Perspectives

According to a study by Ji et al published online on February 11 in the International Journal of Impotence Research, men with psoriasis may be more prone to erectile dysfunction (ED) than those without this skin disease, and their odds of sexual difficulties are even higher if they are depressed or have other health problems such as diabetes mellitus or high blood pressure.

The investigators evaluated 191 psoriasis patients and 191 healthy men. Of the 191 patients with psoriasis, 52.9% had symptoms of ED compared with 40.3% of the control group, reflecting an age-adjusted odds ratio of 1.965 in favor of the psoriasis group. A univariate analysis of the psoriasis cohort demonstrated that age, hypertension, hyperlipidemia, diabetes mellitus, and depressive symptoms were risk factors for ED. A multivariate logistic regression model indicated that increasing age, hypertension, hyperlipidemia, and depressive symptoms were independent risk factors for ED in those with psoriasis. More severe depressive symptoms increased the risk of ED, especially moderate to severe ED.

Ji et al noted that ED is a predictor of future cardiovascular disease; therefore, it is important to identify ED early in treatment to evaluate cardiovascular issues in psoriasis patients. They noted that screening of ED may become a part of routine care in the management of psoriasis patients.

What’s the issue?

Even though it was a small study from one location, it still sheds light on many important issues. Psoriasis and its comorbidities appear to increase the risk for ED. In addition, ED also may be an indicator of cardiovascular disease.

How will these data impact your evaluation of psoriasis patients?

We want to know your views! Tell us what you think.

According to a study by Ji et al published online on February 11 in the International Journal of Impotence Research, men with psoriasis may be more prone to erectile dysfunction (ED) than those without this skin disease, and their odds of sexual difficulties are even higher if they are depressed or have other health problems such as diabetes mellitus or high blood pressure.

The investigators evaluated 191 psoriasis patients and 191 healthy men. Of the 191 patients with psoriasis, 52.9% had symptoms of ED compared with 40.3% of the control group, reflecting an age-adjusted odds ratio of 1.965 in favor of the psoriasis group. A univariate analysis of the psoriasis cohort demonstrated that age, hypertension, hyperlipidemia, diabetes mellitus, and depressive symptoms were risk factors for ED. A multivariate logistic regression model indicated that increasing age, hypertension, hyperlipidemia, and depressive symptoms were independent risk factors for ED in those with psoriasis. More severe depressive symptoms increased the risk of ED, especially moderate to severe ED.

Ji et al noted that ED is a predictor of future cardiovascular disease; therefore, it is important to identify ED early in treatment to evaluate cardiovascular issues in psoriasis patients. They noted that screening of ED may become a part of routine care in the management of psoriasis patients.

What’s the issue?

Even though it was a small study from one location, it still sheds light on many important issues. Psoriasis and its comorbidities appear to increase the risk for ED. In addition, ED also may be an indicator of cardiovascular disease.

How will these data impact your evaluation of psoriasis patients?

We want to know your views! Tell us what you think.

According to a study by Ji et al published online on February 11 in the International Journal of Impotence Research, men with psoriasis may be more prone to erectile dysfunction (ED) than those without this skin disease, and their odds of sexual difficulties are even higher if they are depressed or have other health problems such as diabetes mellitus or high blood pressure.

The investigators evaluated 191 psoriasis patients and 191 healthy men. Of the 191 patients with psoriasis, 52.9% had symptoms of ED compared with 40.3% of the control group, reflecting an age-adjusted odds ratio of 1.965 in favor of the psoriasis group. A univariate analysis of the psoriasis cohort demonstrated that age, hypertension, hyperlipidemia, diabetes mellitus, and depressive symptoms were risk factors for ED. A multivariate logistic regression model indicated that increasing age, hypertension, hyperlipidemia, and depressive symptoms were independent risk factors for ED in those with psoriasis. More severe depressive symptoms increased the risk of ED, especially moderate to severe ED.

Ji et al noted that ED is a predictor of future cardiovascular disease; therefore, it is important to identify ED early in treatment to evaluate cardiovascular issues in psoriasis patients. They noted that screening of ED may become a part of routine care in the management of psoriasis patients.

What’s the issue?

Even though it was a small study from one location, it still sheds light on many important issues. Psoriasis and its comorbidities appear to increase the risk for ED. In addition, ED also may be an indicator of cardiovascular disease.

How will these data impact your evaluation of psoriasis patients?

We want to know your views! Tell us what you think.

Unprecedented collaboration among 900 genetics investigators across 40 countries led to creation of the highly productive Psychiatric Genomics Consortium (PGC), which is analyzing 400,000 individual DNA samples.¹ The Consortium has an open-source approach, with data freely available to all who are interested.^a

The PGC recently published the results of a large Genome Wide Association Study (GWAS) of 36,989 people with schizophrenia and 113,075 controls. Investigators discovered 108 genetic loci (each containing as many as 26 genes), adding up to 341 protein-coding risk genes for schizophrenia, distributed across all 23 chromosomes.² One of these risk genes, on chromosome 6, is in the major histocompatibility complex and has the strongest association with schizophrenia (P = 10^–31). This finding provides insight that schizophrenia might be related to immune dysfunction, supported by evidence for neuro-inflammation and elevated pro-inflammatory biomarkers in this syndrome.³

In addition to heritable risk genes, the PGC has found many copy number variants (CNVs) and rare de novo mutations that are found significantly more often (10-fold or greater) in schizophrenia. But, as reflected by the 50% concordance rate for schizophrenia in monozygotic twins, non-genetic pathways to schizophrenia obviously exist; this is especially so through adverse events during pregnancy, which can disrupt brain development in a manner similar to disruption caused by risk genes, CNVs, and mutations.

The most exciting consequence of these breakthroughs?These genetic discoveries have great implications for novel drug development for the hundreds of biological subtypes of schizophrenia. At latest count, 23,345 genes that code for proteins, the building blocks of the body, are found in the human set of 23 chromosomes.² Approximately 7,000 of those genes are druggable and can open the way to developing new agents. In fact, identifying potential targets for pharmacotherapeutic intervention is the major goal of conducting a GWAS.⁴

What it means to be ‘druggable.’ Two conditions must be met for a gene to be druggable: First, it must code for a protein with folds that can interact with chemical compounds; second, that protein must be associated with a human disease.⁵ A drug that interacts with several target proteins (eg, kinases, proteases, transporters, enzymes) is considered promiscuous. After such a drug is found to have efficacy in 1 disease, it can be repurposed for treating other diseases. Such repositioning of an already approved drug for other conditions could save the pharmaceutical industry an enormous amount of time and billions of research and development dollars in developing new drugs for psychiatric illnesses that might have been used to treat various other medical conditions.

To exploit the principle of re-purposing, Lencz and Malhotra² examined the 341 coding genes associated with schizophrenia, to determine whether available drugs interact with the proteins produced by some of those genes. They identified 40 druggable genes (11.7% of the 341) and reported that:

• 27 coding genes (7.92% of the 341) are drug targets⁶
• 20 of the 40 druggable genes are already approved by the FDA to treat a range of medical disorders, including glaucoma, epilepsy, hypertension, angina, irritable bowel syndrome, incontinence, smoking cessation, nausea, hypertension, prostate cancer, type 2 diabetes mellitus, pulmonary fibrosis, and acute promyelocytic leukemia; in addition, some genes act as a diuretic or an nonsteroidal anti-inflammatory drug
• another 20 druggable genes are not approved for use but are in clinical trials for disorders such as Alzheimer’s disease, heart failure, neuropathic pain, depression, cancer, immune-supported acne psoriasis, and myeloma.

The opportunity to repurpose some of those promiscuous drugs for various medical indications for the treatment of schizophrenia is exciting, and presents Pandora’s box of new mechanisms of action.⁷ It is intriguing how therapeutic mechanisms for a wide range of unrelated medical conditions may have commonality with the neurobiological underpinnings of a serious brain disorder such as schizophrenia.

Journey from genome to clinicPsychiatrists should be heartened by this translational research into the pharmacotherapeutic promise of emerging genetic advances. The parched terrain of psychopharmacology—the result of a drought of truly innovative medications for serious psychiatric brain disorders—soon may be drenched by a shower of translational discoveries from druggable genes.⁸ An auspicious scientific journey, from the genome to the clinic, has begun in earnest.

That is great news for our patients, and uplifting to us as well. Breakthroughs to cure intractable and persistent psychiatric brain disorders will not only vanquish disability and restore functioning, but also will be a powerful, long-awaited antidote to the virulent stigma of mental illness.

^aAvailable at http://pgc.unc.edu/downloads.

Unprecedented collaboration among 900 genetics investigators across 40 countries led to creation of the highly productive Psychiatric Genomics Consortium (PGC), which is analyzing 400,000 individual DNA samples.¹ The Consortium has an open-source approach, with data freely available to all who are interested.^a

The PGC recently published the results of a large Genome Wide Association Study (GWAS) of 36,989 people with schizophrenia and 113,075 controls. Investigators discovered 108 genetic loci (each containing as many as 26 genes), adding up to 341 protein-coding risk genes for schizophrenia, distributed across all 23 chromosomes.² One of these risk genes, on chromosome 6, is in the major histocompatibility complex and has the strongest association with schizophrenia (P = 10^–31). This finding provides insight that schizophrenia might be related to immune dysfunction, supported by evidence for neuro-inflammation and elevated pro-inflammatory biomarkers in this syndrome.³

In addition to heritable risk genes, the PGC has found many copy number variants (CNVs) and rare de novo mutations that are found significantly more often (10-fold or greater) in schizophrenia. But, as reflected by the 50% concordance rate for schizophrenia in monozygotic twins, non-genetic pathways to schizophrenia obviously exist; this is especially so through adverse events during pregnancy, which can disrupt brain development in a manner similar to disruption caused by risk genes, CNVs, and mutations.

The most exciting consequence of these breakthroughs?These genetic discoveries have great implications for novel drug development for the hundreds of biological subtypes of schizophrenia. At latest count, 23,345 genes that code for proteins, the building blocks of the body, are found in the human set of 23 chromosomes.² Approximately 7,000 of those genes are druggable and can open the way to developing new agents. In fact, identifying potential targets for pharmacotherapeutic intervention is the major goal of conducting a GWAS.⁴

What it means to be ‘druggable.’ Two conditions must be met for a gene to be druggable: First, it must code for a protein with folds that can interact with chemical compounds; second, that protein must be associated with a human disease.⁵ A drug that interacts with several target proteins (eg, kinases, proteases, transporters, enzymes) is considered promiscuous. After such a drug is found to have efficacy in 1 disease, it can be repurposed for treating other diseases. Such repositioning of an already approved drug for other conditions could save the pharmaceutical industry an enormous amount of time and billions of research and development dollars in developing new drugs for psychiatric illnesses that might have been used to treat various other medical conditions.

To exploit the principle of re-purposing, Lencz and Malhotra² examined the 341 coding genes associated with schizophrenia, to determine whether available drugs interact with the proteins produced by some of those genes. They identified 40 druggable genes (11.7% of the 341) and reported that:

• 27 coding genes (7.92% of the 341) are drug targets⁶
• 20 of the 40 druggable genes are already approved by the FDA to treat a range of medical disorders, including glaucoma, epilepsy, hypertension, angina, irritable bowel syndrome, incontinence, smoking cessation, nausea, hypertension, prostate cancer, type 2 diabetes mellitus, pulmonary fibrosis, and acute promyelocytic leukemia; in addition, some genes act as a diuretic or an nonsteroidal anti-inflammatory drug
• another 20 druggable genes are not approved for use but are in clinical trials for disorders such as Alzheimer’s disease, heart failure, neuropathic pain, depression, cancer, immune-supported acne psoriasis, and myeloma.

The opportunity to repurpose some of those promiscuous drugs for various medical indications for the treatment of schizophrenia is exciting, and presents Pandora’s box of new mechanisms of action.⁷ It is intriguing how therapeutic mechanisms for a wide range of unrelated medical conditions may have commonality with the neurobiological underpinnings of a serious brain disorder such as schizophrenia.

Journey from genome to clinicPsychiatrists should be heartened by this translational research into the pharmacotherapeutic promise of emerging genetic advances. The parched terrain of psychopharmacology—the result of a drought of truly innovative medications for serious psychiatric brain disorders—soon may be drenched by a shower of translational discoveries from druggable genes.⁸ An auspicious scientific journey, from the genome to the clinic, has begun in earnest.

That is great news for our patients, and uplifting to us as well. Breakthroughs to cure intractable and persistent psychiatric brain disorders will not only vanquish disability and restore functioning, but also will be a powerful, long-awaited antidote to the virulent stigma of mental illness.

^aAvailable at http://pgc.unc.edu/downloads.

Unprecedented collaboration among 900 genetics investigators across 40 countries led to creation of the highly productive Psychiatric Genomics Consortium (PGC), which is analyzing 400,000 individual DNA samples.¹ The Consortium has an open-source approach, with data freely available to all who are interested.^a

The PGC recently published the results of a large Genome Wide Association Study (GWAS) of 36,989 people with schizophrenia and 113,075 controls. Investigators discovered 108 genetic loci (each containing as many as 26 genes), adding up to 341 protein-coding risk genes for schizophrenia, distributed across all 23 chromosomes.² One of these risk genes, on chromosome 6, is in the major histocompatibility complex and has the strongest association with schizophrenia (P = 10^–31). This finding provides insight that schizophrenia might be related to immune dysfunction, supported by evidence for neuro-inflammation and elevated pro-inflammatory biomarkers in this syndrome.³

In addition to heritable risk genes, the PGC has found many copy number variants (CNVs) and rare de novo mutations that are found significantly more often (10-fold or greater) in schizophrenia. But, as reflected by the 50% concordance rate for schizophrenia in monozygotic twins, non-genetic pathways to schizophrenia obviously exist; this is especially so through adverse events during pregnancy, which can disrupt brain development in a manner similar to disruption caused by risk genes, CNVs, and mutations.

The most exciting consequence of these breakthroughs?These genetic discoveries have great implications for novel drug development for the hundreds of biological subtypes of schizophrenia. At latest count, 23,345 genes that code for proteins, the building blocks of the body, are found in the human set of 23 chromosomes.² Approximately 7,000 of those genes are druggable and can open the way to developing new agents. In fact, identifying potential targets for pharmacotherapeutic intervention is the major goal of conducting a GWAS.⁴

What it means to be ‘druggable.’ Two conditions must be met for a gene to be druggable: First, it must code for a protein with folds that can interact with chemical compounds; second, that protein must be associated with a human disease.⁵ A drug that interacts with several target proteins (eg, kinases, proteases, transporters, enzymes) is considered promiscuous. After such a drug is found to have efficacy in 1 disease, it can be repurposed for treating other diseases. Such repositioning of an already approved drug for other conditions could save the pharmaceutical industry an enormous amount of time and billions of research and development dollars in developing new drugs for psychiatric illnesses that might have been used to treat various other medical conditions.

To exploit the principle of re-purposing, Lencz and Malhotra² examined the 341 coding genes associated with schizophrenia, to determine whether available drugs interact with the proteins produced by some of those genes. They identified 40 druggable genes (11.7% of the 341) and reported that:

• 27 coding genes (7.92% of the 341) are drug targets⁶
• 20 of the 40 druggable genes are already approved by the FDA to treat a range of medical disorders, including glaucoma, epilepsy, hypertension, angina, irritable bowel syndrome, incontinence, smoking cessation, nausea, hypertension, prostate cancer, type 2 diabetes mellitus, pulmonary fibrosis, and acute promyelocytic leukemia; in addition, some genes act as a diuretic or an nonsteroidal anti-inflammatory drug
• another 20 druggable genes are not approved for use but are in clinical trials for disorders such as Alzheimer’s disease, heart failure, neuropathic pain, depression, cancer, immune-supported acne psoriasis, and myeloma.

The opportunity to repurpose some of those promiscuous drugs for various medical indications for the treatment of schizophrenia is exciting, and presents Pandora’s box of new mechanisms of action.⁷ It is intriguing how therapeutic mechanisms for a wide range of unrelated medical conditions may have commonality with the neurobiological underpinnings of a serious brain disorder such as schizophrenia.

Journey from genome to clinicPsychiatrists should be heartened by this translational research into the pharmacotherapeutic promise of emerging genetic advances. The parched terrain of psychopharmacology—the result of a drought of truly innovative medications for serious psychiatric brain disorders—soon may be drenched by a shower of translational discoveries from druggable genes.⁸ An auspicious scientific journey, from the genome to the clinic, has begun in earnest.

That is great news for our patients, and uplifting to us as well. Breakthroughs to cure intractable and persistent psychiatric brain disorders will not only vanquish disability and restore functioning, but also will be a powerful, long-awaited antidote to the virulent stigma of mental illness.

^aAvailable at http://pgc.unc.edu/downloads.

In addition to the standard fare at the 74th Annual Meeting of the American Academy of Dermatology (AAD) in Washington, DC (March 4–8, 2016), this year there were several lectures addressing the use of nitric oxide (NO) for the treatment of acne. Therefore, I would like to review how NO gets delivered and the therapeutic implications as well as provide some context and understanding of the varying NO delivery systems being investigated.

Let’s start with some basics: Why should we even consider NO, a diatomic lipophilic gaseous molecule, for acne? It may be a surprise, but you already use NO for this purpose.

• NO is produced on the surface of the skin by action of commensal bacteria and plays a physiologic role in inhibition of infection by pathogenic organisms including bacteria, fungi, and viruses, and a microbicidal role against Propionibacterium acnes.
• NO minimizes inflammation by inhibiting neutrophil chemotaxis; production of lipases by P acnes (minimizes production of immunogenic free fatty acids); production of multiple cytokines such as tumor necrosis factor α, IL-8, and IL-6; antigen-presenting cell recognition of P acnes; and multiple elements of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome, the specific inflammasome reported to be impressively activated when monocytes, and even sebocytes, are exposed to P acnes, thereby inhibiting the conversion of pro–IL-1β to IL-1β.

However, NO’s direct biological action is not enough to explain these effects. It is S-nitrosylation, the covalent modification of a protein cysteine thiol by a NO group to generate an S-nitrosothiol such as nitrosoglutathione, that explains NO’s potent modulation of gene expression and enzymatic functions.

Nitric oxide was first featured in the late-breaking research session presented by Lawrence F. Eichenfield, MD, at the AAD (Efficacy and Safety of SB204 Gel in the Treatment of Acne Vulgaris)(F053). Results were presented from a phase 2b, multicenter, randomized, double-blind study comparing the efficacy, safety, and tolerability of SB204 NO-releasing gel 4% to vehicle in participants with acne vulgaris. The investigators concluded that SB204 once daily was safe and effective for the treatment of acne vulgaris, though they did not present data on the technology itself.

The NO-releasing technology being used in SB204 is an NO donor that falls under a class of NO donors called the diazeniumdiolates, or NONOates, which have been used experimentally for more than 50 years. These compounds consist of a diolate group (N[O-]N=O) bound to a nucleophile adduct (a primary or secondary amine or polyamine) by means of a nitrogen atom. Thus, you have NO bound to a donor that under appropriate environmental conditions will release its NO following first-order kinetics. It simply releases NO, rather then generate or create it.

Two issues are to be raised in relation to Dr. Eichenfield’s presentation:

Accumulation of amines and their metabolites released from NONOates have been shown to induce cytotoxicity in a study by Saavedra et al (J Med Chem. 1997;40:1947-1954). In the study by Blecher et al (Nanomedicine. 2012;8:1364-1371), topical application of DETA (diethylenetriamine) NONOate, another type of NONOate, actually delayed wound closure in NOD-SCID (nonobese diabetic severe combined immunodeficiency) mice as compared to untreated controls in a study by Blecher et al. Systemic infusion at concentrations required to reduce blood pressure resulted in methemoglobinemia and diminished oxygen-carrying capacity in a study by Cabrales et al (Free Radic Biol Med. 2010;49:530-538). The NONOate utilized in SB204 is encapsulated in a hydrogel particle to prevent permeation of said metabolites and donor compounds through the skin; however, a 12-week safety evaluation is certainly not long enough to determine whether local or systemic absorption has occurred. Of note, the NO-np has undergone extensive safety testing from cell culture of embryonic zebra fish to Syrian hamsters and even pigs showing no significant toxicity at any of the effective concentrations in animal studies.

Data published on the NO-np’s preclinical efficacy for the treatment of acne, infected excisions, and burn wounds were presented in 2 of my lectures at the AAD (Nanotechnology and Immunomodulators [F085] and Antimicrobial Dressings: Silver and Beyond [S056])(Chouake et al [J Drugs Dermatol. 2012;11:1471-1477]; Friedman et al [Virulence. 2011;2:217-221]; Han et al [PLoS One. 2009;4:e7804]; Marcherla et al [Front Microbiol. 2012;3:193]; Martinez et al [J Invest Dermatol. 2009;129:2463-2469]; Qin et al [J Invest Dermatol. 2015;135:2723-2731]; Blecher et al [Nanomedicine. 2012;8:1364-1371]). These data can be found within the suggested reading below.

What’s the issue?

Know the awesome biological power of NO. Know the differences between delivery systems, including donors and generators. Know the differences in therapeutic relevance, including efficacy and safety.

Do you know NO?

We want to know your views! Tell us what you think.

Suggested Readings

Multidrug-Resistant Bacterial and Fungal Skin and Soft Tissue Infections

1. Ahmadi M, Lee H, Sanchez D, et al. Sustained nitric oxide releasing nanoparticles induce cell death in Candida albicans yeast and hyphal cells preventing biofilm formation in vitro and in a rodent central venous catheter model. Antimicrob Agents Chemother. 2016;60:2185-2194.
2. Chouake J, Schairer D, Kutner A, et al. Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa–infected wounds. J Drugs Dermatol. 2012;11:1471-1477.
3. Friedman A, Blecher K, Sanchez D, et al. Susceptibility of gram positive and negative bacteria to novel nitric oxide-releasing nanoparticle technology. Virulence. 2011;2:217-221.
4. Friedman A, Blecher K, Schairer D, et al. Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S-nitrosoglutathione. Nitric Oxide. 2011;25:381-386.
5. Han G, Martinez LM, Mihu MR, et al. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in murine model of infection. PLoS One. 2009;4:e7804.
6. Landriscina A, Rosen J, Blecher-Paz K, et al. Nitric oxide-releasing nanoparticles as a treatment for cutaneous dermatophyte infections. Sci Lett. 2015,4:193.
7. Marcherla C, Sanchez DA, Ahmadi M, et al. Nitric oxide releasing nanoparticles for the treatment of Candida albicans burn infections [published online June 8, 2012]. Front Microbiol. 2012;3:193.
8. Martinez L, Han G, Chacko M, et al. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infections. J Invest Dermatol. 2009;129:2463-2469.
9. Mihu MR, Sandkovsky U, Han G, et al. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence. 2010;1:62-67.
10. Mordorski B, Pelgrift R, Adler B, et al. S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology. Nanomedicine. 2015;11:283-291.
11. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731.
12. Schairer D, Martinez L, Blecher K, et al. Nitric oxide nanoparticles: pre-clinical utility as a therapeutic for intramuscular abscesses. Virulence. 2012;3:1-6.

Wound Healing

1. Blecher K, Martinez LR, Tuckman-Vernon C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing in NOD-SCID mice. Nanomedicine. 2012;8:1364-1371.
2. Han G, Nguyen LN, Macherla C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing by promoting fibroblast migration and collagen deposition. Am J Pathol. 2012;180:1465-1473.

Erectile Dysfunction

1. Han G, Tar M, Kuppam DS, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction [published online September 18, 2009. J Sex Med. 2010;7(1 pt 1):224-333.
2. Tar M, CabralesP, Navati M, et al. Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy. J Sex Med. 2014;11:2903-2914.

Cardiovascular Disease

1. Cabrales P, Han G, Nacharaju P, et al. Reversal of hemoglobin-induced vasoconstriction with sustained release of nitric oxide [published online November 5, 2010]. Am J Physiol Heart Circ Physiol. 2011;300:H49-H56.
2. Cabrales P, Han G, Roche C, et al. Sustained release nitric oxide from long-lived circulation nanoparticles. Free Radic Biol Med. 2010;49:530-538.
3. Nacharaju P, Friedman AJ, Friedman JM, et al. Exogenous nitric oxide prevents collapse during hemorrhagic shock. Resuscitation. 2011;82:607-613.

Safety of NO Donors

1. Friedman A, Friedman JM. Novel biomaterials for the sustained release of nitric oxide: past, present, and future. Expert Opin Drug Deliv. 2009;6:1113-1122.
2. Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
3. Saavedra JE, Billiar TR, Williams DL, et al. Targeting nitric oxide (NO) delivery in vivo. design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. J Med Chem. 1997;40:1947-1954.

In addition to the standard fare at the 74th Annual Meeting of the American Academy of Dermatology (AAD) in Washington, DC (March 4–8, 2016), this year there were several lectures addressing the use of nitric oxide (NO) for the treatment of acne. Therefore, I would like to review how NO gets delivered and the therapeutic implications as well as provide some context and understanding of the varying NO delivery systems being investigated.

Let’s start with some basics: Why should we even consider NO, a diatomic lipophilic gaseous molecule, for acne? It may be a surprise, but you already use NO for this purpose.

• NO is produced on the surface of the skin by action of commensal bacteria and plays a physiologic role in inhibition of infection by pathogenic organisms including bacteria, fungi, and viruses, and a microbicidal role against Propionibacterium acnes.
• NO minimizes inflammation by inhibiting neutrophil chemotaxis; production of lipases by P acnes (minimizes production of immunogenic free fatty acids); production of multiple cytokines such as tumor necrosis factor α, IL-8, and IL-6; antigen-presenting cell recognition of P acnes; and multiple elements of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome, the specific inflammasome reported to be impressively activated when monocytes, and even sebocytes, are exposed to P acnes, thereby inhibiting the conversion of pro–IL-1β to IL-1β.

However, NO’s direct biological action is not enough to explain these effects. It is S-nitrosylation, the covalent modification of a protein cysteine thiol by a NO group to generate an S-nitrosothiol such as nitrosoglutathione, that explains NO’s potent modulation of gene expression and enzymatic functions.

Nitric oxide was first featured in the late-breaking research session presented by Lawrence F. Eichenfield, MD, at the AAD (Efficacy and Safety of SB204 Gel in the Treatment of Acne Vulgaris)(F053). Results were presented from a phase 2b, multicenter, randomized, double-blind study comparing the efficacy, safety, and tolerability of SB204 NO-releasing gel 4% to vehicle in participants with acne vulgaris. The investigators concluded that SB204 once daily was safe and effective for the treatment of acne vulgaris, though they did not present data on the technology itself.

The NO-releasing technology being used in SB204 is an NO donor that falls under a class of NO donors called the diazeniumdiolates, or NONOates, which have been used experimentally for more than 50 years. These compounds consist of a diolate group (N[O-]N=O) bound to a nucleophile adduct (a primary or secondary amine or polyamine) by means of a nitrogen atom. Thus, you have NO bound to a donor that under appropriate environmental conditions will release its NO following first-order kinetics. It simply releases NO, rather then generate or create it.

Two issues are to be raised in relation to Dr. Eichenfield’s presentation:

Accumulation of amines and their metabolites released from NONOates have been shown to induce cytotoxicity in a study by Saavedra et al (J Med Chem. 1997;40:1947-1954). In the study by Blecher et al (Nanomedicine. 2012;8:1364-1371), topical application of DETA (diethylenetriamine) NONOate, another type of NONOate, actually delayed wound closure in NOD-SCID (nonobese diabetic severe combined immunodeficiency) mice as compared to untreated controls in a study by Blecher et al. Systemic infusion at concentrations required to reduce blood pressure resulted in methemoglobinemia and diminished oxygen-carrying capacity in a study by Cabrales et al (Free Radic Biol Med. 2010;49:530-538). The NONOate utilized in SB204 is encapsulated in a hydrogel particle to prevent permeation of said metabolites and donor compounds through the skin; however, a 12-week safety evaluation is certainly not long enough to determine whether local or systemic absorption has occurred. Of note, the NO-np has undergone extensive safety testing from cell culture of embryonic zebra fish to Syrian hamsters and even pigs showing no significant toxicity at any of the effective concentrations in animal studies.

Data published on the NO-np’s preclinical efficacy for the treatment of acne, infected excisions, and burn wounds were presented in 2 of my lectures at the AAD (Nanotechnology and Immunomodulators [F085] and Antimicrobial Dressings: Silver and Beyond [S056])(Chouake et al [J Drugs Dermatol. 2012;11:1471-1477]; Friedman et al [Virulence. 2011;2:217-221]; Han et al [PLoS One. 2009;4:e7804]; Marcherla et al [Front Microbiol. 2012;3:193]; Martinez et al [J Invest Dermatol. 2009;129:2463-2469]; Qin et al [J Invest Dermatol. 2015;135:2723-2731]; Blecher et al [Nanomedicine. 2012;8:1364-1371]). These data can be found within the suggested reading below.

What’s the issue?

Know the awesome biological power of NO. Know the differences between delivery systems, including donors and generators. Know the differences in therapeutic relevance, including efficacy and safety.

Do you know NO?

We want to know your views! Tell us what you think.

Suggested Readings

Multidrug-Resistant Bacterial and Fungal Skin and Soft Tissue Infections

1. Ahmadi M, Lee H, Sanchez D, et al. Sustained nitric oxide releasing nanoparticles induce cell death in Candida albicans yeast and hyphal cells preventing biofilm formation in vitro and in a rodent central venous catheter model. Antimicrob Agents Chemother. 2016;60:2185-2194.
2. Chouake J, Schairer D, Kutner A, et al. Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa–infected wounds. J Drugs Dermatol. 2012;11:1471-1477.
3. Friedman A, Blecher K, Sanchez D, et al. Susceptibility of gram positive and negative bacteria to novel nitric oxide-releasing nanoparticle technology. Virulence. 2011;2:217-221.
4. Friedman A, Blecher K, Schairer D, et al. Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S-nitrosoglutathione. Nitric Oxide. 2011;25:381-386.
5. Han G, Martinez LM, Mihu MR, et al. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in murine model of infection. PLoS One. 2009;4:e7804.
6. Landriscina A, Rosen J, Blecher-Paz K, et al. Nitric oxide-releasing nanoparticles as a treatment for cutaneous dermatophyte infections. Sci Lett. 2015,4:193.
7. Marcherla C, Sanchez DA, Ahmadi M, et al. Nitric oxide releasing nanoparticles for the treatment of Candida albicans burn infections [published online June 8, 2012]. Front Microbiol. 2012;3:193.
8. Martinez L, Han G, Chacko M, et al. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infections. J Invest Dermatol. 2009;129:2463-2469.
9. Mihu MR, Sandkovsky U, Han G, et al. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence. 2010;1:62-67.
10. Mordorski B, Pelgrift R, Adler B, et al. S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology. Nanomedicine. 2015;11:283-291.
11. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731.
12. Schairer D, Martinez L, Blecher K, et al. Nitric oxide nanoparticles: pre-clinical utility as a therapeutic for intramuscular abscesses. Virulence. 2012;3:1-6.

Wound Healing

1. Blecher K, Martinez LR, Tuckman-Vernon C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing in NOD-SCID mice. Nanomedicine. 2012;8:1364-1371.
2. Han G, Nguyen LN, Macherla C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing by promoting fibroblast migration and collagen deposition. Am J Pathol. 2012;180:1465-1473.

Erectile Dysfunction

1. Han G, Tar M, Kuppam DS, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction [published online September 18, 2009. J Sex Med. 2010;7(1 pt 1):224-333.
2. Tar M, CabralesP, Navati M, et al. Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy. J Sex Med. 2014;11:2903-2914.

Cardiovascular Disease

1. Cabrales P, Han G, Nacharaju P, et al. Reversal of hemoglobin-induced vasoconstriction with sustained release of nitric oxide [published online November 5, 2010]. Am J Physiol Heart Circ Physiol. 2011;300:H49-H56.
2. Cabrales P, Han G, Roche C, et al. Sustained release nitric oxide from long-lived circulation nanoparticles. Free Radic Biol Med. 2010;49:530-538.
3. Nacharaju P, Friedman AJ, Friedman JM, et al. Exogenous nitric oxide prevents collapse during hemorrhagic shock. Resuscitation. 2011;82:607-613.

Safety of NO Donors

1. Friedman A, Friedman JM. Novel biomaterials for the sustained release of nitric oxide: past, present, and future. Expert Opin Drug Deliv. 2009;6:1113-1122.
2. Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
3. Saavedra JE, Billiar TR, Williams DL, et al. Targeting nitric oxide (NO) delivery in vivo. design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. J Med Chem. 1997;40:1947-1954.

In addition to the standard fare at the 74th Annual Meeting of the American Academy of Dermatology (AAD) in Washington, DC (March 4–8, 2016), this year there were several lectures addressing the use of nitric oxide (NO) for the treatment of acne. Therefore, I would like to review how NO gets delivered and the therapeutic implications as well as provide some context and understanding of the varying NO delivery systems being investigated.

Let’s start with some basics: Why should we even consider NO, a diatomic lipophilic gaseous molecule, for acne? It may be a surprise, but you already use NO for this purpose.

• NO is produced on the surface of the skin by action of commensal bacteria and plays a physiologic role in inhibition of infection by pathogenic organisms including bacteria, fungi, and viruses, and a microbicidal role against Propionibacterium acnes.
• NO minimizes inflammation by inhibiting neutrophil chemotaxis; production of lipases by P acnes (minimizes production of immunogenic free fatty acids); production of multiple cytokines such as tumor necrosis factor α, IL-8, and IL-6; antigen-presenting cell recognition of P acnes; and multiple elements of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome, the specific inflammasome reported to be impressively activated when monocytes, and even sebocytes, are exposed to P acnes, thereby inhibiting the conversion of pro–IL-1β to IL-1β.

However, NO’s direct biological action is not enough to explain these effects. It is S-nitrosylation, the covalent modification of a protein cysteine thiol by a NO group to generate an S-nitrosothiol such as nitrosoglutathione, that explains NO’s potent modulation of gene expression and enzymatic functions.

Nitric oxide was first featured in the late-breaking research session presented by Lawrence F. Eichenfield, MD, at the AAD (Efficacy and Safety of SB204 Gel in the Treatment of Acne Vulgaris)(F053). Results were presented from a phase 2b, multicenter, randomized, double-blind study comparing the efficacy, safety, and tolerability of SB204 NO-releasing gel 4% to vehicle in participants with acne vulgaris. The investigators concluded that SB204 once daily was safe and effective for the treatment of acne vulgaris, though they did not present data on the technology itself.

The NO-releasing technology being used in SB204 is an NO donor that falls under a class of NO donors called the diazeniumdiolates, or NONOates, which have been used experimentally for more than 50 years. These compounds consist of a diolate group (N[O-]N=O) bound to a nucleophile adduct (a primary or secondary amine or polyamine) by means of a nitrogen atom. Thus, you have NO bound to a donor that under appropriate environmental conditions will release its NO following first-order kinetics. It simply releases NO, rather then generate or create it.

Two issues are to be raised in relation to Dr. Eichenfield’s presentation:

Accumulation of amines and their metabolites released from NONOates have been shown to induce cytotoxicity in a study by Saavedra et al (J Med Chem. 1997;40:1947-1954). In the study by Blecher et al (Nanomedicine. 2012;8:1364-1371), topical application of DETA (diethylenetriamine) NONOate, another type of NONOate, actually delayed wound closure in NOD-SCID (nonobese diabetic severe combined immunodeficiency) mice as compared to untreated controls in a study by Blecher et al. Systemic infusion at concentrations required to reduce blood pressure resulted in methemoglobinemia and diminished oxygen-carrying capacity in a study by Cabrales et al (Free Radic Biol Med. 2010;49:530-538). The NONOate utilized in SB204 is encapsulated in a hydrogel particle to prevent permeation of said metabolites and donor compounds through the skin; however, a 12-week safety evaluation is certainly not long enough to determine whether local or systemic absorption has occurred. Of note, the NO-np has undergone extensive safety testing from cell culture of embryonic zebra fish to Syrian hamsters and even pigs showing no significant toxicity at any of the effective concentrations in animal studies.

Data published on the NO-np’s preclinical efficacy for the treatment of acne, infected excisions, and burn wounds were presented in 2 of my lectures at the AAD (Nanotechnology and Immunomodulators [F085] and Antimicrobial Dressings: Silver and Beyond [S056])(Chouake et al [J Drugs Dermatol. 2012;11:1471-1477]; Friedman et al [Virulence. 2011;2:217-221]; Han et al [PLoS One. 2009;4:e7804]; Marcherla et al [Front Microbiol. 2012;3:193]; Martinez et al [J Invest Dermatol. 2009;129:2463-2469]; Qin et al [J Invest Dermatol. 2015;135:2723-2731]; Blecher et al [Nanomedicine. 2012;8:1364-1371]). These data can be found within the suggested reading below.

What’s the issue?

Know the awesome biological power of NO. Know the differences between delivery systems, including donors and generators. Know the differences in therapeutic relevance, including efficacy and safety.

Do you know NO?

We want to know your views! Tell us what you think.

Suggested Readings

Multidrug-Resistant Bacterial and Fungal Skin and Soft Tissue Infections

1. Ahmadi M, Lee H, Sanchez D, et al. Sustained nitric oxide releasing nanoparticles induce cell death in Candida albicans yeast and hyphal cells preventing biofilm formation in vitro and in a rodent central venous catheter model. Antimicrob Agents Chemother. 2016;60:2185-2194.
2. Chouake J, Schairer D, Kutner A, et al. Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa–infected wounds. J Drugs Dermatol. 2012;11:1471-1477.
3. Friedman A, Blecher K, Sanchez D, et al. Susceptibility of gram positive and negative bacteria to novel nitric oxide-releasing nanoparticle technology. Virulence. 2011;2:217-221.
4. Friedman A, Blecher K, Schairer D, et al. Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S-nitrosoglutathione. Nitric Oxide. 2011;25:381-386.
5. Han G, Martinez LM, Mihu MR, et al. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in murine model of infection. PLoS One. 2009;4:e7804.
6. Landriscina A, Rosen J, Blecher-Paz K, et al. Nitric oxide-releasing nanoparticles as a treatment for cutaneous dermatophyte infections. Sci Lett. 2015,4:193.
7. Marcherla C, Sanchez DA, Ahmadi M, et al. Nitric oxide releasing nanoparticles for the treatment of Candida albicans burn infections [published online June 8, 2012]. Front Microbiol. 2012;3:193.
8. Martinez L, Han G, Chacko M, et al. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infections. J Invest Dermatol. 2009;129:2463-2469.
9. Mihu MR, Sandkovsky U, Han G, et al. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence. 2010;1:62-67.
10. Mordorski B, Pelgrift R, Adler B, et al. S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology. Nanomedicine. 2015;11:283-291.
11. Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731.
12. Schairer D, Martinez L, Blecher K, et al. Nitric oxide nanoparticles: pre-clinical utility as a therapeutic for intramuscular abscesses. Virulence. 2012;3:1-6.

Wound Healing

1. Blecher K, Martinez LR, Tuckman-Vernon C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing in NOD-SCID mice. Nanomedicine. 2012;8:1364-1371.
2. Han G, Nguyen LN, Macherla C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing by promoting fibroblast migration and collagen deposition. Am J Pathol. 2012;180:1465-1473.

Erectile Dysfunction

1. Han G, Tar M, Kuppam DS, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction [published online September 18, 2009. J Sex Med. 2010;7(1 pt 1):224-333.
2. Tar M, CabralesP, Navati M, et al. Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy. J Sex Med. 2014;11:2903-2914.

Cardiovascular Disease

1. Cabrales P, Han G, Nacharaju P, et al. Reversal of hemoglobin-induced vasoconstriction with sustained release of nitric oxide [published online November 5, 2010]. Am J Physiol Heart Circ Physiol. 2011;300:H49-H56.
2. Cabrales P, Han G, Roche C, et al. Sustained release nitric oxide from long-lived circulation nanoparticles. Free Radic Biol Med. 2010;49:530-538.
3. Nacharaju P, Friedman AJ, Friedman JM, et al. Exogenous nitric oxide prevents collapse during hemorrhagic shock. Resuscitation. 2011;82:607-613.

Safety of NO Donors

1. Friedman A, Friedman JM. Novel biomaterials for the sustained release of nitric oxide: past, present, and future. Expert Opin Drug Deliv. 2009;6:1113-1122.
2. Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
3. Saavedra JE, Billiar TR, Williams DL, et al. Targeting nitric oxide (NO) delivery in vivo. design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. J Med Chem. 1997;40:1947-1954.

Many male and female patients seek therapy for androgenetic alopecia (AGA) at some point. Results are rarely achieved with single-modality therapy. In fact, the treatment of AGA often requires a combination approach of systemic medications and supplements; topical therapy; and if indicated, some type of minimally invasive procedure or surgical option.

The use of platelet-rich plasma (PRP) to pretreat follicular unit hair grafts may increase hair growth and density. Although the method by which PRP helps promote hair growth remains a source of speculation, it is known that platelets contain many growth factors in the platelet α granules. When these granules become activated, they release many types of growth factors ranging from vascular endothelial growth factor, transforming growth factor ß, epidermal growth factor, platelet-derived growth factor, and insulinlike growth factor.

Injection or topical application of PRP has become a popular treatment for skin rejuvenation, alopecia, and autologous fat grafting; however, many of these treatments are being done without the studies to support them.

Alves and Grimalt (Dermatol Surg. 2016;42:491-497) conducted a prospective, split-scalp, placebo-controlled study evaluating the use of PRP injections in the treatment of AGA in 25 patients (12 men, 13 women) with a mean age of 39 years (age range, 21–62 years). Photographs were taken and 4 areas per split scalp were marked with red tattoo dots. The patients were randomized to receive PRP on 1 side and saline injections on the other side. Patients were blinded, but the physician performing the treatment was not blinded. Treatments were performed monthly for 3 sessions. Follow-up photographs and hair density counts were performed at 3 and 6 months after treatment.

Results showed that after 6 months there was a statistically significant (P<.05) increase in the total hair density and terminal hair counts on the PRP-treated side compared to baseline and to the placebo-treated side. When broken down by demographics, patients who did best were men 40 years or younger with AGA beginning at 25 years or older, a positive family history of AGA, and AGA duration of greater than 10 years.

What’s the issue?

The results of this study suggest that PRP has a mild to modest effect (approximately 10% increase) on increasing hair density in a specific patient population. This split-scalp, placebo-controlled study is one of the few of its kind in the field of PRP research and the authors should be applauded for the design of this study. However, it would be beneficial to have a 1-year follow-up to see if the results are maintained and to better help determine if maintenance injections would be needed to sustain the results.

The field of hair restoration and regeneration will continue to grow as newer technologies in hair stem cell injections come to the forefront as well. Rigorous studies will be needed to better help physicians and patients make the right treatment decisions.

Have patients been asking you about PRP for skin rejuvenation and hair restoration?

We want to know your views! Tell us what you think.

Many male and female patients seek therapy for androgenetic alopecia (AGA) at some point. Results are rarely achieved with single-modality therapy. In fact, the treatment of AGA often requires a combination approach of systemic medications and supplements; topical therapy; and if indicated, some type of minimally invasive procedure or surgical option.

The use of platelet-rich plasma (PRP) to pretreat follicular unit hair grafts may increase hair growth and density. Although the method by which PRP helps promote hair growth remains a source of speculation, it is known that platelets contain many growth factors in the platelet α granules. When these granules become activated, they release many types of growth factors ranging from vascular endothelial growth factor, transforming growth factor ß, epidermal growth factor, platelet-derived growth factor, and insulinlike growth factor.

Injection or topical application of PRP has become a popular treatment for skin rejuvenation, alopecia, and autologous fat grafting; however, many of these treatments are being done without the studies to support them.

Alves and Grimalt (Dermatol Surg. 2016;42:491-497) conducted a prospective, split-scalp, placebo-controlled study evaluating the use of PRP injections in the treatment of AGA in 25 patients (12 men, 13 women) with a mean age of 39 years (age range, 21–62 years). Photographs were taken and 4 areas per split scalp were marked with red tattoo dots. The patients were randomized to receive PRP on 1 side and saline injections on the other side. Patients were blinded, but the physician performing the treatment was not blinded. Treatments were performed monthly for 3 sessions. Follow-up photographs and hair density counts were performed at 3 and 6 months after treatment.

Results showed that after 6 months there was a statistically significant (P<.05) increase in the total hair density and terminal hair counts on the PRP-treated side compared to baseline and to the placebo-treated side. When broken down by demographics, patients who did best were men 40 years or younger with AGA beginning at 25 years or older, a positive family history of AGA, and AGA duration of greater than 10 years.

What’s the issue?

The results of this study suggest that PRP has a mild to modest effect (approximately 10% increase) on increasing hair density in a specific patient population. This split-scalp, placebo-controlled study is one of the few of its kind in the field of PRP research and the authors should be applauded for the design of this study. However, it would be beneficial to have a 1-year follow-up to see if the results are maintained and to better help determine if maintenance injections would be needed to sustain the results.

The field of hair restoration and regeneration will continue to grow as newer technologies in hair stem cell injections come to the forefront as well. Rigorous studies will be needed to better help physicians and patients make the right treatment decisions.

Have patients been asking you about PRP for skin rejuvenation and hair restoration?

We want to know your views! Tell us what you think.

Many male and female patients seek therapy for androgenetic alopecia (AGA) at some point. Results are rarely achieved with single-modality therapy. In fact, the treatment of AGA often requires a combination approach of systemic medications and supplements; topical therapy; and if indicated, some type of minimally invasive procedure or surgical option.

The use of platelet-rich plasma (PRP) to pretreat follicular unit hair grafts may increase hair growth and density. Although the method by which PRP helps promote hair growth remains a source of speculation, it is known that platelets contain many growth factors in the platelet α granules. When these granules become activated, they release many types of growth factors ranging from vascular endothelial growth factor, transforming growth factor ß, epidermal growth factor, platelet-derived growth factor, and insulinlike growth factor.

Injection or topical application of PRP has become a popular treatment for skin rejuvenation, alopecia, and autologous fat grafting; however, many of these treatments are being done without the studies to support them.

Alves and Grimalt (Dermatol Surg. 2016;42:491-497) conducted a prospective, split-scalp, placebo-controlled study evaluating the use of PRP injections in the treatment of AGA in 25 patients (12 men, 13 women) with a mean age of 39 years (age range, 21–62 years). Photographs were taken and 4 areas per split scalp were marked with red tattoo dots. The patients were randomized to receive PRP on 1 side and saline injections on the other side. Patients were blinded, but the physician performing the treatment was not blinded. Treatments were performed monthly for 3 sessions. Follow-up photographs and hair density counts were performed at 3 and 6 months after treatment.

Results showed that after 6 months there was a statistically significant (P<.05) increase in the total hair density and terminal hair counts on the PRP-treated side compared to baseline and to the placebo-treated side. When broken down by demographics, patients who did best were men 40 years or younger with AGA beginning at 25 years or older, a positive family history of AGA, and AGA duration of greater than 10 years.

What’s the issue?

The results of this study suggest that PRP has a mild to modest effect (approximately 10% increase) on increasing hair density in a specific patient population. This split-scalp, placebo-controlled study is one of the few of its kind in the field of PRP research and the authors should be applauded for the design of this study. However, it would be beneficial to have a 1-year follow-up to see if the results are maintained and to better help determine if maintenance injections would be needed to sustain the results.

The field of hair restoration and regeneration will continue to grow as newer technologies in hair stem cell injections come to the forefront as well. Rigorous studies will be needed to better help physicians and patients make the right treatment decisions.

Have patients been asking you about PRP for skin rejuvenation and hair restoration?

We want to know your views! Tell us what you think.

In 1966, Dr. Charles Hammond was wrapping up a 2-year stint at the National Institutes of Health where he served at the behest of the military draft board. He had graduated from medical school just 5 years prior, and was in the middle of his ob.gyn. residency training at Duke University in Durham, N.C. when he was called to serve.

His experience wasn’t unusual for the time.

Courtesy Dr. Charles Hammond

“When the draft board called, you went,” he said in an interview.

When he returned, he picked up where he left off. Residencies at that time were an “open-ended thing,” sometimes lasting 5 or 6 years, depending on staffing needs and other considerations.

Dr. Hammond, now an emeritus professor at Duke, regards his public service commission as an opportunity that advanced his academic career – despite the interruption of his residency training.

Such draft-related interruptions ended in the wake of the Vietnam War, of course, but the late 1960s and the 1970s ushered in a whole new era of changes in ob.gyn. residency training programs.

By 1968, residencies lasted 4 years, and fellowships were for 2 years. Ob.gyn. subspecialties hadn’t yet been introduced, explained Dr. Sandra A. Carson, vice president for education at the American College of Obstetricians and Gynecologists.

“That is essentially how things worked for a long time,” she said in an interview.

That’s not to say there weren’t numerous other changes taking place in the specialty. In a series of interviews with physicians and educators who discussed the myriad ways that residency training has evolved over the last 50 years, a number of themes emerged.

Women in medicine

A striking change over the past 5 decades has been the increasing number of women in medicine. Nowhere has that been in greater evidence than in obstetrics and gynecology.

“There were a few – but very few,” Dr. Hammond said of women in medicine in the 1960s.

There was “a philosophy that men did it better,” he said, adding, “That has been nicely shown to be inaccurate.”

Currently, about 80% of first-year ob.gyn. residents are women, compared with 15% in 1975.

“Maybe even 83% now,” Dr. Carson said, noting that even in the early 1980s when she was in training, women were “few and far between.”

According to a 2011 workforce report by Dr. William F. Rayburn, obstetrics and gynecology has the highest percentage of women residents of any medical specialty – 80% in 2009 versus an average of 46% for other specialties combined, and that figure has remained fairly constant.

Dr. Kasandra Scales, a fourth-year resident at the State University of New York, Syracuse, said she is glad to be part of this era of the specialty where women play an integral role in the advancement of women’s health care.

Courtesy Dr. Kasandra Scales

“I believe our voice and unique perspective to relate with common experiences, such as the physical birth of a child or personal choices in contraception... has enhanced our specialty,” she said.

That said, the fact that men are noticeably absent from the pool of ob.gyn. applicants and residents concerns her. “There should be a balance, she said. “I think it is important to have diversity of all types in the healthcare system.”

Dr. Hammond looked back on his days in residency training and recalled pockets of resistance to the increasing number of women in medicine, but the ultimate effect was good for the specialty, he said, explaining that the quality of the resident pool improved steadily, because the number of qualified candidates increased.

“It has been an interesting interval to watch,” he said, specifically mentioning the demands that women faced in terms of family obligations, childbirth, and childrearing.

Restrictions on work hours instituted in residency programs in more recent years may have played an important role in opening the door to more women, he said.

Work hours down, learning curve up

Dr. Carson agreed that work-hour restrictions instituted in 2003 and updated in 2011, which cap the work week at 80 hours and also apply limits on shift hours, likely encouraged more women to enter the field. One constant over the last 50 years is the biological clock, she said, explaining that the pressures and demands of residency before limits were put in place may have steered women away.

Work-hour restrictions provide more flexibility, but they aren’t without controversy.

Dr. Hammond said he sees the value in work hour restrictions, but working long hours as a resident – sometimes as many as 110 hours per week – had its benefits, too.

“I remember one time when I’d been on call for about 2 and a half days, and up and working the whole time,” Dr. Hammond said. “I left the hospital, walked out to a bench, sat down, and fell asleep. I woke up and distinctly remember thinking, ‘Why am I doing this?’ But I did do it, and that fatigue helped me with learning to endure. You learned from it.”

Not only have long hours been viewed as a rite of passage in medicine, he said, but there were concerns initially that the level of education would diminish and that the risk of patient errors would increase as patients were handed off from one shift to the next, he said.

Data on the effects of work-hour rules have been conflicting. In one study, Dr. Roger P. Smith found little overall effect on total technical experience among residents before and after the restrictions were put in place (there was no statistically significant difference in the average of median total cases in the 3 years before and after). Previous studies had documented increased costs and reduced faculty job satisfaction, while still others had shown no significant changes in 30-day readmission rates, in-hospital mortality, patient length of stay, or resident performance, he noted. “What is emerging is that both the great hopes and the great fears surrounding resident work-hour restrictions have not come to pass,” Dr. Smith wrote (Obstet Gynecol. 2010 Jun;115[6]:1166-71).

Dr. Scales, who is currently chair of the Junior Fellow District II Advisory Council for ACOG, comes down on the side of wishing for more hours.

“[The restrictions] do limit the things we can do and the exposure we may otherwise have,” she said, noting that it’s frustrating to have to leave when she’d rather stay and “see a cool case.”

“It’s a nice idea in principle, but the same amount of work has to be done. It’s not real life,” she said of work-hour restrictions. “It’s hard, at least for me, to want to give up my patients. Our job is to take in as much as you can before you leave to go out into the big bad world.”

It may be difficult to determine the actual impact of work hour limits on patient outcomes because the field of obstetrics and gynecology has changed so much over time.

Dr. David Forstein, vice chair of clinical operations in the department of obstetrics and gynecology at the University of South Carolina, Greenville, and a member of the Accreditation Council for Graduate Medical Education’s task force on work hours said that, for one thing, patients are generally sicker now than ever before, due in part to the obesity epidemic.

Further, changing trends mean that residents are getting less exposure to some procedures like operative vaginal deliveries, while also having to learn more ways to perform hysterectomy. Residents aren’t necessarily less prepared. They’re just having to work very hard because of the depth and breadth of the required knowledge has increased, Dr. Forstein said. “There’s a lot more to learn.”

Dr. Carson agreed that the approach to education has changed, and that those changes are largely a reflection of overall shifts in education and technology.

Technology trends

Every physician interviewed for this article cited laparoscopy and robotic surgery as key technological advances. Fifty years ago, the surgical tools were simpler, Dr. Carson said. Now residents must learn four approaches to hysterectomy: vaginal, abdominal, laparoscopic, and robotic-assisted laparoscopic hysterectomy.

From ultrasound and birth control to genetic screening and robotic surgery, the evolution of the field has been astounding during this time period. The effects of the birth control pill on family planning alone forced an expansion of curriculum not only to the physiology of these things, but also to the treatment of women as a whole person and often as part of a family unit, she said.

Many of the technologies have dramatically changed the landscape, both in terms of how learning is accomplished (for example, simulation), and how physicians interact with patients, Dr. Hammond agreed. With ultrasound, for example, there was a sense that part of the physician-patient relationship was lost.

“To a point, some of us old guys felt like they were doing ultrasound assessment of patients rather than the tried-and-true ‘talk to them and examine them’ [approach],” he said. “I guess whichever generation you are in seems to be the right one, but it’s probably somewhere in between.”

Residency in 2016

If Dr. Scales is any indication, concerns about the loss of a personal touch are unfounded. She says that for her, that’s what it’s all about.

“We were exposed to [technology] since we were 5 or 6 – it’s all we know,” she said of herself and her fellow residents. “It’s not a disadvantage. It’s about efficiency.”

“We have to get things done as quickly as possible and technology helps us with that,” said Dr. Scales, the daughter of a teacher and blue collar worker, who spent most of her life “surrounded by the underprivileged.”

She always desired to help lift that population up, and while she didn’t have a draft board directing her toward public service, she had her own calling of sorts. As a premed major in college, she worked with a nonprofit organization, and later she worked with Hurricane Katrina survivors.

“I liked that aspect of medicine. I wanted to be able to identify with people on an individual level,” she said.

Technology, work-hour restrictions, gender distribution – they’re just part of the journey.

“I’m glad I chose ob.gyn.,” she said. “Sometimes you go through ... reflection ... Am I ready? My answer is yes. I’m excited about the next step, I’m comfortable in the skill I learned in my residency program, I’m excited about the work I do every day, and I’m very excited about the next chapters.”

[email protected]

In 1966, Dr. Charles Hammond was wrapping up a 2-year stint at the National Institutes of Health where he served at the behest of the military draft board. He had graduated from medical school just 5 years prior, and was in the middle of his ob.gyn. residency training at Duke University in Durham, N.C. when he was called to serve.

His experience wasn’t unusual for the time.

Courtesy Dr. Charles Hammond

“When the draft board called, you went,” he said in an interview.

When he returned, he picked up where he left off. Residencies at that time were an “open-ended thing,” sometimes lasting 5 or 6 years, depending on staffing needs and other considerations.

Dr. Hammond, now an emeritus professor at Duke, regards his public service commission as an opportunity that advanced his academic career – despite the interruption of his residency training.

Such draft-related interruptions ended in the wake of the Vietnam War, of course, but the late 1960s and the 1970s ushered in a whole new era of changes in ob.gyn. residency training programs.

By 1968, residencies lasted 4 years, and fellowships were for 2 years. Ob.gyn. subspecialties hadn’t yet been introduced, explained Dr. Sandra A. Carson, vice president for education at the American College of Obstetricians and Gynecologists.

“That is essentially how things worked for a long time,” she said in an interview.

That’s not to say there weren’t numerous other changes taking place in the specialty. In a series of interviews with physicians and educators who discussed the myriad ways that residency training has evolved over the last 50 years, a number of themes emerged.

Women in medicine

A striking change over the past 5 decades has been the increasing number of women in medicine. Nowhere has that been in greater evidence than in obstetrics and gynecology.

“There were a few – but very few,” Dr. Hammond said of women in medicine in the 1960s.

There was “a philosophy that men did it better,” he said, adding, “That has been nicely shown to be inaccurate.”

Currently, about 80% of first-year ob.gyn. residents are women, compared with 15% in 1975.

“Maybe even 83% now,” Dr. Carson said, noting that even in the early 1980s when she was in training, women were “few and far between.”

According to a 2011 workforce report by Dr. William F. Rayburn, obstetrics and gynecology has the highest percentage of women residents of any medical specialty – 80% in 2009 versus an average of 46% for other specialties combined, and that figure has remained fairly constant.

Dr. Kasandra Scales, a fourth-year resident at the State University of New York, Syracuse, said she is glad to be part of this era of the specialty where women play an integral role in the advancement of women’s health care.

Courtesy Dr. Kasandra Scales

“I believe our voice and unique perspective to relate with common experiences, such as the physical birth of a child or personal choices in contraception... has enhanced our specialty,” she said.

That said, the fact that men are noticeably absent from the pool of ob.gyn. applicants and residents concerns her. “There should be a balance, she said. “I think it is important to have diversity of all types in the healthcare system.”

Dr. Hammond looked back on his days in residency training and recalled pockets of resistance to the increasing number of women in medicine, but the ultimate effect was good for the specialty, he said, explaining that the quality of the resident pool improved steadily, because the number of qualified candidates increased.

“It has been an interesting interval to watch,” he said, specifically mentioning the demands that women faced in terms of family obligations, childbirth, and childrearing.

Restrictions on work hours instituted in residency programs in more recent years may have played an important role in opening the door to more women, he said.

Work hours down, learning curve up

Dr. Carson agreed that work-hour restrictions instituted in 2003 and updated in 2011, which cap the work week at 80 hours and also apply limits on shift hours, likely encouraged more women to enter the field. One constant over the last 50 years is the biological clock, she said, explaining that the pressures and demands of residency before limits were put in place may have steered women away.

Work-hour restrictions provide more flexibility, but they aren’t without controversy.

Dr. Hammond said he sees the value in work hour restrictions, but working long hours as a resident – sometimes as many as 110 hours per week – had its benefits, too.

“I remember one time when I’d been on call for about 2 and a half days, and up and working the whole time,” Dr. Hammond said. “I left the hospital, walked out to a bench, sat down, and fell asleep. I woke up and distinctly remember thinking, ‘Why am I doing this?’ But I did do it, and that fatigue helped me with learning to endure. You learned from it.”

Not only have long hours been viewed as a rite of passage in medicine, he said, but there were concerns initially that the level of education would diminish and that the risk of patient errors would increase as patients were handed off from one shift to the next, he said.

Data on the effects of work-hour rules have been conflicting. In one study, Dr. Roger P. Smith found little overall effect on total technical experience among residents before and after the restrictions were put in place (there was no statistically significant difference in the average of median total cases in the 3 years before and after). Previous studies had documented increased costs and reduced faculty job satisfaction, while still others had shown no significant changes in 30-day readmission rates, in-hospital mortality, patient length of stay, or resident performance, he noted. “What is emerging is that both the great hopes and the great fears surrounding resident work-hour restrictions have not come to pass,” Dr. Smith wrote (Obstet Gynecol. 2010 Jun;115[6]:1166-71).

Dr. Scales, who is currently chair of the Junior Fellow District II Advisory Council for ACOG, comes down on the side of wishing for more hours.

“[The restrictions] do limit the things we can do and the exposure we may otherwise have,” she said, noting that it’s frustrating to have to leave when she’d rather stay and “see a cool case.”

“It’s a nice idea in principle, but the same amount of work has to be done. It’s not real life,” she said of work-hour restrictions. “It’s hard, at least for me, to want to give up my patients. Our job is to take in as much as you can before you leave to go out into the big bad world.”

It may be difficult to determine the actual impact of work hour limits on patient outcomes because the field of obstetrics and gynecology has changed so much over time.

Dr. David Forstein, vice chair of clinical operations in the department of obstetrics and gynecology at the University of South Carolina, Greenville, and a member of the Accreditation Council for Graduate Medical Education’s task force on work hours said that, for one thing, patients are generally sicker now than ever before, due in part to the obesity epidemic.

Further, changing trends mean that residents are getting less exposure to some procedures like operative vaginal deliveries, while also having to learn more ways to perform hysterectomy. Residents aren’t necessarily less prepared. They’re just having to work very hard because of the depth and breadth of the required knowledge has increased, Dr. Forstein said. “There’s a lot more to learn.”

Dr. Carson agreed that the approach to education has changed, and that those changes are largely a reflection of overall shifts in education and technology.

Technology trends

Every physician interviewed for this article cited laparoscopy and robotic surgery as key technological advances. Fifty years ago, the surgical tools were simpler, Dr. Carson said. Now residents must learn four approaches to hysterectomy: vaginal, abdominal, laparoscopic, and robotic-assisted laparoscopic hysterectomy.

From ultrasound and birth control to genetic screening and robotic surgery, the evolution of the field has been astounding during this time period. The effects of the birth control pill on family planning alone forced an expansion of curriculum not only to the physiology of these things, but also to the treatment of women as a whole person and often as part of a family unit, she said.

Many of the technologies have dramatically changed the landscape, both in terms of how learning is accomplished (for example, simulation), and how physicians interact with patients, Dr. Hammond agreed. With ultrasound, for example, there was a sense that part of the physician-patient relationship was lost.

“To a point, some of us old guys felt like they were doing ultrasound assessment of patients rather than the tried-and-true ‘talk to them and examine them’ [approach],” he said. “I guess whichever generation you are in seems to be the right one, but it’s probably somewhere in between.”

Residency in 2016

If Dr. Scales is any indication, concerns about the loss of a personal touch are unfounded. She says that for her, that’s what it’s all about.

“We were exposed to [technology] since we were 5 or 6 – it’s all we know,” she said of herself and her fellow residents. “It’s not a disadvantage. It’s about efficiency.”

“We have to get things done as quickly as possible and technology helps us with that,” said Dr. Scales, the daughter of a teacher and blue collar worker, who spent most of her life “surrounded by the underprivileged.”

She always desired to help lift that population up, and while she didn’t have a draft board directing her toward public service, she had her own calling of sorts. As a premed major in college, she worked with a nonprofit organization, and later she worked with Hurricane Katrina survivors.

“I liked that aspect of medicine. I wanted to be able to identify with people on an individual level,” she said.

Technology, work-hour restrictions, gender distribution – they’re just part of the journey.

“I’m glad I chose ob.gyn.,” she said. “Sometimes you go through ... reflection ... Am I ready? My answer is yes. I’m excited about the next step, I’m comfortable in the skill I learned in my residency program, I’m excited about the work I do every day, and I’m very excited about the next chapters.”

[email protected]

In 1966, Dr. Charles Hammond was wrapping up a 2-year stint at the National Institutes of Health where he served at the behest of the military draft board. He had graduated from medical school just 5 years prior, and was in the middle of his ob.gyn. residency training at Duke University in Durham, N.C. when he was called to serve.

His experience wasn’t unusual for the time.

Courtesy Dr. Charles Hammond

“When the draft board called, you went,” he said in an interview.

When he returned, he picked up where he left off. Residencies at that time were an “open-ended thing,” sometimes lasting 5 or 6 years, depending on staffing needs and other considerations.

Dr. Hammond, now an emeritus professor at Duke, regards his public service commission as an opportunity that advanced his academic career – despite the interruption of his residency training.

Such draft-related interruptions ended in the wake of the Vietnam War, of course, but the late 1960s and the 1970s ushered in a whole new era of changes in ob.gyn. residency training programs.

By 1968, residencies lasted 4 years, and fellowships were for 2 years. Ob.gyn. subspecialties hadn’t yet been introduced, explained Dr. Sandra A. Carson, vice president for education at the American College of Obstetricians and Gynecologists.

“That is essentially how things worked for a long time,” she said in an interview.

That’s not to say there weren’t numerous other changes taking place in the specialty. In a series of interviews with physicians and educators who discussed the myriad ways that residency training has evolved over the last 50 years, a number of themes emerged.

Women in medicine

A striking change over the past 5 decades has been the increasing number of women in medicine. Nowhere has that been in greater evidence than in obstetrics and gynecology.

“There were a few – but very few,” Dr. Hammond said of women in medicine in the 1960s.

There was “a philosophy that men did it better,” he said, adding, “That has been nicely shown to be inaccurate.”

Currently, about 80% of first-year ob.gyn. residents are women, compared with 15% in 1975.

“Maybe even 83% now,” Dr. Carson said, noting that even in the early 1980s when she was in training, women were “few and far between.”

According to a 2011 workforce report by Dr. William F. Rayburn, obstetrics and gynecology has the highest percentage of women residents of any medical specialty – 80% in 2009 versus an average of 46% for other specialties combined, and that figure has remained fairly constant.

Dr. Kasandra Scales, a fourth-year resident at the State University of New York, Syracuse, said she is glad to be part of this era of the specialty where women play an integral role in the advancement of women’s health care.

Courtesy Dr. Kasandra Scales

“I believe our voice and unique perspective to relate with common experiences, such as the physical birth of a child or personal choices in contraception... has enhanced our specialty,” she said.

That said, the fact that men are noticeably absent from the pool of ob.gyn. applicants and residents concerns her. “There should be a balance, she said. “I think it is important to have diversity of all types in the healthcare system.”

Dr. Hammond looked back on his days in residency training and recalled pockets of resistance to the increasing number of women in medicine, but the ultimate effect was good for the specialty, he said, explaining that the quality of the resident pool improved steadily, because the number of qualified candidates increased.

“It has been an interesting interval to watch,” he said, specifically mentioning the demands that women faced in terms of family obligations, childbirth, and childrearing.

Restrictions on work hours instituted in residency programs in more recent years may have played an important role in opening the door to more women, he said.

Work hours down, learning curve up

Dr. Carson agreed that work-hour restrictions instituted in 2003 and updated in 2011, which cap the work week at 80 hours and also apply limits on shift hours, likely encouraged more women to enter the field. One constant over the last 50 years is the biological clock, she said, explaining that the pressures and demands of residency before limits were put in place may have steered women away.

Work-hour restrictions provide more flexibility, but they aren’t without controversy.

Dr. Hammond said he sees the value in work hour restrictions, but working long hours as a resident – sometimes as many as 110 hours per week – had its benefits, too.

“I remember one time when I’d been on call for about 2 and a half days, and up and working the whole time,” Dr. Hammond said. “I left the hospital, walked out to a bench, sat down, and fell asleep. I woke up and distinctly remember thinking, ‘Why am I doing this?’ But I did do it, and that fatigue helped me with learning to endure. You learned from it.”

Not only have long hours been viewed as a rite of passage in medicine, he said, but there were concerns initially that the level of education would diminish and that the risk of patient errors would increase as patients were handed off from one shift to the next, he said.

Data on the effects of work-hour rules have been conflicting. In one study, Dr. Roger P. Smith found little overall effect on total technical experience among residents before and after the restrictions were put in place (there was no statistically significant difference in the average of median total cases in the 3 years before and after). Previous studies had documented increased costs and reduced faculty job satisfaction, while still others had shown no significant changes in 30-day readmission rates, in-hospital mortality, patient length of stay, or resident performance, he noted. “What is emerging is that both the great hopes and the great fears surrounding resident work-hour restrictions have not come to pass,” Dr. Smith wrote (Obstet Gynecol. 2010 Jun;115[6]:1166-71).

Dr. Scales, who is currently chair of the Junior Fellow District II Advisory Council for ACOG, comes down on the side of wishing for more hours.

“[The restrictions] do limit the things we can do and the exposure we may otherwise have,” she said, noting that it’s frustrating to have to leave when she’d rather stay and “see a cool case.”

“It’s a nice idea in principle, but the same amount of work has to be done. It’s not real life,” she said of work-hour restrictions. “It’s hard, at least for me, to want to give up my patients. Our job is to take in as much as you can before you leave to go out into the big bad world.”

It may be difficult to determine the actual impact of work hour limits on patient outcomes because the field of obstetrics and gynecology has changed so much over time.

Dr. David Forstein, vice chair of clinical operations in the department of obstetrics and gynecology at the University of South Carolina, Greenville, and a member of the Accreditation Council for Graduate Medical Education’s task force on work hours said that, for one thing, patients are generally sicker now than ever before, due in part to the obesity epidemic.

Further, changing trends mean that residents are getting less exposure to some procedures like operative vaginal deliveries, while also having to learn more ways to perform hysterectomy. Residents aren’t necessarily less prepared. They’re just having to work very hard because of the depth and breadth of the required knowledge has increased, Dr. Forstein said. “There’s a lot more to learn.”

Dr. Carson agreed that the approach to education has changed, and that those changes are largely a reflection of overall shifts in education and technology.

Technology trends

Every physician interviewed for this article cited laparoscopy and robotic surgery as key technological advances. Fifty years ago, the surgical tools were simpler, Dr. Carson said. Now residents must learn four approaches to hysterectomy: vaginal, abdominal, laparoscopic, and robotic-assisted laparoscopic hysterectomy.

From ultrasound and birth control to genetic screening and robotic surgery, the evolution of the field has been astounding during this time period. The effects of the birth control pill on family planning alone forced an expansion of curriculum not only to the physiology of these things, but also to the treatment of women as a whole person and often as part of a family unit, she said.

Many of the technologies have dramatically changed the landscape, both in terms of how learning is accomplished (for example, simulation), and how physicians interact with patients, Dr. Hammond agreed. With ultrasound, for example, there was a sense that part of the physician-patient relationship was lost.

“To a point, some of us old guys felt like they were doing ultrasound assessment of patients rather than the tried-and-true ‘talk to them and examine them’ [approach],” he said. “I guess whichever generation you are in seems to be the right one, but it’s probably somewhere in between.”

Residency in 2016

If Dr. Scales is any indication, concerns about the loss of a personal touch are unfounded. She says that for her, that’s what it’s all about.

“We were exposed to [technology] since we were 5 or 6 – it’s all we know,” she said of herself and her fellow residents. “It’s not a disadvantage. It’s about efficiency.”

“We have to get things done as quickly as possible and technology helps us with that,” said Dr. Scales, the daughter of a teacher and blue collar worker, who spent most of her life “surrounded by the underprivileged.”

She always desired to help lift that population up, and while she didn’t have a draft board directing her toward public service, she had her own calling of sorts. As a premed major in college, she worked with a nonprofit organization, and later she worked with Hurricane Katrina survivors.

“I liked that aspect of medicine. I wanted to be able to identify with people on an individual level,” she said.

Technology, work-hour restrictions, gender distribution – they’re just part of the journey.

“I’m glad I chose ob.gyn.,” she said. “Sometimes you go through ... reflection ... Am I ready? My answer is yes. I’m excited about the next step, I’m comfortable in the skill I learned in my residency program, I’m excited about the work I do every day, and I’m very excited about the next chapters.”

[email protected]

In a case study published online on March 2 in JAMA Dermatology, Geller et al examined the relationship between total nevi, atypical nevi, and melanoma thickness. The study included 566 patients with melanoma. They were administered written surveys and underwent skin examinations at academic centers in Michigan and California within 3 months of diagnosis, measuring current total nevus count and atypical nevus count in addition to cataloguing melanoma thickness, histologic subtype, patient age, sex, marital status, skin self-examination and physician skin examination tendency, other health care visits, and mode of melanoma discovery.

Many epidemiologic trends were noted, but in summary, most melanoma patients had 0 to 20 total nevi (66.4%) and no atypical nevi (73.3%), a trend most pronounced in older patients (≥60 years). In patients younger than 60 years, higher nevus count (>50) was associated with thinner melanomas (≤2.0 mm), and the presence of more than 5 atypical nevi was associated with thicker melanomas (>2.0 mm).

What’s the issue?Studies clarifying the overall clinical characteristics of patients with aggressive melanomas appear every month in reputable journals, touting that concurrent total nevus count is important; or nevus size is important; or atypia is important; or clinical stigmata, medical history, and family history are important. Who is correct? Is everyone correct? On the pathology arm of the argument, Rosendahl et al (J Am Acad Dermatol. 2015;73:507-512) highlighted the same dilemma in which clinicians do not agree on the histopathologic features of nevi that consistently put patients at risk for individual lesion or de novo melanoma.

For me, each clinic day involves performing many total-body skin examinations, and many of these patients have innumerable nevi and various scars from lesions removed over the years with “atypical mole,” “premelanoma,” “precancer,” and various other self-reported labels. Some lesions may have documented pathology reports, but many do not. Some reports refer to dysplasia as a gradient, some do not. Some reports include molecular testing or clinical markers to grade lesions, and each can vary between institutions and pathologists. On the macroscopic level, clinically atypical nevi do not have a widely agreed upon set of criteria or threshold for biopsy; some clinicians use dermoscopic markers, and others utilize some version of the ABCDE (a=asymmetry; b=border; c=color; d=diameter; e=evolving) features.

The Geller et al study supports that these melanoma patients did not necessarily have more total nevi, and younger patients with aggressive melanoma may have a tendency toward more clinically atypical nevi. Although the study establishes what those institutions and clinicians determined to be atypical, I’m not sure that this is something that most clinicians widely agree upon. Additionally, these features were not paired with histopathologic dysplasia because the lesions were not biopsied.

What I find in conversation with colleagues is that some agree with what Geller et al defined as atypical, but some clinicians do not even refer to nevi as clinically atypical in a medical record unless they have pathology evidence of atypia (or the term their pathologist may use), which may be to avoid controversy regarding legal implications of atypia or “open-note” misunderstanding that the patient may have about this term, likening it to Papanicolaou test premalignancy verbiage.

I am not aware of one dermatologist or dermatopathologist who does not find this quandary to be frustrating. How do any of us really know which patients to follow more often for melanoma surveillance? How does your practice or institution report atypia in the clinical and histopathologic setting, and what do you find are the most important markers for development of melanoma?

We want to know your views! Tell us what you think.

In a case study published online on March 2 in JAMA Dermatology, Geller et al examined the relationship between total nevi, atypical nevi, and melanoma thickness. The study included 566 patients with melanoma. They were administered written surveys and underwent skin examinations at academic centers in Michigan and California within 3 months of diagnosis, measuring current total nevus count and atypical nevus count in addition to cataloguing melanoma thickness, histologic subtype, patient age, sex, marital status, skin self-examination and physician skin examination tendency, other health care visits, and mode of melanoma discovery.

Many epidemiologic trends were noted, but in summary, most melanoma patients had 0 to 20 total nevi (66.4%) and no atypical nevi (73.3%), a trend most pronounced in older patients (≥60 years). In patients younger than 60 years, higher nevus count (>50) was associated with thinner melanomas (≤2.0 mm), and the presence of more than 5 atypical nevi was associated with thicker melanomas (>2.0 mm).

What’s the issue?Studies clarifying the overall clinical characteristics of patients with aggressive melanomas appear every month in reputable journals, touting that concurrent total nevus count is important; or nevus size is important; or atypia is important; or clinical stigmata, medical history, and family history are important. Who is correct? Is everyone correct? On the pathology arm of the argument, Rosendahl et al (J Am Acad Dermatol. 2015;73:507-512) highlighted the same dilemma in which clinicians do not agree on the histopathologic features of nevi that consistently put patients at risk for individual lesion or de novo melanoma.

For me, each clinic day involves performing many total-body skin examinations, and many of these patients have innumerable nevi and various scars from lesions removed over the years with “atypical mole,” “premelanoma,” “precancer,” and various other self-reported labels. Some lesions may have documented pathology reports, but many do not. Some reports refer to dysplasia as a gradient, some do not. Some reports include molecular testing or clinical markers to grade lesions, and each can vary between institutions and pathologists. On the macroscopic level, clinically atypical nevi do not have a widely agreed upon set of criteria or threshold for biopsy; some clinicians use dermoscopic markers, and others utilize some version of the ABCDE (a=asymmetry; b=border; c=color; d=diameter; e=evolving) features.

The Geller et al study supports that these melanoma patients did not necessarily have more total nevi, and younger patients with aggressive melanoma may have a tendency toward more clinically atypical nevi. Although the study establishes what those institutions and clinicians determined to be atypical, I’m not sure that this is something that most clinicians widely agree upon. Additionally, these features were not paired with histopathologic dysplasia because the lesions were not biopsied.

What I find in conversation with colleagues is that some agree with what Geller et al defined as atypical, but some clinicians do not even refer to nevi as clinically atypical in a medical record unless they have pathology evidence of atypia (or the term their pathologist may use), which may be to avoid controversy regarding legal implications of atypia or “open-note” misunderstanding that the patient may have about this term, likening it to Papanicolaou test premalignancy verbiage.

I am not aware of one dermatologist or dermatopathologist who does not find this quandary to be frustrating. How do any of us really know which patients to follow more often for melanoma surveillance? How does your practice or institution report atypia in the clinical and histopathologic setting, and what do you find are the most important markers for development of melanoma?

We want to know your views! Tell us what you think.

In a case study published online on March 2 in JAMA Dermatology, Geller et al examined the relationship between total nevi, atypical nevi, and melanoma thickness. The study included 566 patients with melanoma. They were administered written surveys and underwent skin examinations at academic centers in Michigan and California within 3 months of diagnosis, measuring current total nevus count and atypical nevus count in addition to cataloguing melanoma thickness, histologic subtype, patient age, sex, marital status, skin self-examination and physician skin examination tendency, other health care visits, and mode of melanoma discovery.

Many epidemiologic trends were noted, but in summary, most melanoma patients had 0 to 20 total nevi (66.4%) and no atypical nevi (73.3%), a trend most pronounced in older patients (≥60 years). In patients younger than 60 years, higher nevus count (>50) was associated with thinner melanomas (≤2.0 mm), and the presence of more than 5 atypical nevi was associated with thicker melanomas (>2.0 mm).

What’s the issue?Studies clarifying the overall clinical characteristics of patients with aggressive melanomas appear every month in reputable journals, touting that concurrent total nevus count is important; or nevus size is important; or atypia is important; or clinical stigmata, medical history, and family history are important. Who is correct? Is everyone correct? On the pathology arm of the argument, Rosendahl et al (J Am Acad Dermatol. 2015;73:507-512) highlighted the same dilemma in which clinicians do not agree on the histopathologic features of nevi that consistently put patients at risk for individual lesion or de novo melanoma.

For me, each clinic day involves performing many total-body skin examinations, and many of these patients have innumerable nevi and various scars from lesions removed over the years with “atypical mole,” “premelanoma,” “precancer,” and various other self-reported labels. Some lesions may have documented pathology reports, but many do not. Some reports refer to dysplasia as a gradient, some do not. Some reports include molecular testing or clinical markers to grade lesions, and each can vary between institutions and pathologists. On the macroscopic level, clinically atypical nevi do not have a widely agreed upon set of criteria or threshold for biopsy; some clinicians use dermoscopic markers, and others utilize some version of the ABCDE (a=asymmetry; b=border; c=color; d=diameter; e=evolving) features.

The Geller et al study supports that these melanoma patients did not necessarily have more total nevi, and younger patients with aggressive melanoma may have a tendency toward more clinically atypical nevi. Although the study establishes what those institutions and clinicians determined to be atypical, I’m not sure that this is something that most clinicians widely agree upon. Additionally, these features were not paired with histopathologic dysplasia because the lesions were not biopsied.

What I find in conversation with colleagues is that some agree with what Geller et al defined as atypical, but some clinicians do not even refer to nevi as clinically atypical in a medical record unless they have pathology evidence of atypia (or the term their pathologist may use), which may be to avoid controversy regarding legal implications of atypia or “open-note” misunderstanding that the patient may have about this term, likening it to Papanicolaou test premalignancy verbiage.

I am not aware of one dermatologist or dermatopathologist who does not find this quandary to be frustrating. How do any of us really know which patients to follow more often for melanoma surveillance? How does your practice or institution report atypia in the clinical and histopathologic setting, and what do you find are the most important markers for development of melanoma?

We want to know your views! Tell us what you think.

A few weeks ago, a young man, a child psychiatrist, called saying that he had read the first Weighty Issues column and that he agreed that psychiatrists should be actively involved in the weight loss arena.

He shared that he had several children in his practice whose body-mass indices were over 40 and that he was frustrated that the pediatricians he had spoken with seemed to be only watching and waiting for the children to grow taller. I told him what he already knew: Pediatricians have in place a very specific protocol to follow regarding the treatment of overweight and obesity in children.

I had the impression from him that he was not exactly sure that the protocol was being followed and that he was absolutely sure that the pediatricians had no appreciation of the emotional aspects of these children’s weights. He said he was so fired up about this that he was going to pursue American Board of Obesity Medicine diplomate status himself. In addition to his background in child psychiatry, he also had studied public health, and his parents had worked in the area of disease prevention.

I was thrilled by his call because he got it! Overweight and obesity are a public health menace. Every day, psychiatrists see patients with these maladies, and we should be more knowledgeable about them or armed to get the treatment started ourselves. Although this child psychiatrist continues to intervene with his patients’ pediatricians and embarks on his own ABOM studies, he can, as he sees his patients and their families, write prescriptions for exercise and play time for the family, limited screen time (TV and computer) for the youngsters, no sweetened beverages, fewer simple carbohydrates, and more plain water. These interventions all are consistent with routine lifestyle recommendations for children (and adults), and they also can promote improved well-being for children and family members.

A recent report indicated that about a quarter of 2- to 5-year-olds and one-third of school-aged children (6-18 years) are overweight or obese in the United States (JAMA. 2014 Feb 26;311[8]:306-14). By convention, body-mass index, a measure of relative body fat, is used to indicate underweight, normal weight, overweight, and obesity. It is derived from a formula: weight in kilograms divided by height in meters squared. In adults, normal is 18.5-24.9, overweight is 25-29.9, and obese is greater than or equal to 30 (National Institutes of Health/World Health Organization guidelines for BMI). For children, one calculates the BMI and then plots this on a graph in comparison to other children of the same age and sex to derive a percentile scale number. Percentile scale numbers from 58-94 indicate overweight, and percentiles greater than or equal to 95 indicate obesity in children aged 2-18 years. For children aged 0-2, a weight for length above the 95th percentile indicates overweight.

Childhood obesity is a major risk factor for overweight and obesity in adulthood, and for depression and cardiovascular disease in childhood and adulthood. It also sets one up for potential trouble in the areas of self-esteem, body image, body protection, poor school performance, and relationship issues with peers. These are areas of importance for psychiatrists, child and adult, as we assess, plan for, and treat our patients day to day. Furthermore, childhood overweight puts children at risk for type 2 diabetes, metabolic syndrome, high cholesterol and high blood pressure, asthma, sleep disorders, early puberty or menstruation, Blount’s disease (progressive turning of the lower leg, resembling bowleg), and nonalcoholic fatty liver disease. Obesity in adulthood leads to high blood pressure, strokes, type 2 diabetes, dementia, osteoarthritis, sleep apnea, obesity hypoventilation syndrome, reproductive problems, gallstones, and some cancers (esophagus, pancreas, colon, rectum, breast-after menopause, endometrium, kidney, thyroid, and gallbladder).

The late Dr. Hilde Bruch, one of my mentors in the 1970s, was an early thought leader in childhood obesity. She did research in this area starting in 1937 while practicing pediatrics before she became a psychiatrist in 1943. She said that she was struck by the number of overweight and obese children she observed in the United States, compared with what she had observed in Germany and England. (She died in 1984 at the age of 80 and would be greatly saddened that childhood obesity is now a global issue.) In her 1973 book, “Eating Disorders: Obesity, Anorexia Nervosa, and the Person Within,” she grappled with the taking in of calories, and, speaking of hunger, said that “it is not innate, but something that contains important elements of learning.”

As an analyst, she thought of feeding learning as coming primarily from early mother-child interactions, but we now know that this learning can come through any repeated interaction and that genetic, social, cultural and environmental, and biological factors also apply.

The psychiatrist or anyone else working with children and families must endeavor to reduce self-blame, explore influences, and instill hope in the process toward normal weight and/or adequate management of weight. The psychiatrist and anyone else working with the child and family will appreciate that, if energy intake and physical activity output are manipulated consistently, the tendency for the child will be increasing height and decreasing BMI. The Prevention and Management of Obesity for Children and Adolescents Guideline is very clear about when to refer to a tertiary special weight management program for children. The guideline also speaks to use of weight-loss medication (orlistat for children 12 years and older, sibutramine for children 16 years and older). Bariatric surgery is recommended for children who have finished growing up (by growth plate evidence) and face imminent serious health issues if their weight cannot be brought under control. These children, after surgery, will need to radically restrain their eating, take supplements, and be followed for the rest of their lives to forestall complications and return to overweight and obesity. I believe that child and adult psychiatrists can be of tremendous use here in helping sort out both the physical and course-of-life issues that could threaten successful continued weight loss, whether the weight loss comes through lifestyle change, lifestyle change and medications, or bariatric surgery and subsequent lifestyle change.

I would like to thank that young child psychiatrist who called, because he spurred me to continue our “Weighty Issues” journey by looking at childhood and overweight and obesity and how it can affect our work as physicians and psychiatrists. Parental physical condition at conception and gestation, and genetics may set the stage, and then interaction with the family, the culture, the society, and the environment all interplay in the child’s development to produce an outcome of an overweight or obese child. We still are trying to discover why some but not all children in the same family, neighborhood, socioeconomic strata, culture, etc., are burdened by overweight. The reasons may be found through biological inquiry, but it may just as well in found in psychiatric/psychological inquiry.

Dr. Harris, a diplomate of the American Board of Obesity Medicine, is in private practice in adult and geriatric psychiatry in Hartford, Conn. She also works as a psychiatric consultant to continuing care retirement organizations and professional groups. Dr. Harris, a former president of the Black Psychiatrists of America, is a Distinguished Fellow of the American Psychiatric Association. Besides psychotherapy, her major clinical interests include geriatrics, and the interface between general medicine and psychiatry.

A few weeks ago, a young man, a child psychiatrist, called saying that he had read the first Weighty Issues column and that he agreed that psychiatrists should be actively involved in the weight loss arena.

He shared that he had several children in his practice whose body-mass indices were over 40 and that he was frustrated that the pediatricians he had spoken with seemed to be only watching and waiting for the children to grow taller. I told him what he already knew: Pediatricians have in place a very specific protocol to follow regarding the treatment of overweight and obesity in children.

I had the impression from him that he was not exactly sure that the protocol was being followed and that he was absolutely sure that the pediatricians had no appreciation of the emotional aspects of these children’s weights. He said he was so fired up about this that he was going to pursue American Board of Obesity Medicine diplomate status himself. In addition to his background in child psychiatry, he also had studied public health, and his parents had worked in the area of disease prevention.

I was thrilled by his call because he got it! Overweight and obesity are a public health menace. Every day, psychiatrists see patients with these maladies, and we should be more knowledgeable about them or armed to get the treatment started ourselves. Although this child psychiatrist continues to intervene with his patients’ pediatricians and embarks on his own ABOM studies, he can, as he sees his patients and their families, write prescriptions for exercise and play time for the family, limited screen time (TV and computer) for the youngsters, no sweetened beverages, fewer simple carbohydrates, and more plain water. These interventions all are consistent with routine lifestyle recommendations for children (and adults), and they also can promote improved well-being for children and family members.

A recent report indicated that about a quarter of 2- to 5-year-olds and one-third of school-aged children (6-18 years) are overweight or obese in the United States (JAMA. 2014 Feb 26;311[8]:306-14). By convention, body-mass index, a measure of relative body fat, is used to indicate underweight, normal weight, overweight, and obesity. It is derived from a formula: weight in kilograms divided by height in meters squared. In adults, normal is 18.5-24.9, overweight is 25-29.9, and obese is greater than or equal to 30 (National Institutes of Health/World Health Organization guidelines for BMI). For children, one calculates the BMI and then plots this on a graph in comparison to other children of the same age and sex to derive a percentile scale number. Percentile scale numbers from 58-94 indicate overweight, and percentiles greater than or equal to 95 indicate obesity in children aged 2-18 years. For children aged 0-2, a weight for length above the 95th percentile indicates overweight.

Childhood obesity is a major risk factor for overweight and obesity in adulthood, and for depression and cardiovascular disease in childhood and adulthood. It also sets one up for potential trouble in the areas of self-esteem, body image, body protection, poor school performance, and relationship issues with peers. These are areas of importance for psychiatrists, child and adult, as we assess, plan for, and treat our patients day to day. Furthermore, childhood overweight puts children at risk for type 2 diabetes, metabolic syndrome, high cholesterol and high blood pressure, asthma, sleep disorders, early puberty or menstruation, Blount’s disease (progressive turning of the lower leg, resembling bowleg), and nonalcoholic fatty liver disease. Obesity in adulthood leads to high blood pressure, strokes, type 2 diabetes, dementia, osteoarthritis, sleep apnea, obesity hypoventilation syndrome, reproductive problems, gallstones, and some cancers (esophagus, pancreas, colon, rectum, breast-after menopause, endometrium, kidney, thyroid, and gallbladder).

The late Dr. Hilde Bruch, one of my mentors in the 1970s, was an early thought leader in childhood obesity. She did research in this area starting in 1937 while practicing pediatrics before she became a psychiatrist in 1943. She said that she was struck by the number of overweight and obese children she observed in the United States, compared with what she had observed in Germany and England. (She died in 1984 at the age of 80 and would be greatly saddened that childhood obesity is now a global issue.) In her 1973 book, “Eating Disorders: Obesity, Anorexia Nervosa, and the Person Within,” she grappled with the taking in of calories, and, speaking of hunger, said that “it is not innate, but something that contains important elements of learning.”

As an analyst, she thought of feeding learning as coming primarily from early mother-child interactions, but we now know that this learning can come through any repeated interaction and that genetic, social, cultural and environmental, and biological factors also apply.

The psychiatrist or anyone else working with children and families must endeavor to reduce self-blame, explore influences, and instill hope in the process toward normal weight and/or adequate management of weight. The psychiatrist and anyone else working with the child and family will appreciate that, if energy intake and physical activity output are manipulated consistently, the tendency for the child will be increasing height and decreasing BMI. The Prevention and Management of Obesity for Children and Adolescents Guideline is very clear about when to refer to a tertiary special weight management program for children. The guideline also speaks to use of weight-loss medication (orlistat for children 12 years and older, sibutramine for children 16 years and older). Bariatric surgery is recommended for children who have finished growing up (by growth plate evidence) and face imminent serious health issues if their weight cannot be brought under control. These children, after surgery, will need to radically restrain their eating, take supplements, and be followed for the rest of their lives to forestall complications and return to overweight and obesity. I believe that child and adult psychiatrists can be of tremendous use here in helping sort out both the physical and course-of-life issues that could threaten successful continued weight loss, whether the weight loss comes through lifestyle change, lifestyle change and medications, or bariatric surgery and subsequent lifestyle change.

I would like to thank that young child psychiatrist who called, because he spurred me to continue our “Weighty Issues” journey by looking at childhood and overweight and obesity and how it can affect our work as physicians and psychiatrists. Parental physical condition at conception and gestation, and genetics may set the stage, and then interaction with the family, the culture, the society, and the environment all interplay in the child’s development to produce an outcome of an overweight or obese child. We still are trying to discover why some but not all children in the same family, neighborhood, socioeconomic strata, culture, etc., are burdened by overweight. The reasons may be found through biological inquiry, but it may just as well in found in psychiatric/psychological inquiry.

Dr. Harris, a diplomate of the American Board of Obesity Medicine, is in private practice in adult and geriatric psychiatry in Hartford, Conn. She also works as a psychiatric consultant to continuing care retirement organizations and professional groups. Dr. Harris, a former president of the Black Psychiatrists of America, is a Distinguished Fellow of the American Psychiatric Association. Besides psychotherapy, her major clinical interests include geriatrics, and the interface between general medicine and psychiatry.

A few weeks ago, a young man, a child psychiatrist, called saying that he had read the first Weighty Issues column and that he agreed that psychiatrists should be actively involved in the weight loss arena.

He shared that he had several children in his practice whose body-mass indices were over 40 and that he was frustrated that the pediatricians he had spoken with seemed to be only watching and waiting for the children to grow taller. I told him what he already knew: Pediatricians have in place a very specific protocol to follow regarding the treatment of overweight and obesity in children.

I had the impression from him that he was not exactly sure that the protocol was being followed and that he was absolutely sure that the pediatricians had no appreciation of the emotional aspects of these children’s weights. He said he was so fired up about this that he was going to pursue American Board of Obesity Medicine diplomate status himself. In addition to his background in child psychiatry, he also had studied public health, and his parents had worked in the area of disease prevention.

I was thrilled by his call because he got it! Overweight and obesity are a public health menace. Every day, psychiatrists see patients with these maladies, and we should be more knowledgeable about them or armed to get the treatment started ourselves. Although this child psychiatrist continues to intervene with his patients’ pediatricians and embarks on his own ABOM studies, he can, as he sees his patients and their families, write prescriptions for exercise and play time for the family, limited screen time (TV and computer) for the youngsters, no sweetened beverages, fewer simple carbohydrates, and more plain water. These interventions all are consistent with routine lifestyle recommendations for children (and adults), and they also can promote improved well-being for children and family members.

A recent report indicated that about a quarter of 2- to 5-year-olds and one-third of school-aged children (6-18 years) are overweight or obese in the United States (JAMA. 2014 Feb 26;311[8]:306-14). By convention, body-mass index, a measure of relative body fat, is used to indicate underweight, normal weight, overweight, and obesity. It is derived from a formula: weight in kilograms divided by height in meters squared. In adults, normal is 18.5-24.9, overweight is 25-29.9, and obese is greater than or equal to 30 (National Institutes of Health/World Health Organization guidelines for BMI). For children, one calculates the BMI and then plots this on a graph in comparison to other children of the same age and sex to derive a percentile scale number. Percentile scale numbers from 58-94 indicate overweight, and percentiles greater than or equal to 95 indicate obesity in children aged 2-18 years. For children aged 0-2, a weight for length above the 95th percentile indicates overweight.

Childhood obesity is a major risk factor for overweight and obesity in adulthood, and for depression and cardiovascular disease in childhood and adulthood. It also sets one up for potential trouble in the areas of self-esteem, body image, body protection, poor school performance, and relationship issues with peers. These are areas of importance for psychiatrists, child and adult, as we assess, plan for, and treat our patients day to day. Furthermore, childhood overweight puts children at risk for type 2 diabetes, metabolic syndrome, high cholesterol and high blood pressure, asthma, sleep disorders, early puberty or menstruation, Blount’s disease (progressive turning of the lower leg, resembling bowleg), and nonalcoholic fatty liver disease. Obesity in adulthood leads to high blood pressure, strokes, type 2 diabetes, dementia, osteoarthritis, sleep apnea, obesity hypoventilation syndrome, reproductive problems, gallstones, and some cancers (esophagus, pancreas, colon, rectum, breast-after menopause, endometrium, kidney, thyroid, and gallbladder).

The late Dr. Hilde Bruch, one of my mentors in the 1970s, was an early thought leader in childhood obesity. She did research in this area starting in 1937 while practicing pediatrics before she became a psychiatrist in 1943. She said that she was struck by the number of overweight and obese children she observed in the United States, compared with what she had observed in Germany and England. (She died in 1984 at the age of 80 and would be greatly saddened that childhood obesity is now a global issue.) In her 1973 book, “Eating Disorders: Obesity, Anorexia Nervosa, and the Person Within,” she grappled with the taking in of calories, and, speaking of hunger, said that “it is not innate, but something that contains important elements of learning.”

As an analyst, she thought of feeding learning as coming primarily from early mother-child interactions, but we now know that this learning can come through any repeated interaction and that genetic, social, cultural and environmental, and biological factors also apply.

The psychiatrist or anyone else working with children and families must endeavor to reduce self-blame, explore influences, and instill hope in the process toward normal weight and/or adequate management of weight. The psychiatrist and anyone else working with the child and family will appreciate that, if energy intake and physical activity output are manipulated consistently, the tendency for the child will be increasing height and decreasing BMI. The Prevention and Management of Obesity for Children and Adolescents Guideline is very clear about when to refer to a tertiary special weight management program for children. The guideline also speaks to use of weight-loss medication (orlistat for children 12 years and older, sibutramine for children 16 years and older). Bariatric surgery is recommended for children who have finished growing up (by growth plate evidence) and face imminent serious health issues if their weight cannot be brought under control. These children, after surgery, will need to radically restrain their eating, take supplements, and be followed for the rest of their lives to forestall complications and return to overweight and obesity. I believe that child and adult psychiatrists can be of tremendous use here in helping sort out both the physical and course-of-life issues that could threaten successful continued weight loss, whether the weight loss comes through lifestyle change, lifestyle change and medications, or bariatric surgery and subsequent lifestyle change.

I would like to thank that young child psychiatrist who called, because he spurred me to continue our “Weighty Issues” journey by looking at childhood and overweight and obesity and how it can affect our work as physicians and psychiatrists. Parental physical condition at conception and gestation, and genetics may set the stage, and then interaction with the family, the culture, the society, and the environment all interplay in the child’s development to produce an outcome of an overweight or obese child. We still are trying to discover why some but not all children in the same family, neighborhood, socioeconomic strata, culture, etc., are burdened by overweight. The reasons may be found through biological inquiry, but it may just as well in found in psychiatric/psychological inquiry.

Dr. Harris, a diplomate of the American Board of Obesity Medicine, is in private practice in adult and geriatric psychiatry in Hartford, Conn. She also works as a psychiatric consultant to continuing care retirement organizations and professional groups. Dr. Harris, a former president of the Black Psychiatrists of America, is a Distinguished Fellow of the American Psychiatric Association. Besides psychotherapy, her major clinical interests include geriatrics, and the interface between general medicine and psychiatry.

Biologic agents for the treatment of psoriasis are approved for patients 18 years and older. Although some biologics are approved for juvenile idiopathic arthritis, the lack of approved biologic therapies for children with psoriasis has been a major gap in our treatment of the disease. The incidence of moderate to severe psoriasis in the pediatric population is much lower than in adults, but there are still many patients younger than 18 years who would benefit from systemic therapies.

A recent press release indicates that the US Food and Drug Administration has accepted for review a supplemental biologics license application for the expanded use of etanercept to treat pediatric patients with chronic severe plaque psoriasis.

In February 2016 Paller et al (J Am Acad Dermatol. 2016;74:280.e3-287.e3) published data evaluating long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. This 5-year, open-label extension study enrolled those patients aged 4 to 17 years who had participated in an initial 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections as well as rates of 75% and 90% improvement in psoriasis area and severity index (PASI) score and clear or almost clear status on the static physician global assessment.

Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks of treatment. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 Serious AEs (n=8) were reported in 7 patients, and only 1 case of cellulitis was considered treatment related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement (∼60%–70%) and 90% improvement (∼30%–40%) in PASI score were maintained through week 264 as well as static physician global assessment status of clear or almost clear (∼40%–50%).

What’s the issue?

If approved, etanercept would be the first US Food and Drug Administration–approved systemic drug for pediatric psoriasis patients, which would open up options for many patients in need. Would you be willing to treat your pediatric psoriasis patients with a biologic?

We want to know your views! Tell us what you think.

Biologic agents for the treatment of psoriasis are approved for patients 18 years and older. Although some biologics are approved for juvenile idiopathic arthritis, the lack of approved biologic therapies for children with psoriasis has been a major gap in our treatment of the disease. The incidence of moderate to severe psoriasis in the pediatric population is much lower than in adults, but there are still many patients younger than 18 years who would benefit from systemic therapies.

A recent press release indicates that the US Food and Drug Administration has accepted for review a supplemental biologics license application for the expanded use of etanercept to treat pediatric patients with chronic severe plaque psoriasis.

In February 2016 Paller et al (J Am Acad Dermatol. 2016;74:280.e3-287.e3) published data evaluating long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. This 5-year, open-label extension study enrolled those patients aged 4 to 17 years who had participated in an initial 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections as well as rates of 75% and 90% improvement in psoriasis area and severity index (PASI) score and clear or almost clear status on the static physician global assessment.

Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks of treatment. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 Serious AEs (n=8) were reported in 7 patients, and only 1 case of cellulitis was considered treatment related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement (∼60%–70%) and 90% improvement (∼30%–40%) in PASI score were maintained through week 264 as well as static physician global assessment status of clear or almost clear (∼40%–50%).

What’s the issue?

If approved, etanercept would be the first US Food and Drug Administration–approved systemic drug for pediatric psoriasis patients, which would open up options for many patients in need. Would you be willing to treat your pediatric psoriasis patients with a biologic?

We want to know your views! Tell us what you think.

Biologic agents for the treatment of psoriasis are approved for patients 18 years and older. Although some biologics are approved for juvenile idiopathic arthritis, the lack of approved biologic therapies for children with psoriasis has been a major gap in our treatment of the disease. The incidence of moderate to severe psoriasis in the pediatric population is much lower than in adults, but there are still many patients younger than 18 years who would benefit from systemic therapies.

A recent press release indicates that the US Food and Drug Administration has accepted for review a supplemental biologics license application for the expanded use of etanercept to treat pediatric patients with chronic severe plaque psoriasis.

In February 2016 Paller et al (J Am Acad Dermatol. 2016;74:280.e3-287.e3) published data evaluating long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. This 5-year, open-label extension study enrolled those patients aged 4 to 17 years who had participated in an initial 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections as well as rates of 75% and 90% improvement in psoriasis area and severity index (PASI) score and clear or almost clear status on the static physician global assessment.

Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks of treatment. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 Serious AEs (n=8) were reported in 7 patients, and only 1 case of cellulitis was considered treatment related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement (∼60%–70%) and 90% improvement (∼30%–40%) in PASI score were maintained through week 264 as well as static physician global assessment status of clear or almost clear (∼40%–50%).

What’s the issue?

If approved, etanercept would be the first US Food and Drug Administration–approved systemic drug for pediatric psoriasis patients, which would open up options for many patients in need. Would you be willing to treat your pediatric psoriasis patients with a biologic?

We want to know your views! Tell us what you think.

Chen et al (N Engl J Med. 2015;373:1618-1626) performed a multicenter, phase 3, double-blind, randomized, placebo-controlled trial. Results demonstrated that nicotinamide effectively decreased the rates of new nonmelanoma skin cancers (NMSCs) and actinic keratoses (AKs) in high-risk patients who had at least 2 histologically confirmed NMSCs in the last 5 years. In comparison to participants who received placebo, individuals who received nicotinamide 500 mg twice daily during the 12-month study (branded with a predictive acronym ONTRAC [oral nicotinamide to reduce actinic cancer]) had reduced rates of AKs of up to 20%, basal cell carcinomas of 20%, squamous cell carcinomas of 30%, and NMSCs of 23%. However, the effect of nicotinamide on NMSCs was not maintained at evaluation 6 months after discontinuation; the number of basal cell carcinomas was similar, and the number of squamous cell carcinomas was greater in participants who received nicotinamide in comparison to individuals who received placebo.

What’s the issue?

The risk for skin cancer is increased by UV radiation that damages DNA, suppresses cutaneous immunity, and inhibits DNA repair by depleting cellular adenosine triphosphate. Nicotinamide, an amide form of vitamin B₃, has been demonstrated to not only reduce UV radiation–induced immunosuppression but also to prevent UV radiation–induced adenosine triphosphate depletion and glycolic blockade. Nicotinamide, which is classified as a food additive, also has neuroprotective and antioxidant functions and reduces pigmentation, wrinkles, and sebum production. Although oral nicotinamide has been demonstrated to reduce NMSCs and AKs, topical application has been shown to improve many skin conditions such as acne, atopic dermatitis, isoniazid-induced pellagra, and rosacea.

In contrast to nicotinic acid (niacin), nicotinamide is not associated with headaches, hypotension, flushing, itching, or vasodilatation. At high oral doses, side effects of nicotinamide that have been hypothesized or observed in animals, humans, or both have included the development of Parkinson disease, insulin sensitivity and diabetes mellitus, and liver toxicity. Although there are no reports in humans of growth retardation, teratogenicity, or oncogenicity, Rolfe (J Cosmet Dermatol. 2014;13:324-328) discussed that fetal blood levels of nicotinamide are greater than corresponding maternal blood levels because it is able to cross the placenta. However, according to Chen et al, no clinically significant between-group differences were found with respect to the number or types of adverse events that occurred in the placebo participants and the individuals who received 1000 mg daily of nicotinamide. Chen et al implied that there were additional benefits in the recipients of nicotinamide with regards to cognitive function and transepidermal water loss.

Perhaps all patients with a history of AKs, basal cell carcinomas, or squamous cell carcinomas should receive lifelong nicotinamide. Also, it might be reasonable to consider that all individuals older than 18 years who are not pregnant or breastfeeding with increased sun exposure but no history of AKs or NMSC add nicotinamide to their daily diets as a proactive measure for chemoprevention. Would you suggest nicotinamide to your patients?

We want to know your views! Tell us what you think.

Chen et al (N Engl J Med. 2015;373:1618-1626) performed a multicenter, phase 3, double-blind, randomized, placebo-controlled trial. Results demonstrated that nicotinamide effectively decreased the rates of new nonmelanoma skin cancers (NMSCs) and actinic keratoses (AKs) in high-risk patients who had at least 2 histologically confirmed NMSCs in the last 5 years. In comparison to participants who received placebo, individuals who received nicotinamide 500 mg twice daily during the 12-month study (branded with a predictive acronym ONTRAC [oral nicotinamide to reduce actinic cancer]) had reduced rates of AKs of up to 20%, basal cell carcinomas of 20%, squamous cell carcinomas of 30%, and NMSCs of 23%. However, the effect of nicotinamide on NMSCs was not maintained at evaluation 6 months after discontinuation; the number of basal cell carcinomas was similar, and the number of squamous cell carcinomas was greater in participants who received nicotinamide in comparison to individuals who received placebo.

What’s the issue?

The risk for skin cancer is increased by UV radiation that damages DNA, suppresses cutaneous immunity, and inhibits DNA repair by depleting cellular adenosine triphosphate. Nicotinamide, an amide form of vitamin B₃, has been demonstrated to not only reduce UV radiation–induced immunosuppression but also to prevent UV radiation–induced adenosine triphosphate depletion and glycolic blockade. Nicotinamide, which is classified as a food additive, also has neuroprotective and antioxidant functions and reduces pigmentation, wrinkles, and sebum production. Although oral nicotinamide has been demonstrated to reduce NMSCs and AKs, topical application has been shown to improve many skin conditions such as acne, atopic dermatitis, isoniazid-induced pellagra, and rosacea.

In contrast to nicotinic acid (niacin), nicotinamide is not associated with headaches, hypotension, flushing, itching, or vasodilatation. At high oral doses, side effects of nicotinamide that have been hypothesized or observed in animals, humans, or both have included the development of Parkinson disease, insulin sensitivity and diabetes mellitus, and liver toxicity. Although there are no reports in humans of growth retardation, teratogenicity, or oncogenicity, Rolfe (J Cosmet Dermatol. 2014;13:324-328) discussed that fetal blood levels of nicotinamide are greater than corresponding maternal blood levels because it is able to cross the placenta. However, according to Chen et al, no clinically significant between-group differences were found with respect to the number or types of adverse events that occurred in the placebo participants and the individuals who received 1000 mg daily of nicotinamide. Chen et al implied that there were additional benefits in the recipients of nicotinamide with regards to cognitive function and transepidermal water loss.

Perhaps all patients with a history of AKs, basal cell carcinomas, or squamous cell carcinomas should receive lifelong nicotinamide. Also, it might be reasonable to consider that all individuals older than 18 years who are not pregnant or breastfeeding with increased sun exposure but no history of AKs or NMSC add nicotinamide to their daily diets as a proactive measure for chemoprevention. Would you suggest nicotinamide to your patients?

We want to know your views! Tell us what you think.

Chen et al (N Engl J Med. 2015;373:1618-1626) performed a multicenter, phase 3, double-blind, randomized, placebo-controlled trial. Results demonstrated that nicotinamide effectively decreased the rates of new nonmelanoma skin cancers (NMSCs) and actinic keratoses (AKs) in high-risk patients who had at least 2 histologically confirmed NMSCs in the last 5 years. In comparison to participants who received placebo, individuals who received nicotinamide 500 mg twice daily during the 12-month study (branded with a predictive acronym ONTRAC [oral nicotinamide to reduce actinic cancer]) had reduced rates of AKs of up to 20%, basal cell carcinomas of 20%, squamous cell carcinomas of 30%, and NMSCs of 23%. However, the effect of nicotinamide on NMSCs was not maintained at evaluation 6 months after discontinuation; the number of basal cell carcinomas was similar, and the number of squamous cell carcinomas was greater in participants who received nicotinamide in comparison to individuals who received placebo.

What’s the issue?

The risk for skin cancer is increased by UV radiation that damages DNA, suppresses cutaneous immunity, and inhibits DNA repair by depleting cellular adenosine triphosphate. Nicotinamide, an amide form of vitamin B₃, has been demonstrated to not only reduce UV radiation–induced immunosuppression but also to prevent UV radiation–induced adenosine triphosphate depletion and glycolic blockade. Nicotinamide, which is classified as a food additive, also has neuroprotective and antioxidant functions and reduces pigmentation, wrinkles, and sebum production. Although oral nicotinamide has been demonstrated to reduce NMSCs and AKs, topical application has been shown to improve many skin conditions such as acne, atopic dermatitis, isoniazid-induced pellagra, and rosacea.

In contrast to nicotinic acid (niacin), nicotinamide is not associated with headaches, hypotension, flushing, itching, or vasodilatation. At high oral doses, side effects of nicotinamide that have been hypothesized or observed in animals, humans, or both have included the development of Parkinson disease, insulin sensitivity and diabetes mellitus, and liver toxicity. Although there are no reports in humans of growth retardation, teratogenicity, or oncogenicity, Rolfe (J Cosmet Dermatol. 2014;13:324-328) discussed that fetal blood levels of nicotinamide are greater than corresponding maternal blood levels because it is able to cross the placenta. However, according to Chen et al, no clinically significant between-group differences were found with respect to the number or types of adverse events that occurred in the placebo participants and the individuals who received 1000 mg daily of nicotinamide. Chen et al implied that there were additional benefits in the recipients of nicotinamide with regards to cognitive function and transepidermal water loss.

Perhaps all patients with a history of AKs, basal cell carcinomas, or squamous cell carcinomas should receive lifelong nicotinamide. Also, it might be reasonable to consider that all individuals older than 18 years who are not pregnant or breastfeeding with increased sun exposure but no history of AKs or NMSC add nicotinamide to their daily diets as a proactive measure for chemoprevention. Would you suggest nicotinamide to your patients?

We want to know your views! Tell us what you think.

The subspecialty of gynecologic oncology was formalized less than 50 years ago with the creation of the Society of Gynecologic Oncology and subspecialty training and board certification. The formation of the Gynecologic Oncology Group (GOG) – and the many clinical trials spearheaded by that group – has further advanced evidence-based treatments, resulting in improved survival outcomes, quality of life, and preventive strategies.

While it is not possible to provide a comprehensive and exhaustive review of all of the advances, we hope to highlight many of the notable advances in this article.Cervical cancer

Cervical cancer is the fourth most common cancer in women worldwide with 528,000 new cases in 2012. The majority of cervical cancer cases are caused by infection with human papillomavirus (HPV). While the standard therapies for cervical cancer have been long established (radical hysterectomy for stage I and radiation therapy for locally advanced disease), one of the most significant advances in the past 50 years was the addition of radiation-sensitizing chemotherapy (cisplatin) administered concurrently with radiation therapy.

In randomized trials in both early and advanced cervical cancer, the risk of death was reduced by 30%-50%. These studies changed the paradigm for the treatment of cervical cancer (N Engl J Med. 1999 Apr 15;340[15]:1137-43; N Engl J Med. 1999 Apr 15;340[15]:1144-53; J Clin Oncol. 2000 Apr;18[8]:1606-13).

Future studies evaluating biologic adjuncts or additional chemotherapy are currently underway or awaiting data maturation.

The American Society of Clinical Oncology (ASCO) highlighted the “Top 5 advances in 50 years of Modern Oncology” in 2014, and second on the list was the approval of the HPV vaccine to prevent cervical cancer. Vaccines have been developed that can protect against types 2, 4 or 9 of HPV. In a 2014 study, depending on vaccination coverage, the relative number of cervical cancer cases avoided was 34% in Africa, 27% for America, 26% for Asia, 21% for Europe, and worldwide was estimated at 27% (Vaccine. 2014 Feb 3;32[6]:733-9).

While the benefit from HPV vaccination has been proven, in the United States, only about a third of eligible girls and women have been vaccinated. Efforts should focus on expanding vaccination penetration to eligible girls, boys, women, and men.

©xrender/Thinkstock

Endometrial cancer

Endometrial cancer is the most common gynecologic malignancy in the United States with an estimated 54,870 cases and 10,170 deaths annually. Notable advances in the management of women with endometrial cancer have arisen because of a better understanding that there are two types of endometrial cancer – type I and type II.

The type I endometrial cancers tend to be associated with lower stage of disease at the time of diagnosis and fewer recurrences, while type II endometrial cancer is associated with worse outcomes.

Tailoring the surgical approaches and adjuvant therapy for women with endometrial cancer has led to improved outcomes. The GOG conducted a large prospective randomized trial of laparotomy versus laparoscopic surgical staging for women with clinical early-stage endometrial cancer (LAP2). Laparoscopy was associated with improved perioperative outcomes and was found to be noninferior to laparotomy with regards to survival outcomes (J Clin Oncol. 2012 Mar 1;30[7]:695-700). Therefore, minimally invasive surgery has become widely accepted for the surgical staging of women with endometrial cancer.

Appropriate surgical staging allows for tailoring of postoperative adjuvant therapy. The current evidence suggests that vaginal brachytherapy should be the adjuvant treatment of choice over whole pelvic radiation in women with early-stage endometrial cancer (Lancet. 2010 Mar 6;375[9717]:816-23). Studies are underway to evaluate the role of both adjuvant radiation and chemotherapy in women with early-stage type II endometrial cancer who are felt to be at high risk for recurrent disease, as well as how to improve on the therapeutic options for women with advanced or recurrent disease.

Ovarian cancer

Epithelial ovarian cancer is the most deadly gynecologic malignancy in the United States with 21,290 cases and 14,180 deaths in 2015. The concept of ovarian tumor debulking was first described by Dr. Joe Meigs in 1934, but did not gain traction until the mid-1970s when Dr. C. Thomas Griffiths published his work (Natl Cancer Inst Monogr. 1975 Oct;42:101-4).

While there are no randomized trials proving that surgical cytoreduction improves overall survival, most retrospective studies support this concept. In 2009, Chi et al. showed improved median survival in women with ovarian cancer based on the increased percentage of women who underwent optimal cytoreduction (Gynecol Oncol. 2009 Jul;114[1]:26-31). This has led to modifications of surgical techniques and surgical goals with an effort to maximally cytoreduce all of the visible disease.

While initial surgical debulking is the goal, there are circumstances when a different approach may be indicated. Vergote et al. conducted a prospective randomized trial of 670 women with advanced ovarian cancer. In this study, neoadjuvant chemotherapy followed by interval debulking was not inferior to primary debulking followed by chemotherapy with regards to progression-free survival and overall survival. However, initial surgery was associated with increased surgical complications and perioperative mortality as compared with interval surgery. Therefore, in women who are not felt to be candidates for optimal cytoreduction, neoadjuvant chemotherapy followed by interval surgery may be an appropriate treatment strategy (N Engl J Med. 2010 Sep 2;363[10]:943-53.).

Courtesy Wikimedia Commons/James Heilman, MD/CC-BY-SA-3.0

There have been several notable advances and a series of randomized trials – predominately conducted by the GOG – that have resulted in improved overall survival and progression-free interval in women with ovarian cancer. However, none are as significant as the discovery of paclitaxel and platinum-based chemotherapy (cisplatin and carboplatin).

In 1962, samples of the Pacific Yew’s bark were collected and, 2 years later, the extracts from this bark were found to have cytotoxic activity. There were initial difficulties suspending the drug in solution; however, ultimately a formulation in ethanol, cremophor, and saline was found to be effective. In 1984, the National Cancer Institute began clinical trials of paclitaxel and it was found to be highly effective in ovarian cancer. In 1992, it was approved for the treatment of ovarian cancer.

Cisplatin was approved in 1978. Carboplatin entered clinical trials in 1982 and was approved for women with recurrent ovarian cancer in 1989.

There were a series of trials beginning in the late 1980s that established the role of platinum agents and led us to GOG 111. This trial evaluated cisplatin with either cyclophosphamide or paclitaxel. The paclitaxel combination was superior and in 2003 two trials were published that solidified carboplatin and paclitaxel as the cornerstone in the treatment of women with ovarian cancer (J Clin Oncol. 2003 Sep 1;21[17]:3194-200; J Natl Cancer Inst. 2003 Sep 3;95[17]:1320-9).

What has most recently been debated is the route and schedule for both paclitaxel and the platinum agents. In January 2006, the National Cancer Institute released a Clinical Announcement regarding the role of intraperitoneal (IP) chemotherapy for the treatment of women with optimally debulked ovarian cancer. Of the six trials included in the announcement, four trials showed a benefit for progression-free survival and five studies showed an improvement in overall survival. Armstrong et al (GOG 172) showed a 16-month improvement in overall survival with intravenous (IV) paclitaxel, IP cisplatin, and IP paclitaxel. IP chemotherapy has not been universally embraced by physicians and patients in part because of its toxicity, treatment schedule, and the fact that no IP regimen has been compared with the current standard of IV carboplatin and paclitaxel (N Engl J Med. 2006 Jan 5;354[1]:34-43).

While there have been improvements in 5-year survival over time, most women with advanced ovarian cancer will undergo additional chemotherapy in order to achieve subsequent remissions or maintain stability of disease. Other drugs that have Food and Drug Administration approval in the setting of recurrent ovarian cancer include topotecan, liposomal doxorubicin, gemcitabine, bevacizumab, altretamine, carboplatin, cisplatin, cyclophosphamide, and melphalan. Olaparib was recently approved as monotherapy in women with a germline BRCA-mutation who had received three or more prior lines of chemotherapy.

Minimally invasive surgery

Over the last 30 years, minimally invasive surgery (MIS) in gynecologic oncology, particularly for endometrial cancer, has gone from a niche procedure to the standard of care. The introduction of laparoscopy into gynecologic oncology started in the early 1990s. In a series of 59 women undergoing laparoscopy for endometrial cancer, Childers et al. demonstrated feasibility of the technique and low laparotomy conversion rates (Gynecol Oncol. 1993 Oct;51[1]:33-8.). The GOG trial, LAP2, supported the equivalent oncologic outcomes of MIS versus laparotomy for the treatment of endometrial cancer. While many surgeons and centers offered laparoscopic surgery, there were issues with the learning curve that limited its widespread use.

In 2005, the FDA approval of the robotic platform for gynecologic surgery resulted in at least a doubling of the proportion of endometrial cancer patients treated with MIS (Int J Med Robot. 2009 Dec;5[4]:392-7.). In 2012, the Society of Gynecologic Oncology published a consensus statement regarding robotic-assisted surgery in gynecologic oncology (Gynecol Oncol. 2012 Feb;124[2]:180-4.). This review highlights the advantages of the robotics platform with regards to expanding MIS to women with cervical and ovarian cancer; the improvements in outcomes in the obese woman with endometrial cancer; and that the learning curve for robotic surgery is shorter than for traditional laparoscopy. Issues requiring further research include cost analysis as the cost of the new technology decreases, and opportunities for improvement in patient and physician quality of life.

Sentinel node mapping

The rationale for sentinel node mapping is that if one or more sentinel lymph nodes is/are negative for malignancy, then the other regional lymph nodes will also be negative. This would thereby avoid the need for a complete lymph node dissection and its resultant complications, including chronic lymphedema. Much of the work pioneering this strategy has been in breast cancer and melanoma, but data are rapidly emerging for these techniques in gynecologic malignancies.

Candidates for sentinel lymph node biopsy for vulvar cancer include those with a lesion more than 1mm in depth, a tumor less than 4 cm in size, and no obvious metastatic disease on exam or preoperative imaging. Additionally, recommendations have been made regarding case volume in order to achieve limited numbers of false-negative results and to maintain competency. In the study by Van der Zee et al. of 403 patients (623 groins) who underwent sentinel node procedures, the false-negative rate was 0-2%. The overall survival rate was 97% at 3 years (J Clin Oncol. 2008 Feb 20;26[6]:884-9). However, a more recent data from the Gynecologic Oncology Group (GOG 173) showed a slightly higher false-negative rate of 8% (J Clin Oncol. 2012 Nov 1;30[31]:3786-91). Overall survival data are pending from this study.

While sentinel lymph node mapping for endometrial cancer has been feasible for many years and has been well described, the questioned role of completed lymphadenectomy for early-stage endometrial cancer has led to a resurgence of interest in these techniques. While blue dye and radiolabeled tracer methods have historically been the most popular mapping solutions, the advent of endoscopic near-infrared imaging, with its higher sensitivity and good depth penetration, has added options. Indocyanine green fluorescence can be easily detected during robotic surgery and as experience with these techniques increase, successful mapping and sensitivity will increase.

Genetics

While hereditary cancer syndromes have been recognized for many years, detecting the genetic mutations that may increase an individual’s risk of developing a malignancy were not elucidated until the early 1990s. In gynecologic oncology, the most commonly encountered syndromes involve mutations in BRCA1 and BRCA2 and hereditary non–polyposis colorectal cancer, which causes mutations in DNA mismatch-repair genes and increase the risk of endometrial and ovarian cancer.

©Jezperklauzen/ThinkStock

The SGO recently published a statement on risk assessment for inherited gynecologic cancer predispositions. In this statement “the evaluation for the presence of a hereditary cancer syndrome enables physicians to provide individualized and quantified assessment of cancer risk, as well as options for tailored screening and preventions strategies that may reduce morbidity associated with the development of malignancy” (Gynecol Oncol. 2015 Jan;136[1]:3-7). Beyond risk-reducing salpingo-oophorectomy, therapeutic strategies targeting patients with germline mutations have been developed (PARP inhibitors in BRCA-mutated women with ovarian cancer).

In August 2015, ASCO released an updated policy statement on genetic and genomic testing for cancer susceptibility and highlighted five key areas: germ-line implications of somatic mutation profiling; multigene panel testing for cancer susceptibility; quality assurance in genetic testing; education for oncology professionals; and access to cancer genetic services.

Antiemetics

Rounding out ASCO’s “Top 5 advances in 50 years of Modern Oncology” was the improvement in patients’ quality of life from supportive therapies, in particular antinausea medications.

Several of the agents commonly used in gynecologic oncology rate high (cisplatin) to moderate (carboplatin, cyclophosphamide, doxorubicin, ifosfamide) with regards to emetogenicity. The advent of 5-HT3 receptor antagonists (for example, ondansetron) has significantly improved the quality of life of patients undergoing cytotoxic chemotherapy. In addition to improving quality of life, the decrease in nausea and vomiting can also decrease life-threatening complications such as dehydration and electrolyte imbalance. Both ASCO and the National Comprehensive Cancer Network both have guidelines for the management of nausea and vomiting in patients undergoing chemotherapy.

Throughout 2016, Ob.Gyn. News will celebrate its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit. Look for these articles and more special features in the pages of Ob.Gyn. News and online at obgynnews.com.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.

The subspecialty of gynecologic oncology was formalized less than 50 years ago with the creation of the Society of Gynecologic Oncology and subspecialty training and board certification. The formation of the Gynecologic Oncology Group (GOG) – and the many clinical trials spearheaded by that group – has further advanced evidence-based treatments, resulting in improved survival outcomes, quality of life, and preventive strategies.

While it is not possible to provide a comprehensive and exhaustive review of all of the advances, we hope to highlight many of the notable advances in this article.Cervical cancer

Cervical cancer is the fourth most common cancer in women worldwide with 528,000 new cases in 2012. The majority of cervical cancer cases are caused by infection with human papillomavirus (HPV). While the standard therapies for cervical cancer have been long established (radical hysterectomy for stage I and radiation therapy for locally advanced disease), one of the most significant advances in the past 50 years was the addition of radiation-sensitizing chemotherapy (cisplatin) administered concurrently with radiation therapy.

In randomized trials in both early and advanced cervical cancer, the risk of death was reduced by 30%-50%. These studies changed the paradigm for the treatment of cervical cancer (N Engl J Med. 1999 Apr 15;340[15]:1137-43; N Engl J Med. 1999 Apr 15;340[15]:1144-53; J Clin Oncol. 2000 Apr;18[8]:1606-13).

Future studies evaluating biologic adjuncts or additional chemotherapy are currently underway or awaiting data maturation.

The American Society of Clinical Oncology (ASCO) highlighted the “Top 5 advances in 50 years of Modern Oncology” in 2014, and second on the list was the approval of the HPV vaccine to prevent cervical cancer. Vaccines have been developed that can protect against types 2, 4 or 9 of HPV. In a 2014 study, depending on vaccination coverage, the relative number of cervical cancer cases avoided was 34% in Africa, 27% for America, 26% for Asia, 21% for Europe, and worldwide was estimated at 27% (Vaccine. 2014 Feb 3;32[6]:733-9).

While the benefit from HPV vaccination has been proven, in the United States, only about a third of eligible girls and women have been vaccinated. Efforts should focus on expanding vaccination penetration to eligible girls, boys, women, and men.

©xrender/Thinkstock

Endometrial cancer

Endometrial cancer is the most common gynecologic malignancy in the United States with an estimated 54,870 cases and 10,170 deaths annually. Notable advances in the management of women with endometrial cancer have arisen because of a better understanding that there are two types of endometrial cancer – type I and type II.

The type I endometrial cancers tend to be associated with lower stage of disease at the time of diagnosis and fewer recurrences, while type II endometrial cancer is associated with worse outcomes.

Tailoring the surgical approaches and adjuvant therapy for women with endometrial cancer has led to improved outcomes. The GOG conducted a large prospective randomized trial of laparotomy versus laparoscopic surgical staging for women with clinical early-stage endometrial cancer (LAP2). Laparoscopy was associated with improved perioperative outcomes and was found to be noninferior to laparotomy with regards to survival outcomes (J Clin Oncol. 2012 Mar 1;30[7]:695-700). Therefore, minimally invasive surgery has become widely accepted for the surgical staging of women with endometrial cancer.

Appropriate surgical staging allows for tailoring of postoperative adjuvant therapy. The current evidence suggests that vaginal brachytherapy should be the adjuvant treatment of choice over whole pelvic radiation in women with early-stage endometrial cancer (Lancet. 2010 Mar 6;375[9717]:816-23). Studies are underway to evaluate the role of both adjuvant radiation and chemotherapy in women with early-stage type II endometrial cancer who are felt to be at high risk for recurrent disease, as well as how to improve on the therapeutic options for women with advanced or recurrent disease.

Ovarian cancer

Epithelial ovarian cancer is the most deadly gynecologic malignancy in the United States with 21,290 cases and 14,180 deaths in 2015. The concept of ovarian tumor debulking was first described by Dr. Joe Meigs in 1934, but did not gain traction until the mid-1970s when Dr. C. Thomas Griffiths published his work (Natl Cancer Inst Monogr. 1975 Oct;42:101-4).

While there are no randomized trials proving that surgical cytoreduction improves overall survival, most retrospective studies support this concept. In 2009, Chi et al. showed improved median survival in women with ovarian cancer based on the increased percentage of women who underwent optimal cytoreduction (Gynecol Oncol. 2009 Jul;114[1]:26-31). This has led to modifications of surgical techniques and surgical goals with an effort to maximally cytoreduce all of the visible disease.

While initial surgical debulking is the goal, there are circumstances when a different approach may be indicated. Vergote et al. conducted a prospective randomized trial of 670 women with advanced ovarian cancer. In this study, neoadjuvant chemotherapy followed by interval debulking was not inferior to primary debulking followed by chemotherapy with regards to progression-free survival and overall survival. However, initial surgery was associated with increased surgical complications and perioperative mortality as compared with interval surgery. Therefore, in women who are not felt to be candidates for optimal cytoreduction, neoadjuvant chemotherapy followed by interval surgery may be an appropriate treatment strategy (N Engl J Med. 2010 Sep 2;363[10]:943-53.).

Courtesy Wikimedia Commons/James Heilman, MD/CC-BY-SA-3.0

There have been several notable advances and a series of randomized trials – predominately conducted by the GOG – that have resulted in improved overall survival and progression-free interval in women with ovarian cancer. However, none are as significant as the discovery of paclitaxel and platinum-based chemotherapy (cisplatin and carboplatin).

In 1962, samples of the Pacific Yew’s bark were collected and, 2 years later, the extracts from this bark were found to have cytotoxic activity. There were initial difficulties suspending the drug in solution; however, ultimately a formulation in ethanol, cremophor, and saline was found to be effective. In 1984, the National Cancer Institute began clinical trials of paclitaxel and it was found to be highly effective in ovarian cancer. In 1992, it was approved for the treatment of ovarian cancer.

Cisplatin was approved in 1978. Carboplatin entered clinical trials in 1982 and was approved for women with recurrent ovarian cancer in 1989.

There were a series of trials beginning in the late 1980s that established the role of platinum agents and led us to GOG 111. This trial evaluated cisplatin with either cyclophosphamide or paclitaxel. The paclitaxel combination was superior and in 2003 two trials were published that solidified carboplatin and paclitaxel as the cornerstone in the treatment of women with ovarian cancer (J Clin Oncol. 2003 Sep 1;21[17]:3194-200; J Natl Cancer Inst. 2003 Sep 3;95[17]:1320-9).

What has most recently been debated is the route and schedule for both paclitaxel and the platinum agents. In January 2006, the National Cancer Institute released a Clinical Announcement regarding the role of intraperitoneal (IP) chemotherapy for the treatment of women with optimally debulked ovarian cancer. Of the six trials included in the announcement, four trials showed a benefit for progression-free survival and five studies showed an improvement in overall survival. Armstrong et al (GOG 172) showed a 16-month improvement in overall survival with intravenous (IV) paclitaxel, IP cisplatin, and IP paclitaxel. IP chemotherapy has not been universally embraced by physicians and patients in part because of its toxicity, treatment schedule, and the fact that no IP regimen has been compared with the current standard of IV carboplatin and paclitaxel (N Engl J Med. 2006 Jan 5;354[1]:34-43).

While there have been improvements in 5-year survival over time, most women with advanced ovarian cancer will undergo additional chemotherapy in order to achieve subsequent remissions or maintain stability of disease. Other drugs that have Food and Drug Administration approval in the setting of recurrent ovarian cancer include topotecan, liposomal doxorubicin, gemcitabine, bevacizumab, altretamine, carboplatin, cisplatin, cyclophosphamide, and melphalan. Olaparib was recently approved as monotherapy in women with a germline BRCA-mutation who had received three or more prior lines of chemotherapy.

Minimally invasive surgery

Over the last 30 years, minimally invasive surgery (MIS) in gynecologic oncology, particularly for endometrial cancer, has gone from a niche procedure to the standard of care. The introduction of laparoscopy into gynecologic oncology started in the early 1990s. In a series of 59 women undergoing laparoscopy for endometrial cancer, Childers et al. demonstrated feasibility of the technique and low laparotomy conversion rates (Gynecol Oncol. 1993 Oct;51[1]:33-8.). The GOG trial, LAP2, supported the equivalent oncologic outcomes of MIS versus laparotomy for the treatment of endometrial cancer. While many surgeons and centers offered laparoscopic surgery, there were issues with the learning curve that limited its widespread use.

In 2005, the FDA approval of the robotic platform for gynecologic surgery resulted in at least a doubling of the proportion of endometrial cancer patients treated with MIS (Int J Med Robot. 2009 Dec;5[4]:392-7.). In 2012, the Society of Gynecologic Oncology published a consensus statement regarding robotic-assisted surgery in gynecologic oncology (Gynecol Oncol. 2012 Feb;124[2]:180-4.). This review highlights the advantages of the robotics platform with regards to expanding MIS to women with cervical and ovarian cancer; the improvements in outcomes in the obese woman with endometrial cancer; and that the learning curve for robotic surgery is shorter than for traditional laparoscopy. Issues requiring further research include cost analysis as the cost of the new technology decreases, and opportunities for improvement in patient and physician quality of life.

Sentinel node mapping

The rationale for sentinel node mapping is that if one or more sentinel lymph nodes is/are negative for malignancy, then the other regional lymph nodes will also be negative. This would thereby avoid the need for a complete lymph node dissection and its resultant complications, including chronic lymphedema. Much of the work pioneering this strategy has been in breast cancer and melanoma, but data are rapidly emerging for these techniques in gynecologic malignancies.

Candidates for sentinel lymph node biopsy for vulvar cancer include those with a lesion more than 1mm in depth, a tumor less than 4 cm in size, and no obvious metastatic disease on exam or preoperative imaging. Additionally, recommendations have been made regarding case volume in order to achieve limited numbers of false-negative results and to maintain competency. In the study by Van der Zee et al. of 403 patients (623 groins) who underwent sentinel node procedures, the false-negative rate was 0-2%. The overall survival rate was 97% at 3 years (J Clin Oncol. 2008 Feb 20;26[6]:884-9). However, a more recent data from the Gynecologic Oncology Group (GOG 173) showed a slightly higher false-negative rate of 8% (J Clin Oncol. 2012 Nov 1;30[31]:3786-91). Overall survival data are pending from this study.

While sentinel lymph node mapping for endometrial cancer has been feasible for many years and has been well described, the questioned role of completed lymphadenectomy for early-stage endometrial cancer has led to a resurgence of interest in these techniques. While blue dye and radiolabeled tracer methods have historically been the most popular mapping solutions, the advent of endoscopic near-infrared imaging, with its higher sensitivity and good depth penetration, has added options. Indocyanine green fluorescence can be easily detected during robotic surgery and as experience with these techniques increase, successful mapping and sensitivity will increase.

Genetics

While hereditary cancer syndromes have been recognized for many years, detecting the genetic mutations that may increase an individual’s risk of developing a malignancy were not elucidated until the early 1990s. In gynecologic oncology, the most commonly encountered syndromes involve mutations in BRCA1 and BRCA2 and hereditary non–polyposis colorectal cancer, which causes mutations in DNA mismatch-repair genes and increase the risk of endometrial and ovarian cancer.

©Jezperklauzen/ThinkStock

The SGO recently published a statement on risk assessment for inherited gynecologic cancer predispositions. In this statement “the evaluation for the presence of a hereditary cancer syndrome enables physicians to provide individualized and quantified assessment of cancer risk, as well as options for tailored screening and preventions strategies that may reduce morbidity associated with the development of malignancy” (Gynecol Oncol. 2015 Jan;136[1]:3-7). Beyond risk-reducing salpingo-oophorectomy, therapeutic strategies targeting patients with germline mutations have been developed (PARP inhibitors in BRCA-mutated women with ovarian cancer).

In August 2015, ASCO released an updated policy statement on genetic and genomic testing for cancer susceptibility and highlighted five key areas: germ-line implications of somatic mutation profiling; multigene panel testing for cancer susceptibility; quality assurance in genetic testing; education for oncology professionals; and access to cancer genetic services.

Antiemetics

Rounding out ASCO’s “Top 5 advances in 50 years of Modern Oncology” was the improvement in patients’ quality of life from supportive therapies, in particular antinausea medications.

Several of the agents commonly used in gynecologic oncology rate high (cisplatin) to moderate (carboplatin, cyclophosphamide, doxorubicin, ifosfamide) with regards to emetogenicity. The advent of 5-HT3 receptor antagonists (for example, ondansetron) has significantly improved the quality of life of patients undergoing cytotoxic chemotherapy. In addition to improving quality of life, the decrease in nausea and vomiting can also decrease life-threatening complications such as dehydration and electrolyte imbalance. Both ASCO and the National Comprehensive Cancer Network both have guidelines for the management of nausea and vomiting in patients undergoing chemotherapy.

Throughout 2016, Ob.Gyn. News will celebrate its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit. Look for these articles and more special features in the pages of Ob.Gyn. News and online at obgynnews.com.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.

The subspecialty of gynecologic oncology was formalized less than 50 years ago with the creation of the Society of Gynecologic Oncology and subspecialty training and board certification. The formation of the Gynecologic Oncology Group (GOG) – and the many clinical trials spearheaded by that group – has further advanced evidence-based treatments, resulting in improved survival outcomes, quality of life, and preventive strategies.

While it is not possible to provide a comprehensive and exhaustive review of all of the advances, we hope to highlight many of the notable advances in this article.Cervical cancer

Cervical cancer is the fourth most common cancer in women worldwide with 528,000 new cases in 2012. The majority of cervical cancer cases are caused by infection with human papillomavirus (HPV). While the standard therapies for cervical cancer have been long established (radical hysterectomy for stage I and radiation therapy for locally advanced disease), one of the most significant advances in the past 50 years was the addition of radiation-sensitizing chemotherapy (cisplatin) administered concurrently with radiation therapy.

In randomized trials in both early and advanced cervical cancer, the risk of death was reduced by 30%-50%. These studies changed the paradigm for the treatment of cervical cancer (N Engl J Med. 1999 Apr 15;340[15]:1137-43; N Engl J Med. 1999 Apr 15;340[15]:1144-53; J Clin Oncol. 2000 Apr;18[8]:1606-13).

Future studies evaluating biologic adjuncts or additional chemotherapy are currently underway or awaiting data maturation.

The American Society of Clinical Oncology (ASCO) highlighted the “Top 5 advances in 50 years of Modern Oncology” in 2014, and second on the list was the approval of the HPV vaccine to prevent cervical cancer. Vaccines have been developed that can protect against types 2, 4 or 9 of HPV. In a 2014 study, depending on vaccination coverage, the relative number of cervical cancer cases avoided was 34% in Africa, 27% for America, 26% for Asia, 21% for Europe, and worldwide was estimated at 27% (Vaccine. 2014 Feb 3;32[6]:733-9).

While the benefit from HPV vaccination has been proven, in the United States, only about a third of eligible girls and women have been vaccinated. Efforts should focus on expanding vaccination penetration to eligible girls, boys, women, and men.

©xrender/Thinkstock

Endometrial cancer

Endometrial cancer is the most common gynecologic malignancy in the United States with an estimated 54,870 cases and 10,170 deaths annually. Notable advances in the management of women with endometrial cancer have arisen because of a better understanding that there are two types of endometrial cancer – type I and type II.

The type I endometrial cancers tend to be associated with lower stage of disease at the time of diagnosis and fewer recurrences, while type II endometrial cancer is associated with worse outcomes.

Tailoring the surgical approaches and adjuvant therapy for women with endometrial cancer has led to improved outcomes. The GOG conducted a large prospective randomized trial of laparotomy versus laparoscopic surgical staging for women with clinical early-stage endometrial cancer (LAP2). Laparoscopy was associated with improved perioperative outcomes and was found to be noninferior to laparotomy with regards to survival outcomes (J Clin Oncol. 2012 Mar 1;30[7]:695-700). Therefore, minimally invasive surgery has become widely accepted for the surgical staging of women with endometrial cancer.

Appropriate surgical staging allows for tailoring of postoperative adjuvant therapy. The current evidence suggests that vaginal brachytherapy should be the adjuvant treatment of choice over whole pelvic radiation in women with early-stage endometrial cancer (Lancet. 2010 Mar 6;375[9717]:816-23). Studies are underway to evaluate the role of both adjuvant radiation and chemotherapy in women with early-stage type II endometrial cancer who are felt to be at high risk for recurrent disease, as well as how to improve on the therapeutic options for women with advanced or recurrent disease.

Ovarian cancer

Epithelial ovarian cancer is the most deadly gynecologic malignancy in the United States with 21,290 cases and 14,180 deaths in 2015. The concept of ovarian tumor debulking was first described by Dr. Joe Meigs in 1934, but did not gain traction until the mid-1970s when Dr. C. Thomas Griffiths published his work (Natl Cancer Inst Monogr. 1975 Oct;42:101-4).

While there are no randomized trials proving that surgical cytoreduction improves overall survival, most retrospective studies support this concept. In 2009, Chi et al. showed improved median survival in women with ovarian cancer based on the increased percentage of women who underwent optimal cytoreduction (Gynecol Oncol. 2009 Jul;114[1]:26-31). This has led to modifications of surgical techniques and surgical goals with an effort to maximally cytoreduce all of the visible disease.

While initial surgical debulking is the goal, there are circumstances when a different approach may be indicated. Vergote et al. conducted a prospective randomized trial of 670 women with advanced ovarian cancer. In this study, neoadjuvant chemotherapy followed by interval debulking was not inferior to primary debulking followed by chemotherapy with regards to progression-free survival and overall survival. However, initial surgery was associated with increased surgical complications and perioperative mortality as compared with interval surgery. Therefore, in women who are not felt to be candidates for optimal cytoreduction, neoadjuvant chemotherapy followed by interval surgery may be an appropriate treatment strategy (N Engl J Med. 2010 Sep 2;363[10]:943-53.).

Courtesy Wikimedia Commons/James Heilman, MD/CC-BY-SA-3.0

There have been several notable advances and a series of randomized trials – predominately conducted by the GOG – that have resulted in improved overall survival and progression-free interval in women with ovarian cancer. However, none are as significant as the discovery of paclitaxel and platinum-based chemotherapy (cisplatin and carboplatin).

In 1962, samples of the Pacific Yew’s bark were collected and, 2 years later, the extracts from this bark were found to have cytotoxic activity. There were initial difficulties suspending the drug in solution; however, ultimately a formulation in ethanol, cremophor, and saline was found to be effective. In 1984, the National Cancer Institute began clinical trials of paclitaxel and it was found to be highly effective in ovarian cancer. In 1992, it was approved for the treatment of ovarian cancer.

Cisplatin was approved in 1978. Carboplatin entered clinical trials in 1982 and was approved for women with recurrent ovarian cancer in 1989.

There were a series of trials beginning in the late 1980s that established the role of platinum agents and led us to GOG 111. This trial evaluated cisplatin with either cyclophosphamide or paclitaxel. The paclitaxel combination was superior and in 2003 two trials were published that solidified carboplatin and paclitaxel as the cornerstone in the treatment of women with ovarian cancer (J Clin Oncol. 2003 Sep 1;21[17]:3194-200; J Natl Cancer Inst. 2003 Sep 3;95[17]:1320-9).

What has most recently been debated is the route and schedule for both paclitaxel and the platinum agents. In January 2006, the National Cancer Institute released a Clinical Announcement regarding the role of intraperitoneal (IP) chemotherapy for the treatment of women with optimally debulked ovarian cancer. Of the six trials included in the announcement, four trials showed a benefit for progression-free survival and five studies showed an improvement in overall survival. Armstrong et al (GOG 172) showed a 16-month improvement in overall survival with intravenous (IV) paclitaxel, IP cisplatin, and IP paclitaxel. IP chemotherapy has not been universally embraced by physicians and patients in part because of its toxicity, treatment schedule, and the fact that no IP regimen has been compared with the current standard of IV carboplatin and paclitaxel (N Engl J Med. 2006 Jan 5;354[1]:34-43).

While there have been improvements in 5-year survival over time, most women with advanced ovarian cancer will undergo additional chemotherapy in order to achieve subsequent remissions or maintain stability of disease. Other drugs that have Food and Drug Administration approval in the setting of recurrent ovarian cancer include topotecan, liposomal doxorubicin, gemcitabine, bevacizumab, altretamine, carboplatin, cisplatin, cyclophosphamide, and melphalan. Olaparib was recently approved as monotherapy in women with a germline BRCA-mutation who had received three or more prior lines of chemotherapy.

Minimally invasive surgery

Over the last 30 years, minimally invasive surgery (MIS) in gynecologic oncology, particularly for endometrial cancer, has gone from a niche procedure to the standard of care. The introduction of laparoscopy into gynecologic oncology started in the early 1990s. In a series of 59 women undergoing laparoscopy for endometrial cancer, Childers et al. demonstrated feasibility of the technique and low laparotomy conversion rates (Gynecol Oncol. 1993 Oct;51[1]:33-8.). The GOG trial, LAP2, supported the equivalent oncologic outcomes of MIS versus laparotomy for the treatment of endometrial cancer. While many surgeons and centers offered laparoscopic surgery, there were issues with the learning curve that limited its widespread use.

In 2005, the FDA approval of the robotic platform for gynecologic surgery resulted in at least a doubling of the proportion of endometrial cancer patients treated with MIS (Int J Med Robot. 2009 Dec;5[4]:392-7.). In 2012, the Society of Gynecologic Oncology published a consensus statement regarding robotic-assisted surgery in gynecologic oncology (Gynecol Oncol. 2012 Feb;124[2]:180-4.). This review highlights the advantages of the robotics platform with regards to expanding MIS to women with cervical and ovarian cancer; the improvements in outcomes in the obese woman with endometrial cancer; and that the learning curve for robotic surgery is shorter than for traditional laparoscopy. Issues requiring further research include cost analysis as the cost of the new technology decreases, and opportunities for improvement in patient and physician quality of life.

Sentinel node mapping

The rationale for sentinel node mapping is that if one or more sentinel lymph nodes is/are negative for malignancy, then the other regional lymph nodes will also be negative. This would thereby avoid the need for a complete lymph node dissection and its resultant complications, including chronic lymphedema. Much of the work pioneering this strategy has been in breast cancer and melanoma, but data are rapidly emerging for these techniques in gynecologic malignancies.

Candidates for sentinel lymph node biopsy for vulvar cancer include those with a lesion more than 1mm in depth, a tumor less than 4 cm in size, and no obvious metastatic disease on exam or preoperative imaging. Additionally, recommendations have been made regarding case volume in order to achieve limited numbers of false-negative results and to maintain competency. In the study by Van der Zee et al. of 403 patients (623 groins) who underwent sentinel node procedures, the false-negative rate was 0-2%. The overall survival rate was 97% at 3 years (J Clin Oncol. 2008 Feb 20;26[6]:884-9). However, a more recent data from the Gynecologic Oncology Group (GOG 173) showed a slightly higher false-negative rate of 8% (J Clin Oncol. 2012 Nov 1;30[31]:3786-91). Overall survival data are pending from this study.

While sentinel lymph node mapping for endometrial cancer has been feasible for many years and has been well described, the questioned role of completed lymphadenectomy for early-stage endometrial cancer has led to a resurgence of interest in these techniques. While blue dye and radiolabeled tracer methods have historically been the most popular mapping solutions, the advent of endoscopic near-infrared imaging, with its higher sensitivity and good depth penetration, has added options. Indocyanine green fluorescence can be easily detected during robotic surgery and as experience with these techniques increase, successful mapping and sensitivity will increase.

Genetics

While hereditary cancer syndromes have been recognized for many years, detecting the genetic mutations that may increase an individual’s risk of developing a malignancy were not elucidated until the early 1990s. In gynecologic oncology, the most commonly encountered syndromes involve mutations in BRCA1 and BRCA2 and hereditary non–polyposis colorectal cancer, which causes mutations in DNA mismatch-repair genes and increase the risk of endometrial and ovarian cancer.

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The SGO recently published a statement on risk assessment for inherited gynecologic cancer predispositions. In this statement “the evaluation for the presence of a hereditary cancer syndrome enables physicians to provide individualized and quantified assessment of cancer risk, as well as options for tailored screening and preventions strategies that may reduce morbidity associated with the development of malignancy” (Gynecol Oncol. 2015 Jan;136[1]:3-7). Beyond risk-reducing salpingo-oophorectomy, therapeutic strategies targeting patients with germline mutations have been developed (PARP inhibitors in BRCA-mutated women with ovarian cancer).

In August 2015, ASCO released an updated policy statement on genetic and genomic testing for cancer susceptibility and highlighted five key areas: germ-line implications of somatic mutation profiling; multigene panel testing for cancer susceptibility; quality assurance in genetic testing; education for oncology professionals; and access to cancer genetic services.

Antiemetics

Rounding out ASCO’s “Top 5 advances in 50 years of Modern Oncology” was the improvement in patients’ quality of life from supportive therapies, in particular antinausea medications.

Several of the agents commonly used in gynecologic oncology rate high (cisplatin) to moderate (carboplatin, cyclophosphamide, doxorubicin, ifosfamide) with regards to emetogenicity. The advent of 5-HT3 receptor antagonists (for example, ondansetron) has significantly improved the quality of life of patients undergoing cytotoxic chemotherapy. In addition to improving quality of life, the decrease in nausea and vomiting can also decrease life-threatening complications such as dehydration and electrolyte imbalance. Both ASCO and the National Comprehensive Cancer Network both have guidelines for the management of nausea and vomiting in patients undergoing chemotherapy.

Throughout 2016, Ob.Gyn. News will celebrate its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit. Look for these articles and more special features in the pages of Ob.Gyn. News and online at obgynnews.com.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.