Children from socially disadvantaged backgrounds are less likely to be treated for middle ear infections and are likely to experience serious complications from the condition – potentially with lifelong economic consequences – researchers have found.

Problems such as hearing loss and chronic ear infections were more common for children who lived in areas marked by difficult socioeconomic circumstances, according to the researchers, who linked the complications to a lack of adequate treatment in this population. 

“We are treating socially disadvantaged kids differently than we are treating more advantaged kids,” said Jason Qian, MD, a resident in otolaryngology and head and neck surgery at Stanford (Calif.) University, who helped conduct the new study. “We have to think about social inequalities so we can ensure all kids are receiving the same level and type of care.”

In the United States, 80% of children will experience otitis media during their lifetime. Untreated ear infections can lead to symptoms ranging from mild discharge from the ear to life-threatening conditions like mastoiditis and intracranial abscesses.

For the new study, published online  in JAMA Otolaryngology–Head & Neck Surgery, Dr. Qian and colleagues looked at 4.8 million children with private health insurance across the United States using a database with information on inpatient and outpatient visits and medication use. The researchers identified patients between January 2003 and March 2021 who received treatment for recurrent and suppurative otitis media, those who received tympanostomy tubes, and children who experienced severe complications from undertreated ear infections.

Social disadvantage was assessed using the Social Deprivation Index (SDI), a tool used to measure indicators of poverty throughout the United States based on seven demographic factors including level of educational attainment, the number of single-parent households, the share of people living in overcrowded homes, and other factors.

Every point increase in the SDI score was associated with a 14% lower likelihood of being treated for recurrent ear infections despite having them and a 28% greater chance of being hospitalized for severe ear infections, according to the researchers.

Previous research established that children with government health insurance or no coverage have more difficulty receiving proper treatment for ear infections. Although people with commercial insurance are generally wealthier than those without private coverage, Dr. Qian said, the new data indicate that significant social disparities in care exist even within this group.  

Although some studies have found that wealthier children are more likely to develop otitis media, Dr. Qian’s group said that association likely reflects the better access to health care money affords.  

“We found that socially disadvantaged children not only have a higher burden of otitis media but are also undertreated both medically and surgically for [ear infections]. Because chronic and complicated forms of otitis media can cause childhood hearing loss, which in turn limits academic and economic potential, undertreatment of [otitis media] in socially disadvantaged populations can contribute to generational cycles of poverty, unemployment, and low pay,” they write.

“The biggest take home is that we are not treating children equitably when it comes to ear infections,” Dr. Qian added. “In order to give children equal access to care, we as health care providers need to find strategies to do better.”

The study was supported by the Stanford Center for Population Health Science Data Core, which is supported by a grant from the National Institutes of Health and internal funding. Dr. Qian has reported receiving grant funding from Merck. 

A version of this article first appeared on Medscape.com.

Children from socially disadvantaged backgrounds are less likely to be treated for middle ear infections and are likely to experience serious complications from the condition – potentially with lifelong economic consequences – researchers have found.

Problems such as hearing loss and chronic ear infections were more common for children who lived in areas marked by difficult socioeconomic circumstances, according to the researchers, who linked the complications to a lack of adequate treatment in this population. 

“We are treating socially disadvantaged kids differently than we are treating more advantaged kids,” said Jason Qian, MD, a resident in otolaryngology and head and neck surgery at Stanford (Calif.) University, who helped conduct the new study. “We have to think about social inequalities so we can ensure all kids are receiving the same level and type of care.”

In the United States, 80% of children will experience otitis media during their lifetime. Untreated ear infections can lead to symptoms ranging from mild discharge from the ear to life-threatening conditions like mastoiditis and intracranial abscesses.

For the new study, published online  in JAMA Otolaryngology–Head & Neck Surgery, Dr. Qian and colleagues looked at 4.8 million children with private health insurance across the United States using a database with information on inpatient and outpatient visits and medication use. The researchers identified patients between January 2003 and March 2021 who received treatment for recurrent and suppurative otitis media, those who received tympanostomy tubes, and children who experienced severe complications from undertreated ear infections.

Social disadvantage was assessed using the Social Deprivation Index (SDI), a tool used to measure indicators of poverty throughout the United States based on seven demographic factors including level of educational attainment, the number of single-parent households, the share of people living in overcrowded homes, and other factors.

Every point increase in the SDI score was associated with a 14% lower likelihood of being treated for recurrent ear infections despite having them and a 28% greater chance of being hospitalized for severe ear infections, according to the researchers.

Previous research established that children with government health insurance or no coverage have more difficulty receiving proper treatment for ear infections. Although people with commercial insurance are generally wealthier than those without private coverage, Dr. Qian said, the new data indicate that significant social disparities in care exist even within this group.  

Although some studies have found that wealthier children are more likely to develop otitis media, Dr. Qian’s group said that association likely reflects the better access to health care money affords.  

“We found that socially disadvantaged children not only have a higher burden of otitis media but are also undertreated both medically and surgically for [ear infections]. Because chronic and complicated forms of otitis media can cause childhood hearing loss, which in turn limits academic and economic potential, undertreatment of [otitis media] in socially disadvantaged populations can contribute to generational cycles of poverty, unemployment, and low pay,” they write.

“The biggest take home is that we are not treating children equitably when it comes to ear infections,” Dr. Qian added. “In order to give children equal access to care, we as health care providers need to find strategies to do better.”

The study was supported by the Stanford Center for Population Health Science Data Core, which is supported by a grant from the National Institutes of Health and internal funding. Dr. Qian has reported receiving grant funding from Merck. 

A version of this article first appeared on Medscape.com.

Children from socially disadvantaged backgrounds are less likely to be treated for middle ear infections and are likely to experience serious complications from the condition – potentially with lifelong economic consequences – researchers have found.

Problems such as hearing loss and chronic ear infections were more common for children who lived in areas marked by difficult socioeconomic circumstances, according to the researchers, who linked the complications to a lack of adequate treatment in this population. 

“We are treating socially disadvantaged kids differently than we are treating more advantaged kids,” said Jason Qian, MD, a resident in otolaryngology and head and neck surgery at Stanford (Calif.) University, who helped conduct the new study. “We have to think about social inequalities so we can ensure all kids are receiving the same level and type of care.”

In the United States, 80% of children will experience otitis media during their lifetime. Untreated ear infections can lead to symptoms ranging from mild discharge from the ear to life-threatening conditions like mastoiditis and intracranial abscesses.

For the new study, published online  in JAMA Otolaryngology–Head & Neck Surgery, Dr. Qian and colleagues looked at 4.8 million children with private health insurance across the United States using a database with information on inpatient and outpatient visits and medication use. The researchers identified patients between January 2003 and March 2021 who received treatment for recurrent and suppurative otitis media, those who received tympanostomy tubes, and children who experienced severe complications from undertreated ear infections.

Social disadvantage was assessed using the Social Deprivation Index (SDI), a tool used to measure indicators of poverty throughout the United States based on seven demographic factors including level of educational attainment, the number of single-parent households, the share of people living in overcrowded homes, and other factors.

Every point increase in the SDI score was associated with a 14% lower likelihood of being treated for recurrent ear infections despite having them and a 28% greater chance of being hospitalized for severe ear infections, according to the researchers.

Previous research established that children with government health insurance or no coverage have more difficulty receiving proper treatment for ear infections. Although people with commercial insurance are generally wealthier than those without private coverage, Dr. Qian said, the new data indicate that significant social disparities in care exist even within this group.  

Although some studies have found that wealthier children are more likely to develop otitis media, Dr. Qian’s group said that association likely reflects the better access to health care money affords.  

“We found that socially disadvantaged children not only have a higher burden of otitis media but are also undertreated both medically and surgically for [ear infections]. Because chronic and complicated forms of otitis media can cause childhood hearing loss, which in turn limits academic and economic potential, undertreatment of [otitis media] in socially disadvantaged populations can contribute to generational cycles of poverty, unemployment, and low pay,” they write.

“The biggest take home is that we are not treating children equitably when it comes to ear infections,” Dr. Qian added. “In order to give children equal access to care, we as health care providers need to find strategies to do better.”

The study was supported by the Stanford Center for Population Health Science Data Core, which is supported by a grant from the National Institutes of Health and internal funding. Dr. Qian has reported receiving grant funding from Merck. 

A version of this article first appeared on Medscape.com.

Monkeypox virus infections in children and adolescents in the United States are rare, and young patients with known infections have all recovered, according to a study from the Centers for Disease Control and Prevention.

In addition, evidence suggests that secondary transmission in schools or childcare facilities may be unlikely.

The study was the first comprehensive study on the impact of monkeypox on children during the 2022 outbreak, according to a statement emailed to this news organization from the California Department of Public Health, one of the state health departments that partnered with the CDC to share information.

News of low infection rates and relatively mild disease was welcome to clinicians, who had braced for severe findings on the basis of sparse prior data, according to Peter Chin-Hong, MD, a professor of medicine and an infectious diseases physician at the University of California, San Francisco.

“We were on heightened alert that kids may do poorly,” said Dr. Chin-Hong, who was not involved in the study but who cared for monkeypox patients during the outbreak. “I think this study is reassuring.

“The other silver lining about it is that most of the kids got infected in the household setting from ways that you would expect them to get [infected],” Dr. Chin-Hong said in an interview.

However, Black and Hispanic children were more likely to contract the disease, underscoring troubling inequities.

“Early on, individuals of color were much less likely to be able to successfully access vaccination,” said first author Ian Hennessee, PhD, MPH, an epidemic intelligence service officer with the CDC and a member of the Special Case Investigation Unit of the Multinational Monkeypox Response Team at the CDC. “We think those kinds of structural inequities really trickled down towards the children and adolescents that have been affected by this outbreak.”

The study was published  in Morbidity and Mortality Weekly Report.
 

A nationwide look at the data

The researchers discussed 83 children and adolescents with monkeypox who came to the CDC’s attention between May 17 and Sept. 24, 2022.

The 83 cases represent 0.3% of the 25,038 reported monkeypox cases in the United States over that period. Of the 28 children aged 12 years or younger, 18 (64%) were boys. Sixteen children were younger than 4 years.

Exposure data were available for 20 (71%) of those aged 0-12. In that group, 19 were exposed at home; 17 cases were due to routine skin-to-skin contact with a household caregiver; and one case was suspected to be caused by fomites (such as a shared towel). Exposure information was unavailable for the remaining case.

Most of the children experienced lesions on the trunk. No lesions were anogenital. Two patients in the youngest age group were hospitalized because of widespread rash that involved the eyelids, and a patient in the 5- to 12-year-old group was hospitalized because of periorbital cellulitis and conjunctivitis.

Among those aged 13-17, there were 55 cases. Of these patients, 89% were boys. Exposure data were available for 35 (64%). In 32 of these patients, the infection occurred from presumed sexual contact. Twenty-three of those adolescents reported male-to-male sexual contact. No case was found to be connected with sexual abuse.

Lesions in the adolescents were mostly truncal or anogenital. Six in this group were hospitalized, and all of them recovered. One adolescent was found to be HIV positive.

Black and Hispanic children accounted for 47% and 35% of all cases, respectively.

Eleven percent of all the children and adolescents were hospitalized, and none received intensive care.

Treatments, when given, included the antiviral drug tecovirimat, intravenous vaccinia immune globulin, and topical trifluridine. There were no deaths.

Ten symptomatic patients attended school or daycare. Among these patients, no secondary transmissions were found to have occurred. Some contacts were offered the JYNNEOS monkeypox vaccine as postexposure prophylaxis.

Limitations of the study included potentially overlooked cases. Data were collected through routine surveillance, children frequently experience rashes, and access to testing has been a challenge, Dr. Hennessee explained.

In addition, data on exposure characteristics were missing for some children.
 

Inequities and the risks of being judged

The outbreak in the United States has eased in recent months. However, though uncommon in children, monkeypox has affected some racial groups disproportionately.

“Especially in the later course of the outbreak, the majority of cases were among Black and Hispanic individuals,” said co-author Rachel E. Harold, MD, an infectious diseases specialist and supervisory medical officer with the District of Columbia Department of Health’s HIV/AIDS, Hepatitis, STDs, and TB Administration.

“Unfortunately, the pediatric cases do reflect the outbreak overall,” she told this news organization.

Dr. Harold noted there have been efforts in D.C. and other jurisdictions, as well as by the White House monkeypox response team, to reach populations at greatest risk and that they were “really trying to make vaccine available to people of color.”

Vaccination clinics often popped up in unexpected locations at short notice, and that made it hard for some people to get to them, Dr. Chin-Hong pointed out.

Another factor was “the public aspect of accessing diagnostics and vaccines and the way that that’s linked to potential judgment or sexual risk,” he added.

“Not everybody’s out,” Dr. Chin-Hong said, referring to members of the LGBTQ community. “In many communities of color, going to get a test or going to get a vaccine essentially means that you’re out.”

For clinicians who suspect monkeypox in a child, Dr. Harold suggests keeping a broad differential diagnosis, looking for an epidemiologic link, and contacting the CDC for assistance. Infected children should be encouraged to avoid touching their own eyes or mucous membranes, she added.

In addition, she said, tecovirimat is a reasonable treatment and is well tolerated by pediatric monkeypox patients with eczema, an underlying condition that could lead to severe disease.

For infected caregivers, Dr. Hennessee said, measures to prevent infecting children at home include isolation, contact precautions, and in some cases, postexposure prophylaxis via vaccination.

For sexually active adolescents, he advised that clinicians offer vaccination, education on sexual health, and testing for HIV and other sexually transmitted infections.

“It’s important to remember that adolescents may be sexually active, and clinicians should do a thorough and nonjudgmental sexual history,” Dr. Harold added. “That is always true, but especially if there is concern for [monkeypox].”

Dr. Hennessee, Dr. Chin-Hong, and Dr. Harold have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Monkeypox virus infections in children and adolescents in the United States are rare, and young patients with known infections have all recovered, according to a study from the Centers for Disease Control and Prevention.

In addition, evidence suggests that secondary transmission in schools or childcare facilities may be unlikely.

The study was the first comprehensive study on the impact of monkeypox on children during the 2022 outbreak, according to a statement emailed to this news organization from the California Department of Public Health, one of the state health departments that partnered with the CDC to share information.

News of low infection rates and relatively mild disease was welcome to clinicians, who had braced for severe findings on the basis of sparse prior data, according to Peter Chin-Hong, MD, a professor of medicine and an infectious diseases physician at the University of California, San Francisco.

“We were on heightened alert that kids may do poorly,” said Dr. Chin-Hong, who was not involved in the study but who cared for monkeypox patients during the outbreak. “I think this study is reassuring.

“The other silver lining about it is that most of the kids got infected in the household setting from ways that you would expect them to get [infected],” Dr. Chin-Hong said in an interview.

However, Black and Hispanic children were more likely to contract the disease, underscoring troubling inequities.

“Early on, individuals of color were much less likely to be able to successfully access vaccination,” said first author Ian Hennessee, PhD, MPH, an epidemic intelligence service officer with the CDC and a member of the Special Case Investigation Unit of the Multinational Monkeypox Response Team at the CDC. “We think those kinds of structural inequities really trickled down towards the children and adolescents that have been affected by this outbreak.”

The study was published  in Morbidity and Mortality Weekly Report.
 

A nationwide look at the data

The researchers discussed 83 children and adolescents with monkeypox who came to the CDC’s attention between May 17 and Sept. 24, 2022.

The 83 cases represent 0.3% of the 25,038 reported monkeypox cases in the United States over that period. Of the 28 children aged 12 years or younger, 18 (64%) were boys. Sixteen children were younger than 4 years.

Exposure data were available for 20 (71%) of those aged 0-12. In that group, 19 were exposed at home; 17 cases were due to routine skin-to-skin contact with a household caregiver; and one case was suspected to be caused by fomites (such as a shared towel). Exposure information was unavailable for the remaining case.

Most of the children experienced lesions on the trunk. No lesions were anogenital. Two patients in the youngest age group were hospitalized because of widespread rash that involved the eyelids, and a patient in the 5- to 12-year-old group was hospitalized because of periorbital cellulitis and conjunctivitis.

Among those aged 13-17, there were 55 cases. Of these patients, 89% were boys. Exposure data were available for 35 (64%). In 32 of these patients, the infection occurred from presumed sexual contact. Twenty-three of those adolescents reported male-to-male sexual contact. No case was found to be connected with sexual abuse.

Lesions in the adolescents were mostly truncal or anogenital. Six in this group were hospitalized, and all of them recovered. One adolescent was found to be HIV positive.

Black and Hispanic children accounted for 47% and 35% of all cases, respectively.

Eleven percent of all the children and adolescents were hospitalized, and none received intensive care.

Treatments, when given, included the antiviral drug tecovirimat, intravenous vaccinia immune globulin, and topical trifluridine. There were no deaths.

Ten symptomatic patients attended school or daycare. Among these patients, no secondary transmissions were found to have occurred. Some contacts were offered the JYNNEOS monkeypox vaccine as postexposure prophylaxis.

Limitations of the study included potentially overlooked cases. Data were collected through routine surveillance, children frequently experience rashes, and access to testing has been a challenge, Dr. Hennessee explained.

In addition, data on exposure characteristics were missing for some children.
 

Inequities and the risks of being judged

The outbreak in the United States has eased in recent months. However, though uncommon in children, monkeypox has affected some racial groups disproportionately.

“Especially in the later course of the outbreak, the majority of cases were among Black and Hispanic individuals,” said co-author Rachel E. Harold, MD, an infectious diseases specialist and supervisory medical officer with the District of Columbia Department of Health’s HIV/AIDS, Hepatitis, STDs, and TB Administration.

“Unfortunately, the pediatric cases do reflect the outbreak overall,” she told this news organization.

Dr. Harold noted there have been efforts in D.C. and other jurisdictions, as well as by the White House monkeypox response team, to reach populations at greatest risk and that they were “really trying to make vaccine available to people of color.”

Vaccination clinics often popped up in unexpected locations at short notice, and that made it hard for some people to get to them, Dr. Chin-Hong pointed out.

Another factor was “the public aspect of accessing diagnostics and vaccines and the way that that’s linked to potential judgment or sexual risk,” he added.

“Not everybody’s out,” Dr. Chin-Hong said, referring to members of the LGBTQ community. “In many communities of color, going to get a test or going to get a vaccine essentially means that you’re out.”

For clinicians who suspect monkeypox in a child, Dr. Harold suggests keeping a broad differential diagnosis, looking for an epidemiologic link, and contacting the CDC for assistance. Infected children should be encouraged to avoid touching their own eyes or mucous membranes, she added.

In addition, she said, tecovirimat is a reasonable treatment and is well tolerated by pediatric monkeypox patients with eczema, an underlying condition that could lead to severe disease.

For infected caregivers, Dr. Hennessee said, measures to prevent infecting children at home include isolation, contact precautions, and in some cases, postexposure prophylaxis via vaccination.

For sexually active adolescents, he advised that clinicians offer vaccination, education on sexual health, and testing for HIV and other sexually transmitted infections.

“It’s important to remember that adolescents may be sexually active, and clinicians should do a thorough and nonjudgmental sexual history,” Dr. Harold added. “That is always true, but especially if there is concern for [monkeypox].”

Dr. Hennessee, Dr. Chin-Hong, and Dr. Harold have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Monkeypox virus infections in children and adolescents in the United States are rare, and young patients with known infections have all recovered, according to a study from the Centers for Disease Control and Prevention.

In addition, evidence suggests that secondary transmission in schools or childcare facilities may be unlikely.

The study was the first comprehensive study on the impact of monkeypox on children during the 2022 outbreak, according to a statement emailed to this news organization from the California Department of Public Health, one of the state health departments that partnered with the CDC to share information.

News of low infection rates and relatively mild disease was welcome to clinicians, who had braced for severe findings on the basis of sparse prior data, according to Peter Chin-Hong, MD, a professor of medicine and an infectious diseases physician at the University of California, San Francisco.

“We were on heightened alert that kids may do poorly,” said Dr. Chin-Hong, who was not involved in the study but who cared for monkeypox patients during the outbreak. “I think this study is reassuring.

“The other silver lining about it is that most of the kids got infected in the household setting from ways that you would expect them to get [infected],” Dr. Chin-Hong said in an interview.

However, Black and Hispanic children were more likely to contract the disease, underscoring troubling inequities.

“Early on, individuals of color were much less likely to be able to successfully access vaccination,” said first author Ian Hennessee, PhD, MPH, an epidemic intelligence service officer with the CDC and a member of the Special Case Investigation Unit of the Multinational Monkeypox Response Team at the CDC. “We think those kinds of structural inequities really trickled down towards the children and adolescents that have been affected by this outbreak.”

The study was published  in Morbidity and Mortality Weekly Report.
 

A nationwide look at the data

The researchers discussed 83 children and adolescents with monkeypox who came to the CDC’s attention between May 17 and Sept. 24, 2022.

The 83 cases represent 0.3% of the 25,038 reported monkeypox cases in the United States over that period. Of the 28 children aged 12 years or younger, 18 (64%) were boys. Sixteen children were younger than 4 years.

Exposure data were available for 20 (71%) of those aged 0-12. In that group, 19 were exposed at home; 17 cases were due to routine skin-to-skin contact with a household caregiver; and one case was suspected to be caused by fomites (such as a shared towel). Exposure information was unavailable for the remaining case.

Most of the children experienced lesions on the trunk. No lesions were anogenital. Two patients in the youngest age group were hospitalized because of widespread rash that involved the eyelids, and a patient in the 5- to 12-year-old group was hospitalized because of periorbital cellulitis and conjunctivitis.

Among those aged 13-17, there were 55 cases. Of these patients, 89% were boys. Exposure data were available for 35 (64%). In 32 of these patients, the infection occurred from presumed sexual contact. Twenty-three of those adolescents reported male-to-male sexual contact. No case was found to be connected with sexual abuse.

Lesions in the adolescents were mostly truncal or anogenital. Six in this group were hospitalized, and all of them recovered. One adolescent was found to be HIV positive.

Black and Hispanic children accounted for 47% and 35% of all cases, respectively.

Eleven percent of all the children and adolescents were hospitalized, and none received intensive care.

Treatments, when given, included the antiviral drug tecovirimat, intravenous vaccinia immune globulin, and topical trifluridine. There were no deaths.

Ten symptomatic patients attended school or daycare. Among these patients, no secondary transmissions were found to have occurred. Some contacts were offered the JYNNEOS monkeypox vaccine as postexposure prophylaxis.

Limitations of the study included potentially overlooked cases. Data were collected through routine surveillance, children frequently experience rashes, and access to testing has been a challenge, Dr. Hennessee explained.

In addition, data on exposure characteristics were missing for some children.
 

Inequities and the risks of being judged

The outbreak in the United States has eased in recent months. However, though uncommon in children, monkeypox has affected some racial groups disproportionately.

“Especially in the later course of the outbreak, the majority of cases were among Black and Hispanic individuals,” said co-author Rachel E. Harold, MD, an infectious diseases specialist and supervisory medical officer with the District of Columbia Department of Health’s HIV/AIDS, Hepatitis, STDs, and TB Administration.

“Unfortunately, the pediatric cases do reflect the outbreak overall,” she told this news organization.

Dr. Harold noted there have been efforts in D.C. and other jurisdictions, as well as by the White House monkeypox response team, to reach populations at greatest risk and that they were “really trying to make vaccine available to people of color.”

Vaccination clinics often popped up in unexpected locations at short notice, and that made it hard for some people to get to them, Dr. Chin-Hong pointed out.

Another factor was “the public aspect of accessing diagnostics and vaccines and the way that that’s linked to potential judgment or sexual risk,” he added.

“Not everybody’s out,” Dr. Chin-Hong said, referring to members of the LGBTQ community. “In many communities of color, going to get a test or going to get a vaccine essentially means that you’re out.”

For clinicians who suspect monkeypox in a child, Dr. Harold suggests keeping a broad differential diagnosis, looking for an epidemiologic link, and contacting the CDC for assistance. Infected children should be encouraged to avoid touching their own eyes or mucous membranes, she added.

In addition, she said, tecovirimat is a reasonable treatment and is well tolerated by pediatric monkeypox patients with eczema, an underlying condition that could lead to severe disease.

For infected caregivers, Dr. Hennessee said, measures to prevent infecting children at home include isolation, contact precautions, and in some cases, postexposure prophylaxis via vaccination.

For sexually active adolescents, he advised that clinicians offer vaccination, education on sexual health, and testing for HIV and other sexually transmitted infections.

“It’s important to remember that adolescents may be sexually active, and clinicians should do a thorough and nonjudgmental sexual history,” Dr. Harold added. “That is always true, but especially if there is concern for [monkeypox].”

Dr. Hennessee, Dr. Chin-Hong, and Dr. Harold have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Every year, around 7,000 people in Germany develop a brain tumor, and around half of those cases involve a glioblastoma, a particularly aggressive form of the disease. Glioblastomas are incurable, but advances are being made in both diagnostics and therapy. Scientists from the Heidelberg University Hospital (UKHD) and from the German Cancer Research Center (DKFZ) in Heidelberg have discovered a fundamentally new way in which glioblastomas spread within the brain.

This news organization spoke to Wolfgang Wick, MD, medical director of the neurologic clinic at UKHD, about how glioblastomas are treated; the role that vaccinations, recombinant proteins, and parvoviruses play; and what therapeutic approaches might be derived from the discovery of this method by which glioblastomas spread.

Question: Glioblastomas spread through the brain like a fungal network. So how would a glioblastoma currently be treated? The tumor can only be partially removed through surgery.

Answer: Nevertheless, glioblastoma would be operated on. This would have a significant effect. Relieving the strain of the main tumor mass, without generating a new deficit, is prognostically very good for the patient concerned. However, surgery on glioblastoma is never curative.

The reason a cure is not possible is down to the special form and spread of the glioblastoma. Nevertheless, an operation helps. This seems to be because removing the main tumor mass maybe has a positive immunological effect. But it may also be connected to the tumor’s network communication. The surgical intervention stimulates the network by increasing resistance.

If the main tumor mass is decreased through a surgical procedure, this results in an at least temporarily improved starting position for the patient until the mass regenerates. This could also be connected to the fact that tumor communication is not unregulated but is rather in accordance with a certain hierarchy and order, which requires a certain structure and mass.

The other aspect is that support can be requested via this communication. You can imagine that a cell connected to another cell via a conduit receives help from this other cell in the form of organelles by exchanging ions and that, for example, stress or toxicity can be much better balanced out in large networks than in small networks. That means that external attacks, such as a surgical intervention, can be much better balanced by a well-organized network than by isolated cells.
 

Resistance to chemotherapy

Q: How do irradiation and chemotherapy rank in the treatment of glioblastomas?

A: Irradiation is another therapeutic approach. It causes cells to be stuck in the growth phase of the cell cycle. The cells are not killed through radiation, but they are practically halted. And this arrest of the cell cycle is often sufficient to help people with glioblastomas for a very long time. But the same is true for irradiation as for surgery. This deep network of cells cannot be addressed.

Attempts have been made in the past to reduce the radiation dose to the extent that the brain is no longer damaged by it, but this low dose was then not sufficient to exert any control. If you want to control the tumor, the dose must be high and the volume must be correspondingly low, since there is a clear limit.

Every patient is offered alkylating chemotherapy. At the moment, just one substance is used here in the primary therapy: temozolomide. The problem with this is that two-thirds of tumors in all cells exhibit a resistance to this alkylating chemotherapy, which means that the efficacy of this therapy is highly limited in two-thirds of patients.

In the one-third of patients in whom this resistance is not present, the chemotherapy works fairly well. But even then, it is unfortunately only a matter of time until there is a relapse or disease progression. In my practice, this has always been the case, but there are people who have been living with this disease for 20 years now. There seem to be tumor cells that calmly and silently survive this phase of chemotherapy and then restart the cell cycle at some point.

Q: What do you think of alternating electric fields as a therapy option?

A: Therapy with alternating electric fields is currently being used and offered to patients. This means that patients who have survived well through radiochemotherapy should also be offered treatment with alternating electric fields.

However, what happens in this process is not as well understood as with other therapies. It is assumed that the cell cycle, i.e., cell division, is altered by disrupting the mitotic spindle. But you can imagine, and this is now speculation, but quite sound speculation I believe, that alternating electric fields also cause a certain amount of confusion in the previously described networks. But this still needs to be investigated in more detail.

It is not implausible. We know that such alternating electric fields disturb the organization of cell organelles. And we also know that for this communication, we need fairly good order and also organization. This would definitely be a starting point on the way to understanding why this therapy potentially shows a certain effect in some patients.
 

Nerve cell precursors

Q: Scientists from the UKHD and the DKFZ have discovered a new glioblastoma spreading strategy and have learned that the tumor cells imitate the properties and movement patterns of nerve cells. They are labeling the results a “milestone in the field of cancer neuroscience.” Could you explain a bit more?

A: Glioblastoma does not grow on its own as a solid mass, but instead, the entire brain is affected by the disease. The question of how the tumor’s individual cells move the main tumor mass from afar, how they get there, how they continue to be supplied, and what their interaction partners are – an entirely new light has been shed on all of this in our work.

The development of tumor cell mobility has been recognized as a remnant of brain development. The tumor cells have retained properties that the precursor cells for nervous-system development require for an organized nervous system to emerge from just a few cells. This means that the tumor cells copy or eventually retain properties of the nerve-cell precursors that, unlike mature nerve cells, are mobile to a fairly high degree.

Mobility here means that it can advance along a network, despite said network being very densely packed. This also means that certain processes, such as releasing and then continuing to move again, must function and that the communication regarding the original disease must be maintained.

First, we understand what the different glioblastoma cell types do, which molecular properties are associated with which behaviors, and which cell type (namely the swarming cells) is responsible for the invasive tumor growth. In contrast, the network-forming cell type, which only develops from these, is responsible for the resistance.
 

Interrupting communication

Q: Which starting points for new therapies do you see?

A: In terms of new therapies, these movement phenomena are one good starting point. The other starting point – I find this one much more interesting – is that the programming steps that these tumor cells use [are] no longer needed. This is because our mature nervous system no longer requires this program, which was necessary for the mobility of cells in development.

Our central nervous system exhibits little cell movement. This is to do with programs of nervous-system development that are switched off in the mature nervous system. But they are then reactivated or remain active in the tumor cells. This process reveals potential starting points for therapy.

Addressing the movement of cells, that has been investigated for the last 20 years, but it seems to have an extraordinarily high number of side effects, because these movement mechanisms are also important for other, healthy cells in the body. For example, digestive mechanisms and other proliferation mechanisms, on mucous membranes, in the blood system, in the bone marrow, are then affected and no longer function.

There is another possible approach: the more-or-less specific interaction between the nerve cells and the tumor cells also offers starting points for therapies, from our point of view. The key word is epilepsy treatment. We know that people with brain tumors suffer badly, or worse than usual, from epileptic seizures. This was often regarded purely as a pressure problem. There is a disruptive element in the brain, and this causes the electrical activity in the brain to become disorganized. For some people, this can lead to seizures in certain situations.

The communication between tumor cells and nerve cells takes place via transmission substances, e.g., through the neurotransmitter glutamate. Now you can consider whether a “surplus” of communication, such as an excessively strong stimulus, can trigger epileptic seizures.

In this work, we demonstrate that by interrupting this communication, we can also prevent the movement of these cells and the growth, the proliferation, of these cells.

Q: What is the significance of parvoviruses for therapy?

A: The major topic for cancer is immunotherapy. And one option for performing immunotherapies lies with viruses. Parvoviruses are a plausible therapy for proliferating cells.

Parvoviruses are usually administered locally. This means that a surgical cavity is infected with the viruses and the tumor cells that remain after an operation will then hopefully be killed off by these viruses.

This is the first step and the immediate effect of virus therapy. The attempt is made to kill off cells in the same way as with a medication. The advantage of viruses is the high specificity, i.e., only dividing cells will be attacked. In addition, parvoviruses are so small that they can also spread well and circulate through the brain.

The second reason for immunotherapy is that when killing off cells with viruses, antigens are often released that otherwise would not be, depending on the virus. But it’s the case with parvoviruses. They integrate with the virus’s genetic material. When cells rupture, certain proteins are then revealed, hybrids of viruses and the human genome, and these are attractive to the immune system.

There is a whole range of studies on this subject. However, there are currently no randomized studies that directly compare the therapies. But the expectation is that the use of parvoviruses could be a good addition to therapy.

One limitation that should be mentioned is that the use of viruses may be beneficial for some patients, but it will not have an effect in every patient. What is exciting about parvoviruses is that these viruses can be injected via the bloodstream and still achieve a good effect in the brain.
 

Protein APG101

Q: How relevant is the recombinant protein APG101 to therapy?

A: APG101 is a protein that simulates the cell-death receptor CD95 and binds with a stable antibody fragment. By doing so, it blocks the signaling pathway between CD95 ligand and receptor. The interaction between the CD95 ligand and the CD95 receptor activates an intracellular signaling pathway, which in turn stimulates the invasive growth and migration of tumor cells.

APG101 blocks the CD95 ligand and thereby prevents the activation of the CD95 signaling pathway, which leads to a reduction in the invasive cell growth and migration.

Apoptosis, programmed cell death, is a system we have used throughout our evolution to kill off the cell components we no longer need. During tumor development, this system is perverted, so to speak. Here, the stimulation of this system does not actually lead to cell death but rather to cell movement (i.e., to cell mobility). And in principle, APG101 blocks this mobility.

To date, I only know of three studies in which the medication has been used for tumors. One study was published 8 years ago. We demonstrated that we can achieve a relatively good effect with APG101 in connection with repeat irradiation, compared with repeat irradiation alone. We consider this effect to most likely be due to this influence on cell mobility.

There is a study on primary therapy: a four-arm study by the Neuro-Oncological Working Group. The results are still not available, however. In addition, a study on primary therapy with APG101 is currently being conducted in China. It is investigating whether the mechanism of action influences mobility. Whether it will be pushed through as therapy remains to be seen.
 

Vaccinations and antigens

Q: Vaccinations are of course a part of immunotherapy. What is their status?

A: We are looking at the IDH1 protein, which is present in mutated form in a group of brain tumors, as a very good target for a vaccine. The reason is that the protein is present in its mutated form in every cell of the tumor but not in healthy cells. That is a prerequisite for immunotherapy.

We started a study with peptides a few years ago. These peptides are injected under the skin on the stomach and leg. They cause an immune response systemically and in the brain tumor. This immune response may cause an inflammatory reaction (we can demonstrate this inflammatory reaction). And in this noncontrolled study, the approach was successful, at least compared to historical controls. There is no randomized study with treatment-naive control patients.

However, we are cautious because we know that peptide, unlike CAR T cells or RNA-based vaccines, for example, only triggers a relatively small immune response in many patients. The scale of the immune response is important, rather than the specificity. The scale is probably not large enough in most patients for a long-term effect to be expected.

But there are exceptions. Patients we vaccinated many years ago still have a very remarkable immune status. But we also have patients in whom an immune status cannot even be seen anymore, after just a short period of time.

Therefore, our aim is to perform the immune strategy with more effective, stronger measures – not more specific, but stronger. Unfortunately, it is often the case with glioblastomas that there is not a single antigen that can be vaccinated against. Instead, a relatively large cocktail is needed, which unfortunately also often varies from patient to patient. The conditions are difficult.

Q: You mentioned that glioblastomas can be classified into subgroups. Does this improve the prognosis?

A: Yes, in certain subgroups the prognosis improves. That is the case with those usually very small groups that are molecularly well defined. I believe that by better understanding the individual groups, we have succeeded in making major progress in those groups. But where there is light, there is also shadow. We know that there are many groups with which we have not achieved a great deal.

Fundamental research leads to a better understanding, and the next step in this is to be able to adapt the therapy. Instead of it being one therapy for everyone, it will become a part of various differing therapies for these quite different groups. We are making a lot of progress with individual groups. But unfortunately, we have not come quite as far as we want with many patients.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

Every year, around 7,000 people in Germany develop a brain tumor, and around half of those cases involve a glioblastoma, a particularly aggressive form of the disease. Glioblastomas are incurable, but advances are being made in both diagnostics and therapy. Scientists from the Heidelberg University Hospital (UKHD) and from the German Cancer Research Center (DKFZ) in Heidelberg have discovered a fundamentally new way in which glioblastomas spread within the brain.

This news organization spoke to Wolfgang Wick, MD, medical director of the neurologic clinic at UKHD, about how glioblastomas are treated; the role that vaccinations, recombinant proteins, and parvoviruses play; and what therapeutic approaches might be derived from the discovery of this method by which glioblastomas spread.

Question: Glioblastomas spread through the brain like a fungal network. So how would a glioblastoma currently be treated? The tumor can only be partially removed through surgery.

Answer: Nevertheless, glioblastoma would be operated on. This would have a significant effect. Relieving the strain of the main tumor mass, without generating a new deficit, is prognostically very good for the patient concerned. However, surgery on glioblastoma is never curative.

The reason a cure is not possible is down to the special form and spread of the glioblastoma. Nevertheless, an operation helps. This seems to be because removing the main tumor mass maybe has a positive immunological effect. But it may also be connected to the tumor’s network communication. The surgical intervention stimulates the network by increasing resistance.

If the main tumor mass is decreased through a surgical procedure, this results in an at least temporarily improved starting position for the patient until the mass regenerates. This could also be connected to the fact that tumor communication is not unregulated but is rather in accordance with a certain hierarchy and order, which requires a certain structure and mass.

The other aspect is that support can be requested via this communication. You can imagine that a cell connected to another cell via a conduit receives help from this other cell in the form of organelles by exchanging ions and that, for example, stress or toxicity can be much better balanced out in large networks than in small networks. That means that external attacks, such as a surgical intervention, can be much better balanced by a well-organized network than by isolated cells.
 

Resistance to chemotherapy

Q: How do irradiation and chemotherapy rank in the treatment of glioblastomas?

A: Irradiation is another therapeutic approach. It causes cells to be stuck in the growth phase of the cell cycle. The cells are not killed through radiation, but they are practically halted. And this arrest of the cell cycle is often sufficient to help people with glioblastomas for a very long time. But the same is true for irradiation as for surgery. This deep network of cells cannot be addressed.

Attempts have been made in the past to reduce the radiation dose to the extent that the brain is no longer damaged by it, but this low dose was then not sufficient to exert any control. If you want to control the tumor, the dose must be high and the volume must be correspondingly low, since there is a clear limit.

Every patient is offered alkylating chemotherapy. At the moment, just one substance is used here in the primary therapy: temozolomide. The problem with this is that two-thirds of tumors in all cells exhibit a resistance to this alkylating chemotherapy, which means that the efficacy of this therapy is highly limited in two-thirds of patients.

In the one-third of patients in whom this resistance is not present, the chemotherapy works fairly well. But even then, it is unfortunately only a matter of time until there is a relapse or disease progression. In my practice, this has always been the case, but there are people who have been living with this disease for 20 years now. There seem to be tumor cells that calmly and silently survive this phase of chemotherapy and then restart the cell cycle at some point.

Q: What do you think of alternating electric fields as a therapy option?

A: Therapy with alternating electric fields is currently being used and offered to patients. This means that patients who have survived well through radiochemotherapy should also be offered treatment with alternating electric fields.

However, what happens in this process is not as well understood as with other therapies. It is assumed that the cell cycle, i.e., cell division, is altered by disrupting the mitotic spindle. But you can imagine, and this is now speculation, but quite sound speculation I believe, that alternating electric fields also cause a certain amount of confusion in the previously described networks. But this still needs to be investigated in more detail.

It is not implausible. We know that such alternating electric fields disturb the organization of cell organelles. And we also know that for this communication, we need fairly good order and also organization. This would definitely be a starting point on the way to understanding why this therapy potentially shows a certain effect in some patients.
 

Nerve cell precursors

Q: Scientists from the UKHD and the DKFZ have discovered a new glioblastoma spreading strategy and have learned that the tumor cells imitate the properties and movement patterns of nerve cells. They are labeling the results a “milestone in the field of cancer neuroscience.” Could you explain a bit more?

A: Glioblastoma does not grow on its own as a solid mass, but instead, the entire brain is affected by the disease. The question of how the tumor’s individual cells move the main tumor mass from afar, how they get there, how they continue to be supplied, and what their interaction partners are – an entirely new light has been shed on all of this in our work.

The development of tumor cell mobility has been recognized as a remnant of brain development. The tumor cells have retained properties that the precursor cells for nervous-system development require for an organized nervous system to emerge from just a few cells. This means that the tumor cells copy or eventually retain properties of the nerve-cell precursors that, unlike mature nerve cells, are mobile to a fairly high degree.

Mobility here means that it can advance along a network, despite said network being very densely packed. This also means that certain processes, such as releasing and then continuing to move again, must function and that the communication regarding the original disease must be maintained.

First, we understand what the different glioblastoma cell types do, which molecular properties are associated with which behaviors, and which cell type (namely the swarming cells) is responsible for the invasive tumor growth. In contrast, the network-forming cell type, which only develops from these, is responsible for the resistance.
 

Interrupting communication

Q: Which starting points for new therapies do you see?

A: In terms of new therapies, these movement phenomena are one good starting point. The other starting point – I find this one much more interesting – is that the programming steps that these tumor cells use [are] no longer needed. This is because our mature nervous system no longer requires this program, which was necessary for the mobility of cells in development.

Our central nervous system exhibits little cell movement. This is to do with programs of nervous-system development that are switched off in the mature nervous system. But they are then reactivated or remain active in the tumor cells. This process reveals potential starting points for therapy.

Addressing the movement of cells, that has been investigated for the last 20 years, but it seems to have an extraordinarily high number of side effects, because these movement mechanisms are also important for other, healthy cells in the body. For example, digestive mechanisms and other proliferation mechanisms, on mucous membranes, in the blood system, in the bone marrow, are then affected and no longer function.

There is another possible approach: the more-or-less specific interaction between the nerve cells and the tumor cells also offers starting points for therapies, from our point of view. The key word is epilepsy treatment. We know that people with brain tumors suffer badly, or worse than usual, from epileptic seizures. This was often regarded purely as a pressure problem. There is a disruptive element in the brain, and this causes the electrical activity in the brain to become disorganized. For some people, this can lead to seizures in certain situations.

The communication between tumor cells and nerve cells takes place via transmission substances, e.g., through the neurotransmitter glutamate. Now you can consider whether a “surplus” of communication, such as an excessively strong stimulus, can trigger epileptic seizures.

In this work, we demonstrate that by interrupting this communication, we can also prevent the movement of these cells and the growth, the proliferation, of these cells.

Q: What is the significance of parvoviruses for therapy?

A: The major topic for cancer is immunotherapy. And one option for performing immunotherapies lies with viruses. Parvoviruses are a plausible therapy for proliferating cells.

Parvoviruses are usually administered locally. This means that a surgical cavity is infected with the viruses and the tumor cells that remain after an operation will then hopefully be killed off by these viruses.

This is the first step and the immediate effect of virus therapy. The attempt is made to kill off cells in the same way as with a medication. The advantage of viruses is the high specificity, i.e., only dividing cells will be attacked. In addition, parvoviruses are so small that they can also spread well and circulate through the brain.

The second reason for immunotherapy is that when killing off cells with viruses, antigens are often released that otherwise would not be, depending on the virus. But it’s the case with parvoviruses. They integrate with the virus’s genetic material. When cells rupture, certain proteins are then revealed, hybrids of viruses and the human genome, and these are attractive to the immune system.

There is a whole range of studies on this subject. However, there are currently no randomized studies that directly compare the therapies. But the expectation is that the use of parvoviruses could be a good addition to therapy.

One limitation that should be mentioned is that the use of viruses may be beneficial for some patients, but it will not have an effect in every patient. What is exciting about parvoviruses is that these viruses can be injected via the bloodstream and still achieve a good effect in the brain.
 

Protein APG101

Q: How relevant is the recombinant protein APG101 to therapy?

A: APG101 is a protein that simulates the cell-death receptor CD95 and binds with a stable antibody fragment. By doing so, it blocks the signaling pathway between CD95 ligand and receptor. The interaction between the CD95 ligand and the CD95 receptor activates an intracellular signaling pathway, which in turn stimulates the invasive growth and migration of tumor cells.

APG101 blocks the CD95 ligand and thereby prevents the activation of the CD95 signaling pathway, which leads to a reduction in the invasive cell growth and migration.

Apoptosis, programmed cell death, is a system we have used throughout our evolution to kill off the cell components we no longer need. During tumor development, this system is perverted, so to speak. Here, the stimulation of this system does not actually lead to cell death but rather to cell movement (i.e., to cell mobility). And in principle, APG101 blocks this mobility.

To date, I only know of three studies in which the medication has been used for tumors. One study was published 8 years ago. We demonstrated that we can achieve a relatively good effect with APG101 in connection with repeat irradiation, compared with repeat irradiation alone. We consider this effect to most likely be due to this influence on cell mobility.

There is a study on primary therapy: a four-arm study by the Neuro-Oncological Working Group. The results are still not available, however. In addition, a study on primary therapy with APG101 is currently being conducted in China. It is investigating whether the mechanism of action influences mobility. Whether it will be pushed through as therapy remains to be seen.
 

Vaccinations and antigens

Q: Vaccinations are of course a part of immunotherapy. What is their status?

A: We are looking at the IDH1 protein, which is present in mutated form in a group of brain tumors, as a very good target for a vaccine. The reason is that the protein is present in its mutated form in every cell of the tumor but not in healthy cells. That is a prerequisite for immunotherapy.

We started a study with peptides a few years ago. These peptides are injected under the skin on the stomach and leg. They cause an immune response systemically and in the brain tumor. This immune response may cause an inflammatory reaction (we can demonstrate this inflammatory reaction). And in this noncontrolled study, the approach was successful, at least compared to historical controls. There is no randomized study with treatment-naive control patients.

However, we are cautious because we know that peptide, unlike CAR T cells or RNA-based vaccines, for example, only triggers a relatively small immune response in many patients. The scale of the immune response is important, rather than the specificity. The scale is probably not large enough in most patients for a long-term effect to be expected.

But there are exceptions. Patients we vaccinated many years ago still have a very remarkable immune status. But we also have patients in whom an immune status cannot even be seen anymore, after just a short period of time.

Therefore, our aim is to perform the immune strategy with more effective, stronger measures – not more specific, but stronger. Unfortunately, it is often the case with glioblastomas that there is not a single antigen that can be vaccinated against. Instead, a relatively large cocktail is needed, which unfortunately also often varies from patient to patient. The conditions are difficult.

Q: You mentioned that glioblastomas can be classified into subgroups. Does this improve the prognosis?

A: Yes, in certain subgroups the prognosis improves. That is the case with those usually very small groups that are molecularly well defined. I believe that by better understanding the individual groups, we have succeeded in making major progress in those groups. But where there is light, there is also shadow. We know that there are many groups with which we have not achieved a great deal.

Fundamental research leads to a better understanding, and the next step in this is to be able to adapt the therapy. Instead of it being one therapy for everyone, it will become a part of various differing therapies for these quite different groups. We are making a lot of progress with individual groups. But unfortunately, we have not come quite as far as we want with many patients.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

Every year, around 7,000 people in Germany develop a brain tumor, and around half of those cases involve a glioblastoma, a particularly aggressive form of the disease. Glioblastomas are incurable, but advances are being made in both diagnostics and therapy. Scientists from the Heidelberg University Hospital (UKHD) and from the German Cancer Research Center (DKFZ) in Heidelberg have discovered a fundamentally new way in which glioblastomas spread within the brain.

This news organization spoke to Wolfgang Wick, MD, medical director of the neurologic clinic at UKHD, about how glioblastomas are treated; the role that vaccinations, recombinant proteins, and parvoviruses play; and what therapeutic approaches might be derived from the discovery of this method by which glioblastomas spread.

Question: Glioblastomas spread through the brain like a fungal network. So how would a glioblastoma currently be treated? The tumor can only be partially removed through surgery.

Answer: Nevertheless, glioblastoma would be operated on. This would have a significant effect. Relieving the strain of the main tumor mass, without generating a new deficit, is prognostically very good for the patient concerned. However, surgery on glioblastoma is never curative.

The reason a cure is not possible is down to the special form and spread of the glioblastoma. Nevertheless, an operation helps. This seems to be because removing the main tumor mass maybe has a positive immunological effect. But it may also be connected to the tumor’s network communication. The surgical intervention stimulates the network by increasing resistance.

If the main tumor mass is decreased through a surgical procedure, this results in an at least temporarily improved starting position for the patient until the mass regenerates. This could also be connected to the fact that tumor communication is not unregulated but is rather in accordance with a certain hierarchy and order, which requires a certain structure and mass.

The other aspect is that support can be requested via this communication. You can imagine that a cell connected to another cell via a conduit receives help from this other cell in the form of organelles by exchanging ions and that, for example, stress or toxicity can be much better balanced out in large networks than in small networks. That means that external attacks, such as a surgical intervention, can be much better balanced by a well-organized network than by isolated cells.
 

Resistance to chemotherapy

Q: How do irradiation and chemotherapy rank in the treatment of glioblastomas?

A: Irradiation is another therapeutic approach. It causes cells to be stuck in the growth phase of the cell cycle. The cells are not killed through radiation, but they are practically halted. And this arrest of the cell cycle is often sufficient to help people with glioblastomas for a very long time. But the same is true for irradiation as for surgery. This deep network of cells cannot be addressed.

Attempts have been made in the past to reduce the radiation dose to the extent that the brain is no longer damaged by it, but this low dose was then not sufficient to exert any control. If you want to control the tumor, the dose must be high and the volume must be correspondingly low, since there is a clear limit.

Every patient is offered alkylating chemotherapy. At the moment, just one substance is used here in the primary therapy: temozolomide. The problem with this is that two-thirds of tumors in all cells exhibit a resistance to this alkylating chemotherapy, which means that the efficacy of this therapy is highly limited in two-thirds of patients.

In the one-third of patients in whom this resistance is not present, the chemotherapy works fairly well. But even then, it is unfortunately only a matter of time until there is a relapse or disease progression. In my practice, this has always been the case, but there are people who have been living with this disease for 20 years now. There seem to be tumor cells that calmly and silently survive this phase of chemotherapy and then restart the cell cycle at some point.

Q: What do you think of alternating electric fields as a therapy option?

A: Therapy with alternating electric fields is currently being used and offered to patients. This means that patients who have survived well through radiochemotherapy should also be offered treatment with alternating electric fields.

However, what happens in this process is not as well understood as with other therapies. It is assumed that the cell cycle, i.e., cell division, is altered by disrupting the mitotic spindle. But you can imagine, and this is now speculation, but quite sound speculation I believe, that alternating electric fields also cause a certain amount of confusion in the previously described networks. But this still needs to be investigated in more detail.

It is not implausible. We know that such alternating electric fields disturb the organization of cell organelles. And we also know that for this communication, we need fairly good order and also organization. This would definitely be a starting point on the way to understanding why this therapy potentially shows a certain effect in some patients.
 

Nerve cell precursors

Q: Scientists from the UKHD and the DKFZ have discovered a new glioblastoma spreading strategy and have learned that the tumor cells imitate the properties and movement patterns of nerve cells. They are labeling the results a “milestone in the field of cancer neuroscience.” Could you explain a bit more?

A: Glioblastoma does not grow on its own as a solid mass, but instead, the entire brain is affected by the disease. The question of how the tumor’s individual cells move the main tumor mass from afar, how they get there, how they continue to be supplied, and what their interaction partners are – an entirely new light has been shed on all of this in our work.

The development of tumor cell mobility has been recognized as a remnant of brain development. The tumor cells have retained properties that the precursor cells for nervous-system development require for an organized nervous system to emerge from just a few cells. This means that the tumor cells copy or eventually retain properties of the nerve-cell precursors that, unlike mature nerve cells, are mobile to a fairly high degree.

Mobility here means that it can advance along a network, despite said network being very densely packed. This also means that certain processes, such as releasing and then continuing to move again, must function and that the communication regarding the original disease must be maintained.

First, we understand what the different glioblastoma cell types do, which molecular properties are associated with which behaviors, and which cell type (namely the swarming cells) is responsible for the invasive tumor growth. In contrast, the network-forming cell type, which only develops from these, is responsible for the resistance.
 

Interrupting communication

Q: Which starting points for new therapies do you see?

A: In terms of new therapies, these movement phenomena are one good starting point. The other starting point – I find this one much more interesting – is that the programming steps that these tumor cells use [are] no longer needed. This is because our mature nervous system no longer requires this program, which was necessary for the mobility of cells in development.

Our central nervous system exhibits little cell movement. This is to do with programs of nervous-system development that are switched off in the mature nervous system. But they are then reactivated or remain active in the tumor cells. This process reveals potential starting points for therapy.

Addressing the movement of cells, that has been investigated for the last 20 years, but it seems to have an extraordinarily high number of side effects, because these movement mechanisms are also important for other, healthy cells in the body. For example, digestive mechanisms and other proliferation mechanisms, on mucous membranes, in the blood system, in the bone marrow, are then affected and no longer function.

There is another possible approach: the more-or-less specific interaction between the nerve cells and the tumor cells also offers starting points for therapies, from our point of view. The key word is epilepsy treatment. We know that people with brain tumors suffer badly, or worse than usual, from epileptic seizures. This was often regarded purely as a pressure problem. There is a disruptive element in the brain, and this causes the electrical activity in the brain to become disorganized. For some people, this can lead to seizures in certain situations.

The communication between tumor cells and nerve cells takes place via transmission substances, e.g., through the neurotransmitter glutamate. Now you can consider whether a “surplus” of communication, such as an excessively strong stimulus, can trigger epileptic seizures.

In this work, we demonstrate that by interrupting this communication, we can also prevent the movement of these cells and the growth, the proliferation, of these cells.

Q: What is the significance of parvoviruses for therapy?

A: The major topic for cancer is immunotherapy. And one option for performing immunotherapies lies with viruses. Parvoviruses are a plausible therapy for proliferating cells.

Parvoviruses are usually administered locally. This means that a surgical cavity is infected with the viruses and the tumor cells that remain after an operation will then hopefully be killed off by these viruses.

This is the first step and the immediate effect of virus therapy. The attempt is made to kill off cells in the same way as with a medication. The advantage of viruses is the high specificity, i.e., only dividing cells will be attacked. In addition, parvoviruses are so small that they can also spread well and circulate through the brain.

The second reason for immunotherapy is that when killing off cells with viruses, antigens are often released that otherwise would not be, depending on the virus. But it’s the case with parvoviruses. They integrate with the virus’s genetic material. When cells rupture, certain proteins are then revealed, hybrids of viruses and the human genome, and these are attractive to the immune system.

There is a whole range of studies on this subject. However, there are currently no randomized studies that directly compare the therapies. But the expectation is that the use of parvoviruses could be a good addition to therapy.

One limitation that should be mentioned is that the use of viruses may be beneficial for some patients, but it will not have an effect in every patient. What is exciting about parvoviruses is that these viruses can be injected via the bloodstream and still achieve a good effect in the brain.
 

Protein APG101

Q: How relevant is the recombinant protein APG101 to therapy?

A: APG101 is a protein that simulates the cell-death receptor CD95 and binds with a stable antibody fragment. By doing so, it blocks the signaling pathway between CD95 ligand and receptor. The interaction between the CD95 ligand and the CD95 receptor activates an intracellular signaling pathway, which in turn stimulates the invasive growth and migration of tumor cells.

APG101 blocks the CD95 ligand and thereby prevents the activation of the CD95 signaling pathway, which leads to a reduction in the invasive cell growth and migration.

Apoptosis, programmed cell death, is a system we have used throughout our evolution to kill off the cell components we no longer need. During tumor development, this system is perverted, so to speak. Here, the stimulation of this system does not actually lead to cell death but rather to cell movement (i.e., to cell mobility). And in principle, APG101 blocks this mobility.

To date, I only know of three studies in which the medication has been used for tumors. One study was published 8 years ago. We demonstrated that we can achieve a relatively good effect with APG101 in connection with repeat irradiation, compared with repeat irradiation alone. We consider this effect to most likely be due to this influence on cell mobility.

There is a study on primary therapy: a four-arm study by the Neuro-Oncological Working Group. The results are still not available, however. In addition, a study on primary therapy with APG101 is currently being conducted in China. It is investigating whether the mechanism of action influences mobility. Whether it will be pushed through as therapy remains to be seen.
 

Vaccinations and antigens

Q: Vaccinations are of course a part of immunotherapy. What is their status?

A: We are looking at the IDH1 protein, which is present in mutated form in a group of brain tumors, as a very good target for a vaccine. The reason is that the protein is present in its mutated form in every cell of the tumor but not in healthy cells. That is a prerequisite for immunotherapy.

We started a study with peptides a few years ago. These peptides are injected under the skin on the stomach and leg. They cause an immune response systemically and in the brain tumor. This immune response may cause an inflammatory reaction (we can demonstrate this inflammatory reaction). And in this noncontrolled study, the approach was successful, at least compared to historical controls. There is no randomized study with treatment-naive control patients.

However, we are cautious because we know that peptide, unlike CAR T cells or RNA-based vaccines, for example, only triggers a relatively small immune response in many patients. The scale of the immune response is important, rather than the specificity. The scale is probably not large enough in most patients for a long-term effect to be expected.

But there are exceptions. Patients we vaccinated many years ago still have a very remarkable immune status. But we also have patients in whom an immune status cannot even be seen anymore, after just a short period of time.

Therefore, our aim is to perform the immune strategy with more effective, stronger measures – not more specific, but stronger. Unfortunately, it is often the case with glioblastomas that there is not a single antigen that can be vaccinated against. Instead, a relatively large cocktail is needed, which unfortunately also often varies from patient to patient. The conditions are difficult.

Q: You mentioned that glioblastomas can be classified into subgroups. Does this improve the prognosis?

A: Yes, in certain subgroups the prognosis improves. That is the case with those usually very small groups that are molecularly well defined. I believe that by better understanding the individual groups, we have succeeded in making major progress in those groups. But where there is light, there is also shadow. We know that there are many groups with which we have not achieved a great deal.

Fundamental research leads to a better understanding, and the next step in this is to be able to adapt the therapy. Instead of it being one therapy for everyone, it will become a part of various differing therapies for these quite different groups. We are making a lot of progress with individual groups. But unfortunately, we have not come quite as far as we want with many patients.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

The Diagnosis: Tuberous Xanthoma

The skin biopsy revealed a nodular collection of foam cells (quiz image [bottom]). Tuberous xanthoma was the most likely diagnosis based on the patient’s history as well as the clinical and histologic findings. Tuberous xanthomas are flat or elevated nodules in the dermis and subcutaneous tissue, commonly occurring on the skin over the joints.¹ Smaller nodules and papules often are referred to as tuberoeruptive xanthomas and exist on a continuum with the larger tuberous xanthomas. All xanthomas appear histologically similar, with collections of foam cells present within the dermis.² Foam cells form when serum lipoproteins diffuse through capillary walls, deposit in the skin or tendons, and are scavenged by monocytes.3 Tuberous xanthomas, along with tendinous, eruptive, and planar xanthomas, are the most likely to be associated with hyperlipidemia.⁴ They may indicate an underlying disorder of lipid metabolism, such as familial hypercholesterolemia.^1,3 This is the most common cause of inheritable cardiovascular disease, with a prevalence of approximately 1:250.² Premature cardiovascular disease risk increases 2 to 4 times in patients with familial hypercholesterolemia and tendinous xanthomas,¹ illustrating that recognition of cutaneous lesions can lead to earlier diagnosis and prevention of patient morbidity and mortality.

Juvenile xanthogranuloma typically presents as smooth yellow papules or nodules on the head and neck, with a characteristic “setting-sun” appearance (ie, yellow center with an erythematous halo) on dermoscopy.⁵ Histologically, juvenile xanthogranulomas are composed of foam cells and a mixed lymphohistiocytic infiltrate with eosinophils within the dermis. Giant cells with a ring of nuclei surrounded by cytoplasm containing lipid vacuoles (called Touton giant cells) are characteristic (Figure 1). In contrast to tuberous xanthomas, juvenile xanthogranulomas often present within the first year of life.⁶

Keloid scars are more prevalent in patients with skin of color. They are characterized by eosinophilic keloidal collagen with a whorled proliferation of fibroblasts on histology (Figure 2).⁷ They occur spontaneously or at sites of injury and present as bluish-red or flesh-colored firm papules or nodules.⁸ In our patient, keloid scars were an unlikely diagnosis due to the lack of trauma and the absence of keloidal collagen on histology.

Necrobiosis lipoidica diabeticorum typically presents as an erythematous, yellow-brown, circular plaque on the anterior lower leg in patients with diabetes mellitus; it rarely occurs in children.⁹ Microscopy shows palisaded granulomas surrounding necrobiotic collagen arranged horizontally in a layer cake–like fashion (Figure 3).^9,10 The etiology of necrobiosis lipoidica diabeticorum currently is unknown, though immune complex deposition may contribute to its pathology. It has been associated with type 1 diabetes mellitus, though severity of the lesions is not associated with extent of glycemic control.¹⁰

Rosai-Dorfman disease is an uncommon disorder characterized by a proliferation of histiocytes that most often presents as bilateral cervical lymphadenopathy in children and young adults but rarely can present with cutaneous lesions when extranodal involvement is present.^11,12 The cutaneous form most commonly presents as red papules or nodules. On histology, the lesions exhibit a nodular dermal proliferation of histiocytes and smaller lymphocytoid cells with a marbled or starry sky–like appearance on low power (Figure 4). On higher magnification, the characteristic finding of emperipolesis can be seen.11 On immunohistochemistry, the histiocytes stain positively for CD68 and S-100. Although the pathogenesis currently is unknown, evidence of clonality indicates the disease may be related to a neoplastic process.¹²

The Diagnosis: Tuberous Xanthoma

The skin biopsy revealed a nodular collection of foam cells (quiz image [bottom]). Tuberous xanthoma was the most likely diagnosis based on the patient’s history as well as the clinical and histologic findings. Tuberous xanthomas are flat or elevated nodules in the dermis and subcutaneous tissue, commonly occurring on the skin over the joints.¹ Smaller nodules and papules often are referred to as tuberoeruptive xanthomas and exist on a continuum with the larger tuberous xanthomas. All xanthomas appear histologically similar, with collections of foam cells present within the dermis.² Foam cells form when serum lipoproteins diffuse through capillary walls, deposit in the skin or tendons, and are scavenged by monocytes.3 Tuberous xanthomas, along with tendinous, eruptive, and planar xanthomas, are the most likely to be associated with hyperlipidemia.⁴ They may indicate an underlying disorder of lipid metabolism, such as familial hypercholesterolemia.^1,3 This is the most common cause of inheritable cardiovascular disease, with a prevalence of approximately 1:250.² Premature cardiovascular disease risk increases 2 to 4 times in patients with familial hypercholesterolemia and tendinous xanthomas,¹ illustrating that recognition of cutaneous lesions can lead to earlier diagnosis and prevention of patient morbidity and mortality.

Juvenile xanthogranuloma typically presents as smooth yellow papules or nodules on the head and neck, with a characteristic “setting-sun” appearance (ie, yellow center with an erythematous halo) on dermoscopy.⁵ Histologically, juvenile xanthogranulomas are composed of foam cells and a mixed lymphohistiocytic infiltrate with eosinophils within the dermis. Giant cells with a ring of nuclei surrounded by cytoplasm containing lipid vacuoles (called Touton giant cells) are characteristic (Figure 1). In contrast to tuberous xanthomas, juvenile xanthogranulomas often present within the first year of life.⁶

Keloid scars are more prevalent in patients with skin of color. They are characterized by eosinophilic keloidal collagen with a whorled proliferation of fibroblasts on histology (Figure 2).⁷ They occur spontaneously or at sites of injury and present as bluish-red or flesh-colored firm papules or nodules.⁸ In our patient, keloid scars were an unlikely diagnosis due to the lack of trauma and the absence of keloidal collagen on histology.

Necrobiosis lipoidica diabeticorum typically presents as an erythematous, yellow-brown, circular plaque on the anterior lower leg in patients with diabetes mellitus; it rarely occurs in children.⁹ Microscopy shows palisaded granulomas surrounding necrobiotic collagen arranged horizontally in a layer cake–like fashion (Figure 3).^9,10 The etiology of necrobiosis lipoidica diabeticorum currently is unknown, though immune complex deposition may contribute to its pathology. It has been associated with type 1 diabetes mellitus, though severity of the lesions is not associated with extent of glycemic control.¹⁰

Rosai-Dorfman disease is an uncommon disorder characterized by a proliferation of histiocytes that most often presents as bilateral cervical lymphadenopathy in children and young adults but rarely can present with cutaneous lesions when extranodal involvement is present.^11,12 The cutaneous form most commonly presents as red papules or nodules. On histology, the lesions exhibit a nodular dermal proliferation of histiocytes and smaller lymphocytoid cells with a marbled or starry sky–like appearance on low power (Figure 4). On higher magnification, the characteristic finding of emperipolesis can be seen.11 On immunohistochemistry, the histiocytes stain positively for CD68 and S-100. Although the pathogenesis currently is unknown, evidence of clonality indicates the disease may be related to a neoplastic process.¹²

The Diagnosis: Tuberous Xanthoma

The skin biopsy revealed a nodular collection of foam cells (quiz image [bottom]). Tuberous xanthoma was the most likely diagnosis based on the patient’s history as well as the clinical and histologic findings. Tuberous xanthomas are flat or elevated nodules in the dermis and subcutaneous tissue, commonly occurring on the skin over the joints.¹ Smaller nodules and papules often are referred to as tuberoeruptive xanthomas and exist on a continuum with the larger tuberous xanthomas. All xanthomas appear histologically similar, with collections of foam cells present within the dermis.² Foam cells form when serum lipoproteins diffuse through capillary walls, deposit in the skin or tendons, and are scavenged by monocytes.3 Tuberous xanthomas, along with tendinous, eruptive, and planar xanthomas, are the most likely to be associated with hyperlipidemia.⁴ They may indicate an underlying disorder of lipid metabolism, such as familial hypercholesterolemia.^1,3 This is the most common cause of inheritable cardiovascular disease, with a prevalence of approximately 1:250.² Premature cardiovascular disease risk increases 2 to 4 times in patients with familial hypercholesterolemia and tendinous xanthomas,¹ illustrating that recognition of cutaneous lesions can lead to earlier diagnosis and prevention of patient morbidity and mortality.

Juvenile xanthogranuloma typically presents as smooth yellow papules or nodules on the head and neck, with a characteristic “setting-sun” appearance (ie, yellow center with an erythematous halo) on dermoscopy.⁵ Histologically, juvenile xanthogranulomas are composed of foam cells and a mixed lymphohistiocytic infiltrate with eosinophils within the dermis. Giant cells with a ring of nuclei surrounded by cytoplasm containing lipid vacuoles (called Touton giant cells) are characteristic (Figure 1). In contrast to tuberous xanthomas, juvenile xanthogranulomas often present within the first year of life.⁶

Keloid scars are more prevalent in patients with skin of color. They are characterized by eosinophilic keloidal collagen with a whorled proliferation of fibroblasts on histology (Figure 2).⁷ They occur spontaneously or at sites of injury and present as bluish-red or flesh-colored firm papules or nodules.⁸ In our patient, keloid scars were an unlikely diagnosis due to the lack of trauma and the absence of keloidal collagen on histology.

Necrobiosis lipoidica diabeticorum typically presents as an erythematous, yellow-brown, circular plaque on the anterior lower leg in patients with diabetes mellitus; it rarely occurs in children.⁹ Microscopy shows palisaded granulomas surrounding necrobiotic collagen arranged horizontally in a layer cake–like fashion (Figure 3).^9,10 The etiology of necrobiosis lipoidica diabeticorum currently is unknown, though immune complex deposition may contribute to its pathology. It has been associated with type 1 diabetes mellitus, though severity of the lesions is not associated with extent of glycemic control.¹⁰

Rosai-Dorfman disease is an uncommon disorder characterized by a proliferation of histiocytes that most often presents as bilateral cervical lymphadenopathy in children and young adults but rarely can present with cutaneous lesions when extranodal involvement is present.^11,12 The cutaneous form most commonly presents as red papules or nodules. On histology, the lesions exhibit a nodular dermal proliferation of histiocytes and smaller lymphocytoid cells with a marbled or starry sky–like appearance on low power (Figure 4). On higher magnification, the characteristic finding of emperipolesis can be seen.11 On immunohistochemistry, the histiocytes stain positively for CD68 and S-100. Although the pathogenesis currently is unknown, evidence of clonality indicates the disease may be related to a neoplastic process.¹²

A novel approach in which two products were co-administered achieved a 99% complete response rate in children with relapsed or treatment-resistant B-cell acute lymphoblastic leukemia (B-ALL).

In this trial, the largest study to date of a CAR T-cell therapy for such patients, the researchers co-administered two CAR T-cell therapies, one targeting CD19 and the other targeting CD22.

The results showed that 192 of 194 patients (99%) achieved a complete remission.

The combined overall 12-month event-free survival was 73.5%.

The study was published online in the Journal of Clinical Oncology.

These results are better than what has been reported for CAR T cells that are already on the market. These products, which target CD19, have achieved complete remission in 85.5% of cases and a 12-month event-free survival of 52.4% in children with B-ALL.

“We do believe [this approach] will become standard of care,” said study author Ching-Hon Pui, MD, of the departments of oncology, pathology, and global pediatric medicine, St. Jude Children’s Research Hospital, Memphis.

He noted that this work builds on the huge success that has already been achieved in this field with CAR T-cell products directed at CD19. The first of these products to reach the market was tisagenlecleucel-T (Novartis).

“To put this study in context, the first child who received CAR T-cell therapy for B-ALL after multiple relapses has recently celebrated her 10-year cancer-free survival milestone, and we hope that our finding will result in many more such milestones,” he said.

These new results are very impressive, said Stephen P. Hunger, MD, an expert commenting for the American Society of Clinical Oncology, which highlighted the research in a press release. “They were also able to treat almost 200 patients in a relatively short time.”

Hunger pointed out that dual administration and targeting is not a new idea and is one of the strategies that is currently under investigation. But it is too early to consider this to be the standard of care, he said. “We want to see it replicated in other centers and to see longer follow-up,” said Dr. Hunger, who is Distinguished Chair in Pediatrics and director of the center for childhood cancer research at Children’s Hospital of Philadelphia. “We can establish this as a first step down the road, and we will see if others will achieve similar results.”
 

Strategy of dual targeting

Despite the success CAR T-cell therapy in childhood leukemia, the currently available products have limitations, Dr. Pui and colleagues note.

About half of patients treated with CD19 CAR T cells experience relapse within 1 year, owing either to loss of CAR T-cell persistence or to loss of CD19 antigen because of splice variants, acquired genetic mutations, or lineage switch.

With further treatment with CAR T cells directed against CD22, 70%-80% of patients who failed CD19 CAR T will achieve into complete remission. However, most will experience relapse.

Recent efforts in the field have turned to exploring the safety and feasibility of CAR T cells that target both CD19 and CD22. The results were not superior to those of the CD19 CAR T-cell therapy given alone, although sequential treatment has yielded promising response rates, the authors note.

They hypothesized that co-administration of CD19- and CD22-targeted CAR T cells would improve efficacy, as it could forestall the development of drug resistance.
 

Achieved 99% remission

Dr. Pui and colleagues conducted a phase 2 trial that included 225 evaluable patients aged 20 years or younger who were being treated at five urban hospitals in and near Shanghai, China. Of this group, 194 had refractory disease or hematologic relapse, and 31 patients had isolated extramedullary relapse.

A safety run-in stage to determine the recommended dose was initially conducted. An interim analysis of the first 30 patients who were treated (27 at the recommended dose) showed that the approach was safe and effective. Additional patients were then enrolled.

The 192 patients (of 194) who achieved complete remission attained negative minimal residual disease status.

At a median follow-up of 11 months, 43 patients experienced relapse (24 with CD191/CD221 relapse, 16 with CD19– /CD221, one with CD19– /CD22– , and two unknown), for a cumulative risk of 22.2%.
 

Transplant and relapse options

In an interview, Dr. Pui noted that various treatment options were available for the children who experienced relapse. “For patients who were in good clinical condition, we will treat them with molecular therapeutics, allogeneic CAR T cells from donor, or even repeated humanized CD19 and/or CD22 CAR T cells with or without CD20 CAR T cells in an attempt to induce a remission for allogeneic transplantation,” he said.

The site-specific 12-month event-free survival rate in the trial was 69.2% for patients who did not receive a transplant, 95% for those children who had an isolated relapse to the testicles, and 68.6% for those who had an isolated central nervous system relapse.

After censoring 78 patients for consolidative transplantation, the 12-month overall survival was 87.7%.

Consolidative transplantation was performed in 24 of the 37 patients with KMT2A-rearranged or ZNF384-rearranged ALL and in 54 patients because of parental request. The reason for this was that patients with these two genetic subtypes of leukemia (KMT2A-rearranged and ZNF384-rearranged), under the pressure of phenotype-specific treatment (such as CAR T cells or blinatumomab) are at risk of lineage switch and development of secondary acute myeloid leukemia, explained Dr. Pui. “That is an even more resistant form of leukemia, and up to 5%-10% of the patients have been reported to develop this complication.

“We performed consolidation transplantation in these patients to avoid the risk of lineage switch but would accept the parental request not to perform allogeneic transplant after they were clearly informed of the risk,” he told this news organization.

He also suggested that this approach of co-administration of two types of CAR T cells would be especially suitable for “patients with extramedullary involvement, because most of them will be spared of local irradiation so that they can preserve their neurocognitive function and fertility and avoid radiation-induced second cancer, such as brain tumor,” he said.
 

Lower toxicity

With regard to toxicity, the majority of patients (n = 98, 88%) developed cytokine release syndrome, which was grade ≥3 in 64 (28.4%) patients and fatal in one. Neurotoxicity occurred in 47 (20.9%) patients, was of grade ≥3 in 9 (4.0%) patients, and was fatal in 2 patients who received 12 x 106 and 5.6 x 106 CAR T cells/kg.

In addition, grade 3 or 4 seizure developed in 14.2% of the patients; it was more common in those who had presented with isolated or combined CNS leukemia. Grade 3 or 4 hypotension occurred in 40.9% of the patients. About three-quarters of the patients were treated with tocilizumab (n = 67, 74.2%), and 79 (35.1%) were treated with corticosteroids.

“In general, CD19 and CD22 CAR T cells were less toxic than CD19 CAR T cells, the historical controls, in our experience,” said Dr. Pui. “There were three fatal complications, a rate not excessive considering a large number of patients were treated.”
 

Future studies needed

The researchers note that in this trial, the CD22 CAR T cells did not expand as robustly or persist as long as did the CD19 CAR T cells, and they hope that future studies will elucidate whether enhancing CD22 CAR T-cell persistence and activity would further improve outcomes.

The study was supported in part by the National Natural Science Foundation of China, the Shanghai Collaborative Innovation Center for Translational Medicine, the Research Programs of Shanghai Science, the Technology Commission Foundation, the U.S. National Cancer Institute, the VIVA China Children’s Cancer Foundation, and the American Lebanese Syrian Associated Charities.

A version of this article first appeared on Medscape.com.

A novel approach in which two products were co-administered achieved a 99% complete response rate in children with relapsed or treatment-resistant B-cell acute lymphoblastic leukemia (B-ALL).

In this trial, the largest study to date of a CAR T-cell therapy for such patients, the researchers co-administered two CAR T-cell therapies, one targeting CD19 and the other targeting CD22.

The results showed that 192 of 194 patients (99%) achieved a complete remission.

The combined overall 12-month event-free survival was 73.5%.

The study was published online in the Journal of Clinical Oncology.

These results are better than what has been reported for CAR T cells that are already on the market. These products, which target CD19, have achieved complete remission in 85.5% of cases and a 12-month event-free survival of 52.4% in children with B-ALL.

“We do believe [this approach] will become standard of care,” said study author Ching-Hon Pui, MD, of the departments of oncology, pathology, and global pediatric medicine, St. Jude Children’s Research Hospital, Memphis.

He noted that this work builds on the huge success that has already been achieved in this field with CAR T-cell products directed at CD19. The first of these products to reach the market was tisagenlecleucel-T (Novartis).

“To put this study in context, the first child who received CAR T-cell therapy for B-ALL after multiple relapses has recently celebrated her 10-year cancer-free survival milestone, and we hope that our finding will result in many more such milestones,” he said.

These new results are very impressive, said Stephen P. Hunger, MD, an expert commenting for the American Society of Clinical Oncology, which highlighted the research in a press release. “They were also able to treat almost 200 patients in a relatively short time.”

Hunger pointed out that dual administration and targeting is not a new idea and is one of the strategies that is currently under investigation. But it is too early to consider this to be the standard of care, he said. “We want to see it replicated in other centers and to see longer follow-up,” said Dr. Hunger, who is Distinguished Chair in Pediatrics and director of the center for childhood cancer research at Children’s Hospital of Philadelphia. “We can establish this as a first step down the road, and we will see if others will achieve similar results.”
 

Strategy of dual targeting

Despite the success CAR T-cell therapy in childhood leukemia, the currently available products have limitations, Dr. Pui and colleagues note.

About half of patients treated with CD19 CAR T cells experience relapse within 1 year, owing either to loss of CAR T-cell persistence or to loss of CD19 antigen because of splice variants, acquired genetic mutations, or lineage switch.

With further treatment with CAR T cells directed against CD22, 70%-80% of patients who failed CD19 CAR T will achieve into complete remission. However, most will experience relapse.

Recent efforts in the field have turned to exploring the safety and feasibility of CAR T cells that target both CD19 and CD22. The results were not superior to those of the CD19 CAR T-cell therapy given alone, although sequential treatment has yielded promising response rates, the authors note.

They hypothesized that co-administration of CD19- and CD22-targeted CAR T cells would improve efficacy, as it could forestall the development of drug resistance.
 

Achieved 99% remission

Dr. Pui and colleagues conducted a phase 2 trial that included 225 evaluable patients aged 20 years or younger who were being treated at five urban hospitals in and near Shanghai, China. Of this group, 194 had refractory disease or hematologic relapse, and 31 patients had isolated extramedullary relapse.

A safety run-in stage to determine the recommended dose was initially conducted. An interim analysis of the first 30 patients who were treated (27 at the recommended dose) showed that the approach was safe and effective. Additional patients were then enrolled.

The 192 patients (of 194) who achieved complete remission attained negative minimal residual disease status.

At a median follow-up of 11 months, 43 patients experienced relapse (24 with CD191/CD221 relapse, 16 with CD19– /CD221, one with CD19– /CD22– , and two unknown), for a cumulative risk of 22.2%.
 

Transplant and relapse options

In an interview, Dr. Pui noted that various treatment options were available for the children who experienced relapse. “For patients who were in good clinical condition, we will treat them with molecular therapeutics, allogeneic CAR T cells from donor, or even repeated humanized CD19 and/or CD22 CAR T cells with or without CD20 CAR T cells in an attempt to induce a remission for allogeneic transplantation,” he said.

The site-specific 12-month event-free survival rate in the trial was 69.2% for patients who did not receive a transplant, 95% for those children who had an isolated relapse to the testicles, and 68.6% for those who had an isolated central nervous system relapse.

After censoring 78 patients for consolidative transplantation, the 12-month overall survival was 87.7%.

Consolidative transplantation was performed in 24 of the 37 patients with KMT2A-rearranged or ZNF384-rearranged ALL and in 54 patients because of parental request. The reason for this was that patients with these two genetic subtypes of leukemia (KMT2A-rearranged and ZNF384-rearranged), under the pressure of phenotype-specific treatment (such as CAR T cells or blinatumomab) are at risk of lineage switch and development of secondary acute myeloid leukemia, explained Dr. Pui. “That is an even more resistant form of leukemia, and up to 5%-10% of the patients have been reported to develop this complication.

“We performed consolidation transplantation in these patients to avoid the risk of lineage switch but would accept the parental request not to perform allogeneic transplant after they were clearly informed of the risk,” he told this news organization.

He also suggested that this approach of co-administration of two types of CAR T cells would be especially suitable for “patients with extramedullary involvement, because most of them will be spared of local irradiation so that they can preserve their neurocognitive function and fertility and avoid radiation-induced second cancer, such as brain tumor,” he said.
 

Lower toxicity

With regard to toxicity, the majority of patients (n = 98, 88%) developed cytokine release syndrome, which was grade ≥3 in 64 (28.4%) patients and fatal in one. Neurotoxicity occurred in 47 (20.9%) patients, was of grade ≥3 in 9 (4.0%) patients, and was fatal in 2 patients who received 12 x 106 and 5.6 x 106 CAR T cells/kg.

In addition, grade 3 or 4 seizure developed in 14.2% of the patients; it was more common in those who had presented with isolated or combined CNS leukemia. Grade 3 or 4 hypotension occurred in 40.9% of the patients. About three-quarters of the patients were treated with tocilizumab (n = 67, 74.2%), and 79 (35.1%) were treated with corticosteroids.

“In general, CD19 and CD22 CAR T cells were less toxic than CD19 CAR T cells, the historical controls, in our experience,” said Dr. Pui. “There were three fatal complications, a rate not excessive considering a large number of patients were treated.”
 

Future studies needed

The researchers note that in this trial, the CD22 CAR T cells did not expand as robustly or persist as long as did the CD19 CAR T cells, and they hope that future studies will elucidate whether enhancing CD22 CAR T-cell persistence and activity would further improve outcomes.

The study was supported in part by the National Natural Science Foundation of China, the Shanghai Collaborative Innovation Center for Translational Medicine, the Research Programs of Shanghai Science, the Technology Commission Foundation, the U.S. National Cancer Institute, the VIVA China Children’s Cancer Foundation, and the American Lebanese Syrian Associated Charities.

A version of this article first appeared on Medscape.com.

A novel approach in which two products were co-administered achieved a 99% complete response rate in children with relapsed or treatment-resistant B-cell acute lymphoblastic leukemia (B-ALL).

In this trial, the largest study to date of a CAR T-cell therapy for such patients, the researchers co-administered two CAR T-cell therapies, one targeting CD19 and the other targeting CD22.

The results showed that 192 of 194 patients (99%) achieved a complete remission.

The combined overall 12-month event-free survival was 73.5%.

The study was published online in the Journal of Clinical Oncology.

These results are better than what has been reported for CAR T cells that are already on the market. These products, which target CD19, have achieved complete remission in 85.5% of cases and a 12-month event-free survival of 52.4% in children with B-ALL.

“We do believe [this approach] will become standard of care,” said study author Ching-Hon Pui, MD, of the departments of oncology, pathology, and global pediatric medicine, St. Jude Children’s Research Hospital, Memphis.

He noted that this work builds on the huge success that has already been achieved in this field with CAR T-cell products directed at CD19. The first of these products to reach the market was tisagenlecleucel-T (Novartis).

“To put this study in context, the first child who received CAR T-cell therapy for B-ALL after multiple relapses has recently celebrated her 10-year cancer-free survival milestone, and we hope that our finding will result in many more such milestones,” he said.

These new results are very impressive, said Stephen P. Hunger, MD, an expert commenting for the American Society of Clinical Oncology, which highlighted the research in a press release. “They were also able to treat almost 200 patients in a relatively short time.”

Hunger pointed out that dual administration and targeting is not a new idea and is one of the strategies that is currently under investigation. But it is too early to consider this to be the standard of care, he said. “We want to see it replicated in other centers and to see longer follow-up,” said Dr. Hunger, who is Distinguished Chair in Pediatrics and director of the center for childhood cancer research at Children’s Hospital of Philadelphia. “We can establish this as a first step down the road, and we will see if others will achieve similar results.”
 

Strategy of dual targeting

Despite the success CAR T-cell therapy in childhood leukemia, the currently available products have limitations, Dr. Pui and colleagues note.

About half of patients treated with CD19 CAR T cells experience relapse within 1 year, owing either to loss of CAR T-cell persistence or to loss of CD19 antigen because of splice variants, acquired genetic mutations, or lineage switch.

With further treatment with CAR T cells directed against CD22, 70%-80% of patients who failed CD19 CAR T will achieve into complete remission. However, most will experience relapse.

Recent efforts in the field have turned to exploring the safety and feasibility of CAR T cells that target both CD19 and CD22. The results were not superior to those of the CD19 CAR T-cell therapy given alone, although sequential treatment has yielded promising response rates, the authors note.

They hypothesized that co-administration of CD19- and CD22-targeted CAR T cells would improve efficacy, as it could forestall the development of drug resistance.
 

Achieved 99% remission

Dr. Pui and colleagues conducted a phase 2 trial that included 225 evaluable patients aged 20 years or younger who were being treated at five urban hospitals in and near Shanghai, China. Of this group, 194 had refractory disease or hematologic relapse, and 31 patients had isolated extramedullary relapse.

A safety run-in stage to determine the recommended dose was initially conducted. An interim analysis of the first 30 patients who were treated (27 at the recommended dose) showed that the approach was safe and effective. Additional patients were then enrolled.

The 192 patients (of 194) who achieved complete remission attained negative minimal residual disease status.

At a median follow-up of 11 months, 43 patients experienced relapse (24 with CD191/CD221 relapse, 16 with CD19– /CD221, one with CD19– /CD22– , and two unknown), for a cumulative risk of 22.2%.
 

Transplant and relapse options

In an interview, Dr. Pui noted that various treatment options were available for the children who experienced relapse. “For patients who were in good clinical condition, we will treat them with molecular therapeutics, allogeneic CAR T cells from donor, or even repeated humanized CD19 and/or CD22 CAR T cells with or without CD20 CAR T cells in an attempt to induce a remission for allogeneic transplantation,” he said.

The site-specific 12-month event-free survival rate in the trial was 69.2% for patients who did not receive a transplant, 95% for those children who had an isolated relapse to the testicles, and 68.6% for those who had an isolated central nervous system relapse.

After censoring 78 patients for consolidative transplantation, the 12-month overall survival was 87.7%.

Consolidative transplantation was performed in 24 of the 37 patients with KMT2A-rearranged or ZNF384-rearranged ALL and in 54 patients because of parental request. The reason for this was that patients with these two genetic subtypes of leukemia (KMT2A-rearranged and ZNF384-rearranged), under the pressure of phenotype-specific treatment (such as CAR T cells or blinatumomab) are at risk of lineage switch and development of secondary acute myeloid leukemia, explained Dr. Pui. “That is an even more resistant form of leukemia, and up to 5%-10% of the patients have been reported to develop this complication.

“We performed consolidation transplantation in these patients to avoid the risk of lineage switch but would accept the parental request not to perform allogeneic transplant after they were clearly informed of the risk,” he told this news organization.

He also suggested that this approach of co-administration of two types of CAR T cells would be especially suitable for “patients with extramedullary involvement, because most of them will be spared of local irradiation so that they can preserve their neurocognitive function and fertility and avoid radiation-induced second cancer, such as brain tumor,” he said.
 

Lower toxicity

With regard to toxicity, the majority of patients (n = 98, 88%) developed cytokine release syndrome, which was grade ≥3 in 64 (28.4%) patients and fatal in one. Neurotoxicity occurred in 47 (20.9%) patients, was of grade ≥3 in 9 (4.0%) patients, and was fatal in 2 patients who received 12 x 106 and 5.6 x 106 CAR T cells/kg.

In addition, grade 3 or 4 seizure developed in 14.2% of the patients; it was more common in those who had presented with isolated or combined CNS leukemia. Grade 3 or 4 hypotension occurred in 40.9% of the patients. About three-quarters of the patients were treated with tocilizumab (n = 67, 74.2%), and 79 (35.1%) were treated with corticosteroids.

“In general, CD19 and CD22 CAR T cells were less toxic than CD19 CAR T cells, the historical controls, in our experience,” said Dr. Pui. “There were three fatal complications, a rate not excessive considering a large number of patients were treated.”
 

Future studies needed

The researchers note that in this trial, the CD22 CAR T cells did not expand as robustly or persist as long as did the CD19 CAR T cells, and they hope that future studies will elucidate whether enhancing CD22 CAR T-cell persistence and activity would further improve outcomes.

The study was supported in part by the National Natural Science Foundation of China, the Shanghai Collaborative Innovation Center for Translational Medicine, the Research Programs of Shanghai Science, the Technology Commission Foundation, the U.S. National Cancer Institute, the VIVA China Children’s Cancer Foundation, and the American Lebanese Syrian Associated Charities.

A version of this article first appeared on Medscape.com.

The correct answer is (D), molluscum contagiosum. Upon surgical excision, the pathology indicated the lesion was consistent with molluscum contagiosum.

Molluscum contagiosum is a benign skin disorder caused by a pox virus and is frequently seen in children. This disease is transmitted primarily through direct skin contact with an infected individual.¹ Contaminated fomites have been suggested as another source of infection.² The typical lesion appears dome-shaped, round, and pinkish-purple in color.¹ The incubation period ranges from 2 weeks to 6 months and is typically self-limited in immunocompetent hosts; however, in immunocompromised persons, molluscum contagiosum lesions may present atypically such that they are larger in size and/or resemble malignancies, such as basal cell carcinoma or keratoacanthoma (for single lesions), or other infectious diseases, such as cryptococcosis and histoplasmosis (for more numerous lesions).^{3,4 A} giant atypical molluscum contagiosum is rarely seen in healthy individuals.
 

What’s on the differential?

The recent episode of bleeding raises concern for other neoplastic processes of the skin including squamous cell carcinoma or basal cell carcinoma as well as cutaneous metastatic rhabdoid tumor, given the patient’s history.

Eruptive keratoacanthomas are also reported in patients taking nivolumab, an anti-PD-1 immunotherapy, which the patient has received for treatment of his recurrent metastatic rhabdoid tumor.⁵ More common entities such as a pyogenic granuloma or verruca are also included on the differential. The initial presentation of the lesion, however, is more consistent with the pearly umbilicated papules associated with molluscum contagiosum.

Comments from Dr. Eichenfield

This is a very hard diagnosis to make with the clinical findings and history.

Molluscum contagiosum infections are common, but with this patient’s medical history, biopsy and excision with pathologic examination was an appropriate approach to make a certain diagnosis.

Ms. Moyal is a research associate in the division of pediatric and adolescent dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital, San Diego.

References

1. Brown J et al. Int J Dermatol. 2006 Feb;45(2):93-9.

2. Hanson D and Diven DG. Dermatol Online J. 2003 Mar;9(2).

3. Badri T and Gandhi GR. Molluscum contagiosum. 2022. In: StatPearls [Internet]. Treasure Island, Fla.: StatPearls Publishing.

4. Schwartz JJ and Myskowski PL. J Am Acad Dermatol. 1992 Oct 1;27(4):583-8.

5. Antonov NK et al. JAAD Case Rep. 2019 Apr 5;5(4):342-5.

The correct answer is (D), molluscum contagiosum. Upon surgical excision, the pathology indicated the lesion was consistent with molluscum contagiosum.

Molluscum contagiosum is a benign skin disorder caused by a pox virus and is frequently seen in children. This disease is transmitted primarily through direct skin contact with an infected individual.¹ Contaminated fomites have been suggested as another source of infection.² The typical lesion appears dome-shaped, round, and pinkish-purple in color.¹ The incubation period ranges from 2 weeks to 6 months and is typically self-limited in immunocompetent hosts; however, in immunocompromised persons, molluscum contagiosum lesions may present atypically such that they are larger in size and/or resemble malignancies, such as basal cell carcinoma or keratoacanthoma (for single lesions), or other infectious diseases, such as cryptococcosis and histoplasmosis (for more numerous lesions).^{3,4 A} giant atypical molluscum contagiosum is rarely seen in healthy individuals.
 

What’s on the differential?

The recent episode of bleeding raises concern for other neoplastic processes of the skin including squamous cell carcinoma or basal cell carcinoma as well as cutaneous metastatic rhabdoid tumor, given the patient’s history.

Eruptive keratoacanthomas are also reported in patients taking nivolumab, an anti-PD-1 immunotherapy, which the patient has received for treatment of his recurrent metastatic rhabdoid tumor.⁵ More common entities such as a pyogenic granuloma or verruca are also included on the differential. The initial presentation of the lesion, however, is more consistent with the pearly umbilicated papules associated with molluscum contagiosum.

Comments from Dr. Eichenfield

This is a very hard diagnosis to make with the clinical findings and history.

Molluscum contagiosum infections are common, but with this patient’s medical history, biopsy and excision with pathologic examination was an appropriate approach to make a certain diagnosis.

Ms. Moyal is a research associate in the division of pediatric and adolescent dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital, San Diego.

References

1. Brown J et al. Int J Dermatol. 2006 Feb;45(2):93-9.

2. Hanson D and Diven DG. Dermatol Online J. 2003 Mar;9(2).

3. Badri T and Gandhi GR. Molluscum contagiosum. 2022. In: StatPearls [Internet]. Treasure Island, Fla.: StatPearls Publishing.

4. Schwartz JJ and Myskowski PL. J Am Acad Dermatol. 1992 Oct 1;27(4):583-8.

5. Antonov NK et al. JAAD Case Rep. 2019 Apr 5;5(4):342-5.

The correct answer is (D), molluscum contagiosum. Upon surgical excision, the pathology indicated the lesion was consistent with molluscum contagiosum.

Molluscum contagiosum is a benign skin disorder caused by a pox virus and is frequently seen in children. This disease is transmitted primarily through direct skin contact with an infected individual.¹ Contaminated fomites have been suggested as another source of infection.² The typical lesion appears dome-shaped, round, and pinkish-purple in color.¹ The incubation period ranges from 2 weeks to 6 months and is typically self-limited in immunocompetent hosts; however, in immunocompromised persons, molluscum contagiosum lesions may present atypically such that they are larger in size and/or resemble malignancies, such as basal cell carcinoma or keratoacanthoma (for single lesions), or other infectious diseases, such as cryptococcosis and histoplasmosis (for more numerous lesions).^{3,4 A} giant atypical molluscum contagiosum is rarely seen in healthy individuals.
 

What’s on the differential?

The recent episode of bleeding raises concern for other neoplastic processes of the skin including squamous cell carcinoma or basal cell carcinoma as well as cutaneous metastatic rhabdoid tumor, given the patient’s history.

Eruptive keratoacanthomas are also reported in patients taking nivolumab, an anti-PD-1 immunotherapy, which the patient has received for treatment of his recurrent metastatic rhabdoid tumor.⁵ More common entities such as a pyogenic granuloma or verruca are also included on the differential. The initial presentation of the lesion, however, is more consistent with the pearly umbilicated papules associated with molluscum contagiosum.

Comments from Dr. Eichenfield

This is a very hard diagnosis to make with the clinical findings and history.

Molluscum contagiosum infections are common, but with this patient’s medical history, biopsy and excision with pathologic examination was an appropriate approach to make a certain diagnosis.

Ms. Moyal is a research associate in the division of pediatric and adolescent dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital, San Diego.

References

1. Brown J et al. Int J Dermatol. 2006 Feb;45(2):93-9.

2. Hanson D and Diven DG. Dermatol Online J. 2003 Mar;9(2).

3. Badri T and Gandhi GR. Molluscum contagiosum. 2022. In: StatPearls [Internet]. Treasure Island, Fla.: StatPearls Publishing.

4. Schwartz JJ and Myskowski PL. J Am Acad Dermatol. 1992 Oct 1;27(4):583-8.

5. Antonov NK et al. JAAD Case Rep. 2019 Apr 5;5(4):342-5.

The patients of Jill Krapf, MD, are often too embarrassed to tell her about discomfort in their clitoris.

“I ask all of my patients about clitoral pain, and it is often the first time they have ever been asked about this,” says Dr. Krapf, the associate director of the Center for Vulvovaginal Disorders, a private clinic in Washington and New York. 

Dr. Krapf is an ob.gyn. who specializes in female sexual pain that involves the pelvis, vagina, and vulva. 

Many of the conditions Dr. Krapf treats don’t have outward symptoms that appear abnormal, but internally, there are damaged or irritated nerves that can result in hypersensitivity, unwanted arousal, or pain.

“Most recent research indicates that even a herniated disk or tear in the spine can lead to clitoral or vulvar symptoms, just like sciatica pain that shoots down the leg is related to issues in the spine,” Dr. Krapf says.

Dr. Krapf was excited to read of a new discovery: The clitoris has more than 10,000 nerve fibers – 2,000 more than previously reported in 1976 – a medical breakthrough for a part of the body that has often been neglected by the scientific field. Dr. Krapf and other doctors are hopeful that the attention to the clitoris will spark more interest and comprehensive education among people in their field. They also hope it will empower patients to seek medical help if they are having issues with their clitoris.

“Female sexual health has historically been underfunded, especially compared with male sexual health, like erectile dysfunction,” Dr. Krapf says. “Optimizing vulvar and vaginal health is not only necessary for sexual well-being.”

Blair Peters, MD, a plastic surgeon who specializes in gender-affirming care, led the study, which was presented at the Sexual Medicine Society of North America conference in October. Dr. Peters says he hopes that the new information decreases stigma that the clitoris is not worthy of the same medical attention that other organs of the body receive. 

When the clitoris doesn’t properly function, there can be harm to a person’s physical and mental health. Paying attention to discomfort in the clitoris, and seeking medical attention, can help catch and prevent some urinary and vaginal infections.  

“The fact that it took until 2022 for someone to do this work speaks to how little attention the clitoris has received,” says Dr. Peters, an assistant professor of surgery at the Oregon Health and Science University School of Medicine, Portland. 
 

What’s inside? 

Dr. Peters and his colleagues completed the study by taking clitoral nerve tissue from seven adult transgender men who had received gender-affirming genital surgery. The tissues were dyed and magnified 1,000 times under a microscope so the researchers could count nerve fibers. 

Dr. Peters says the finding is important because many surgeries take place in the groin region – like hip replacements, episiotomies during childbirth, and pelvic mesh procedures – and the revived attention to the clitoris may help health care providers know where nerves are so that injuries from medical mistakes are prevented. 

“Nerves are at risk of damage if it’s not understood where they are at all times,” he says. 

Dr. Peters hopes the new finding will help create new surgical techniques for nerve repair and offer insight for gender-affirming phalloplasty, which is the surgical construction of a penis often for transmasculine people.
 

Ownership of the body part 

When it comes to the clitoris, no one type of doctor has specialized in the sex organ.   

Urologists, gynecologists, plastic surgeons, and sex therapists all address potential problems that can arise with the clitoris and its surrounding body parts. But specialists like Dr. Krapf are few and far between.

It wasn’t until 2005 that Australian urologist Helen O’Connell found that the clitoris is filled with erectile and non-erectile tissues that are often hidden in anatomy drawings by fat and bone. And it wasn’t until the early 2000s that researchers began delving in earnest into the anatomy of the clitoris and how it functions.

And a 2018 study showed that if more doctors examined the clitoris, they could identify issues like adhesions or infections in the area, most of which can be treated without surgery.
 

A body part built for pleasure 

Randi Levinson, a sex, marriage, and family therapist in Los Angeles, sees patients who have less sensation in the clitoris or pain while having sex, many of whom have recently given birth or are going through menopause. 

Women often become embarrassed when they can’t orgasm, or have less sensation in the clitoris, but tend to avoid seeking medical advice, she says. Normalizing discussions about women’s pleasure and the vast anatomy that supports it may help some of her patients.

“The more normal it is to talk about and explore women’s pleasure, the less shame women will have when getting help when they aren’t experiencing pleasure,” Ms. Levinson says. “I have many ... clients who experience pain and discomfort with sex [after pregnancy] and no longer feel pleasure and are concerned that something is wrong with them.”

A version of this article first appeared on WebMD.com. 

The patients of Jill Krapf, MD, are often too embarrassed to tell her about discomfort in their clitoris.

“I ask all of my patients about clitoral pain, and it is often the first time they have ever been asked about this,” says Dr. Krapf, the associate director of the Center for Vulvovaginal Disorders, a private clinic in Washington and New York. 

Dr. Krapf is an ob.gyn. who specializes in female sexual pain that involves the pelvis, vagina, and vulva. 

Many of the conditions Dr. Krapf treats don’t have outward symptoms that appear abnormal, but internally, there are damaged or irritated nerves that can result in hypersensitivity, unwanted arousal, or pain.

“Most recent research indicates that even a herniated disk or tear in the spine can lead to clitoral or vulvar symptoms, just like sciatica pain that shoots down the leg is related to issues in the spine,” Dr. Krapf says.

Dr. Krapf was excited to read of a new discovery: The clitoris has more than 10,000 nerve fibers – 2,000 more than previously reported in 1976 – a medical breakthrough for a part of the body that has often been neglected by the scientific field. Dr. Krapf and other doctors are hopeful that the attention to the clitoris will spark more interest and comprehensive education among people in their field. They also hope it will empower patients to seek medical help if they are having issues with their clitoris.

“Female sexual health has historically been underfunded, especially compared with male sexual health, like erectile dysfunction,” Dr. Krapf says. “Optimizing vulvar and vaginal health is not only necessary for sexual well-being.”

Blair Peters, MD, a plastic surgeon who specializes in gender-affirming care, led the study, which was presented at the Sexual Medicine Society of North America conference in October. Dr. Peters says he hopes that the new information decreases stigma that the clitoris is not worthy of the same medical attention that other organs of the body receive. 

When the clitoris doesn’t properly function, there can be harm to a person’s physical and mental health. Paying attention to discomfort in the clitoris, and seeking medical attention, can help catch and prevent some urinary and vaginal infections.  

“The fact that it took until 2022 for someone to do this work speaks to how little attention the clitoris has received,” says Dr. Peters, an assistant professor of surgery at the Oregon Health and Science University School of Medicine, Portland. 
 

What’s inside? 

Dr. Peters and his colleagues completed the study by taking clitoral nerve tissue from seven adult transgender men who had received gender-affirming genital surgery. The tissues were dyed and magnified 1,000 times under a microscope so the researchers could count nerve fibers. 

Dr. Peters says the finding is important because many surgeries take place in the groin region – like hip replacements, episiotomies during childbirth, and pelvic mesh procedures – and the revived attention to the clitoris may help health care providers know where nerves are so that injuries from medical mistakes are prevented. 

“Nerves are at risk of damage if it’s not understood where they are at all times,” he says. 

Dr. Peters hopes the new finding will help create new surgical techniques for nerve repair and offer insight for gender-affirming phalloplasty, which is the surgical construction of a penis often for transmasculine people.
 

Ownership of the body part 

When it comes to the clitoris, no one type of doctor has specialized in the sex organ.   

Urologists, gynecologists, plastic surgeons, and sex therapists all address potential problems that can arise with the clitoris and its surrounding body parts. But specialists like Dr. Krapf are few and far between.

It wasn’t until 2005 that Australian urologist Helen O’Connell found that the clitoris is filled with erectile and non-erectile tissues that are often hidden in anatomy drawings by fat and bone. And it wasn’t until the early 2000s that researchers began delving in earnest into the anatomy of the clitoris and how it functions.

And a 2018 study showed that if more doctors examined the clitoris, they could identify issues like adhesions or infections in the area, most of which can be treated without surgery.
 

A body part built for pleasure 

Randi Levinson, a sex, marriage, and family therapist in Los Angeles, sees patients who have less sensation in the clitoris or pain while having sex, many of whom have recently given birth or are going through menopause. 

Women often become embarrassed when they can’t orgasm, or have less sensation in the clitoris, but tend to avoid seeking medical advice, she says. Normalizing discussions about women’s pleasure and the vast anatomy that supports it may help some of her patients.

“The more normal it is to talk about and explore women’s pleasure, the less shame women will have when getting help when they aren’t experiencing pleasure,” Ms. Levinson says. “I have many ... clients who experience pain and discomfort with sex [after pregnancy] and no longer feel pleasure and are concerned that something is wrong with them.”

A version of this article first appeared on WebMD.com. 

The patients of Jill Krapf, MD, are often too embarrassed to tell her about discomfort in their clitoris.

“I ask all of my patients about clitoral pain, and it is often the first time they have ever been asked about this,” says Dr. Krapf, the associate director of the Center for Vulvovaginal Disorders, a private clinic in Washington and New York. 

Dr. Krapf is an ob.gyn. who specializes in female sexual pain that involves the pelvis, vagina, and vulva. 

Many of the conditions Dr. Krapf treats don’t have outward symptoms that appear abnormal, but internally, there are damaged or irritated nerves that can result in hypersensitivity, unwanted arousal, or pain.

“Most recent research indicates that even a herniated disk or tear in the spine can lead to clitoral or vulvar symptoms, just like sciatica pain that shoots down the leg is related to issues in the spine,” Dr. Krapf says.

Dr. Krapf was excited to read of a new discovery: The clitoris has more than 10,000 nerve fibers – 2,000 more than previously reported in 1976 – a medical breakthrough for a part of the body that has often been neglected by the scientific field. Dr. Krapf and other doctors are hopeful that the attention to the clitoris will spark more interest and comprehensive education among people in their field. They also hope it will empower patients to seek medical help if they are having issues with their clitoris.

“Female sexual health has historically been underfunded, especially compared with male sexual health, like erectile dysfunction,” Dr. Krapf says. “Optimizing vulvar and vaginal health is not only necessary for sexual well-being.”

Blair Peters, MD, a plastic surgeon who specializes in gender-affirming care, led the study, which was presented at the Sexual Medicine Society of North America conference in October. Dr. Peters says he hopes that the new information decreases stigma that the clitoris is not worthy of the same medical attention that other organs of the body receive. 

When the clitoris doesn’t properly function, there can be harm to a person’s physical and mental health. Paying attention to discomfort in the clitoris, and seeking medical attention, can help catch and prevent some urinary and vaginal infections.  

“The fact that it took until 2022 for someone to do this work speaks to how little attention the clitoris has received,” says Dr. Peters, an assistant professor of surgery at the Oregon Health and Science University School of Medicine, Portland. 
 

What’s inside? 

Dr. Peters and his colleagues completed the study by taking clitoral nerve tissue from seven adult transgender men who had received gender-affirming genital surgery. The tissues were dyed and magnified 1,000 times under a microscope so the researchers could count nerve fibers. 

Dr. Peters says the finding is important because many surgeries take place in the groin region – like hip replacements, episiotomies during childbirth, and pelvic mesh procedures – and the revived attention to the clitoris may help health care providers know where nerves are so that injuries from medical mistakes are prevented. 

“Nerves are at risk of damage if it’s not understood where they are at all times,” he says. 

Dr. Peters hopes the new finding will help create new surgical techniques for nerve repair and offer insight for gender-affirming phalloplasty, which is the surgical construction of a penis often for transmasculine people.
 

Ownership of the body part 

When it comes to the clitoris, no one type of doctor has specialized in the sex organ.   

Urologists, gynecologists, plastic surgeons, and sex therapists all address potential problems that can arise with the clitoris and its surrounding body parts. But specialists like Dr. Krapf are few and far between.

It wasn’t until 2005 that Australian urologist Helen O’Connell found that the clitoris is filled with erectile and non-erectile tissues that are often hidden in anatomy drawings by fat and bone. And it wasn’t until the early 2000s that researchers began delving in earnest into the anatomy of the clitoris and how it functions.

And a 2018 study showed that if more doctors examined the clitoris, they could identify issues like adhesions or infections in the area, most of which can be treated without surgery.
 

A body part built for pleasure 

Randi Levinson, a sex, marriage, and family therapist in Los Angeles, sees patients who have less sensation in the clitoris or pain while having sex, many of whom have recently given birth or are going through menopause. 

Women often become embarrassed when they can’t orgasm, or have less sensation in the clitoris, but tend to avoid seeking medical advice, she says. Normalizing discussions about women’s pleasure and the vast anatomy that supports it may help some of her patients.

“The more normal it is to talk about and explore women’s pleasure, the less shame women will have when getting help when they aren’t experiencing pleasure,” Ms. Levinson says. “I have many ... clients who experience pain and discomfort with sex [after pregnancy] and no longer feel pleasure and are concerned that something is wrong with them.”

A version of this article first appeared on WebMD.com. 

Shortly into the COVID-19 pandemic, Dr. Robert Califf, the commissioner of the US Food and Drug Administration, warned of a coming tsunami of chronic diseases, exacerbated by missed care during the pandemic.¹ According to a Centers for Disease Control and Prevention (CDC) survey, more than 30% of adults reported delaying or avoiding routine medical care in the first 6 months of 2020. This rate was highest in people with comorbidities.² Multiple studies demonstrated declines in hypertension care, hemoglobin A_1c testing, mammography, and colon cancer screening.^3-5 There has been a resultant increase in colon cancer complications, wounds, and amputations.^6,7 The United Kingdom is expected to have a 7.9% to 16.6% increase in future deaths due to breast and colorectal cancer (CRC).⁸ The World Health Organization estimates an excess 14.9 million people died in 2020 and 2021, either directly from or indirectly related to COVID-19.⁹

Due to the large-scale conversion from face-to-face care to telehealth modalities, COVID-19 vaccination events offered a unique opportunity to perform preventive health care that requires in-person visits, since most US adults have sought vaccination. However, vaccine events may not reach people most at risk for COVID-19 or chronic disease. Groups of Americans with lower vaccination rates were concerned about driving times and missing work to get the vaccine.¹⁰

Distance and travel time may be a particular challenge in Hawaii. Oahu is considered rural by the US Department of Veterans Affairs (VA); some communities are 80 minutes away from the VA Pacific Islands Health Care System (VAPIHCS) main facility. Oahu has approximately 150 veterans experiencing homelessness who may not have transportation to vaccine events. Additionally, VAPIHCS serves veterans that may be at higher risk of not receiving COVID-19 vaccination. Racial and ethnic minority residents have lower vaccination rates, yet are at a higher risk of COVID-19 infection and complications, and through the pandemic, this vaccination gap worsened.^11,12 More than 10% of the population of Hawaii is Native Hawaiian or Pacific Islander, and this population is at elevated risk for diabetes mellitus, hypertension, and COVID-19 mortality.^13-16

Health Fair Program

The VA provides clinical reminders in its electronic health record (EHR) that are specified by age, gender assigned at birth, and comorbidities. The clinical reminder program is intended to provide clinically relevant reminders for preventive care at the point of care. Veterans with overdue clinical reminders can be identified by name and address, allowing for the creation of health fair events that were directed towards communities with veterans with clinical reminders, including COVID-19 vaccination need. A team of health care professionals from VAPIHCS conceived of a health fair program to increase the reach of vaccine events and include preventive care in partnership with the VAPIHCS Vet Center Program, local communities, U.S.VETS, and the Hawaii Institute of Health Services (HIHS). We sought to determine which services could be offered in community settings; large vaccine events; and at homeless emergency, transitional, or permanent housing. We tracked veterans who received care in the different locations of the directed health fair.

This project was determined to be a quality improvement initiative by the VAPIHCS Office of Research and Development. It was jointly planned by the VAPIHCS pharmacy, infectious diseases, Vet Center Program, and homeless team to make the COVID-19 vaccines available to more rural and to veterans experiencing homelessness, and in response to a decline in facility face-to-face visits. Monthly meetings were held to select sites within zip codes with higher numbers of open clinical reminders and lower vaccination uptake. Informatics developed a list of clinical reminders by zip code for care performed at face-to-face visits.

Partners

The Vet Center Program, suicide prevention coordinator, and the homeless outreach team have a mandate to perform outreach events.^17,18 These services collaborate with community partners to locate sites for events. The team was able to leverage these contacts to set up sites for events. The Vet Center Program readjustment counselor and the suicide prevention coordinator provide mental health counseling. The Vet Center counsels on veteran benefits. They supplied a mobile van with WiFi, counseling and examination spaces, and refrigeration, which became the mobile clinic for the preventive care offered at events. The homeless program works with multiple community partners. They contract with HIHS and U.S.VETS to provide emergency and permanent housing for veterans. Each event is reviewed with HIHS and U.S.VETS staff for permission to be on site. The suicide prevention coordinator or the Vet Center readjustment counselor and the homeless team became regular attendees of events. The homeless team provided resources for housing or food insecurity.

Preventive Health Measures

The VA clinical reminder system supports caregivers for both preventive health care and chronic condition management.¹⁹ Clinical reminders appear as due in the EHR, and reminder reports can be run by clinical informatics to determine groups of patients who have not had a reminder completed. The following reminders were completed: vaccinations (including COVID-19), CRC screening, diabetic foot check and teaching of foot care, diabetic retinal consultations, laboratory studies (lipids, hemoglobin A_1c, microalbumin), mammogram and pap smear referrals, mental health reminders, homeless and food insecurity screening, HIV and hepatitis C testing, and blood pressure (BP) measurement. Health records were reviewed 3 months after each event to determine whether they were completed by the veteran. Additionally, we determined whether BP was controlled (< 130/80 mm Hg).

Settings

Large urban event. The first setting for the health fair was a large vaccination event near the VAPIHCS center in April 2021. Attendance was solicited by VEText, phone calls, and social media advertisements. At check-in, veterans with relevant open clinical reminders were invited to receive preventive health care during the 15-minute monitoring period after the COVID-19 vaccine. The Vet Center Program stationed the mobile van outside the vaccination event, where a physician and a clinical pharmacy specialist (CPS) did assessments, completed reminders, and entered follow-up requests for about 4 hours. A medical support assistant registered veterans who had never signed up for VA health care.

Community Settings. Nine events occurred at least monthly between March and September 2021 at 4 different sites in Oahu. Texts and phone calls were used to solicit attendance; there was no prior publicity on social media. Community events required scheduling resources; this required about 30 hours of medical staff assistant time. Seven sites were visited for about 3 hours each. A physician, pharmacy technician, and CPS conducted assessments, completed reminders, and entered follow-up requests. A medical support assistant registered veterans who had never signed up for VA health care.

Homeless veteran outreach. Five events occurred at 2 homeless veteran housing sites between August 2021 and January 2022. These sites were emergency housing sites (2 events) and transitional and permanent housing (2 events). U.S.VETS and HIHS contacted veterans living in those settings to promote the event. A physician, registered nurse, licensed practical nurse, and CPS conducted assessments, completed reminders, and entered follow-up requests. A medical support assistant registered veterans that had never signed up for VA health care. Each event lasted approximate 3 hours.

Process Quality Improvement

After the CDC changed recommendations to allow concurrent vaccination with the COVID-19 vaccine, we added other vaccinations to the events. This occurred during the course of community events. In June of 2021, there was a health advisory concerning hepatitis A among people experiencing homelessness in Oahu, so hepatitis vaccinations were added for events for veterans.²⁰

Veterans Served

The EHR was used to determine demographics, open clinical reminders, and attendance at follow-up. Simple descriptive statistics were performed in Microsoft Excel. A total of 115 veterans were seen for preventive health visits, and 404 clinical reminders were completed. Seven hundred veterans attended the large centrally located vaccine event and 43 agreed to have a preventive health visit. Thirty-eight veterans had a preventive health visit at homeless outreach events and 34 veterans had a preventive health visit at the community events. Veterans at community

Of the 166 vaccines given, 73 were for COVID-19. Besides vaccination,

Discussion

This program provided evidence that adding preventive screenings to vaccine events may help reach veterans who may have missed important preventive care due to the COVID-19 pandemic. The involvement of clinical informatics service allowed the outreach to be targeted to communities with incomplete clinical reminders. Interventions that could not be completed at the event had high levels of follow-up by veterans with important findings. The presence of a physician or nurse and a CPS allowed for point-of-care testing, as well as entering orders for medication, laboratory tests, and consultations. The attendance by representatives from the Vet Center, suicide prevention, and homeless services allowed counseling regarding benefits, and mental health follow-up. We believe that we were able to reach communities of veterans with unmet preventive needs and had higher risk of severe COVID-19, given the high numbers with open clinical reminders, the number of vaccines provided, and the high percentage of racial and ethnic minority veterans at events in the community. Our program experience provides some evidence that mobile and pop-up vaccination clinics may be beneficial for screening and managing chronic diseases, as proposed elsewhere.^21-24

Strengths of this intervention include that we were able to show a high level of follow-up for recommended medical care as well as the results of our interventions. We have found no similar articles that provide data on completion of follow-up appointments after a health fair. A prior study showed only 23% to 63% of participants at a health fair reported having a recommended follow-up discussion with doctors, but the study reported no outcome of completed cancer screenings.²⁵

Limitations

Weaknesses include the fact that health fair events may reach only healthy people, since attendees generally report better health and better health behaviors than nonattendees.^26,27 We felt this was more problematic for the large-scale urban event and that offering rural events and events in homeless housing improved the reach. Future efforts will involve the use of social media and mailings to solicit attendance. To improve follow-up, future work will include adding to the events: phlebotomy or expanded point-of-care testing; specialty care telehealth capability; cervical cancer screen self-collection; and tele-retinal services.

Conclusions

This program provided evidence that directed, preventive screening can be performed in outreach settings paired with vaccine events. These vaccination events in rural and homeless settings reached communities with demonstrable COVID-19 vaccination and other preventive care needs. This approach could be used to help veterans catch up on needed preventive care.

Acknowledgments

Veterans Affairs Pacific Islands Health Care System: Anthony Chance, LCSW; Nicholas Chang, PharmD; Andrew Dahlburg, LCSW; Wilminia G. Ellorimo-Gil, RN; Paul Guillory, RN; Wendy D. Joy; Arthur Minor, LCSW; Avalua Smith; Jessica Spurrier, RN. Veterans Health Administration Vet Center Program: Rolly O. Alvarado; Edmond G. DeGuzman; Richard T. Teel. Hawaii Institute for Human Services. U.S.VETS.

Shortly into the COVID-19 pandemic, Dr. Robert Califf, the commissioner of the US Food and Drug Administration, warned of a coming tsunami of chronic diseases, exacerbated by missed care during the pandemic.¹ According to a Centers for Disease Control and Prevention (CDC) survey, more than 30% of adults reported delaying or avoiding routine medical care in the first 6 months of 2020. This rate was highest in people with comorbidities.² Multiple studies demonstrated declines in hypertension care, hemoglobin A_1c testing, mammography, and colon cancer screening.^3-5 There has been a resultant increase in colon cancer complications, wounds, and amputations.^6,7 The United Kingdom is expected to have a 7.9% to 16.6% increase in future deaths due to breast and colorectal cancer (CRC).⁸ The World Health Organization estimates an excess 14.9 million people died in 2020 and 2021, either directly from or indirectly related to COVID-19.⁹

Due to the large-scale conversion from face-to-face care to telehealth modalities, COVID-19 vaccination events offered a unique opportunity to perform preventive health care that requires in-person visits, since most US adults have sought vaccination. However, vaccine events may not reach people most at risk for COVID-19 or chronic disease. Groups of Americans with lower vaccination rates were concerned about driving times and missing work to get the vaccine.¹⁰

Distance and travel time may be a particular challenge in Hawaii. Oahu is considered rural by the US Department of Veterans Affairs (VA); some communities are 80 minutes away from the VA Pacific Islands Health Care System (VAPIHCS) main facility. Oahu has approximately 150 veterans experiencing homelessness who may not have transportation to vaccine events. Additionally, VAPIHCS serves veterans that may be at higher risk of not receiving COVID-19 vaccination. Racial and ethnic minority residents have lower vaccination rates, yet are at a higher risk of COVID-19 infection and complications, and through the pandemic, this vaccination gap worsened.^11,12 More than 10% of the population of Hawaii is Native Hawaiian or Pacific Islander, and this population is at elevated risk for diabetes mellitus, hypertension, and COVID-19 mortality.^13-16

Health Fair Program

The VA provides clinical reminders in its electronic health record (EHR) that are specified by age, gender assigned at birth, and comorbidities. The clinical reminder program is intended to provide clinically relevant reminders for preventive care at the point of care. Veterans with overdue clinical reminders can be identified by name and address, allowing for the creation of health fair events that were directed towards communities with veterans with clinical reminders, including COVID-19 vaccination need. A team of health care professionals from VAPIHCS conceived of a health fair program to increase the reach of vaccine events and include preventive care in partnership with the VAPIHCS Vet Center Program, local communities, U.S.VETS, and the Hawaii Institute of Health Services (HIHS). We sought to determine which services could be offered in community settings; large vaccine events; and at homeless emergency, transitional, or permanent housing. We tracked veterans who received care in the different locations of the directed health fair.

This project was determined to be a quality improvement initiative by the VAPIHCS Office of Research and Development. It was jointly planned by the VAPIHCS pharmacy, infectious diseases, Vet Center Program, and homeless team to make the COVID-19 vaccines available to more rural and to veterans experiencing homelessness, and in response to a decline in facility face-to-face visits. Monthly meetings were held to select sites within zip codes with higher numbers of open clinical reminders and lower vaccination uptake. Informatics developed a list of clinical reminders by zip code for care performed at face-to-face visits.

Partners

The Vet Center Program, suicide prevention coordinator, and the homeless outreach team have a mandate to perform outreach events.^17,18 These services collaborate with community partners to locate sites for events. The team was able to leverage these contacts to set up sites for events. The Vet Center Program readjustment counselor and the suicide prevention coordinator provide mental health counseling. The Vet Center counsels on veteran benefits. They supplied a mobile van with WiFi, counseling and examination spaces, and refrigeration, which became the mobile clinic for the preventive care offered at events. The homeless program works with multiple community partners. They contract with HIHS and U.S.VETS to provide emergency and permanent housing for veterans. Each event is reviewed with HIHS and U.S.VETS staff for permission to be on site. The suicide prevention coordinator or the Vet Center readjustment counselor and the homeless team became regular attendees of events. The homeless team provided resources for housing or food insecurity.

Preventive Health Measures

The VA clinical reminder system supports caregivers for both preventive health care and chronic condition management.¹⁹ Clinical reminders appear as due in the EHR, and reminder reports can be run by clinical informatics to determine groups of patients who have not had a reminder completed. The following reminders were completed: vaccinations (including COVID-19), CRC screening, diabetic foot check and teaching of foot care, diabetic retinal consultations, laboratory studies (lipids, hemoglobin A_1c, microalbumin), mammogram and pap smear referrals, mental health reminders, homeless and food insecurity screening, HIV and hepatitis C testing, and blood pressure (BP) measurement. Health records were reviewed 3 months after each event to determine whether they were completed by the veteran. Additionally, we determined whether BP was controlled (< 130/80 mm Hg).

Settings

Large urban event. The first setting for the health fair was a large vaccination event near the VAPIHCS center in April 2021. Attendance was solicited by VEText, phone calls, and social media advertisements. At check-in, veterans with relevant open clinical reminders were invited to receive preventive health care during the 15-minute monitoring period after the COVID-19 vaccine. The Vet Center Program stationed the mobile van outside the vaccination event, where a physician and a clinical pharmacy specialist (CPS) did assessments, completed reminders, and entered follow-up requests for about 4 hours. A medical support assistant registered veterans who had never signed up for VA health care.

Community Settings. Nine events occurred at least monthly between March and September 2021 at 4 different sites in Oahu. Texts and phone calls were used to solicit attendance; there was no prior publicity on social media. Community events required scheduling resources; this required about 30 hours of medical staff assistant time. Seven sites were visited for about 3 hours each. A physician, pharmacy technician, and CPS conducted assessments, completed reminders, and entered follow-up requests. A medical support assistant registered veterans who had never signed up for VA health care.

Homeless veteran outreach. Five events occurred at 2 homeless veteran housing sites between August 2021 and January 2022. These sites were emergency housing sites (2 events) and transitional and permanent housing (2 events). U.S.VETS and HIHS contacted veterans living in those settings to promote the event. A physician, registered nurse, licensed practical nurse, and CPS conducted assessments, completed reminders, and entered follow-up requests. A medical support assistant registered veterans that had never signed up for VA health care. Each event lasted approximate 3 hours.

Process Quality Improvement

After the CDC changed recommendations to allow concurrent vaccination with the COVID-19 vaccine, we added other vaccinations to the events. This occurred during the course of community events. In June of 2021, there was a health advisory concerning hepatitis A among people experiencing homelessness in Oahu, so hepatitis vaccinations were added for events for veterans.²⁰

Veterans Served

The EHR was used to determine demographics, open clinical reminders, and attendance at follow-up. Simple descriptive statistics were performed in Microsoft Excel. A total of 115 veterans were seen for preventive health visits, and 404 clinical reminders were completed. Seven hundred veterans attended the large centrally located vaccine event and 43 agreed to have a preventive health visit. Thirty-eight veterans had a preventive health visit at homeless outreach events and 34 veterans had a preventive health visit at the community events. Veterans at community

Of the 166 vaccines given, 73 were for COVID-19. Besides vaccination,

Discussion

This program provided evidence that adding preventive screenings to vaccine events may help reach veterans who may have missed important preventive care due to the COVID-19 pandemic. The involvement of clinical informatics service allowed the outreach to be targeted to communities with incomplete clinical reminders. Interventions that could not be completed at the event had high levels of follow-up by veterans with important findings. The presence of a physician or nurse and a CPS allowed for point-of-care testing, as well as entering orders for medication, laboratory tests, and consultations. The attendance by representatives from the Vet Center, suicide prevention, and homeless services allowed counseling regarding benefits, and mental health follow-up. We believe that we were able to reach communities of veterans with unmet preventive needs and had higher risk of severe COVID-19, given the high numbers with open clinical reminders, the number of vaccines provided, and the high percentage of racial and ethnic minority veterans at events in the community. Our program experience provides some evidence that mobile and pop-up vaccination clinics may be beneficial for screening and managing chronic diseases, as proposed elsewhere.^21-24

Strengths of this intervention include that we were able to show a high level of follow-up for recommended medical care as well as the results of our interventions. We have found no similar articles that provide data on completion of follow-up appointments after a health fair. A prior study showed only 23% to 63% of participants at a health fair reported having a recommended follow-up discussion with doctors, but the study reported no outcome of completed cancer screenings.²⁵

Limitations

Weaknesses include the fact that health fair events may reach only healthy people, since attendees generally report better health and better health behaviors than nonattendees.^26,27 We felt this was more problematic for the large-scale urban event and that offering rural events and events in homeless housing improved the reach. Future efforts will involve the use of social media and mailings to solicit attendance. To improve follow-up, future work will include adding to the events: phlebotomy or expanded point-of-care testing; specialty care telehealth capability; cervical cancer screen self-collection; and tele-retinal services.

Conclusions

This program provided evidence that directed, preventive screening can be performed in outreach settings paired with vaccine events. These vaccination events in rural and homeless settings reached communities with demonstrable COVID-19 vaccination and other preventive care needs. This approach could be used to help veterans catch up on needed preventive care.

Acknowledgments

Veterans Affairs Pacific Islands Health Care System: Anthony Chance, LCSW; Nicholas Chang, PharmD; Andrew Dahlburg, LCSW; Wilminia G. Ellorimo-Gil, RN; Paul Guillory, RN; Wendy D. Joy; Arthur Minor, LCSW; Avalua Smith; Jessica Spurrier, RN. Veterans Health Administration Vet Center Program: Rolly O. Alvarado; Edmond G. DeGuzman; Richard T. Teel. Hawaii Institute for Human Services. U.S.VETS.

Shortly into the COVID-19 pandemic, Dr. Robert Califf, the commissioner of the US Food and Drug Administration, warned of a coming tsunami of chronic diseases, exacerbated by missed care during the pandemic.¹ According to a Centers for Disease Control and Prevention (CDC) survey, more than 30% of adults reported delaying or avoiding routine medical care in the first 6 months of 2020. This rate was highest in people with comorbidities.² Multiple studies demonstrated declines in hypertension care, hemoglobin A_1c testing, mammography, and colon cancer screening.^3-5 There has been a resultant increase in colon cancer complications, wounds, and amputations.^6,7 The United Kingdom is expected to have a 7.9% to 16.6% increase in future deaths due to breast and colorectal cancer (CRC).⁸ The World Health Organization estimates an excess 14.9 million people died in 2020 and 2021, either directly from or indirectly related to COVID-19.⁹

Due to the large-scale conversion from face-to-face care to telehealth modalities, COVID-19 vaccination events offered a unique opportunity to perform preventive health care that requires in-person visits, since most US adults have sought vaccination. However, vaccine events may not reach people most at risk for COVID-19 or chronic disease. Groups of Americans with lower vaccination rates were concerned about driving times and missing work to get the vaccine.¹⁰

Distance and travel time may be a particular challenge in Hawaii. Oahu is considered rural by the US Department of Veterans Affairs (VA); some communities are 80 minutes away from the VA Pacific Islands Health Care System (VAPIHCS) main facility. Oahu has approximately 150 veterans experiencing homelessness who may not have transportation to vaccine events. Additionally, VAPIHCS serves veterans that may be at higher risk of not receiving COVID-19 vaccination. Racial and ethnic minority residents have lower vaccination rates, yet are at a higher risk of COVID-19 infection and complications, and through the pandemic, this vaccination gap worsened.^11,12 More than 10% of the population of Hawaii is Native Hawaiian or Pacific Islander, and this population is at elevated risk for diabetes mellitus, hypertension, and COVID-19 mortality.^13-16

Health Fair Program

The VA provides clinical reminders in its electronic health record (EHR) that are specified by age, gender assigned at birth, and comorbidities. The clinical reminder program is intended to provide clinically relevant reminders for preventive care at the point of care. Veterans with overdue clinical reminders can be identified by name and address, allowing for the creation of health fair events that were directed towards communities with veterans with clinical reminders, including COVID-19 vaccination need. A team of health care professionals from VAPIHCS conceived of a health fair program to increase the reach of vaccine events and include preventive care in partnership with the VAPIHCS Vet Center Program, local communities, U.S.VETS, and the Hawaii Institute of Health Services (HIHS). We sought to determine which services could be offered in community settings; large vaccine events; and at homeless emergency, transitional, or permanent housing. We tracked veterans who received care in the different locations of the directed health fair.

This project was determined to be a quality improvement initiative by the VAPIHCS Office of Research and Development. It was jointly planned by the VAPIHCS pharmacy, infectious diseases, Vet Center Program, and homeless team to make the COVID-19 vaccines available to more rural and to veterans experiencing homelessness, and in response to a decline in facility face-to-face visits. Monthly meetings were held to select sites within zip codes with higher numbers of open clinical reminders and lower vaccination uptake. Informatics developed a list of clinical reminders by zip code for care performed at face-to-face visits.

Partners

The Vet Center Program, suicide prevention coordinator, and the homeless outreach team have a mandate to perform outreach events.^17,18 These services collaborate with community partners to locate sites for events. The team was able to leverage these contacts to set up sites for events. The Vet Center Program readjustment counselor and the suicide prevention coordinator provide mental health counseling. The Vet Center counsels on veteran benefits. They supplied a mobile van with WiFi, counseling and examination spaces, and refrigeration, which became the mobile clinic for the preventive care offered at events. The homeless program works with multiple community partners. They contract with HIHS and U.S.VETS to provide emergency and permanent housing for veterans. Each event is reviewed with HIHS and U.S.VETS staff for permission to be on site. The suicide prevention coordinator or the Vet Center readjustment counselor and the homeless team became regular attendees of events. The homeless team provided resources for housing or food insecurity.

Preventive Health Measures

The VA clinical reminder system supports caregivers for both preventive health care and chronic condition management.¹⁹ Clinical reminders appear as due in the EHR, and reminder reports can be run by clinical informatics to determine groups of patients who have not had a reminder completed. The following reminders were completed: vaccinations (including COVID-19), CRC screening, diabetic foot check and teaching of foot care, diabetic retinal consultations, laboratory studies (lipids, hemoglobin A_1c, microalbumin), mammogram and pap smear referrals, mental health reminders, homeless and food insecurity screening, HIV and hepatitis C testing, and blood pressure (BP) measurement. Health records were reviewed 3 months after each event to determine whether they were completed by the veteran. Additionally, we determined whether BP was controlled (< 130/80 mm Hg).

Settings

Large urban event. The first setting for the health fair was a large vaccination event near the VAPIHCS center in April 2021. Attendance was solicited by VEText, phone calls, and social media advertisements. At check-in, veterans with relevant open clinical reminders were invited to receive preventive health care during the 15-minute monitoring period after the COVID-19 vaccine. The Vet Center Program stationed the mobile van outside the vaccination event, where a physician and a clinical pharmacy specialist (CPS) did assessments, completed reminders, and entered follow-up requests for about 4 hours. A medical support assistant registered veterans who had never signed up for VA health care.

Community Settings. Nine events occurred at least monthly between March and September 2021 at 4 different sites in Oahu. Texts and phone calls were used to solicit attendance; there was no prior publicity on social media. Community events required scheduling resources; this required about 30 hours of medical staff assistant time. Seven sites were visited for about 3 hours each. A physician, pharmacy technician, and CPS conducted assessments, completed reminders, and entered follow-up requests. A medical support assistant registered veterans who had never signed up for VA health care.

Homeless veteran outreach. Five events occurred at 2 homeless veteran housing sites between August 2021 and January 2022. These sites were emergency housing sites (2 events) and transitional and permanent housing (2 events). U.S.VETS and HIHS contacted veterans living in those settings to promote the event. A physician, registered nurse, licensed practical nurse, and CPS conducted assessments, completed reminders, and entered follow-up requests. A medical support assistant registered veterans that had never signed up for VA health care. Each event lasted approximate 3 hours.

Process Quality Improvement

After the CDC changed recommendations to allow concurrent vaccination with the COVID-19 vaccine, we added other vaccinations to the events. This occurred during the course of community events. In June of 2021, there was a health advisory concerning hepatitis A among people experiencing homelessness in Oahu, so hepatitis vaccinations were added for events for veterans.²⁰

Veterans Served

The EHR was used to determine demographics, open clinical reminders, and attendance at follow-up. Simple descriptive statistics were performed in Microsoft Excel. A total of 115 veterans were seen for preventive health visits, and 404 clinical reminders were completed. Seven hundred veterans attended the large centrally located vaccine event and 43 agreed to have a preventive health visit. Thirty-eight veterans had a preventive health visit at homeless outreach events and 34 veterans had a preventive health visit at the community events. Veterans at community

Of the 166 vaccines given, 73 were for COVID-19. Besides vaccination,

Discussion

This program provided evidence that adding preventive screenings to vaccine events may help reach veterans who may have missed important preventive care due to the COVID-19 pandemic. The involvement of clinical informatics service allowed the outreach to be targeted to communities with incomplete clinical reminders. Interventions that could not be completed at the event had high levels of follow-up by veterans with important findings. The presence of a physician or nurse and a CPS allowed for point-of-care testing, as well as entering orders for medication, laboratory tests, and consultations. The attendance by representatives from the Vet Center, suicide prevention, and homeless services allowed counseling regarding benefits, and mental health follow-up. We believe that we were able to reach communities of veterans with unmet preventive needs and had higher risk of severe COVID-19, given the high numbers with open clinical reminders, the number of vaccines provided, and the high percentage of racial and ethnic minority veterans at events in the community. Our program experience provides some evidence that mobile and pop-up vaccination clinics may be beneficial for screening and managing chronic diseases, as proposed elsewhere.^21-24

Strengths of this intervention include that we were able to show a high level of follow-up for recommended medical care as well as the results of our interventions. We have found no similar articles that provide data on completion of follow-up appointments after a health fair. A prior study showed only 23% to 63% of participants at a health fair reported having a recommended follow-up discussion with doctors, but the study reported no outcome of completed cancer screenings.²⁵

Limitations

Weaknesses include the fact that health fair events may reach only healthy people, since attendees generally report better health and better health behaviors than nonattendees.^26,27 We felt this was more problematic for the large-scale urban event and that offering rural events and events in homeless housing improved the reach. Future efforts will involve the use of social media and mailings to solicit attendance. To improve follow-up, future work will include adding to the events: phlebotomy or expanded point-of-care testing; specialty care telehealth capability; cervical cancer screen self-collection; and tele-retinal services.

Conclusions

This program provided evidence that directed, preventive screening can be performed in outreach settings paired with vaccine events. These vaccination events in rural and homeless settings reached communities with demonstrable COVID-19 vaccination and other preventive care needs. This approach could be used to help veterans catch up on needed preventive care.

Acknowledgments

Veterans Affairs Pacific Islands Health Care System: Anthony Chance, LCSW; Nicholas Chang, PharmD; Andrew Dahlburg, LCSW; Wilminia G. Ellorimo-Gil, RN; Paul Guillory, RN; Wendy D. Joy; Arthur Minor, LCSW; Avalua Smith; Jessica Spurrier, RN. Veterans Health Administration Vet Center Program: Rolly O. Alvarado; Edmond G. DeGuzman; Richard T. Teel. Hawaii Institute for Human Services. U.S.VETS.

Ultrasound & Chest Imaging Section

VExUS scan: The missing piece of hemodynamic puzzle?

Volume status and tailoring the correct level of fluid resuscitation is challenging for the intensivist. Determining “fluid overload,” especially in the setting of acute kidney injury, can be difficult. While a Swan-Ganz catheter, central venous pressure, or inferior vena cava (IVC) ultrasound measurement can suggest elevated right atrial pressure, the effect on organ level hemodynamics is unknown.

Abdominal venous Doppler is a method to view the effects of venous pressure on abdominal organ venous flow. An application of this is the Venous Excess Ultrasound Score (VExUS) (Rola, et al. Ultrasound J. 2021;13[1]:32). VExUS uses IVC diameter and pulse wave doppler waveforms from the hepatic, portal, and renal veins to grade venous congestion from none to severe. Studies demonstrate an association between venous congestion and renal dysfunction in cardiac surgery (Beaubien-Souligny, et al. Ultrasound J. 2020;12[1]:16) and general ICU patients (Spiegel, et al. Crit Care. 2020;24[1]:615).

This practice of identifying venous congestion and avoiding over-resuscitation could improve patient care. However, acquiring quality images and waveforms may prove to be difficult, and interpretation may be confounded by other disease states such as cirrhosis. Though it is postulated that removing fluid could be beneficial to patients with high VExUS scores, this has yet to be proven and may be difficult to prove. While the score estimates volume status well, the source of venous congestion is not identified such that it should be used as a clinical supplement to other data.

VExUS has a strong physiologic basis, and early clinical experience indicates a strong role in improving assessment of venous congestion, an important aspect of volume status. This is an area of ongoing research to ensure appropriate and effective use.

Kyle Swartz, DO
Fellow-in-Training

Steven Fox, MD
Fellow-in-Training

John Levasseur, DO

Ultrasound & Chest Imaging Section

VExUS scan: The missing piece of hemodynamic puzzle?

Volume status and tailoring the correct level of fluid resuscitation is challenging for the intensivist. Determining “fluid overload,” especially in the setting of acute kidney injury, can be difficult. While a Swan-Ganz catheter, central venous pressure, or inferior vena cava (IVC) ultrasound measurement can suggest elevated right atrial pressure, the effect on organ level hemodynamics is unknown.

Abdominal venous Doppler is a method to view the effects of venous pressure on abdominal organ venous flow. An application of this is the Venous Excess Ultrasound Score (VExUS) (Rola, et al. Ultrasound J. 2021;13[1]:32). VExUS uses IVC diameter and pulse wave doppler waveforms from the hepatic, portal, and renal veins to grade venous congestion from none to severe. Studies demonstrate an association between venous congestion and renal dysfunction in cardiac surgery (Beaubien-Souligny, et al. Ultrasound J. 2020;12[1]:16) and general ICU patients (Spiegel, et al. Crit Care. 2020;24[1]:615).

This practice of identifying venous congestion and avoiding over-resuscitation could improve patient care. However, acquiring quality images and waveforms may prove to be difficult, and interpretation may be confounded by other disease states such as cirrhosis. Though it is postulated that removing fluid could be beneficial to patients with high VExUS scores, this has yet to be proven and may be difficult to prove. While the score estimates volume status well, the source of venous congestion is not identified such that it should be used as a clinical supplement to other data.

VExUS has a strong physiologic basis, and early clinical experience indicates a strong role in improving assessment of venous congestion, an important aspect of volume status. This is an area of ongoing research to ensure appropriate and effective use.

Kyle Swartz, DO
Fellow-in-Training

Steven Fox, MD
Fellow-in-Training

John Levasseur, DO

Ultrasound & Chest Imaging Section

VExUS scan: The missing piece of hemodynamic puzzle?

Volume status and tailoring the correct level of fluid resuscitation is challenging for the intensivist. Determining “fluid overload,” especially in the setting of acute kidney injury, can be difficult. While a Swan-Ganz catheter, central venous pressure, or inferior vena cava (IVC) ultrasound measurement can suggest elevated right atrial pressure, the effect on organ level hemodynamics is unknown.

Abdominal venous Doppler is a method to view the effects of venous pressure on abdominal organ venous flow. An application of this is the Venous Excess Ultrasound Score (VExUS) (Rola, et al. Ultrasound J. 2021;13[1]:32). VExUS uses IVC diameter and pulse wave doppler waveforms from the hepatic, portal, and renal veins to grade venous congestion from none to severe. Studies demonstrate an association between venous congestion and renal dysfunction in cardiac surgery (Beaubien-Souligny, et al. Ultrasound J. 2020;12[1]:16) and general ICU patients (Spiegel, et al. Crit Care. 2020;24[1]:615).

This practice of identifying venous congestion and avoiding over-resuscitation could improve patient care. However, acquiring quality images and waveforms may prove to be difficult, and interpretation may be confounded by other disease states such as cirrhosis. Though it is postulated that removing fluid could be beneficial to patients with high VExUS scores, this has yet to be proven and may be difficult to prove. While the score estimates volume status well, the source of venous congestion is not identified such that it should be used as a clinical supplement to other data.

VExUS has a strong physiologic basis, and early clinical experience indicates a strong role in improving assessment of venous congestion, an important aspect of volume status. This is an area of ongoing research to ensure appropriate and effective use.

Kyle Swartz, DO
Fellow-in-Training

Steven Fox, MD
Fellow-in-Training

John Levasseur, DO

Sepsis/Shock Section

Fluid Resuscitation – Back to BaSICS

The age-old debate regarding the appropriate timing, volume, and type of fluid resuscitation for patients in septic shock rages on – or does it? In October 2021, the Surviving Sepsis Campaign published updated guidelines for the management of sepsis. One of the biggest changes from prior versions was downgrading the recommendation for an initial 30mL/kg bolus of IV crystalloid for the initial resuscitation of a patient in septic shock to a suggestion, based on dynamic measures to assess individual patients’ fluid balance (Evans, et al. Crit Care Med. 2021;49[11]:e1063-e1143).

Courtesy CHEST

Traditionally, 0.9% saline had been the resuscitative fluid of choice in sepsis. But it has a propensity to cause physiologic derangements such as hyperchloremic metabolic acidosis, renal afferent vasoconstriction, and reduced glomerular filtration rate – not to mention, can be a signal for possibly increased mortality, as seen in the SMART trial (Semler, et al. N Engl J Med. 2018;378[9]:829-839). Normal saline had subsequently fallen from grace in favor of balanced crystalloids such as Lactated Ringer’s and Plasma-Lyte. However, the recent PLUS and BaSICS trials showed no significant difference in 90-day mortality or secondary outcomes of acute kidney injury, need for renal replacement therapy, or ICU mortality (Finfer, et al. N Engl J Med. 2022;386[9]:815-826; Zampieri, et al. JAMA. 2021;326[9]:818-829). While these are large randomized controlled trials, a major weakness is the administration of uncontrolled resuscitative fluids prior to randomization and even postenrollment, which may have biased results.

Ultimately, does the choice between salt water or balanced crystalloids matter? Despite the limitations in the newest trials, probably less than the timely administration of antibiotics and pressors, unless your patient also has a traumatic TBI – then go with the saline. But, in the everlasting quest for medical excellence, choosing the balanced fluid that causes the least physiologic derangement seems to make the most sense.

LCDR Meredith Olsen, MD, USN
Fellow-in-Training

Ankita Agarwal, MD
Fellow-in-Training

The views expressed are those of the authors and do not reflect the official policy or position of the U.S. Navy, Department of Defense, or the U.S. Government.

Sepsis/Shock Section

Fluid Resuscitation – Back to BaSICS

The age-old debate regarding the appropriate timing, volume, and type of fluid resuscitation for patients in septic shock rages on – or does it? In October 2021, the Surviving Sepsis Campaign published updated guidelines for the management of sepsis. One of the biggest changes from prior versions was downgrading the recommendation for an initial 30mL/kg bolus of IV crystalloid for the initial resuscitation of a patient in septic shock to a suggestion, based on dynamic measures to assess individual patients’ fluid balance (Evans, et al. Crit Care Med. 2021;49[11]:e1063-e1143).

Courtesy CHEST

Traditionally, 0.9% saline had been the resuscitative fluid of choice in sepsis. But it has a propensity to cause physiologic derangements such as hyperchloremic metabolic acidosis, renal afferent vasoconstriction, and reduced glomerular filtration rate – not to mention, can be a signal for possibly increased mortality, as seen in the SMART trial (Semler, et al. N Engl J Med. 2018;378[9]:829-839). Normal saline had subsequently fallen from grace in favor of balanced crystalloids such as Lactated Ringer’s and Plasma-Lyte. However, the recent PLUS and BaSICS trials showed no significant difference in 90-day mortality or secondary outcomes of acute kidney injury, need for renal replacement therapy, or ICU mortality (Finfer, et al. N Engl J Med. 2022;386[9]:815-826; Zampieri, et al. JAMA. 2021;326[9]:818-829). While these are large randomized controlled trials, a major weakness is the administration of uncontrolled resuscitative fluids prior to randomization and even postenrollment, which may have biased results.

Ultimately, does the choice between salt water or balanced crystalloids matter? Despite the limitations in the newest trials, probably less than the timely administration of antibiotics and pressors, unless your patient also has a traumatic TBI – then go with the saline. But, in the everlasting quest for medical excellence, choosing the balanced fluid that causes the least physiologic derangement seems to make the most sense.

LCDR Meredith Olsen, MD, USN
Fellow-in-Training

Ankita Agarwal, MD
Fellow-in-Training

The views expressed are those of the authors and do not reflect the official policy or position of the U.S. Navy, Department of Defense, or the U.S. Government.

Sepsis/Shock Section

Fluid Resuscitation – Back to BaSICS

The age-old debate regarding the appropriate timing, volume, and type of fluid resuscitation for patients in septic shock rages on – or does it? In October 2021, the Surviving Sepsis Campaign published updated guidelines for the management of sepsis. One of the biggest changes from prior versions was downgrading the recommendation for an initial 30mL/kg bolus of IV crystalloid for the initial resuscitation of a patient in septic shock to a suggestion, based on dynamic measures to assess individual patients’ fluid balance (Evans, et al. Crit Care Med. 2021;49[11]:e1063-e1143).

Courtesy CHEST

Traditionally, 0.9% saline had been the resuscitative fluid of choice in sepsis. But it has a propensity to cause physiologic derangements such as hyperchloremic metabolic acidosis, renal afferent vasoconstriction, and reduced glomerular filtration rate – not to mention, can be a signal for possibly increased mortality, as seen in the SMART trial (Semler, et al. N Engl J Med. 2018;378[9]:829-839). Normal saline had subsequently fallen from grace in favor of balanced crystalloids such as Lactated Ringer’s and Plasma-Lyte. However, the recent PLUS and BaSICS trials showed no significant difference in 90-day mortality or secondary outcomes of acute kidney injury, need for renal replacement therapy, or ICU mortality (Finfer, et al. N Engl J Med. 2022;386[9]:815-826; Zampieri, et al. JAMA. 2021;326[9]:818-829). While these are large randomized controlled trials, a major weakness is the administration of uncontrolled resuscitative fluids prior to randomization and even postenrollment, which may have biased results.

Ultimately, does the choice between salt water or balanced crystalloids matter? Despite the limitations in the newest trials, probably less than the timely administration of antibiotics and pressors, unless your patient also has a traumatic TBI – then go with the saline. But, in the everlasting quest for medical excellence, choosing the balanced fluid that causes the least physiologic derangement seems to make the most sense.

LCDR Meredith Olsen, MD, USN
Fellow-in-Training

Ankita Agarwal, MD
Fellow-in-Training

The views expressed are those of the authors and do not reflect the official policy or position of the U.S. Navy, Department of Defense, or the U.S. Government.