of mental health parity.

“In December the APA Board of Trustees carefully reviewed its strategy, principles and options for reform and unanimously voted to fully support the efforts of Chairman Murphy and his lead Democratic cosponsor, Rep. Eddie Bernice Johnson. Their efforts are historic in scope, and we are hopeful that Congress will through the legislative process act to pass comprehensive mental health reform with the bipartisan support it deserves.”

Still, I heard the news and was terribly disappointed in the APA. The decision to support this sweeping legislation was made without a vote by the Assembly, with the knowledge that some of these issues are quite polarizing. In addition to the HIPAA disqualification, the issue of outpatient civil commitment, in particular, is controversial. Although proponents are quick to point to research that show its benefits – the research has been done specifically on Kendra’s Law in New York, where $125 million was placed into that state’s mental health system to shore up services – we don’t have the research to know if what helps is providing more services or strong-armed coercion. The text of the bill will be released in the coming weeks. At the very least, couldn’t the APA have waited to see exactly what it is we endorsed?

 

Dr. Miller is writing a book on involuntary psychiatric care.

After the school shooting in Newtown, Conn., in December 2012, we saw an unprecedented amount of proposed legislation at both the state and national levels. The legislation was aimed at fixing whatever it is that is broken in our country that either causes or allows a young man to kill more than two dozen innocent people. Some legislators focused on gun control, while others focused on changing the mental health system, with the idea that the shooter’s actions were caused by his untreated mental illness.

Rep. Tim Murphy, Ph.D., has the distinction of being the only clinical psychologist in Congress, so it’s certainly understandable that he would focus on making long-overdue changes to our troubled mental health system. In addition, Rep. Murphy, a Republican from Pennsylvania, has a strong history of voting against legislation that would curb gun rights, and he carries an “A” grade from the National Rifle Association. When Rep. Murphy publicly promised the families of the Newtown victims that he would enact change, it was clear that his passion was for changing the mental health system. In 2013, Rep. Murphy, with bipartisan support, proposed The Helping Families in Mental Health Crisis Act.

The Murphy bill proposed sweeping and complex changes, and the text was 135 pages long. A major component of the bill was to create a position for an assistant secretary for mental health and substance use disorders within the Department of Health & Human Services to coordinate federal programs and ensure that evidence-based treatments were being used.

The bill also called for shifting money from the Substance Abuse and Mental Health Services Administration (SAMHSA) to the National Institute of Mental Health in the wake of recent thought that SAMHSA has become insensitive to severe mental illness and too oriented toward a recovery model that carries a vague antipsychiatry sentiment.

From there, the issues of patients’ rights versus a doctor-knows-best sentiment have influenced the act, as though one can’t be in favor of both. Perhaps the most controversial requirements include a provision that mandates all states to have outpatient civil commitment programs and a provision that says that health care providers may release information to caretakers of patients with psychiatric disorders without the patient’s consent if the information is felt to be necessary for the patient’s safety or welfare.

This last point is likely to be interpreted as suggesting that psychiatric patients don’t have the same right to confidentiality that other patients have, which would be true. It has the potential to be stigmatizing and infantilizing, and there are people who will not seek care because of the perception this creates. In addition, it may create tension between family members who feel the law now entitles them to information and psychiatrists who don’t see this is as necessary or who fear that releasing information will damage the therapeutic relationship.

Many components of the Helping Families in Mental Health Crisis Act have been applauded universally, but the American Psychiatric Association did not formally support the bill, and an opposing bill was proposed in Congress by Rep. Ron Barber, a Democrat from Arizona who took Gabrielle Giffords’ seat after an assassination attempt by a mentally ill man left her unable to serve. Both bills died when the congressional session ended in December, and Mr. Barber lost a re-election bid and has not returned to Congress.

A new Congress has convened, and Rep. Murphy will be re-introducing the Helping Families in Mental Health Crisis Act with numerous changes. Although the APA did not endorse the previous legislation, the association last week announced, with unanimous backing by the Board of Trustees, its support for the Murphy bill.

“We are pleased that Chairman Murphy is refining and reintroducing his comprehensive mental health reform bill, the Helping Families in Mental Health Crisis Act,” APA President Paul Summergrad said in the last week of January. At an event in early February, he said that he intends to add reforms that align well with APA priorities, including boosting the psychiatric workforce and monitoring and enforcement of mental health parity.

“In December the APA Board of Trustees carefully reviewed its strategy, principles and options for reform and unanimously voted to fully support the efforts of Chairman Murphy and his lead Democratic cosponsor, Rep. Eddie Bernice Johnson. Their efforts are historic in scope, and we are hopeful that Congress will through the legislative process act to pass comprehensive mental health reform with the bipartisan support it deserves.”

Still, I heard the news and was terribly disappointed in the APA. The decision to support this sweeping legislation was made without a vote by the Assembly, with the knowledge that some of these issues are quite polarizing. In addition to the HIPAA disqualification, the issue of outpatient civil commitment, in particular, is controversial. Although proponents are quick to point to research that show its benefits – the research has been done specifically on Kendra’s Law in New York, where $125 million was placed into that state’s mental health system to shore up services – we don’t have the research to know if what helps is providing more services or strong-armed coercion. The text of the bill will be released in the coming weeks. At the very least, couldn’t the APA have waited to see exactly what it is we endorsed?

 

Dr. Miller is writing a book on involuntary psychiatric care.

Kaempferol (3,5,7,4’-tetrahydroxyflavone; C₁₅H₁₀O₆) is among the natural flavonols found in green tea, broccoli, cabbage, kale, endive, beans, leeks, tomatoes, grapes, apples, grapefruit, berries, and propolis, as well as myriad other plant sources, including Brassica and species (J. Agric. Food Chem. 2006;54:2951-6; Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]).

It is one of the most commonly found dietary flavonoids and is also present in beer, particularly hops (Carcinogenesis 2010;31:1338-43; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]). Significantly, kaempferol is known to exhibit anticancer, anti-inflammatory, antioxidant, cytoprotective, and antiapoptotic activity (Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Exp. Mol. Med. 2008;40:208-19), and is believed to play a role in protecting plants from ultraviolet (UV)-induced damage (J. Agric. Food Chem. 2012;60:6966-76).

Skin protection: antioxidant and anti-inflammatory activity

Among 35 flavonoids tested by Cos et al. in 2001 for lipid peroxidation-inhibiting activity, kaempferol was identified as having the highest antioxidant selectivity index (Planta Med. 2001;67:515-9).

Work by Kim et al. in 2002 revealed that four kaempferol glycosides are key active ingredients in the flowers of Prunus persica, which has long been used in traditional Chinese medicine to treat skin disorders (J. Cosmet. Sci. 2002;53:27-34). Kim and colleagues have also shown in animal studies that the topical application of P. persica may be effective at thwarting UVB-induced skin damage (J. Cosmet. Sci. 2002;53:27-34).

In addition, kaempferol is a key component in Punica granatum, which has been found to act as an effective protector against UVB-induced photodamage and aging in cultured skin fibroblasts (Int. J. Dermatol. 2010;49:276-82).

In various tests on the effects of natural flavonoids on matrix metalloproteinase (MMP)-1 activity and expression, Lim et al. reported in 2007 that kaempferol and quercetin potently inhibited recombinant human MMP-1, and both flavonols along with apigenin and wogonin were found to be strong inhibitors of MMP-1 induction in 12-O-tetradecanoylphorbol-13-acetate–treated human dermal fibroblasts. All four flavonoids also suppressed the activation of activator protein (AP)-1. Kaempferol also hindered p38 mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) activation. The investigators concluded that kaempferol is among the flavonoids or plant extracts containing them that may be useful as an agent to protect against photoaging and to treat some cutaneous inflammatory conditions (Planta Med. 2007;73:1267-74).

In 2010, Park et al. demonstrated that kaempferol alleviated burn injuries in mice and that expression of tumor necrosis factor–alpha (TNF-alpha) induced by burn injuries was reduced by kaempferol. They concluded that their findings suggest the possible application of kaempferol to treat thermal burn–induced skin injuries (BMB Rep. 2010;43:46-51).

Anti-inflammatory as well as depigmenting activity was found by Rho et al. in 2011 to be associated with kaempferol and kaempferol rhamnosides isolated from Hibiscus cannabinus (Molecules 2011;16:3338-44).

In 2014, Kim et al. found that extracts of Aceriphyllum rossii (native to Korea and China) and its active constituents, quercetin and kaempferol, blocked secretion of beta-hexosaminidase and histamine; lowered the production and mRNA expression of interleukin-4 and TNF-alpha; and reduced prostaglandin E₂ and leukotriene B₄ synthesis as well as the expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase. These and other findings led the investigators to conclude that A. rossii and its active ingredients kaempferol and quercetin may be effective agents for the treatment of immediate-type hypersensitivity (J. Agric. Food Chem. 2014;62:3750-8).

Anticancer activity

Lee et al. reported in 2010 that the inhibition by kaempferol of phosphatidylinositol 3-kinase (PI3K) activity, a key factor in carcinogenesis, and its concomitant effects may account for the chemopreventive activity of the flavonol (Carcinogenesis 2010;31:1338-43).

At the end of that year, Lee et al. found that kaempferol inhibited UVB-induced COX-2 protein expression in mouse skin epidermal JB6 P+ cells, by blocking Src kinase activity and attenuated the UVB-induced transcriptional activities of COX-2 gene and the transcription factor AP-1. They concluded that kaempferol exerts robust chemopreventive activity against skin cancer by suppressing Src (Biochem. Pharmacol. 2010;80:2042-9).

In 2014, Yao et al. found that kaempferol acted as a safe and potent inhibitor of solar ultraviolet-induced mouse skin carcinogenesis that acted by targeting RSK2 and MSK1 (Cancer Prev. Res. (Phila) 2014;7:958-67).

Significantly, in terms of topical delivery, Chao et al. recently showed that submicron emulsions are effective carriers for the transdermal delivery of kaempferol (Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5).

Conclusion

Kaempferol is one among the many natural flavonols found to exert significant salutary effects. Evidence suggests reasons for confidence that kaempferol can play a role in skin health. More research is necessary to determine the effectiveness of topical products intended to harness the benefits of this flavonoid as proper formulation is challenging.

 

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Kaempferol (3,5,7,4’-tetrahydroxyflavone; C₁₅H₁₀O₆) is among the natural flavonols found in green tea, broccoli, cabbage, kale, endive, beans, leeks, tomatoes, grapes, apples, grapefruit, berries, and propolis, as well as myriad other plant sources, including Brassica and species (J. Agric. Food Chem. 2006;54:2951-6; Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]).

It is one of the most commonly found dietary flavonoids and is also present in beer, particularly hops (Carcinogenesis 2010;31:1338-43; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]). Significantly, kaempferol is known to exhibit anticancer, anti-inflammatory, antioxidant, cytoprotective, and antiapoptotic activity (Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Exp. Mol. Med. 2008;40:208-19), and is believed to play a role in protecting plants from ultraviolet (UV)-induced damage (J. Agric. Food Chem. 2012;60:6966-76).

Skin protection: antioxidant and anti-inflammatory activity

Among 35 flavonoids tested by Cos et al. in 2001 for lipid peroxidation-inhibiting activity, kaempferol was identified as having the highest antioxidant selectivity index (Planta Med. 2001;67:515-9).

Work by Kim et al. in 2002 revealed that four kaempferol glycosides are key active ingredients in the flowers of Prunus persica, which has long been used in traditional Chinese medicine to treat skin disorders (J. Cosmet. Sci. 2002;53:27-34). Kim and colleagues have also shown in animal studies that the topical application of P. persica may be effective at thwarting UVB-induced skin damage (J. Cosmet. Sci. 2002;53:27-34).

In addition, kaempferol is a key component in Punica granatum, which has been found to act as an effective protector against UVB-induced photodamage and aging in cultured skin fibroblasts (Int. J. Dermatol. 2010;49:276-82).

In various tests on the effects of natural flavonoids on matrix metalloproteinase (MMP)-1 activity and expression, Lim et al. reported in 2007 that kaempferol and quercetin potently inhibited recombinant human MMP-1, and both flavonols along with apigenin and wogonin were found to be strong inhibitors of MMP-1 induction in 12-O-tetradecanoylphorbol-13-acetate–treated human dermal fibroblasts. All four flavonoids also suppressed the activation of activator protein (AP)-1. Kaempferol also hindered p38 mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) activation. The investigators concluded that kaempferol is among the flavonoids or plant extracts containing them that may be useful as an agent to protect against photoaging and to treat some cutaneous inflammatory conditions (Planta Med. 2007;73:1267-74).

In 2010, Park et al. demonstrated that kaempferol alleviated burn injuries in mice and that expression of tumor necrosis factor–alpha (TNF-alpha) induced by burn injuries was reduced by kaempferol. They concluded that their findings suggest the possible application of kaempferol to treat thermal burn–induced skin injuries (BMB Rep. 2010;43:46-51).

Anti-inflammatory as well as depigmenting activity was found by Rho et al. in 2011 to be associated with kaempferol and kaempferol rhamnosides isolated from Hibiscus cannabinus (Molecules 2011;16:3338-44).

In 2014, Kim et al. found that extracts of Aceriphyllum rossii (native to Korea and China) and its active constituents, quercetin and kaempferol, blocked secretion of beta-hexosaminidase and histamine; lowered the production and mRNA expression of interleukin-4 and TNF-alpha; and reduced prostaglandin E₂ and leukotriene B₄ synthesis as well as the expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase. These and other findings led the investigators to conclude that A. rossii and its active ingredients kaempferol and quercetin may be effective agents for the treatment of immediate-type hypersensitivity (J. Agric. Food Chem. 2014;62:3750-8).

Anticancer activity

Lee et al. reported in 2010 that the inhibition by kaempferol of phosphatidylinositol 3-kinase (PI3K) activity, a key factor in carcinogenesis, and its concomitant effects may account for the chemopreventive activity of the flavonol (Carcinogenesis 2010;31:1338-43).

At the end of that year, Lee et al. found that kaempferol inhibited UVB-induced COX-2 protein expression in mouse skin epidermal JB6 P+ cells, by blocking Src kinase activity and attenuated the UVB-induced transcriptional activities of COX-2 gene and the transcription factor AP-1. They concluded that kaempferol exerts robust chemopreventive activity against skin cancer by suppressing Src (Biochem. Pharmacol. 2010;80:2042-9).

In 2014, Yao et al. found that kaempferol acted as a safe and potent inhibitor of solar ultraviolet-induced mouse skin carcinogenesis that acted by targeting RSK2 and MSK1 (Cancer Prev. Res. (Phila) 2014;7:958-67).

Significantly, in terms of topical delivery, Chao et al. recently showed that submicron emulsions are effective carriers for the transdermal delivery of kaempferol (Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5).

Conclusion

Kaempferol is one among the many natural flavonols found to exert significant salutary effects. Evidence suggests reasons for confidence that kaempferol can play a role in skin health. More research is necessary to determine the effectiveness of topical products intended to harness the benefits of this flavonoid as proper formulation is challenging.

 

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Kaempferol (3,5,7,4’-tetrahydroxyflavone; C₁₅H₁₀O₆) is among the natural flavonols found in green tea, broccoli, cabbage, kale, endive, beans, leeks, tomatoes, grapes, apples, grapefruit, berries, and propolis, as well as myriad other plant sources, including Brassica and species (J. Agric. Food Chem. 2006;54:2951-6; Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]).

It is one of the most commonly found dietary flavonoids and is also present in beer, particularly hops (Carcinogenesis 2010;31:1338-43; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]). Significantly, kaempferol is known to exhibit anticancer, anti-inflammatory, antioxidant, cytoprotective, and antiapoptotic activity (Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Exp. Mol. Med. 2008;40:208-19), and is believed to play a role in protecting plants from ultraviolet (UV)-induced damage (J. Agric. Food Chem. 2012;60:6966-76).

Skin protection: antioxidant and anti-inflammatory activity

Among 35 flavonoids tested by Cos et al. in 2001 for lipid peroxidation-inhibiting activity, kaempferol was identified as having the highest antioxidant selectivity index (Planta Med. 2001;67:515-9).

Work by Kim et al. in 2002 revealed that four kaempferol glycosides are key active ingredients in the flowers of Prunus persica, which has long been used in traditional Chinese medicine to treat skin disorders (J. Cosmet. Sci. 2002;53:27-34). Kim and colleagues have also shown in animal studies that the topical application of P. persica may be effective at thwarting UVB-induced skin damage (J. Cosmet. Sci. 2002;53:27-34).

In addition, kaempferol is a key component in Punica granatum, which has been found to act as an effective protector against UVB-induced photodamage and aging in cultured skin fibroblasts (Int. J. Dermatol. 2010;49:276-82).

In various tests on the effects of natural flavonoids on matrix metalloproteinase (MMP)-1 activity and expression, Lim et al. reported in 2007 that kaempferol and quercetin potently inhibited recombinant human MMP-1, and both flavonols along with apigenin and wogonin were found to be strong inhibitors of MMP-1 induction in 12-O-tetradecanoylphorbol-13-acetate–treated human dermal fibroblasts. All four flavonoids also suppressed the activation of activator protein (AP)-1. Kaempferol also hindered p38 mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) activation. The investigators concluded that kaempferol is among the flavonoids or plant extracts containing them that may be useful as an agent to protect against photoaging and to treat some cutaneous inflammatory conditions (Planta Med. 2007;73:1267-74).

In 2010, Park et al. demonstrated that kaempferol alleviated burn injuries in mice and that expression of tumor necrosis factor–alpha (TNF-alpha) induced by burn injuries was reduced by kaempferol. They concluded that their findings suggest the possible application of kaempferol to treat thermal burn–induced skin injuries (BMB Rep. 2010;43:46-51).

Anti-inflammatory as well as depigmenting activity was found by Rho et al. in 2011 to be associated with kaempferol and kaempferol rhamnosides isolated from Hibiscus cannabinus (Molecules 2011;16:3338-44).

In 2014, Kim et al. found that extracts of Aceriphyllum rossii (native to Korea and China) and its active constituents, quercetin and kaempferol, blocked secretion of beta-hexosaminidase and histamine; lowered the production and mRNA expression of interleukin-4 and TNF-alpha; and reduced prostaglandin E₂ and leukotriene B₄ synthesis as well as the expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase. These and other findings led the investigators to conclude that A. rossii and its active ingredients kaempferol and quercetin may be effective agents for the treatment of immediate-type hypersensitivity (J. Agric. Food Chem. 2014;62:3750-8).

Anticancer activity

Lee et al. reported in 2010 that the inhibition by kaempferol of phosphatidylinositol 3-kinase (PI3K) activity, a key factor in carcinogenesis, and its concomitant effects may account for the chemopreventive activity of the flavonol (Carcinogenesis 2010;31:1338-43).

At the end of that year, Lee et al. found that kaempferol inhibited UVB-induced COX-2 protein expression in mouse skin epidermal JB6 P+ cells, by blocking Src kinase activity and attenuated the UVB-induced transcriptional activities of COX-2 gene and the transcription factor AP-1. They concluded that kaempferol exerts robust chemopreventive activity against skin cancer by suppressing Src (Biochem. Pharmacol. 2010;80:2042-9).

In 2014, Yao et al. found that kaempferol acted as a safe and potent inhibitor of solar ultraviolet-induced mouse skin carcinogenesis that acted by targeting RSK2 and MSK1 (Cancer Prev. Res. (Phila) 2014;7:958-67).

Significantly, in terms of topical delivery, Chao et al. recently showed that submicron emulsions are effective carriers for the transdermal delivery of kaempferol (Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5).

Conclusion

Kaempferol is one among the many natural flavonols found to exert significant salutary effects. Evidence suggests reasons for confidence that kaempferol can play a role in skin health. More research is necessary to determine the effectiveness of topical products intended to harness the benefits of this flavonoid as proper formulation is challenging.

 

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

 

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

 

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

 

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

A new study indicates that transfusing a balanced ratio of plasma, platelets, and red blood cells (RBCs) can decrease bleeding better than blood products with a higher ratio of RBCs, but this does not seem to affect mortality rates.

Patients who received blood products with a plasma-platelet-RBC ratio of 1:1:1 were more likely to achieve hemostasis and less likely to experience exsanguination than patients who received blood products with a ratio of 1:1:2.

However, there was no significant difference between the two transfusion strategies in overall death rates at 24 hours or at 30 days.

John B. Holcomb, MD, of the University of Texas Health Science Center at Houston, and his colleagues reported these results in JAMA.

The team conducted a study of 680 severely injured patients who arrived at 1 of 12 Level 1 trauma centers. The patients were predicted to require massive transfusion and were randomly assigned to receive blood products with ratios of 1:1:1 or 1:1:2 during active resuscitation, in addition to all local standard-of-care interventions.

The researchers found no significant differences for the primary outcomes of the study: mortality at 24 hours—12.7% in the 1:1:1 group and 17.0% in the 1:1:2 group (P=0.12)—or at 30 days—22.4% and 26.1%, respectively (P=0.26).

However, the incidence of exsanguination, which was the predominant cause of death within the first 24 hours, was significantly lower in the 1:1:1 group than in the 1:1:2 group—9.2% and 14.6%, respectively (P=0.03).

And more patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group—86% and 78%, respectively (P=0.006).

On the other hand, there were no significant differences between the two groups for rates of multiple inflammatory-mediated complications, such as acute respiratory distress syndrome, multiple organ failure, infection, sepsis, venous thromboembolism, and transfusion-related complications.

Based on these results, Dr Holcomb and his colleagues recommended that clinicians consider using a 1:1:1 transfusion protocol, starting with the initial units transfused while patients are actively bleeding, and then transitioning to laboratory-guided treatment once they’ve achieved hemorrhage control.

The team added that future studies should concentrate on the physiologically relevant period of active bleeding after injury and use acute complications and later deaths as safety endpoints.

A new study indicates that transfusing a balanced ratio of plasma, platelets, and red blood cells (RBCs) can decrease bleeding better than blood products with a higher ratio of RBCs, but this does not seem to affect mortality rates.

Patients who received blood products with a plasma-platelet-RBC ratio of 1:1:1 were more likely to achieve hemostasis and less likely to experience exsanguination than patients who received blood products with a ratio of 1:1:2.

However, there was no significant difference between the two transfusion strategies in overall death rates at 24 hours or at 30 days.

John B. Holcomb, MD, of the University of Texas Health Science Center at Houston, and his colleagues reported these results in JAMA.

The team conducted a study of 680 severely injured patients who arrived at 1 of 12 Level 1 trauma centers. The patients were predicted to require massive transfusion and were randomly assigned to receive blood products with ratios of 1:1:1 or 1:1:2 during active resuscitation, in addition to all local standard-of-care interventions.

The researchers found no significant differences for the primary outcomes of the study: mortality at 24 hours—12.7% in the 1:1:1 group and 17.0% in the 1:1:2 group (P=0.12)—or at 30 days—22.4% and 26.1%, respectively (P=0.26).

However, the incidence of exsanguination, which was the predominant cause of death within the first 24 hours, was significantly lower in the 1:1:1 group than in the 1:1:2 group—9.2% and 14.6%, respectively (P=0.03).

And more patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group—86% and 78%, respectively (P=0.006).

On the other hand, there were no significant differences between the two groups for rates of multiple inflammatory-mediated complications, such as acute respiratory distress syndrome, multiple organ failure, infection, sepsis, venous thromboembolism, and transfusion-related complications.

Based on these results, Dr Holcomb and his colleagues recommended that clinicians consider using a 1:1:1 transfusion protocol, starting with the initial units transfused while patients are actively bleeding, and then transitioning to laboratory-guided treatment once they’ve achieved hemorrhage control.

The team added that future studies should concentrate on the physiologically relevant period of active bleeding after injury and use acute complications and later deaths as safety endpoints.

A new study indicates that transfusing a balanced ratio of plasma, platelets, and red blood cells (RBCs) can decrease bleeding better than blood products with a higher ratio of RBCs, but this does not seem to affect mortality rates.

Patients who received blood products with a plasma-platelet-RBC ratio of 1:1:1 were more likely to achieve hemostasis and less likely to experience exsanguination than patients who received blood products with a ratio of 1:1:2.

However, there was no significant difference between the two transfusion strategies in overall death rates at 24 hours or at 30 days.

John B. Holcomb, MD, of the University of Texas Health Science Center at Houston, and his colleagues reported these results in JAMA.

The team conducted a study of 680 severely injured patients who arrived at 1 of 12 Level 1 trauma centers. The patients were predicted to require massive transfusion and were randomly assigned to receive blood products with ratios of 1:1:1 or 1:1:2 during active resuscitation, in addition to all local standard-of-care interventions.

The researchers found no significant differences for the primary outcomes of the study: mortality at 24 hours—12.7% in the 1:1:1 group and 17.0% in the 1:1:2 group (P=0.12)—or at 30 days—22.4% and 26.1%, respectively (P=0.26).

However, the incidence of exsanguination, which was the predominant cause of death within the first 24 hours, was significantly lower in the 1:1:1 group than in the 1:1:2 group—9.2% and 14.6%, respectively (P=0.03).

And more patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group—86% and 78%, respectively (P=0.006).

On the other hand, there were no significant differences between the two groups for rates of multiple inflammatory-mediated complications, such as acute respiratory distress syndrome, multiple organ failure, infection, sepsis, venous thromboembolism, and transfusion-related complications.

Based on these results, Dr Holcomb and his colleagues recommended that clinicians consider using a 1:1:1 transfusion protocol, starting with the initial units transfused while patients are actively bleeding, and then transitioning to laboratory-guided treatment once they’ve achieved hemorrhage control.

The team added that future studies should concentrate on the physiologically relevant period of active bleeding after injury and use acute complications and later deaths as safety endpoints.

Single-agent daratumumab can elicit responses in patients with multiple myeloma (MM) who have failed treatment with proteasome inhibitors and immunomodulatory agents (IMiDs), preliminary results of a phase 2 study suggest.

The study enrolled MM patients who have received at least 3 different lines of therapy, including both a proteasome inhibitor and an IMiD, and patients who are double-refractory to a proteasome inhibitor and an IMiD.

Daratumumab, an anti-CD38 monoclonal antibody, has breakthrough therapy designation from the US Food and Drug Administration to treat this patient population.

Genmab A/S, the company that discovered daratumumab and licensed it to Janssen Biotech, Inc. for development, announced results from the phase 2 trial (Sirius MMY2002) yesterday.

This 2-part study enrolled 124 MM patients. The goal of part 1 was to define an optimal daratumumab regimen going forward, and part 2 was an expansion based on the optimal regimen.

Patients were randomized to receive daratumumab at 8 mg/kg every 4 weeks continuously by intravenous infusion or at 16 mg/kg administered at weekly intervals for 8 weeks, then every 2 weeks for an additional 16 weeks, and every 4 weeks thereafter by intravenous infusion.

Genmab reported that the overall response rate was 29.2% in the 16 mg/kg dosing group. And the median duration of response was 7.4 months, as determined by an independent review committee.

Daratumumab also showed a manageable safety profile, according to Genmab. The company said the data will be discussed with health authorities at upcoming meetings, pending their agreement.

Single-agent daratumumab can elicit responses in patients with multiple myeloma (MM) who have failed treatment with proteasome inhibitors and immunomodulatory agents (IMiDs), preliminary results of a phase 2 study suggest.

The study enrolled MM patients who have received at least 3 different lines of therapy, including both a proteasome inhibitor and an IMiD, and patients who are double-refractory to a proteasome inhibitor and an IMiD.

Daratumumab, an anti-CD38 monoclonal antibody, has breakthrough therapy designation from the US Food and Drug Administration to treat this patient population.

Genmab A/S, the company that discovered daratumumab and licensed it to Janssen Biotech, Inc. for development, announced results from the phase 2 trial (Sirius MMY2002) yesterday.

This 2-part study enrolled 124 MM patients. The goal of part 1 was to define an optimal daratumumab regimen going forward, and part 2 was an expansion based on the optimal regimen.

Patients were randomized to receive daratumumab at 8 mg/kg every 4 weeks continuously by intravenous infusion or at 16 mg/kg administered at weekly intervals for 8 weeks, then every 2 weeks for an additional 16 weeks, and every 4 weeks thereafter by intravenous infusion.

Genmab reported that the overall response rate was 29.2% in the 16 mg/kg dosing group. And the median duration of response was 7.4 months, as determined by an independent review committee.

Daratumumab also showed a manageable safety profile, according to Genmab. The company said the data will be discussed with health authorities at upcoming meetings, pending their agreement.

Single-agent daratumumab can elicit responses in patients with multiple myeloma (MM) who have failed treatment with proteasome inhibitors and immunomodulatory agents (IMiDs), preliminary results of a phase 2 study suggest.

The study enrolled MM patients who have received at least 3 different lines of therapy, including both a proteasome inhibitor and an IMiD, and patients who are double-refractory to a proteasome inhibitor and an IMiD.

Daratumumab, an anti-CD38 monoclonal antibody, has breakthrough therapy designation from the US Food and Drug Administration to treat this patient population.

Genmab A/S, the company that discovered daratumumab and licensed it to Janssen Biotech, Inc. for development, announced results from the phase 2 trial (Sirius MMY2002) yesterday.

This 2-part study enrolled 124 MM patients. The goal of part 1 was to define an optimal daratumumab regimen going forward, and part 2 was an expansion based on the optimal regimen.

Patients were randomized to receive daratumumab at 8 mg/kg every 4 weeks continuously by intravenous infusion or at 16 mg/kg administered at weekly intervals for 8 weeks, then every 2 weeks for an additional 16 weeks, and every 4 weeks thereafter by intravenous infusion.

Genmab reported that the overall response rate was 29.2% in the 16 mg/kg dosing group. And the median duration of response was 7.4 months, as determined by an independent review committee.

Daratumumab also showed a manageable safety profile, according to Genmab. The company said the data will be discussed with health authorities at upcoming meetings, pending their agreement.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to LentiGlobin® BB305 for the treatment of transfusion-dependent patients with beta-thalassemia major.

The product is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are returned to the patient via transplant.

The product is intended to treat sickle cell disease as well as beta-thalassemia major.

“The FDA’s breakthrough designation of LentiGlobin highlights that new therapies are needed for the treatment of patients with beta-thalassemia major, especially treatments with the potential to meaningfully reduce or liberate patients from transfusion dependence,” said David Davidson, MD, chief medical officer of bluebird bio, the company developing LentiGlobin.

“Our early clinical data investigating the use of LentiGlobin in patients with multiple genotypes of beta-thalassemia major . . . are very encouraging, and we remain on track to complete enrollment in the Northstar and HGB-205 studies in 2015.”

Early study results

The breakthrough designation is supported by data from the ongoing phase 1/2 Northstar (HGB-204) and HGB-205 studies. Findings in 8 subjects from both studies were presented at the 2014 ASH Annual Meeting.

As of December 1, five subjects with beta-thalassemia major had received LentiGlobin in the Northstar Study. The first 2 subjects were producing steadily increasing amounts of beta-T87Q-globin and were free of the need for transfusion for 5 months and 3 months, respectively.

Three additional subjects have received LentiGlobin as well, but researchers said it is too early to draw any meaningful conclusions on clinical efficacy.

As of December 1, two subjects with beta-thalassemia major received LentiGlobin as part of the HGB-205 study. Both achieved rapid transfusion independence with near-normal hemoglobin levels. And they were free from the need for transfusions for 12 months and 9 months, respectively.

The third treated subject, the first individual with sickle cell disease ever to be treated with gene therapy, has achieved neutrophil engraftment. But researchers said it is too early to draw any meaningful conclusions on clinical efficacy.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

For a drug to gain the designation, preliminary clinical evidence must suggest the drug could offer substantial improvement over existing therapies on one or more clinically significant endpoints.

The benefits of breakthrough designation include the same benefits as fast track designation (priority review, rolling review, etc.), plus an organizational commitment involving the FDA’s senior managers with more intensive guidance from the FDA.

Breakthrough therapy designation does not change the standards for approval.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to LentiGlobin® BB305 for the treatment of transfusion-dependent patients with beta-thalassemia major.

The product is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are returned to the patient via transplant.

The product is intended to treat sickle cell disease as well as beta-thalassemia major.

“The FDA’s breakthrough designation of LentiGlobin highlights that new therapies are needed for the treatment of patients with beta-thalassemia major, especially treatments with the potential to meaningfully reduce or liberate patients from transfusion dependence,” said David Davidson, MD, chief medical officer of bluebird bio, the company developing LentiGlobin.

“Our early clinical data investigating the use of LentiGlobin in patients with multiple genotypes of beta-thalassemia major . . . are very encouraging, and we remain on track to complete enrollment in the Northstar and HGB-205 studies in 2015.”

Early study results

The breakthrough designation is supported by data from the ongoing phase 1/2 Northstar (HGB-204) and HGB-205 studies. Findings in 8 subjects from both studies were presented at the 2014 ASH Annual Meeting.

As of December 1, five subjects with beta-thalassemia major had received LentiGlobin in the Northstar Study. The first 2 subjects were producing steadily increasing amounts of beta-T87Q-globin and were free of the need for transfusion for 5 months and 3 months, respectively.

Three additional subjects have received LentiGlobin as well, but researchers said it is too early to draw any meaningful conclusions on clinical efficacy.

As of December 1, two subjects with beta-thalassemia major received LentiGlobin as part of the HGB-205 study. Both achieved rapid transfusion independence with near-normal hemoglobin levels. And they were free from the need for transfusions for 12 months and 9 months, respectively.

The third treated subject, the first individual with sickle cell disease ever to be treated with gene therapy, has achieved neutrophil engraftment. But researchers said it is too early to draw any meaningful conclusions on clinical efficacy.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

For a drug to gain the designation, preliminary clinical evidence must suggest the drug could offer substantial improvement over existing therapies on one or more clinically significant endpoints.

The benefits of breakthrough designation include the same benefits as fast track designation (priority review, rolling review, etc.), plus an organizational commitment involving the FDA’s senior managers with more intensive guidance from the FDA.

Breakthrough therapy designation does not change the standards for approval.

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to LentiGlobin® BB305 for the treatment of transfusion-dependent patients with beta-thalassemia major.

The product is created by inserting a functional human beta-globin gene into a patient’s hematopoietic stem cells ex vivo. The cells are returned to the patient via transplant.

The product is intended to treat sickle cell disease as well as beta-thalassemia major.

“The FDA’s breakthrough designation of LentiGlobin highlights that new therapies are needed for the treatment of patients with beta-thalassemia major, especially treatments with the potential to meaningfully reduce or liberate patients from transfusion dependence,” said David Davidson, MD, chief medical officer of bluebird bio, the company developing LentiGlobin.

“Our early clinical data investigating the use of LentiGlobin in patients with multiple genotypes of beta-thalassemia major . . . are very encouraging, and we remain on track to complete enrollment in the Northstar and HGB-205 studies in 2015.”

Early study results

The breakthrough designation is supported by data from the ongoing phase 1/2 Northstar (HGB-204) and HGB-205 studies. Findings in 8 subjects from both studies were presented at the 2014 ASH Annual Meeting.

As of December 1, five subjects with beta-thalassemia major had received LentiGlobin in the Northstar Study. The first 2 subjects were producing steadily increasing amounts of beta-T87Q-globin and were free of the need for transfusion for 5 months and 3 months, respectively.

Three additional subjects have received LentiGlobin as well, but researchers said it is too early to draw any meaningful conclusions on clinical efficacy.

As of December 1, two subjects with beta-thalassemia major received LentiGlobin as part of the HGB-205 study. Both achieved rapid transfusion independence with near-normal hemoglobin levels. And they were free from the need for transfusions for 12 months and 9 months, respectively.

The third treated subject, the first individual with sickle cell disease ever to be treated with gene therapy, has achieved neutrophil engraftment. But researchers said it is too early to draw any meaningful conclusions on clinical efficacy.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

For a drug to gain the designation, preliminary clinical evidence must suggest the drug could offer substantial improvement over existing therapies on one or more clinically significant endpoints.

The benefits of breakthrough designation include the same benefits as fast track designation (priority review, rolling review, etc.), plus an organizational commitment involving the FDA’s senior managers with more intensive guidance from the FDA.

Breakthrough therapy designation does not change the standards for approval.

As we all know, professional life gets more complicated every passing year. Meaningful use regulations grow more burdensome, even as the medical records we get fill up with electronic medical records boilerplate. To renew my medical license, my state board has me take a course in opioid management and end-of-life issues. Fill in your own examples.

But recently I’ve become aware of a new wrinkle that complicates daily practice life for both doctors and patients in a significant way. I can’t make any sense if it.

I mean the high price of desonide.

When I was student many years ago, my teachers told me that I should prescribe generic drugs whenever possible. This would help hold down medical costs. It was the right thing to do.

Because I am a good person who tries to do the right thing, I prescribe generics because it’s the right thing to do. I also do it for Pavlovian reasons: prescribing brand-name drugs means more prior authorization forms – we have enough of those anyway – and more calls from patients unhappy with high copays or other out-of-pocket costs. Also, fewer threats of sanctions from insurers or hospital purchasing groups over my pricey prescribing habits.

Besides, most patients I prescribe generics for do just fine.

Of course, some of the anomalous realities of generic prescribing filter through at times. Generic terbinafine and finasteride, for instance, may have higher profit margins, but don’t save patients much money.

But lately I’ve been getting complaints from patients about the high cost of desonide. My first reaction to these was, “How on earth is that possible?”

One patient a few months ago insisted that I contact his mail order pharmacy in Nevada to find a cheaper alternative. I considered this an unreasonable demand – I obviously can’t do a cost comparison for every patient, but this time I went along. The pharmacist came up with another nonfluorinated steroid that was much less expensive under that patient’s particular contract.

Then this week it happened again. I prescribed hydrocortisone valerate 0.2% for a groin rash. The patient left a message asking me for an over-the-counter suggestion, since the prescription was going to cost him $52.70 out of pocket.

I asked my secretary to call the pharmacy to get a price for other generic steroid creams. Triamcinolone would cost $14.70. Alclometasone would cost $35.20.

And desonide – generic desonide – would cost $111.70. For a 15-g tube. $111.70 for 15 g of a generic cream that’s been on the market forever! Does that make any sense?

I’ve gotten similar calls, by the way, from patients unhappy with the cost of generic doxycycline.

There are no doubt economic reasons for such pricing anomalies. Maybe generic manufacturers have dropped out of making certain drugs because they don’t make enough money on them, leaving the ones who remain in a position to charge whatever they can get away with. Maybe insurers or pharmacies cut deals with the makers of some drugs at the expense of others.

I don’t know. And that’s the point.

Because I have no way of knowing any more which of the plain-vanilla generic drugs I’ve prescribed forever are going to be fine, and which are going to cost my patients an arm and a leg and encourage them to call back and yell at me – or else not bother to pick up the medication at all – I don’t even know half the time what to recommend anymore. I certainly don’t have the time to go shopping for every prescription I order. There are just too many drugs, too many prescriptions, too many patients, too many pharmacies, too many insurance contracts, each with its own formulary quirks.

If anyone out there has any explanations or suggestions, I’m all ears.

In the meantime, I may try to simplify my life by sending all my patients to the local Russian deli and prescribing topical caviar. It’s likely to be cheaper than desonide. 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

As we all know, professional life gets more complicated every passing year. Meaningful use regulations grow more burdensome, even as the medical records we get fill up with electronic medical records boilerplate. To renew my medical license, my state board has me take a course in opioid management and end-of-life issues. Fill in your own examples.

But recently I’ve become aware of a new wrinkle that complicates daily practice life for both doctors and patients in a significant way. I can’t make any sense if it.

I mean the high price of desonide.

When I was student many years ago, my teachers told me that I should prescribe generic drugs whenever possible. This would help hold down medical costs. It was the right thing to do.

Because I am a good person who tries to do the right thing, I prescribe generics because it’s the right thing to do. I also do it for Pavlovian reasons: prescribing brand-name drugs means more prior authorization forms – we have enough of those anyway – and more calls from patients unhappy with high copays or other out-of-pocket costs. Also, fewer threats of sanctions from insurers or hospital purchasing groups over my pricey prescribing habits.

Besides, most patients I prescribe generics for do just fine.

Of course, some of the anomalous realities of generic prescribing filter through at times. Generic terbinafine and finasteride, for instance, may have higher profit margins, but don’t save patients much money.

But lately I’ve been getting complaints from patients about the high cost of desonide. My first reaction to these was, “How on earth is that possible?”

One patient a few months ago insisted that I contact his mail order pharmacy in Nevada to find a cheaper alternative. I considered this an unreasonable demand – I obviously can’t do a cost comparison for every patient, but this time I went along. The pharmacist came up with another nonfluorinated steroid that was much less expensive under that patient’s particular contract.

Then this week it happened again. I prescribed hydrocortisone valerate 0.2% for a groin rash. The patient left a message asking me for an over-the-counter suggestion, since the prescription was going to cost him $52.70 out of pocket.

I asked my secretary to call the pharmacy to get a price for other generic steroid creams. Triamcinolone would cost $14.70. Alclometasone would cost $35.20.

And desonide – generic desonide – would cost $111.70. For a 15-g tube. $111.70 for 15 g of a generic cream that’s been on the market forever! Does that make any sense?

I’ve gotten similar calls, by the way, from patients unhappy with the cost of generic doxycycline.

There are no doubt economic reasons for such pricing anomalies. Maybe generic manufacturers have dropped out of making certain drugs because they don’t make enough money on them, leaving the ones who remain in a position to charge whatever they can get away with. Maybe insurers or pharmacies cut deals with the makers of some drugs at the expense of others.

I don’t know. And that’s the point.

Because I have no way of knowing any more which of the plain-vanilla generic drugs I’ve prescribed forever are going to be fine, and which are going to cost my patients an arm and a leg and encourage them to call back and yell at me – or else not bother to pick up the medication at all – I don’t even know half the time what to recommend anymore. I certainly don’t have the time to go shopping for every prescription I order. There are just too many drugs, too many prescriptions, too many patients, too many pharmacies, too many insurance contracts, each with its own formulary quirks.

If anyone out there has any explanations or suggestions, I’m all ears.

In the meantime, I may try to simplify my life by sending all my patients to the local Russian deli and prescribing topical caviar. It’s likely to be cheaper than desonide. 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

As we all know, professional life gets more complicated every passing year. Meaningful use regulations grow more burdensome, even as the medical records we get fill up with electronic medical records boilerplate. To renew my medical license, my state board has me take a course in opioid management and end-of-life issues. Fill in your own examples.

But recently I’ve become aware of a new wrinkle that complicates daily practice life for both doctors and patients in a significant way. I can’t make any sense if it.

I mean the high price of desonide.

When I was student many years ago, my teachers told me that I should prescribe generic drugs whenever possible. This would help hold down medical costs. It was the right thing to do.

Because I am a good person who tries to do the right thing, I prescribe generics because it’s the right thing to do. I also do it for Pavlovian reasons: prescribing brand-name drugs means more prior authorization forms – we have enough of those anyway – and more calls from patients unhappy with high copays or other out-of-pocket costs. Also, fewer threats of sanctions from insurers or hospital purchasing groups over my pricey prescribing habits.

Besides, most patients I prescribe generics for do just fine.

Of course, some of the anomalous realities of generic prescribing filter through at times. Generic terbinafine and finasteride, for instance, may have higher profit margins, but don’t save patients much money.

But lately I’ve been getting complaints from patients about the high cost of desonide. My first reaction to these was, “How on earth is that possible?”

One patient a few months ago insisted that I contact his mail order pharmacy in Nevada to find a cheaper alternative. I considered this an unreasonable demand – I obviously can’t do a cost comparison for every patient, but this time I went along. The pharmacist came up with another nonfluorinated steroid that was much less expensive under that patient’s particular contract.

Then this week it happened again. I prescribed hydrocortisone valerate 0.2% for a groin rash. The patient left a message asking me for an over-the-counter suggestion, since the prescription was going to cost him $52.70 out of pocket.

I asked my secretary to call the pharmacy to get a price for other generic steroid creams. Triamcinolone would cost $14.70. Alclometasone would cost $35.20.

And desonide – generic desonide – would cost $111.70. For a 15-g tube. $111.70 for 15 g of a generic cream that’s been on the market forever! Does that make any sense?

I’ve gotten similar calls, by the way, from patients unhappy with the cost of generic doxycycline.

There are no doubt economic reasons for such pricing anomalies. Maybe generic manufacturers have dropped out of making certain drugs because they don’t make enough money on them, leaving the ones who remain in a position to charge whatever they can get away with. Maybe insurers or pharmacies cut deals with the makers of some drugs at the expense of others.

I don’t know. And that’s the point.

Because I have no way of knowing any more which of the plain-vanilla generic drugs I’ve prescribed forever are going to be fine, and which are going to cost my patients an arm and a leg and encourage them to call back and yell at me – or else not bother to pick up the medication at all – I don’t even know half the time what to recommend anymore. I certainly don’t have the time to go shopping for every prescription I order. There are just too many drugs, too many prescriptions, too many patients, too many pharmacies, too many insurance contracts, each with its own formulary quirks.

If anyone out there has any explanations or suggestions, I’m all ears.

In the meantime, I may try to simplify my life by sending all my patients to the local Russian deli and prescribing topical caviar. It’s likely to be cheaper than desonide. 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

Question: C, age 17 years, was diagnosed with Hodgkin’s lymphoma. According to her oncologists, chemotherapy would offer an 80% chance of cure, whereas death within 2 years was almost a certainty without treatment. C refused treatment, a decision supported by her mother. Under these facts, which of the following is best?

A. C has a constitutional right to forgo medical treatment.

B. C is a minor and needs parental consent regarding all medical intervention.

C. The mother’s refusal to give consent means the doctors have no recourse but to accept the joint decision of mother and daughter.

D. If C can show she is a mature minor or an emancipated minor, she can then decide for herself.

E. In life-and-death matters, the state has the authority to compel lifesaving beneficial treatment without prior judicial approval.

Answer: D. The above scenario raises the issue of doing what’s best when a minor refuses clearly beneficial medical treatment. It is taken from a very recent case wherein the Connecticut Supreme Court held that the state could force treatment in a minor with Hodgkin’s lymphoma. The patient, a 17-year-old teenager, knowingly and with full information, objected to receiving treatment, a decision supported by her mother. There was no finding of mental incompetence or deficiency in either mother or daughter. Can the daughter, against her will, be forced to receive treatment?

The teenager, known as Cassandra, was diagnosed with Hodgkin’s lymphoma, which her oncologists believed had an 80% chance of remission if treated with chemotherapy. Cassandra refused, a decision supported by her mother with whom she lives. Placed under the jurisdiction of Connecticut’s Department of Children and Families (DCF), she initially agreed to a trial of medication if the state allowed her to stay at home with her mother, but she ran away. The case is reminiscent of Billy Best, a 16-year-old diagnosed with Hodgkin’s disease in August 1994, who ran away from his Massachusetts home after 2½ months of chemotherapy because he felt the medicine was killing him instead of helping him.¹

In order to compel treatment, DCF had to obtain judicial approval, which the lower court granted notwithstanding arguments that forcing Cassandra to undergo unwanted medical treatment against her will violated her constitutional substantive due process rights. Also, as there was no competency hearing, so the litigants asserted that this was also a violation of her procedural due process rights. On appeal, the Supreme Court of Connecticut found that Cassandra was not a mature minor, and thus had no constitutional claim to the right of medical decision-making autonomy.² The Court unanimously ruled that the state could compel treatment. Its final opinion is yet to be published, but in its preliminary order, the Court wrote: “… Cassandra is suffering from Hodgkin’s lymphoma, a cancer that has a high rate of cure if treated and that will certainly kill Cassandra if not treated … Cassandra represented, under oath … that she would undergo treatment for her cancer if she were allowed to return home, and then was allowed to do so, she ran away from home and stopped treatment. Thus, … Cassandra either intentionally misrepresented her intentions to the trial court or she changed her mind on this issue of life and death. In either case, her conduct amply supports Judge Quinn’s finding that the respondents have failed to prove that Cassandra was a mature minor under any standard.”

Whereas all adults of sound mind are presumed to be competent to give informed consent, the doctor typically needs permission from the parents or guardian for a minor unless emancipated, i.e., conducting himself or herself as an adult and is no longer under the support or control of the parents. Another exception is the “mature minor,” a term used to describe the minor who is able to understand the nature and consequences of treatment. In 1987, the Tennessee Supreme Court was the first to recognize a mature minor exception to the common law rule that requires a physician to obtain parental consent.³ The issue there was whether Sandra, an alleged malpractice victim 5 months shy of her 18th birthday, was capable of giving consent for an osteopathic treatment. The court acknowledged that for well over a century, the common law recognized that minors achieved varying degrees of maturity and responsibility, and referenced the common law rule of capacity, known as “The Rule of Sevens.” The Rule presumes differing levels of capacity depending on whether the individual is less than 7 years old, between the ages of 7 and 14, or older than 14 years. The youngest group lacks capacity, but a rebuttable presumption of lack of capacity exists for children between the ages of 7 and 14, and one presuming capacity exists for children between the ages of 14 and 21. In Commonwealth jurisdictions, the term “Gillick competence” is used to describe a minor under the age of 16 years who is deemed to have legal capacity to consent to medical treatment if there is sufficient intelligence and maturity to understand the nature, implications, and consequences of treatment.

 

Two years later in a landmark case,⁴ the Illinois Supreme Court specifically recognized the right of some minors to refuse medical treatment. The litigant was a 17-year-old girl with leukemia who needed life-sustaining blood transfusions. Both the minor and her mother were Jehovah’s Witnesses, and withheld consent to the blood transfusion because of their religious beliefs. The Court opined that the age of majority, “is not an impenetrable barrier that magically precludes a minor from possessing and exercising certain rights normally associated with adulthood,” and that if clear and convincing evidence was presented regarding maturity, then the “mature minor doctrine affords [the minor] the common law right to consent to or refuse medical treatment.” The following year, the Maine Supreme Judicial Court held that a minor’s clear and convincing decision not to be maintained by life-sustaining procedures must be respected.⁵ In that instance, Chad, a minor just under 18, had lapsed into a persistent vegetative state following an auto accident.

Other court decisions favoring the minor abound.⁶ For example, a court held that a 14-year-old boy could decide whether he wanted his cleft palate and harelip repaired, regardless of his father’s objections to the operation. In another case, the court ordered treatment for a 12-year-old arthritis victim whose parents relied on faith healing, where there was uncontested medical testimony in favor of treatment. In yet another, a 13-year-old boy was placed under state supervision for purposes of receiving chemotherapy and surgery that was estimated to have a 65% of curing his cancer. The court ruled that the information given by his father regarding the preference for and effectiveness of herbal therapy was wrong, and the minor’s refusal of consent was not an informed one. On the other hand, even a mature minor does not have an unfettered right to refuse treatment, especially where such refusal is against medical advice. For example, a 16-year-old was forced, against her will, to accept tube feedings to treat her condition of anorexia nervosa.

In addressing the right of mature minors to refuse life-sustaining treatment, the 1985 New York Task Force on Life and the Law acknowledged the need to balance “the developing rights of the minor and parental rights,” and society’s interest “in promoting the autonomy and well-being of minors.” The Task Force recognized that some minors have the maturity and capacity to participate in medical decisions, and recommended that the treating physician assess the minor’s maturity, conceptual ability and life’s experience in order for the minor to assume a substantial, though not exclusive, role in decisions to refuse life-sustaining treatment.

Notes

1. Joan-Margaret Kun, Rejecting the Adage Children Should Be Seen and Not Heard – The Mature Minor Doctrine, 16 Pace L. Rev. 423 (1996). Available at http://digitalcommons.pace.edu/plr/vol16/iss2/13.

2. In re Cassandra C., Supreme Court, State of Connecticut, No. 19426, Jan. 8, 2015.

3. Cardwell v. Bechtol, 724 S.W. 2d 739 (Tenn. 1987)

4. In re E.G., 549 N.E. 2d 322 (Ill. 1990).

5. In re Swan, 569 A. 2d 1202 (Me. 1990).

6. Weir RF and Peters C. Affirming the Decisions Adolescents Make about Life and Death. Hastings Center Report 1997; 27:29-40.

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu, and currently directs the St. Francis International Center for Healthcare Ethics, also in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].

Question: C, age 17 years, was diagnosed with Hodgkin’s lymphoma. According to her oncologists, chemotherapy would offer an 80% chance of cure, whereas death within 2 years was almost a certainty without treatment. C refused treatment, a decision supported by her mother. Under these facts, which of the following is best?

A. C has a constitutional right to forgo medical treatment.

B. C is a minor and needs parental consent regarding all medical intervention.

C. The mother’s refusal to give consent means the doctors have no recourse but to accept the joint decision of mother and daughter.

D. If C can show she is a mature minor or an emancipated minor, she can then decide for herself.

E. In life-and-death matters, the state has the authority to compel lifesaving beneficial treatment without prior judicial approval.

Answer: D. The above scenario raises the issue of doing what’s best when a minor refuses clearly beneficial medical treatment. It is taken from a very recent case wherein the Connecticut Supreme Court held that the state could force treatment in a minor with Hodgkin’s lymphoma. The patient, a 17-year-old teenager, knowingly and with full information, objected to receiving treatment, a decision supported by her mother. There was no finding of mental incompetence or deficiency in either mother or daughter. Can the daughter, against her will, be forced to receive treatment?

The teenager, known as Cassandra, was diagnosed with Hodgkin’s lymphoma, which her oncologists believed had an 80% chance of remission if treated with chemotherapy. Cassandra refused, a decision supported by her mother with whom she lives. Placed under the jurisdiction of Connecticut’s Department of Children and Families (DCF), she initially agreed to a trial of medication if the state allowed her to stay at home with her mother, but she ran away. The case is reminiscent of Billy Best, a 16-year-old diagnosed with Hodgkin’s disease in August 1994, who ran away from his Massachusetts home after 2½ months of chemotherapy because he felt the medicine was killing him instead of helping him.¹

In order to compel treatment, DCF had to obtain judicial approval, which the lower court granted notwithstanding arguments that forcing Cassandra to undergo unwanted medical treatment against her will violated her constitutional substantive due process rights. Also, as there was no competency hearing, so the litigants asserted that this was also a violation of her procedural due process rights. On appeal, the Supreme Court of Connecticut found that Cassandra was not a mature minor, and thus had no constitutional claim to the right of medical decision-making autonomy.² The Court unanimously ruled that the state could compel treatment. Its final opinion is yet to be published, but in its preliminary order, the Court wrote: “… Cassandra is suffering from Hodgkin’s lymphoma, a cancer that has a high rate of cure if treated and that will certainly kill Cassandra if not treated … Cassandra represented, under oath … that she would undergo treatment for her cancer if she were allowed to return home, and then was allowed to do so, she ran away from home and stopped treatment. Thus, … Cassandra either intentionally misrepresented her intentions to the trial court or she changed her mind on this issue of life and death. In either case, her conduct amply supports Judge Quinn’s finding that the respondents have failed to prove that Cassandra was a mature minor under any standard.”

Whereas all adults of sound mind are presumed to be competent to give informed consent, the doctor typically needs permission from the parents or guardian for a minor unless emancipated, i.e., conducting himself or herself as an adult and is no longer under the support or control of the parents. Another exception is the “mature minor,” a term used to describe the minor who is able to understand the nature and consequences of treatment. In 1987, the Tennessee Supreme Court was the first to recognize a mature minor exception to the common law rule that requires a physician to obtain parental consent.³ The issue there was whether Sandra, an alleged malpractice victim 5 months shy of her 18th birthday, was capable of giving consent for an osteopathic treatment. The court acknowledged that for well over a century, the common law recognized that minors achieved varying degrees of maturity and responsibility, and referenced the common law rule of capacity, known as “The Rule of Sevens.” The Rule presumes differing levels of capacity depending on whether the individual is less than 7 years old, between the ages of 7 and 14, or older than 14 years. The youngest group lacks capacity, but a rebuttable presumption of lack of capacity exists for children between the ages of 7 and 14, and one presuming capacity exists for children between the ages of 14 and 21. In Commonwealth jurisdictions, the term “Gillick competence” is used to describe a minor under the age of 16 years who is deemed to have legal capacity to consent to medical treatment if there is sufficient intelligence and maturity to understand the nature, implications, and consequences of treatment.

 

Two years later in a landmark case,⁴ the Illinois Supreme Court specifically recognized the right of some minors to refuse medical treatment. The litigant was a 17-year-old girl with leukemia who needed life-sustaining blood transfusions. Both the minor and her mother were Jehovah’s Witnesses, and withheld consent to the blood transfusion because of their religious beliefs. The Court opined that the age of majority, “is not an impenetrable barrier that magically precludes a minor from possessing and exercising certain rights normally associated with adulthood,” and that if clear and convincing evidence was presented regarding maturity, then the “mature minor doctrine affords [the minor] the common law right to consent to or refuse medical treatment.” The following year, the Maine Supreme Judicial Court held that a minor’s clear and convincing decision not to be maintained by life-sustaining procedures must be respected.⁵ In that instance, Chad, a minor just under 18, had lapsed into a persistent vegetative state following an auto accident.

Other court decisions favoring the minor abound.⁶ For example, a court held that a 14-year-old boy could decide whether he wanted his cleft palate and harelip repaired, regardless of his father’s objections to the operation. In another case, the court ordered treatment for a 12-year-old arthritis victim whose parents relied on faith healing, where there was uncontested medical testimony in favor of treatment. In yet another, a 13-year-old boy was placed under state supervision for purposes of receiving chemotherapy and surgery that was estimated to have a 65% of curing his cancer. The court ruled that the information given by his father regarding the preference for and effectiveness of herbal therapy was wrong, and the minor’s refusal of consent was not an informed one. On the other hand, even a mature minor does not have an unfettered right to refuse treatment, especially where such refusal is against medical advice. For example, a 16-year-old was forced, against her will, to accept tube feedings to treat her condition of anorexia nervosa.

In addressing the right of mature minors to refuse life-sustaining treatment, the 1985 New York Task Force on Life and the Law acknowledged the need to balance “the developing rights of the minor and parental rights,” and society’s interest “in promoting the autonomy and well-being of minors.” The Task Force recognized that some minors have the maturity and capacity to participate in medical decisions, and recommended that the treating physician assess the minor’s maturity, conceptual ability and life’s experience in order for the minor to assume a substantial, though not exclusive, role in decisions to refuse life-sustaining treatment.

Notes

1. Joan-Margaret Kun, Rejecting the Adage Children Should Be Seen and Not Heard – The Mature Minor Doctrine, 16 Pace L. Rev. 423 (1996). Available at http://digitalcommons.pace.edu/plr/vol16/iss2/13.

2. In re Cassandra C., Supreme Court, State of Connecticut, No. 19426, Jan. 8, 2015.

3. Cardwell v. Bechtol, 724 S.W. 2d 739 (Tenn. 1987)

4. In re E.G., 549 N.E. 2d 322 (Ill. 1990).

5. In re Swan, 569 A. 2d 1202 (Me. 1990).

6. Weir RF and Peters C. Affirming the Decisions Adolescents Make about Life and Death. Hastings Center Report 1997; 27:29-40.

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu, and currently directs the St. Francis International Center for Healthcare Ethics, also in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].

Question: C, age 17 years, was diagnosed with Hodgkin’s lymphoma. According to her oncologists, chemotherapy would offer an 80% chance of cure, whereas death within 2 years was almost a certainty without treatment. C refused treatment, a decision supported by her mother. Under these facts, which of the following is best?

A. C has a constitutional right to forgo medical treatment.

B. C is a minor and needs parental consent regarding all medical intervention.

C. The mother’s refusal to give consent means the doctors have no recourse but to accept the joint decision of mother and daughter.

D. If C can show she is a mature minor or an emancipated minor, she can then decide for herself.

E. In life-and-death matters, the state has the authority to compel lifesaving beneficial treatment without prior judicial approval.

Answer: D. The above scenario raises the issue of doing what’s best when a minor refuses clearly beneficial medical treatment. It is taken from a very recent case wherein the Connecticut Supreme Court held that the state could force treatment in a minor with Hodgkin’s lymphoma. The patient, a 17-year-old teenager, knowingly and with full information, objected to receiving treatment, a decision supported by her mother. There was no finding of mental incompetence or deficiency in either mother or daughter. Can the daughter, against her will, be forced to receive treatment?

The teenager, known as Cassandra, was diagnosed with Hodgkin’s lymphoma, which her oncologists believed had an 80% chance of remission if treated with chemotherapy. Cassandra refused, a decision supported by her mother with whom she lives. Placed under the jurisdiction of Connecticut’s Department of Children and Families (DCF), she initially agreed to a trial of medication if the state allowed her to stay at home with her mother, but she ran away. The case is reminiscent of Billy Best, a 16-year-old diagnosed with Hodgkin’s disease in August 1994, who ran away from his Massachusetts home after 2½ months of chemotherapy because he felt the medicine was killing him instead of helping him.¹

In order to compel treatment, DCF had to obtain judicial approval, which the lower court granted notwithstanding arguments that forcing Cassandra to undergo unwanted medical treatment against her will violated her constitutional substantive due process rights. Also, as there was no competency hearing, so the litigants asserted that this was also a violation of her procedural due process rights. On appeal, the Supreme Court of Connecticut found that Cassandra was not a mature minor, and thus had no constitutional claim to the right of medical decision-making autonomy.² The Court unanimously ruled that the state could compel treatment. Its final opinion is yet to be published, but in its preliminary order, the Court wrote: “… Cassandra is suffering from Hodgkin’s lymphoma, a cancer that has a high rate of cure if treated and that will certainly kill Cassandra if not treated … Cassandra represented, under oath … that she would undergo treatment for her cancer if she were allowed to return home, and then was allowed to do so, she ran away from home and stopped treatment. Thus, … Cassandra either intentionally misrepresented her intentions to the trial court or she changed her mind on this issue of life and death. In either case, her conduct amply supports Judge Quinn’s finding that the respondents have failed to prove that Cassandra was a mature minor under any standard.”

Whereas all adults of sound mind are presumed to be competent to give informed consent, the doctor typically needs permission from the parents or guardian for a minor unless emancipated, i.e., conducting himself or herself as an adult and is no longer under the support or control of the parents. Another exception is the “mature minor,” a term used to describe the minor who is able to understand the nature and consequences of treatment. In 1987, the Tennessee Supreme Court was the first to recognize a mature minor exception to the common law rule that requires a physician to obtain parental consent.³ The issue there was whether Sandra, an alleged malpractice victim 5 months shy of her 18th birthday, was capable of giving consent for an osteopathic treatment. The court acknowledged that for well over a century, the common law recognized that minors achieved varying degrees of maturity and responsibility, and referenced the common law rule of capacity, known as “The Rule of Sevens.” The Rule presumes differing levels of capacity depending on whether the individual is less than 7 years old, between the ages of 7 and 14, or older than 14 years. The youngest group lacks capacity, but a rebuttable presumption of lack of capacity exists for children between the ages of 7 and 14, and one presuming capacity exists for children between the ages of 14 and 21. In Commonwealth jurisdictions, the term “Gillick competence” is used to describe a minor under the age of 16 years who is deemed to have legal capacity to consent to medical treatment if there is sufficient intelligence and maturity to understand the nature, implications, and consequences of treatment.

 

Two years later in a landmark case,⁴ the Illinois Supreme Court specifically recognized the right of some minors to refuse medical treatment. The litigant was a 17-year-old girl with leukemia who needed life-sustaining blood transfusions. Both the minor and her mother were Jehovah’s Witnesses, and withheld consent to the blood transfusion because of their religious beliefs. The Court opined that the age of majority, “is not an impenetrable barrier that magically precludes a minor from possessing and exercising certain rights normally associated with adulthood,” and that if clear and convincing evidence was presented regarding maturity, then the “mature minor doctrine affords [the minor] the common law right to consent to or refuse medical treatment.” The following year, the Maine Supreme Judicial Court held that a minor’s clear and convincing decision not to be maintained by life-sustaining procedures must be respected.⁵ In that instance, Chad, a minor just under 18, had lapsed into a persistent vegetative state following an auto accident.

Other court decisions favoring the minor abound.⁶ For example, a court held that a 14-year-old boy could decide whether he wanted his cleft palate and harelip repaired, regardless of his father’s objections to the operation. In another case, the court ordered treatment for a 12-year-old arthritis victim whose parents relied on faith healing, where there was uncontested medical testimony in favor of treatment. In yet another, a 13-year-old boy was placed under state supervision for purposes of receiving chemotherapy and surgery that was estimated to have a 65% of curing his cancer. The court ruled that the information given by his father regarding the preference for and effectiveness of herbal therapy was wrong, and the minor’s refusal of consent was not an informed one. On the other hand, even a mature minor does not have an unfettered right to refuse treatment, especially where such refusal is against medical advice. For example, a 16-year-old was forced, against her will, to accept tube feedings to treat her condition of anorexia nervosa.

In addressing the right of mature minors to refuse life-sustaining treatment, the 1985 New York Task Force on Life and the Law acknowledged the need to balance “the developing rights of the minor and parental rights,” and society’s interest “in promoting the autonomy and well-being of minors.” The Task Force recognized that some minors have the maturity and capacity to participate in medical decisions, and recommended that the treating physician assess the minor’s maturity, conceptual ability and life’s experience in order for the minor to assume a substantial, though not exclusive, role in decisions to refuse life-sustaining treatment.

Notes

1. Joan-Margaret Kun, Rejecting the Adage Children Should Be Seen and Not Heard – The Mature Minor Doctrine, 16 Pace L. Rev. 423 (1996). Available at http://digitalcommons.pace.edu/plr/vol16/iss2/13.

2. In re Cassandra C., Supreme Court, State of Connecticut, No. 19426, Jan. 8, 2015.

3. Cardwell v. Bechtol, 724 S.W. 2d 739 (Tenn. 1987)

4. In re E.G., 549 N.E. 2d 322 (Ill. 1990).

5. In re Swan, 569 A. 2d 1202 (Me. 1990).

6. Weir RF and Peters C. Affirming the Decisions Adolescents Make about Life and Death. Hastings Center Report 1997; 27:29-40.

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu, and currently directs the St. Francis International Center for Healthcare Ethics, also in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].