No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

mlesney@mdedge.com

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

mlesney@mdedge.com

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

mlesney@mdedge.com

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

Whether “retirement” is withdrawing from one’s occupation or from an active working life, it is of utmost importance to not let one’s mind degenerate. Some individuals move on to gathering new intellectual skills by attending new educational courses or meetings, some travel, some become semiprofessional golfers or fishermen, and some find other forms of personal extension. I now serve to develop cost-saving medical programs for county jails in the state of Texas while attempting to improve the overall quality of inmate care.

Initially I was a pediatrician in Houston with special training in allergy and immunology, but because of a medical problem I was forced to abandon my first love – primary pediatrics. My move to a small town at the age of 40 required me to reevaluate my professional life, and I opted to provide care only in my allergy and immunology specialty.

However, living in a small town is different from life in a metropolis, and it was not uncommon for doctors to be asked to assist the community. A number of years ago, our county judge asked if I would help evaluate why our county jail was spending so much money. After several attempts to refuse, I eventually did evaluate the program there, and was flabbergasted by how much money was being wasted. I made some rather simple suggestions as how to correct the problem, but when no primary care doctor stepped forward to implement the changes and run the jail medical program, I became its medical director. When we saved $120,000 the first year, even I was astounded.

While I continued to run my private practice, I did accept other small community’s offers to look into their county jails’ programs. I found that their problems in cost control and quality of health care mirrored those I found in the first jail, and they were easily solvable if the county judge and the local sheriff wanted solutions. I also found that politics makes strange bedfellows, as the saying goes, and often the obvious changes were met with obstruction in one form or another. Nonetheless, I found that I could serve these communities in addition to my individual patients. When it was time for retirement, I continued to have a real desire to make the towns around which I lived and my own community more livable. So I made my retirement life one that included jail medicine.

In most things, I found that the same business philosophy and personal medical approach I learned in my pediatrics training and as a private practitioner applied to the jail system. Let me mention some specifics. Using generic medicines was less expensive than using brand names. The diagnoses which patients claimed when they entered jail might or might not be correct, so reevaluating the diagnosis and treatment was appropriate as soon as possible. Hospital and ED visits should be limited to patients’ medically requiring them rather than using the ED as a screening tool.

But I did come to understand that medical care in the county jail is different from medical care outside an incarcerated facility in that sometimes the prisoners had their own reasons for seeking medical care. This was complicated by the fact that often there were critically ill patients presenting to county jails. So carefully established criteria and protocols were an absolute necessity to save lives.

Let me expand on the topic of seeking medical care by the inmate-patients. A relatively small number of these individuals required immediate emergency treatment, without which they could not do well: The diabetic who was not taking his insulin, the out-of-control paranoid schizophrenic who decided he was cured and therefore was unattended, the alcoholic or drug addict who would develop delirium tremens if medications were stopped abruptly. These people had to be identified as quickly as possible and correctly treated. Confounding the problem was the fact that many, and I repeat many, individuals try to use the medical route to manipulate their incarceration environment. I called this the B problem: beds, blankets, barter, buzz, better food, and be out of here. They might claim an illness existed, and often they might believe it did.

A related situation might exist when individuals would demand psychiatric and pain medications, often in large quantities, when they in fact had not taken them for some time in the outside world. Often these patients were addicts, and of course this could create an entire other relationship with the medical team. A third example would be the claim of hypoglycemia so that the prisoner would receive more frequent meals.

One might think that as a pediatrician I was ill prepared to treat adults, and in fact, there was much review of the general medical care needed when I began this program. However, the internists and family physicians in town were glad to assist me whenever I encountered a difficult patient. When hospitalizations were required, the inpatient always was covered by one of the internists on hospital staff. Quite frankly, the doctors seemed pleased to not be dealing with this group of individuals as much as they had in the past.

On a slightly different note, skills honed during my pediatric career were extremely valuable. Children, particularly young children, do not verbally communicate with their parents or their doctor particularly well, so pediatricians are well trained in the skill of observation. The patient who claims a guard hurt his shoulder so badly during an altercation that he cannot move it is found out when he easily whips his arms over his head when asked to remove his shirt. It is not uncommon for an individual to demand antidepressant medications from the medical staff, but when evaluated more thoroughly and for a longer period of time, the patient ends up laughing, even denying any suicidal ideation or any other sign of depression. One also deals with a lot of adolescent behavior from the inmates, such as the individuals who say that unless they don’t get their way (more food) they are not going to take their medications and thus get sicker. That’s Adolescent Medicine 101.

Some of the modalities I utilized in modifying the jail programs will be familiar to every practicing pediatrician. I educate; I teach; I train. Parents of my asthmatic patients had to know what medications to keep handy and when to use them. It is pretty easy to see how that relates to jail medicine. Many patients come into jail with inhalers and with a diagnosis of asthma. Some have the condition, and some do not. By training jail and medical staff how to observe breathing patterns and by performing pulse oximetry, we eliminated a large number of unnecessary ED visits, and we often made the diagnosis of hyperventilation syndrome rather than misdiagnosed asthma.

Jail medicine is a large part of the cost of housing inmates. I did consultation work for a large urban jail, and we saved over $7 million in 1 year. In a medium-sized jail, the cost-savings after a 4-month consultation was over $300,000. This is a lot of money to me, and I suspect is to you, too. Just as in our general communities, we have enough resources to provide medical care and to provide a high level of care for all. However, we cannot waste money by providing inappropriate care or overtesting or overtreating. The medical care must be what treats the disease the patient actually has ... nothing more and nothing less!

If it sounds as if I am cynical about inmate patients, that is not true. However, I am realistic that no one wishes to be in jail. I realize that the medical route is just one that prisoners can and do use to modify their situation. I understand that the medical staff within a jail needs constant education and supervision at first, and with time they become more astute – just like a physician in this arena – at distinguishing the very serious from the mildly serious from malingering. In spite of this, we doctors also can be fooled. However, through constant vigilance and constant education we can get better.

Jail medicine is not for everyone in retirement. Heck, it is not for everyone ever. I found it interesting because it required me to match my diagnostic skills against the diseases and the psychodynamics of individuals who often – not always – made that diagnosis more difficult. Diagnosing illness and curing it – isn’t this why we all went into medicine?
 

Dr. Yoffe is a retired pediatrician specializing in allergy and immunology who resides in Brenham, Tex. Email him at pdnews@mdedge.com.

This article was updated 2/13/2020.

Whether “retirement” is withdrawing from one’s occupation or from an active working life, it is of utmost importance to not let one’s mind degenerate. Some individuals move on to gathering new intellectual skills by attending new educational courses or meetings, some travel, some become semiprofessional golfers or fishermen, and some find other forms of personal extension. I now serve to develop cost-saving medical programs for county jails in the state of Texas while attempting to improve the overall quality of inmate care.

Initially I was a pediatrician in Houston with special training in allergy and immunology, but because of a medical problem I was forced to abandon my first love – primary pediatrics. My move to a small town at the age of 40 required me to reevaluate my professional life, and I opted to provide care only in my allergy and immunology specialty.

However, living in a small town is different from life in a metropolis, and it was not uncommon for doctors to be asked to assist the community. A number of years ago, our county judge asked if I would help evaluate why our county jail was spending so much money. After several attempts to refuse, I eventually did evaluate the program there, and was flabbergasted by how much money was being wasted. I made some rather simple suggestions as how to correct the problem, but when no primary care doctor stepped forward to implement the changes and run the jail medical program, I became its medical director. When we saved $120,000 the first year, even I was astounded.

While I continued to run my private practice, I did accept other small community’s offers to look into their county jails’ programs. I found that their problems in cost control and quality of health care mirrored those I found in the first jail, and they were easily solvable if the county judge and the local sheriff wanted solutions. I also found that politics makes strange bedfellows, as the saying goes, and often the obvious changes were met with obstruction in one form or another. Nonetheless, I found that I could serve these communities in addition to my individual patients. When it was time for retirement, I continued to have a real desire to make the towns around which I lived and my own community more livable. So I made my retirement life one that included jail medicine.

In most things, I found that the same business philosophy and personal medical approach I learned in my pediatrics training and as a private practitioner applied to the jail system. Let me mention some specifics. Using generic medicines was less expensive than using brand names. The diagnoses which patients claimed when they entered jail might or might not be correct, so reevaluating the diagnosis and treatment was appropriate as soon as possible. Hospital and ED visits should be limited to patients’ medically requiring them rather than using the ED as a screening tool.

But I did come to understand that medical care in the county jail is different from medical care outside an incarcerated facility in that sometimes the prisoners had their own reasons for seeking medical care. This was complicated by the fact that often there were critically ill patients presenting to county jails. So carefully established criteria and protocols were an absolute necessity to save lives.

Let me expand on the topic of seeking medical care by the inmate-patients. A relatively small number of these individuals required immediate emergency treatment, without which they could not do well: The diabetic who was not taking his insulin, the out-of-control paranoid schizophrenic who decided he was cured and therefore was unattended, the alcoholic or drug addict who would develop delirium tremens if medications were stopped abruptly. These people had to be identified as quickly as possible and correctly treated. Confounding the problem was the fact that many, and I repeat many, individuals try to use the medical route to manipulate their incarceration environment. I called this the B problem: beds, blankets, barter, buzz, better food, and be out of here. They might claim an illness existed, and often they might believe it did.

A related situation might exist when individuals would demand psychiatric and pain medications, often in large quantities, when they in fact had not taken them for some time in the outside world. Often these patients were addicts, and of course this could create an entire other relationship with the medical team. A third example would be the claim of hypoglycemia so that the prisoner would receive more frequent meals.

One might think that as a pediatrician I was ill prepared to treat adults, and in fact, there was much review of the general medical care needed when I began this program. However, the internists and family physicians in town were glad to assist me whenever I encountered a difficult patient. When hospitalizations were required, the inpatient always was covered by one of the internists on hospital staff. Quite frankly, the doctors seemed pleased to not be dealing with this group of individuals as much as they had in the past.

On a slightly different note, skills honed during my pediatric career were extremely valuable. Children, particularly young children, do not verbally communicate with their parents or their doctor particularly well, so pediatricians are well trained in the skill of observation. The patient who claims a guard hurt his shoulder so badly during an altercation that he cannot move it is found out when he easily whips his arms over his head when asked to remove his shirt. It is not uncommon for an individual to demand antidepressant medications from the medical staff, but when evaluated more thoroughly and for a longer period of time, the patient ends up laughing, even denying any suicidal ideation or any other sign of depression. One also deals with a lot of adolescent behavior from the inmates, such as the individuals who say that unless they don’t get their way (more food) they are not going to take their medications and thus get sicker. That’s Adolescent Medicine 101.

Some of the modalities I utilized in modifying the jail programs will be familiar to every practicing pediatrician. I educate; I teach; I train. Parents of my asthmatic patients had to know what medications to keep handy and when to use them. It is pretty easy to see how that relates to jail medicine. Many patients come into jail with inhalers and with a diagnosis of asthma. Some have the condition, and some do not. By training jail and medical staff how to observe breathing patterns and by performing pulse oximetry, we eliminated a large number of unnecessary ED visits, and we often made the diagnosis of hyperventilation syndrome rather than misdiagnosed asthma.

Jail medicine is a large part of the cost of housing inmates. I did consultation work for a large urban jail, and we saved over $7 million in 1 year. In a medium-sized jail, the cost-savings after a 4-month consultation was over $300,000. This is a lot of money to me, and I suspect is to you, too. Just as in our general communities, we have enough resources to provide medical care and to provide a high level of care for all. However, we cannot waste money by providing inappropriate care or overtesting or overtreating. The medical care must be what treats the disease the patient actually has ... nothing more and nothing less!

If it sounds as if I am cynical about inmate patients, that is not true. However, I am realistic that no one wishes to be in jail. I realize that the medical route is just one that prisoners can and do use to modify their situation. I understand that the medical staff within a jail needs constant education and supervision at first, and with time they become more astute – just like a physician in this arena – at distinguishing the very serious from the mildly serious from malingering. In spite of this, we doctors also can be fooled. However, through constant vigilance and constant education we can get better.

Jail medicine is not for everyone in retirement. Heck, it is not for everyone ever. I found it interesting because it required me to match my diagnostic skills against the diseases and the psychodynamics of individuals who often – not always – made that diagnosis more difficult. Diagnosing illness and curing it – isn’t this why we all went into medicine?
 

Dr. Yoffe is a retired pediatrician specializing in allergy and immunology who resides in Brenham, Tex. Email him at pdnews@mdedge.com.

This article was updated 2/13/2020.

Whether “retirement” is withdrawing from one’s occupation or from an active working life, it is of utmost importance to not let one’s mind degenerate. Some individuals move on to gathering new intellectual skills by attending new educational courses or meetings, some travel, some become semiprofessional golfers or fishermen, and some find other forms of personal extension. I now serve to develop cost-saving medical programs for county jails in the state of Texas while attempting to improve the overall quality of inmate care.

Initially I was a pediatrician in Houston with special training in allergy and immunology, but because of a medical problem I was forced to abandon my first love – primary pediatrics. My move to a small town at the age of 40 required me to reevaluate my professional life, and I opted to provide care only in my allergy and immunology specialty.

However, living in a small town is different from life in a metropolis, and it was not uncommon for doctors to be asked to assist the community. A number of years ago, our county judge asked if I would help evaluate why our county jail was spending so much money. After several attempts to refuse, I eventually did evaluate the program there, and was flabbergasted by how much money was being wasted. I made some rather simple suggestions as how to correct the problem, but when no primary care doctor stepped forward to implement the changes and run the jail medical program, I became its medical director. When we saved $120,000 the first year, even I was astounded.

While I continued to run my private practice, I did accept other small community’s offers to look into their county jails’ programs. I found that their problems in cost control and quality of health care mirrored those I found in the first jail, and they were easily solvable if the county judge and the local sheriff wanted solutions. I also found that politics makes strange bedfellows, as the saying goes, and often the obvious changes were met with obstruction in one form or another. Nonetheless, I found that I could serve these communities in addition to my individual patients. When it was time for retirement, I continued to have a real desire to make the towns around which I lived and my own community more livable. So I made my retirement life one that included jail medicine.

In most things, I found that the same business philosophy and personal medical approach I learned in my pediatrics training and as a private practitioner applied to the jail system. Let me mention some specifics. Using generic medicines was less expensive than using brand names. The diagnoses which patients claimed when they entered jail might or might not be correct, so reevaluating the diagnosis and treatment was appropriate as soon as possible. Hospital and ED visits should be limited to patients’ medically requiring them rather than using the ED as a screening tool.

But I did come to understand that medical care in the county jail is different from medical care outside an incarcerated facility in that sometimes the prisoners had their own reasons for seeking medical care. This was complicated by the fact that often there were critically ill patients presenting to county jails. So carefully established criteria and protocols were an absolute necessity to save lives.

Let me expand on the topic of seeking medical care by the inmate-patients. A relatively small number of these individuals required immediate emergency treatment, without which they could not do well: The diabetic who was not taking his insulin, the out-of-control paranoid schizophrenic who decided he was cured and therefore was unattended, the alcoholic or drug addict who would develop delirium tremens if medications were stopped abruptly. These people had to be identified as quickly as possible and correctly treated. Confounding the problem was the fact that many, and I repeat many, individuals try to use the medical route to manipulate their incarceration environment. I called this the B problem: beds, blankets, barter, buzz, better food, and be out of here. They might claim an illness existed, and often they might believe it did.

A related situation might exist when individuals would demand psychiatric and pain medications, often in large quantities, when they in fact had not taken them for some time in the outside world. Often these patients were addicts, and of course this could create an entire other relationship with the medical team. A third example would be the claim of hypoglycemia so that the prisoner would receive more frequent meals.

One might think that as a pediatrician I was ill prepared to treat adults, and in fact, there was much review of the general medical care needed when I began this program. However, the internists and family physicians in town were glad to assist me whenever I encountered a difficult patient. When hospitalizations were required, the inpatient always was covered by one of the internists on hospital staff. Quite frankly, the doctors seemed pleased to not be dealing with this group of individuals as much as they had in the past.

On a slightly different note, skills honed during my pediatric career were extremely valuable. Children, particularly young children, do not verbally communicate with their parents or their doctor particularly well, so pediatricians are well trained in the skill of observation. The patient who claims a guard hurt his shoulder so badly during an altercation that he cannot move it is found out when he easily whips his arms over his head when asked to remove his shirt. It is not uncommon for an individual to demand antidepressant medications from the medical staff, but when evaluated more thoroughly and for a longer period of time, the patient ends up laughing, even denying any suicidal ideation or any other sign of depression. One also deals with a lot of adolescent behavior from the inmates, such as the individuals who say that unless they don’t get their way (more food) they are not going to take their medications and thus get sicker. That’s Adolescent Medicine 101.

Some of the modalities I utilized in modifying the jail programs will be familiar to every practicing pediatrician. I educate; I teach; I train. Parents of my asthmatic patients had to know what medications to keep handy and when to use them. It is pretty easy to see how that relates to jail medicine. Many patients come into jail with inhalers and with a diagnosis of asthma. Some have the condition, and some do not. By training jail and medical staff how to observe breathing patterns and by performing pulse oximetry, we eliminated a large number of unnecessary ED visits, and we often made the diagnosis of hyperventilation syndrome rather than misdiagnosed asthma.

Jail medicine is a large part of the cost of housing inmates. I did consultation work for a large urban jail, and we saved over $7 million in 1 year. In a medium-sized jail, the cost-savings after a 4-month consultation was over $300,000. This is a lot of money to me, and I suspect is to you, too. Just as in our general communities, we have enough resources to provide medical care and to provide a high level of care for all. However, we cannot waste money by providing inappropriate care or overtesting or overtreating. The medical care must be what treats the disease the patient actually has ... nothing more and nothing less!

If it sounds as if I am cynical about inmate patients, that is not true. However, I am realistic that no one wishes to be in jail. I realize that the medical route is just one that prisoners can and do use to modify their situation. I understand that the medical staff within a jail needs constant education and supervision at first, and with time they become more astute – just like a physician in this arena – at distinguishing the very serious from the mildly serious from malingering. In spite of this, we doctors also can be fooled. However, through constant vigilance and constant education we can get better.

Jail medicine is not for everyone in retirement. Heck, it is not for everyone ever. I found it interesting because it required me to match my diagnostic skills against the diseases and the psychodynamics of individuals who often – not always – made that diagnosis more difficult. Diagnosing illness and curing it – isn’t this why we all went into medicine?
 

Dr. Yoffe is a retired pediatrician specializing in allergy and immunology who resides in Brenham, Tex. Email him at pdnews@mdedge.com.

This article was updated 2/13/2020.

The patient’s biopsy showed sparse and grouped and slightly enlarged atypical stained mononuclear cells in mostly perifollicular areas with focal epidermotropism. CD30 staining was positive. She responded to potent topical steroids.

Lymphomatoid papulosis (LyP) is an uncommon skin disorder. While all ages may be affected, the peak incidence occurs in the fourth or fifth decade. The etiology of LyP is unknown. It is unclear whether the proliferation of T-cells is a benign and chronic disorder, or an indolent T-cell malignancy.

In addition, 10% of LyP cases are associated with anaplastic large-cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin lymphoma. Borderline cases are those that overlap LyP and lymphoma.

Patients typically present with crops of asymptomatic erythematous to brown papules that may become pustular, vesicular, or necrotic. Lesions tend to resolve within 2-8 weeks with or without scarring. The trunk and extremities are commonly affected. The condition tends to be chronic over months to years. The waxing and waning course is characteristic of LyP. Constitutional symptoms are generally absent in cases not associated with systemic disease.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

The patient’s biopsy showed sparse and grouped and slightly enlarged atypical stained mononuclear cells in mostly perifollicular areas with focal epidermotropism. CD30 staining was positive. She responded to potent topical steroids.

Lymphomatoid papulosis (LyP) is an uncommon skin disorder. While all ages may be affected, the peak incidence occurs in the fourth or fifth decade. The etiology of LyP is unknown. It is unclear whether the proliferation of T-cells is a benign and chronic disorder, or an indolent T-cell malignancy.

In addition, 10% of LyP cases are associated with anaplastic large-cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin lymphoma. Borderline cases are those that overlap LyP and lymphoma.

Patients typically present with crops of asymptomatic erythematous to brown papules that may become pustular, vesicular, or necrotic. Lesions tend to resolve within 2-8 weeks with or without scarring. The trunk and extremities are commonly affected. The condition tends to be chronic over months to years. The waxing and waning course is characteristic of LyP. Constitutional symptoms are generally absent in cases not associated with systemic disease.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

The patient’s biopsy showed sparse and grouped and slightly enlarged atypical stained mononuclear cells in mostly perifollicular areas with focal epidermotropism. CD30 staining was positive. She responded to potent topical steroids.

Lymphomatoid papulosis (LyP) is an uncommon skin disorder. While all ages may be affected, the peak incidence occurs in the fourth or fifth decade. The etiology of LyP is unknown. It is unclear whether the proliferation of T-cells is a benign and chronic disorder, or an indolent T-cell malignancy.

In addition, 10% of LyP cases are associated with anaplastic large-cell lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), or Hodgkin lymphoma. Borderline cases are those that overlap LyP and lymphoma.

Patients typically present with crops of asymptomatic erythematous to brown papules that may become pustular, vesicular, or necrotic. Lesions tend to resolve within 2-8 weeks with or without scarring. The trunk and extremities are commonly affected. The condition tends to be chronic over months to years. The waxing and waning course is characteristic of LyP. Constitutional symptoms are generally absent in cases not associated with systemic disease.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Pediatricians are twice as likely to be happy outside the office than they are at work, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 29% of pediatricians reported being happy at work, with dermatologists taking the top spot at 41%. Pediatricians did much better when it came to finding happiness outside the office, with 57% reporting that they were very happy when away from work, according to the Medscape report.

The rate of burnout in pediatricians (41%) was the same as it was in physicians overall. The biggest contributing factors to burnout in pediatricians were an overabundance of bureaucratic tasks (59%), insufficient compensation/reimbursement (37%), and spending too many hours at work (34%).

Pediatricians most commonly dealt with burnout by talking with friends/family (54%), exercising (47%), and sleeping (41%). Just over half of pediatricians reported taking 3-4 weeks of vacation, compared with 44% of all physicians; 32% took less than 3 weeks’ vacation.

About 8% of pediatricians reported that they’d contemplated suicide, but 0% reported that they’d attempted it; 85% said that they’d never thought about it. Just under one-quarter of pediatricians said that were currently seeking or planning to seek professional help for depression and/or burnout; 55% said they were not seeking help and had never made use of it in the past.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

lfranki@mdedge.com

Pediatricians are twice as likely to be happy outside the office than they are at work, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 29% of pediatricians reported being happy at work, with dermatologists taking the top spot at 41%. Pediatricians did much better when it came to finding happiness outside the office, with 57% reporting that they were very happy when away from work, according to the Medscape report.

The rate of burnout in pediatricians (41%) was the same as it was in physicians overall. The biggest contributing factors to burnout in pediatricians were an overabundance of bureaucratic tasks (59%), insufficient compensation/reimbursement (37%), and spending too many hours at work (34%).

Pediatricians most commonly dealt with burnout by talking with friends/family (54%), exercising (47%), and sleeping (41%). Just over half of pediatricians reported taking 3-4 weeks of vacation, compared with 44% of all physicians; 32% took less than 3 weeks’ vacation.

About 8% of pediatricians reported that they’d contemplated suicide, but 0% reported that they’d attempted it; 85% said that they’d never thought about it. Just under one-quarter of pediatricians said that were currently seeking or planning to seek professional help for depression and/or burnout; 55% said they were not seeking help and had never made use of it in the past.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

lfranki@mdedge.com

Pediatricians are twice as likely to be happy outside the office than they are at work, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 29% of pediatricians reported being happy at work, with dermatologists taking the top spot at 41%. Pediatricians did much better when it came to finding happiness outside the office, with 57% reporting that they were very happy when away from work, according to the Medscape report.

The rate of burnout in pediatricians (41%) was the same as it was in physicians overall. The biggest contributing factors to burnout in pediatricians were an overabundance of bureaucratic tasks (59%), insufficient compensation/reimbursement (37%), and spending too many hours at work (34%).

Pediatricians most commonly dealt with burnout by talking with friends/family (54%), exercising (47%), and sleeping (41%). Just over half of pediatricians reported taking 3-4 weeks of vacation, compared with 44% of all physicians; 32% took less than 3 weeks’ vacation.

About 8% of pediatricians reported that they’d contemplated suicide, but 0% reported that they’d attempted it; 85% said that they’d never thought about it. Just under one-quarter of pediatricians said that were currently seeking or planning to seek professional help for depression and/or burnout; 55% said they were not seeking help and had never made use of it in the past.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

lfranki@mdedge.com

Neonatal transfer was the factor most often associated with unexpected, severe complications at birth, particularly at hospitals that had the highest rates of complications, according to a cross-sectional study published online in JAMA Network Open (2020;3[2]:e1919498).

“Transfers were more likely to be necessary when infants were born in hospitals with lower levels of neonatal care,” Mark A. Clapp, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues wrote. “Thus, if this metric is to be used in its current form, it would appear that accreditors, regulatory bodies, and payers should consider adjusting for or stratifying by a hospital’s level of neonatal care to avoid disincentivizing against appropriate transfers.”

The Joint Commission recently included unexpected complications in term newborns as a marker of quality of obstetric care, but it does not currently recommend any risk adjustment for the metric. The authors aimed to learn which factors regarding patients and hospitals were associated with such complications. Severe, unexpected newborn complications include death, seizure, use of assisted ventilation for at least 6 hours, transfer to another facility, or a 5-minute Apgar score of 3 or less.

“This measure has been proposed to serve as a balancing measure to maternal metrics, such as the rate of nulliparous, term, singleton, vertex-presenting cesarean deliveries,” the authors explained.

This study was supported by a Health Policy Award from the Society for Maternal-Fetal Medicine. The authors reported no relevant financial disclosures.

This story first appeared on Medscape.

Neonatal transfer was the factor most often associated with unexpected, severe complications at birth, particularly at hospitals that had the highest rates of complications, according to a cross-sectional study published online in JAMA Network Open (2020;3[2]:e1919498).

“Transfers were more likely to be necessary when infants were born in hospitals with lower levels of neonatal care,” Mark A. Clapp, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues wrote. “Thus, if this metric is to be used in its current form, it would appear that accreditors, regulatory bodies, and payers should consider adjusting for or stratifying by a hospital’s level of neonatal care to avoid disincentivizing against appropriate transfers.”

The Joint Commission recently included unexpected complications in term newborns as a marker of quality of obstetric care, but it does not currently recommend any risk adjustment for the metric. The authors aimed to learn which factors regarding patients and hospitals were associated with such complications. Severe, unexpected newborn complications include death, seizure, use of assisted ventilation for at least 6 hours, transfer to another facility, or a 5-minute Apgar score of 3 or less.

“This measure has been proposed to serve as a balancing measure to maternal metrics, such as the rate of nulliparous, term, singleton, vertex-presenting cesarean deliveries,” the authors explained.

This study was supported by a Health Policy Award from the Society for Maternal-Fetal Medicine. The authors reported no relevant financial disclosures.

This story first appeared on Medscape.

Neonatal transfer was the factor most often associated with unexpected, severe complications at birth, particularly at hospitals that had the highest rates of complications, according to a cross-sectional study published online in JAMA Network Open (2020;3[2]:e1919498).

“Transfers were more likely to be necessary when infants were born in hospitals with lower levels of neonatal care,” Mark A. Clapp, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues wrote. “Thus, if this metric is to be used in its current form, it would appear that accreditors, regulatory bodies, and payers should consider adjusting for or stratifying by a hospital’s level of neonatal care to avoid disincentivizing against appropriate transfers.”

The Joint Commission recently included unexpected complications in term newborns as a marker of quality of obstetric care, but it does not currently recommend any risk adjustment for the metric. The authors aimed to learn which factors regarding patients and hospitals were associated with such complications. Severe, unexpected newborn complications include death, seizure, use of assisted ventilation for at least 6 hours, transfer to another facility, or a 5-minute Apgar score of 3 or less.

“This measure has been proposed to serve as a balancing measure to maternal metrics, such as the rate of nulliparous, term, singleton, vertex-presenting cesarean deliveries,” the authors explained.

This study was supported by a Health Policy Award from the Society for Maternal-Fetal Medicine. The authors reported no relevant financial disclosures.

This story first appeared on Medscape.

Men with low-volume, advanced prostate cancer who carry one or more adrenal-permissive alleles of the HSD3B1 gene have worse prognosis than do men with adrenal-restrictive alleles of HSD3B1, a retrospective analysis suggests.

Among 475 white men in the CHAARTED trial, those with the adrenal-permissive allele, HSD3B1(1245C), had a nearly twofold greater risk for developing early castration-resistant prostate cancer (CRPC) and for lower overall survival, compared with men who had the adrenal-restrictive allele, HSD3B1(1245A).

“Our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume, metastatic prostate cancer,” Jason W.D. Hearn, MD, of the University of Michigan in Ann Arbor and colleagues wrote in JAMA Oncology.

HSD3B1 encodes for an enzyme involved in regulating the rate of metabolic conversion of the precursor hormone dehydroepiandrosterone into testosterone and dihydrotestosterone in prostate tissues. A common missense-encoding germline mutation in the gene leads to variant metabolic phenotypes, including the adrenal-permissive type that allows for ramped-up conversion of the precursor hormone into dihydrotestosterone and the adrenal-restrictive type that results in more rapid enzyme degradation, limiting the conversion from the precursor into the active hormone.

“The population frequency of the adrenal-permissive HSD3B1(1245C) allele varies tremendously by race and is disproportionally high in white men (e.g., carried in approximately 70% of Italian and Spanish men and only about 9% of Yoruba Nigerian men),” Dr. Hearn and colleagues wrote.

Previous studies have suggested that men with both metastatic and nonmetastatic prostate cancer who inherit the adrenal permissive HSD3B1(1245C) allele have worse clinical outcomes, compared with men without that allele.

To validate these findings, Dr. Hearn and colleagues retrospectively determined the germline genotype of HSD3B1 for 475 white men enrolled in CHAARTED. In that trial, men with metastatic, hormone-sensitive prostate cancer were randomized to either castration alone or castration plus docetaxel. The current analysis showed that 270 of those patients carried the adrenal-permissive allele.

Among patients with low-volume disease, the adrenal-permissive genotype was associated with significantly lower freedom from CRPC at 2 years, compared with the adrenal-restrictive genotype: 51% and 70.5%, respectively (hazard ratio, 1.89; P = .02). The 5-year overall survival rate was significantly lower for adrenal-permissive allele carriers than adrenal-restrictive allele carriers: 57.5% and 70.8%, respectively (HR, 1.74; P = .045).

Among men with high-volume disease, there was no association between HSD3B1 genotypes and outcomes, and there was no interaction between genotype and benefit from docetaxel. High-volume disease was defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebral bodies.

“Regardless of genotype, men with high-volume disease achieved better outcomes when docetaxel was added to ADT [androgen deprivation therapy], whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” the investigators wrote.

The trial was funded by the National Cancer Institute. The authors disclosed relationships with several pharmaceutical companies. One author is a coinventor on a patent for a treatment method based on HSD3B1.

SOURCE: Hearn JWD et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6496.

Men with low-volume, advanced prostate cancer who carry one or more adrenal-permissive alleles of the HSD3B1 gene have worse prognosis than do men with adrenal-restrictive alleles of HSD3B1, a retrospective analysis suggests.

Among 475 white men in the CHAARTED trial, those with the adrenal-permissive allele, HSD3B1(1245C), had a nearly twofold greater risk for developing early castration-resistant prostate cancer (CRPC) and for lower overall survival, compared with men who had the adrenal-restrictive allele, HSD3B1(1245A).

“Our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume, metastatic prostate cancer,” Jason W.D. Hearn, MD, of the University of Michigan in Ann Arbor and colleagues wrote in JAMA Oncology.

HSD3B1 encodes for an enzyme involved in regulating the rate of metabolic conversion of the precursor hormone dehydroepiandrosterone into testosterone and dihydrotestosterone in prostate tissues. A common missense-encoding germline mutation in the gene leads to variant metabolic phenotypes, including the adrenal-permissive type that allows for ramped-up conversion of the precursor hormone into dihydrotestosterone and the adrenal-restrictive type that results in more rapid enzyme degradation, limiting the conversion from the precursor into the active hormone.

“The population frequency of the adrenal-permissive HSD3B1(1245C) allele varies tremendously by race and is disproportionally high in white men (e.g., carried in approximately 70% of Italian and Spanish men and only about 9% of Yoruba Nigerian men),” Dr. Hearn and colleagues wrote.

Previous studies have suggested that men with both metastatic and nonmetastatic prostate cancer who inherit the adrenal permissive HSD3B1(1245C) allele have worse clinical outcomes, compared with men without that allele.

To validate these findings, Dr. Hearn and colleagues retrospectively determined the germline genotype of HSD3B1 for 475 white men enrolled in CHAARTED. In that trial, men with metastatic, hormone-sensitive prostate cancer were randomized to either castration alone or castration plus docetaxel. The current analysis showed that 270 of those patients carried the adrenal-permissive allele.

Among patients with low-volume disease, the adrenal-permissive genotype was associated with significantly lower freedom from CRPC at 2 years, compared with the adrenal-restrictive genotype: 51% and 70.5%, respectively (hazard ratio, 1.89; P = .02). The 5-year overall survival rate was significantly lower for adrenal-permissive allele carriers than adrenal-restrictive allele carriers: 57.5% and 70.8%, respectively (HR, 1.74; P = .045).

Among men with high-volume disease, there was no association between HSD3B1 genotypes and outcomes, and there was no interaction between genotype and benefit from docetaxel. High-volume disease was defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebral bodies.

“Regardless of genotype, men with high-volume disease achieved better outcomes when docetaxel was added to ADT [androgen deprivation therapy], whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” the investigators wrote.

The trial was funded by the National Cancer Institute. The authors disclosed relationships with several pharmaceutical companies. One author is a coinventor on a patent for a treatment method based on HSD3B1.

SOURCE: Hearn JWD et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6496.

Men with low-volume, advanced prostate cancer who carry one or more adrenal-permissive alleles of the HSD3B1 gene have worse prognosis than do men with adrenal-restrictive alleles of HSD3B1, a retrospective analysis suggests.

Among 475 white men in the CHAARTED trial, those with the adrenal-permissive allele, HSD3B1(1245C), had a nearly twofold greater risk for developing early castration-resistant prostate cancer (CRPC) and for lower overall survival, compared with men who had the adrenal-restrictive allele, HSD3B1(1245A).

“Our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume, metastatic prostate cancer,” Jason W.D. Hearn, MD, of the University of Michigan in Ann Arbor and colleagues wrote in JAMA Oncology.

HSD3B1 encodes for an enzyme involved in regulating the rate of metabolic conversion of the precursor hormone dehydroepiandrosterone into testosterone and dihydrotestosterone in prostate tissues. A common missense-encoding germline mutation in the gene leads to variant metabolic phenotypes, including the adrenal-permissive type that allows for ramped-up conversion of the precursor hormone into dihydrotestosterone and the adrenal-restrictive type that results in more rapid enzyme degradation, limiting the conversion from the precursor into the active hormone.

“The population frequency of the adrenal-permissive HSD3B1(1245C) allele varies tremendously by race and is disproportionally high in white men (e.g., carried in approximately 70% of Italian and Spanish men and only about 9% of Yoruba Nigerian men),” Dr. Hearn and colleagues wrote.

Previous studies have suggested that men with both metastatic and nonmetastatic prostate cancer who inherit the adrenal permissive HSD3B1(1245C) allele have worse clinical outcomes, compared with men without that allele.

To validate these findings, Dr. Hearn and colleagues retrospectively determined the germline genotype of HSD3B1 for 475 white men enrolled in CHAARTED. In that trial, men with metastatic, hormone-sensitive prostate cancer were randomized to either castration alone or castration plus docetaxel. The current analysis showed that 270 of those patients carried the adrenal-permissive allele.

Among patients with low-volume disease, the adrenal-permissive genotype was associated with significantly lower freedom from CRPC at 2 years, compared with the adrenal-restrictive genotype: 51% and 70.5%, respectively (hazard ratio, 1.89; P = .02). The 5-year overall survival rate was significantly lower for adrenal-permissive allele carriers than adrenal-restrictive allele carriers: 57.5% and 70.8%, respectively (HR, 1.74; P = .045).

Among men with high-volume disease, there was no association between HSD3B1 genotypes and outcomes, and there was no interaction between genotype and benefit from docetaxel. High-volume disease was defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebral bodies.

“Regardless of genotype, men with high-volume disease achieved better outcomes when docetaxel was added to ADT [androgen deprivation therapy], whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” the investigators wrote.

The trial was funded by the National Cancer Institute. The authors disclosed relationships with several pharmaceutical companies. One author is a coinventor on a patent for a treatment method based on HSD3B1.

SOURCE: Hearn JWD et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6496.

Adding pembrolizumab to neoadjuvant chemotherapy more than doubled the rate of pathologic complete response, compared with chemotherapy alone, in women with early-stage breast cancer enrolled in the phase 2 I-SPY2 trial.

Dr. Cecil Fox/National Cancer Institute

Pathologic complete response (pCR) rates up to 60% were reported for patients with high-risk, stage II/III breast cancer who received pembrolizumab plus chemotherapy in I-SPY2, an ongoing platform trial designed to rapidly screen multiple agents and pinpoint those with a high probability of success.

The doubling of pCR rates was seen in all three biomarker signatures studied, including ERBB2(HER2)-negative, hormone receptor (HR)-positive/ERBB2-negative, or triple-negative breast cancer.

These results mean that pembrolizumab can “graduate” from I-SPY2 and suggest a greater than 99% predictive probability that the pembrolizumab-plus-chemotherapy approach will be superior to chemotherapy alone in a phase 3 trial, according to Rita Nanda, MD, of the University of Chicago, and colleagues.

“Notably, pembrolizumab was the first agent of 10 studied to graduate in the HR-positive/ERBB2-negative signature since I-SPY2 opened in 2010,” Dr. Nanda and colleagues wrote in JAMA Oncology.

The I-SPY2 study has enrolled adult women with stage II/III breast cancer at high risk of recurrence. The control arm included 181 patients randomized to receive standard neoadjuvant paclitaxel followed by doxorubicin plus cyclophosphamide. The pembrolizumab arm included 69 patients who received the same chemotherapy regimen plus pembrolizumab given concurrently with paclitaxel.

In ERBB2-negative patients, the estimated pCR rates were 44% in the pembrolizumab arm and 17% in the control arm. In HR-positive/ERBB2-negative patients, the estimated pCR rates were 30% and 13%, respectively. In triple-negative patients, the estimated pCR rates were 60% and 22%, respectively.

Residual cancer burden classified as extensive was less often seen in the pembrolizumab-treated patients, the investigators noted.

Event-free survival was qualitatively similar between the pembrolizumab and control arms, although the investigators cautioned against drawing conclusions based on this exploratory analysis in a small number of patients.

“Patients who achieved pCR had excellent outcomes regardless of arm,” the investigators wrote.

Immune-related adverse events (irAEs) were seen in the pembrolizumab-treated patients, although most were grade 1 or 2 and managed with dose interruption or corticosteroid therapy.

The most common irAE was thyroid dysfunction in 13% of patients, which was on par with what was seen in previously published reports. By contrast, adrenal insufficiency was observed in about 9% of patients, which is higher than in published reports for reasons that are unclear.

“Future work to characterize the risk factors for developing irAEs is warranted to improve the therapeutic index of these agents,” Dr. Nanda and colleagues wrote.

Pembrolizumab plus standard neoadjuvant chemotherapy is being evaluated in two ongoing, randomized phase 3 trials – KEYNOTE 522, which is evaluating patients with triple-negative breast cancer, and KEYNOTE 756, which is focused on high-risk, HR-positive/ERBB2-negative breast cancer.

The ongoing I-SPY2 study is supported by a grant from the National Cancer Institute as well as funding from charitable organizations, pharmaceutical companies, and private individuals. The investigators disclosed relationships with a range of pharmaceutical companies.
 

SOURCE: Nanda R et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6650.

Adding pembrolizumab to neoadjuvant chemotherapy more than doubled the rate of pathologic complete response, compared with chemotherapy alone, in women with early-stage breast cancer enrolled in the phase 2 I-SPY2 trial.

Dr. Cecil Fox/National Cancer Institute

Pathologic complete response (pCR) rates up to 60% were reported for patients with high-risk, stage II/III breast cancer who received pembrolizumab plus chemotherapy in I-SPY2, an ongoing platform trial designed to rapidly screen multiple agents and pinpoint those with a high probability of success.

The doubling of pCR rates was seen in all three biomarker signatures studied, including ERBB2(HER2)-negative, hormone receptor (HR)-positive/ERBB2-negative, or triple-negative breast cancer.

These results mean that pembrolizumab can “graduate” from I-SPY2 and suggest a greater than 99% predictive probability that the pembrolizumab-plus-chemotherapy approach will be superior to chemotherapy alone in a phase 3 trial, according to Rita Nanda, MD, of the University of Chicago, and colleagues.

“Notably, pembrolizumab was the first agent of 10 studied to graduate in the HR-positive/ERBB2-negative signature since I-SPY2 opened in 2010,” Dr. Nanda and colleagues wrote in JAMA Oncology.

The I-SPY2 study has enrolled adult women with stage II/III breast cancer at high risk of recurrence. The control arm included 181 patients randomized to receive standard neoadjuvant paclitaxel followed by doxorubicin plus cyclophosphamide. The pembrolizumab arm included 69 patients who received the same chemotherapy regimen plus pembrolizumab given concurrently with paclitaxel.

In ERBB2-negative patients, the estimated pCR rates were 44% in the pembrolizumab arm and 17% in the control arm. In HR-positive/ERBB2-negative patients, the estimated pCR rates were 30% and 13%, respectively. In triple-negative patients, the estimated pCR rates were 60% and 22%, respectively.

Residual cancer burden classified as extensive was less often seen in the pembrolizumab-treated patients, the investigators noted.

Event-free survival was qualitatively similar between the pembrolizumab and control arms, although the investigators cautioned against drawing conclusions based on this exploratory analysis in a small number of patients.

“Patients who achieved pCR had excellent outcomes regardless of arm,” the investigators wrote.

Immune-related adverse events (irAEs) were seen in the pembrolizumab-treated patients, although most were grade 1 or 2 and managed with dose interruption or corticosteroid therapy.

The most common irAE was thyroid dysfunction in 13% of patients, which was on par with what was seen in previously published reports. By contrast, adrenal insufficiency was observed in about 9% of patients, which is higher than in published reports for reasons that are unclear.

“Future work to characterize the risk factors for developing irAEs is warranted to improve the therapeutic index of these agents,” Dr. Nanda and colleagues wrote.

Pembrolizumab plus standard neoadjuvant chemotherapy is being evaluated in two ongoing, randomized phase 3 trials – KEYNOTE 522, which is evaluating patients with triple-negative breast cancer, and KEYNOTE 756, which is focused on high-risk, HR-positive/ERBB2-negative breast cancer.

The ongoing I-SPY2 study is supported by a grant from the National Cancer Institute as well as funding from charitable organizations, pharmaceutical companies, and private individuals. The investigators disclosed relationships with a range of pharmaceutical companies.
 

SOURCE: Nanda R et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6650.

Adding pembrolizumab to neoadjuvant chemotherapy more than doubled the rate of pathologic complete response, compared with chemotherapy alone, in women with early-stage breast cancer enrolled in the phase 2 I-SPY2 trial.

Dr. Cecil Fox/National Cancer Institute

Pathologic complete response (pCR) rates up to 60% were reported for patients with high-risk, stage II/III breast cancer who received pembrolizumab plus chemotherapy in I-SPY2, an ongoing platform trial designed to rapidly screen multiple agents and pinpoint those with a high probability of success.

The doubling of pCR rates was seen in all three biomarker signatures studied, including ERBB2(HER2)-negative, hormone receptor (HR)-positive/ERBB2-negative, or triple-negative breast cancer.

These results mean that pembrolizumab can “graduate” from I-SPY2 and suggest a greater than 99% predictive probability that the pembrolizumab-plus-chemotherapy approach will be superior to chemotherapy alone in a phase 3 trial, according to Rita Nanda, MD, of the University of Chicago, and colleagues.

“Notably, pembrolizumab was the first agent of 10 studied to graduate in the HR-positive/ERBB2-negative signature since I-SPY2 opened in 2010,” Dr. Nanda and colleagues wrote in JAMA Oncology.

The I-SPY2 study has enrolled adult women with stage II/III breast cancer at high risk of recurrence. The control arm included 181 patients randomized to receive standard neoadjuvant paclitaxel followed by doxorubicin plus cyclophosphamide. The pembrolizumab arm included 69 patients who received the same chemotherapy regimen plus pembrolizumab given concurrently with paclitaxel.

In ERBB2-negative patients, the estimated pCR rates were 44% in the pembrolizumab arm and 17% in the control arm. In HR-positive/ERBB2-negative patients, the estimated pCR rates were 30% and 13%, respectively. In triple-negative patients, the estimated pCR rates were 60% and 22%, respectively.

Residual cancer burden classified as extensive was less often seen in the pembrolizumab-treated patients, the investigators noted.

Event-free survival was qualitatively similar between the pembrolizumab and control arms, although the investigators cautioned against drawing conclusions based on this exploratory analysis in a small number of patients.

“Patients who achieved pCR had excellent outcomes regardless of arm,” the investigators wrote.

Immune-related adverse events (irAEs) were seen in the pembrolizumab-treated patients, although most were grade 1 or 2 and managed with dose interruption or corticosteroid therapy.

The most common irAE was thyroid dysfunction in 13% of patients, which was on par with what was seen in previously published reports. By contrast, adrenal insufficiency was observed in about 9% of patients, which is higher than in published reports for reasons that are unclear.

“Future work to characterize the risk factors for developing irAEs is warranted to improve the therapeutic index of these agents,” Dr. Nanda and colleagues wrote.

Pembrolizumab plus standard neoadjuvant chemotherapy is being evaluated in two ongoing, randomized phase 3 trials – KEYNOTE 522, which is evaluating patients with triple-negative breast cancer, and KEYNOTE 756, which is focused on high-risk, HR-positive/ERBB2-negative breast cancer.

The ongoing I-SPY2 study is supported by a grant from the National Cancer Institute as well as funding from charitable organizations, pharmaceutical companies, and private individuals. The investigators disclosed relationships with a range of pharmaceutical companies.
 

SOURCE: Nanda R et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6650.

The Diagnosis: Capillary Malformation-Arteriovenous Malformation Syndrome 

Capillary malformation-arteriovenous malformation (CM-AVM) was suspected, and a sample of the patient's blood was sent for a diagnostic genetic workup. DNA sequencing evaluated the following 5 genes that have been implicated in telangiectasia or AVM disorders: ACVRL1 (activin A receptorlike type 1), ENG (endoglin), GDF2 (growth differentiation factor 2), RASA1 (RAS p21 protein activator 1), and SMAD4 (SMAD family member 4). The patient was found to be heterozygous for a known pathogenic splice-site mutation in the RASA1 gene, consistent with a diagnosis of CM-AVM. 

Capillary malformation-arteriovenous malformation presents with multiple small cutaneous CMs and associated arteriovenous fistulas as well as high-flow AVMs located in the soft tissues, bones, or central nervous system (CNS). Occasionally, the cutaneous CMs are surrounded by a blanched halo.¹ Because of the potential for CNS involvement in CM-AVM, our patient was further evaluated with spine and brain magnetic resonance imaging (MRI). The brain MRI revealed 2 right occipital pole and fusiform gyral AVMs (Figure). No vascular abnormalities were found in the spine. The patient was referred to interventional neuroradiology to assess the feasibility of ablation to reduce the risk for complications, including intracranial hemorrhage.

Compared to other well-established congenital vascular disorders, CM-AVM has only recently been described in the literature. It was first reported by Eerola and colleagues² in 2003. They studied several families with CMs and identified heterozygous inactivating RASA1 mutations in 6 families manifesting atypical CMs that were multiple small, round to oval, and pinkish red.² 

It has been estimated that RASA1 mutations contribute to 68% of CM-AVM cases. Another gene--EPHB4 (EPH receptor B4)--has been implicated in patients with RASA1-negative disease. Two separate subtypes for patients with CM-AVM have been described: (1) CM-AVM type 1 for patients with RASA1 mutations, and (2) CM-AVM type 2 for those with EPHB4 mutations.³  

Both CM-AVM types are characterized by small multifocal CMs and an increased risk for CNS fast-flow vascular malformations.⁴ It has been suggested that there are morphologic differences between the cutaneous manifestations of the 2 types. For example, one group stated Bier spots are more frequently observed in CM-AVM type 2. This same group suggested telangiectases seen primarily on the lips but also in the perioral region and on the upper thorax were seen in CM-AVM type 2 but not in CM-AVM type 1.4 In our patient, it is plausible that the pinpoint red macules on the lips and oral mucosa could be confused for telangiectases (quiz image [bottom]). At this time, we do not feel that there is sufficient evidence to clinically distinguish between CM-AVM types 1 and 2.  

Central nervous system involvement seems to be more common in patients with CM-AVM type 1 (10%) than those with CM-AVM type 2 (3%).^1,4 Of the 2 CM-AVM type 2 patients found to have intracranial AVMs in one study, both were found to have vein of Galen aneurysmal malformations (VGAMs).⁴ The study examining CNS involvement in CM-AVM type 1 did not comment on the percentage of VGAMs seen in all patients.¹ However, in the retrospective component of the study, the authors reported that in 161 patients with CM-AVM type 1, 24 AVMs were observed, 6 of which were intracranial. Half of these intracranial AVMs were at the vein of Galen, demonstrating that VGAMs are seen in both types of CM-AVM.¹ Further study is necessary to better characterize potential phenotypic differences between the 2 forms of CM-AVM.  

Overall, the annual risk for hemorrhage associated with brain AVMs is approximately 2% per year.⁵ Because the morbidity and mortality of undiagnosed CNS malformations is high, it is recommended that patients with both types of CM-AVM undergo spine and brain MRI evaluation. If CNS malformations are identified, patients should be referred to interventional neuroradiology to assess the feasibility of ablation.  

It is unclear if patients who initially screen negative for AVMs will go on to develop these fast-flow lesions later. We have noted that new CMs develop over time in our patients. Therefore, it does not seem far-fetched to hypothesize that AVMs of CNS are similarly dynamic. Ultimately, we recommend ongoing screening for brain and spinal AVMs at regular intervals, determined by discussions of risks and benefits between the treating team and patient/family.  

It is important to distinguish CM-AVM from hereditary hemorrhagic telangiectasia (HHT), as the distinction affects patient management. Unlike the AVMs found in HHT, AVMs in CM-AVM seldom are found in the lungs or liver.¹ Thus, asymptomatic patients with HHT, but not CM-AVM, often are screened for pulmonary AVMs. 

The diagnosis of HHT is based on the following 4 findings: spontaneous and recurrent epistaxis; multiple mucocutaneous telangiectasia at characteristic sites, including the lips, oral cavity, fingers, and nose; visceral involvement, such as gastrointestinal, pulmonary, cerebral, or hepatic AVMs; and a first-degree relative with the disorder. Three of the criteria are required for diagnosis. 

Notably, the lesions seen in HHT and CM-AVM are morphologically different. Our patient did have 1-mm red macules on the lower lip that had clinical features overlapping with telangiectases, but other cutaneous findings including the presence of red macules and small patches, some with blanched halos, were clearly characteristic of CMs, not telangiectases.⁶ Furthermore, our patient did not have a personal history of epistaxis or a family history of any affected first-degree relatives. Finally, individuals with HHT tend to develop symptoms later in life compared to patients with CM-AVM, starting with epistaxis at 12 years of age.⁶ 

Patients with Henoch-Schönlein purpura also present in childhood but typically demonstrate palpable purpura and acute abdominal pain. Patients with Klippel-Trenaunay syndrome present with CM and venous malformation but also typically display limb overgrowth. Most patients with Klippel-Trenaunay syndrome are born with a port-wine stain.  

Diffuse neonatal hemangiomatosis is characterized by multiple progressive, rapidly growing cutaneous hemangiomas associated with widespread visceral hemangiomas in the liver, lungs, gastrointestinal tract, brain, and meninges. Our patient's macules were much more slowly progressive.  

The Diagnosis: Capillary Malformation-Arteriovenous Malformation Syndrome 

Capillary malformation-arteriovenous malformation (CM-AVM) was suspected, and a sample of the patient's blood was sent for a diagnostic genetic workup. DNA sequencing evaluated the following 5 genes that have been implicated in telangiectasia or AVM disorders: ACVRL1 (activin A receptorlike type 1), ENG (endoglin), GDF2 (growth differentiation factor 2), RASA1 (RAS p21 protein activator 1), and SMAD4 (SMAD family member 4). The patient was found to be heterozygous for a known pathogenic splice-site mutation in the RASA1 gene, consistent with a diagnosis of CM-AVM. 

Capillary malformation-arteriovenous malformation presents with multiple small cutaneous CMs and associated arteriovenous fistulas as well as high-flow AVMs located in the soft tissues, bones, or central nervous system (CNS). Occasionally, the cutaneous CMs are surrounded by a blanched halo.¹ Because of the potential for CNS involvement in CM-AVM, our patient was further evaluated with spine and brain magnetic resonance imaging (MRI). The brain MRI revealed 2 right occipital pole and fusiform gyral AVMs (Figure). No vascular abnormalities were found in the spine. The patient was referred to interventional neuroradiology to assess the feasibility of ablation to reduce the risk for complications, including intracranial hemorrhage.

Compared to other well-established congenital vascular disorders, CM-AVM has only recently been described in the literature. It was first reported by Eerola and colleagues² in 2003. They studied several families with CMs and identified heterozygous inactivating RASA1 mutations in 6 families manifesting atypical CMs that were multiple small, round to oval, and pinkish red.² 

It has been estimated that RASA1 mutations contribute to 68% of CM-AVM cases. Another gene--EPHB4 (EPH receptor B4)--has been implicated in patients with RASA1-negative disease. Two separate subtypes for patients with CM-AVM have been described: (1) CM-AVM type 1 for patients with RASA1 mutations, and (2) CM-AVM type 2 for those with EPHB4 mutations.³  

Both CM-AVM types are characterized by small multifocal CMs and an increased risk for CNS fast-flow vascular malformations.⁴ It has been suggested that there are morphologic differences between the cutaneous manifestations of the 2 types. For example, one group stated Bier spots are more frequently observed in CM-AVM type 2. This same group suggested telangiectases seen primarily on the lips but also in the perioral region and on the upper thorax were seen in CM-AVM type 2 but not in CM-AVM type 1.4 In our patient, it is plausible that the pinpoint red macules on the lips and oral mucosa could be confused for telangiectases (quiz image [bottom]). At this time, we do not feel that there is sufficient evidence to clinically distinguish between CM-AVM types 1 and 2.  

Central nervous system involvement seems to be more common in patients with CM-AVM type 1 (10%) than those with CM-AVM type 2 (3%).^1,4 Of the 2 CM-AVM type 2 patients found to have intracranial AVMs in one study, both were found to have vein of Galen aneurysmal malformations (VGAMs).⁴ The study examining CNS involvement in CM-AVM type 1 did not comment on the percentage of VGAMs seen in all patients.¹ However, in the retrospective component of the study, the authors reported that in 161 patients with CM-AVM type 1, 24 AVMs were observed, 6 of which were intracranial. Half of these intracranial AVMs were at the vein of Galen, demonstrating that VGAMs are seen in both types of CM-AVM.¹ Further study is necessary to better characterize potential phenotypic differences between the 2 forms of CM-AVM.  

Overall, the annual risk for hemorrhage associated with brain AVMs is approximately 2% per year.⁵ Because the morbidity and mortality of undiagnosed CNS malformations is high, it is recommended that patients with both types of CM-AVM undergo spine and brain MRI evaluation. If CNS malformations are identified, patients should be referred to interventional neuroradiology to assess the feasibility of ablation.  

It is unclear if patients who initially screen negative for AVMs will go on to develop these fast-flow lesions later. We have noted that new CMs develop over time in our patients. Therefore, it does not seem far-fetched to hypothesize that AVMs of CNS are similarly dynamic. Ultimately, we recommend ongoing screening for brain and spinal AVMs at regular intervals, determined by discussions of risks and benefits between the treating team and patient/family.  

It is important to distinguish CM-AVM from hereditary hemorrhagic telangiectasia (HHT), as the distinction affects patient management. Unlike the AVMs found in HHT, AVMs in CM-AVM seldom are found in the lungs or liver.¹ Thus, asymptomatic patients with HHT, but not CM-AVM, often are screened for pulmonary AVMs. 

The diagnosis of HHT is based on the following 4 findings: spontaneous and recurrent epistaxis; multiple mucocutaneous telangiectasia at characteristic sites, including the lips, oral cavity, fingers, and nose; visceral involvement, such as gastrointestinal, pulmonary, cerebral, or hepatic AVMs; and a first-degree relative with the disorder. Three of the criteria are required for diagnosis. 

Notably, the lesions seen in HHT and CM-AVM are morphologically different. Our patient did have 1-mm red macules on the lower lip that had clinical features overlapping with telangiectases, but other cutaneous findings including the presence of red macules and small patches, some with blanched halos, were clearly characteristic of CMs, not telangiectases.⁶ Furthermore, our patient did not have a personal history of epistaxis or a family history of any affected first-degree relatives. Finally, individuals with HHT tend to develop symptoms later in life compared to patients with CM-AVM, starting with epistaxis at 12 years of age.⁶ 

Patients with Henoch-Schönlein purpura also present in childhood but typically demonstrate palpable purpura and acute abdominal pain. Patients with Klippel-Trenaunay syndrome present with CM and venous malformation but also typically display limb overgrowth. Most patients with Klippel-Trenaunay syndrome are born with a port-wine stain.  

Diffuse neonatal hemangiomatosis is characterized by multiple progressive, rapidly growing cutaneous hemangiomas associated with widespread visceral hemangiomas in the liver, lungs, gastrointestinal tract, brain, and meninges. Our patient's macules were much more slowly progressive.  

The Diagnosis: Capillary Malformation-Arteriovenous Malformation Syndrome 

Capillary malformation-arteriovenous malformation (CM-AVM) was suspected, and a sample of the patient's blood was sent for a diagnostic genetic workup. DNA sequencing evaluated the following 5 genes that have been implicated in telangiectasia or AVM disorders: ACVRL1 (activin A receptorlike type 1), ENG (endoglin), GDF2 (growth differentiation factor 2), RASA1 (RAS p21 protein activator 1), and SMAD4 (SMAD family member 4). The patient was found to be heterozygous for a known pathogenic splice-site mutation in the RASA1 gene, consistent with a diagnosis of CM-AVM. 

Capillary malformation-arteriovenous malformation presents with multiple small cutaneous CMs and associated arteriovenous fistulas as well as high-flow AVMs located in the soft tissues, bones, or central nervous system (CNS). Occasionally, the cutaneous CMs are surrounded by a blanched halo.¹ Because of the potential for CNS involvement in CM-AVM, our patient was further evaluated with spine and brain magnetic resonance imaging (MRI). The brain MRI revealed 2 right occipital pole and fusiform gyral AVMs (Figure). No vascular abnormalities were found in the spine. The patient was referred to interventional neuroradiology to assess the feasibility of ablation to reduce the risk for complications, including intracranial hemorrhage.

Compared to other well-established congenital vascular disorders, CM-AVM has only recently been described in the literature. It was first reported by Eerola and colleagues² in 2003. They studied several families with CMs and identified heterozygous inactivating RASA1 mutations in 6 families manifesting atypical CMs that were multiple small, round to oval, and pinkish red.² 

It has been estimated that RASA1 mutations contribute to 68% of CM-AVM cases. Another gene--EPHB4 (EPH receptor B4)--has been implicated in patients with RASA1-negative disease. Two separate subtypes for patients with CM-AVM have been described: (1) CM-AVM type 1 for patients with RASA1 mutations, and (2) CM-AVM type 2 for those with EPHB4 mutations.³  

Both CM-AVM types are characterized by small multifocal CMs and an increased risk for CNS fast-flow vascular malformations.⁴ It has been suggested that there are morphologic differences between the cutaneous manifestations of the 2 types. For example, one group stated Bier spots are more frequently observed in CM-AVM type 2. This same group suggested telangiectases seen primarily on the lips but also in the perioral region and on the upper thorax were seen in CM-AVM type 2 but not in CM-AVM type 1.4 In our patient, it is plausible that the pinpoint red macules on the lips and oral mucosa could be confused for telangiectases (quiz image [bottom]). At this time, we do not feel that there is sufficient evidence to clinically distinguish between CM-AVM types 1 and 2.  

Central nervous system involvement seems to be more common in patients with CM-AVM type 1 (10%) than those with CM-AVM type 2 (3%).^1,4 Of the 2 CM-AVM type 2 patients found to have intracranial AVMs in one study, both were found to have vein of Galen aneurysmal malformations (VGAMs).⁴ The study examining CNS involvement in CM-AVM type 1 did not comment on the percentage of VGAMs seen in all patients.¹ However, in the retrospective component of the study, the authors reported that in 161 patients with CM-AVM type 1, 24 AVMs were observed, 6 of which were intracranial. Half of these intracranial AVMs were at the vein of Galen, demonstrating that VGAMs are seen in both types of CM-AVM.¹ Further study is necessary to better characterize potential phenotypic differences between the 2 forms of CM-AVM.  

Overall, the annual risk for hemorrhage associated with brain AVMs is approximately 2% per year.⁵ Because the morbidity and mortality of undiagnosed CNS malformations is high, it is recommended that patients with both types of CM-AVM undergo spine and brain MRI evaluation. If CNS malformations are identified, patients should be referred to interventional neuroradiology to assess the feasibility of ablation.  

It is unclear if patients who initially screen negative for AVMs will go on to develop these fast-flow lesions later. We have noted that new CMs develop over time in our patients. Therefore, it does not seem far-fetched to hypothesize that AVMs of CNS are similarly dynamic. Ultimately, we recommend ongoing screening for brain and spinal AVMs at regular intervals, determined by discussions of risks and benefits between the treating team and patient/family.  

It is important to distinguish CM-AVM from hereditary hemorrhagic telangiectasia (HHT), as the distinction affects patient management. Unlike the AVMs found in HHT, AVMs in CM-AVM seldom are found in the lungs or liver.¹ Thus, asymptomatic patients with HHT, but not CM-AVM, often are screened for pulmonary AVMs. 

The diagnosis of HHT is based on the following 4 findings: spontaneous and recurrent epistaxis; multiple mucocutaneous telangiectasia at characteristic sites, including the lips, oral cavity, fingers, and nose; visceral involvement, such as gastrointestinal, pulmonary, cerebral, or hepatic AVMs; and a first-degree relative with the disorder. Three of the criteria are required for diagnosis. 

Notably, the lesions seen in HHT and CM-AVM are morphologically different. Our patient did have 1-mm red macules on the lower lip that had clinical features overlapping with telangiectases, but other cutaneous findings including the presence of red macules and small patches, some with blanched halos, were clearly characteristic of CMs, not telangiectases.⁶ Furthermore, our patient did not have a personal history of epistaxis or a family history of any affected first-degree relatives. Finally, individuals with HHT tend to develop symptoms later in life compared to patients with CM-AVM, starting with epistaxis at 12 years of age.⁶ 

Patients with Henoch-Schönlein purpura also present in childhood but typically demonstrate palpable purpura and acute abdominal pain. Patients with Klippel-Trenaunay syndrome present with CM and venous malformation but also typically display limb overgrowth. Most patients with Klippel-Trenaunay syndrome are born with a port-wine stain.  

Diffuse neonatal hemangiomatosis is characterized by multiple progressive, rapidly growing cutaneous hemangiomas associated with widespread visceral hemangiomas in the liver, lungs, gastrointestinal tract, brain, and meninges. Our patient's macules were much more slowly progressive.  

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.