Researchers derived and validated a risk score for major NSAID adverse events. Also today, the ACIP resuscitates pertussis working group, it’s important to talk to adolescents about sexual assault, and costs increase for gun injuries in children.
Amazon Alexa
Apple Podcasts
Spotify

Researchers derived and validated a risk score for major NSAID adverse events. Also today, the ACIP resuscitates pertussis working group, it’s important to talk to adolescents about sexual assault, and costs increase for gun injuries in children.
Amazon Alexa
Apple Podcasts
Spotify

Researchers derived and validated a risk score for major NSAID adverse events. Also today, the ACIP resuscitates pertussis working group, it’s important to talk to adolescents about sexual assault, and costs increase for gun injuries in children.
Amazon Alexa
Apple Podcasts
Spotify

Although there have been significant improvements in patient outcomes for some forms of pediatric cancer, progress has been painfully slow for others. An increasing understanding of pediatric cancers is highlighting the unique molecular drivers and challenging the assumption that drugs developed in adults can be applied to children and young adults. Here, we discuss game-changing therapeutic advances and a shifting view of childhood cancers.

Unique genomic background

Although pediatric cancers are rare, representing just 1% of all new cancers diagnosed annually in the United States, they are the second leading cause of death in children aged 1 to 14 years. There are many different histological tumor types under the umbrella of childhood cancers, of which the most common are leukemias, central nervous system tumors, and lymphomas (Figure 1).^1,2

A ‘magic bullet’?

Chromosomal rearrangements are common in pediatric cancers. This type of molecular abnormality can result in a fusion of 2 different genes when the chromosome breaks apart and the pieces join back together in a muddled order. If the genetic code fuses in a manner that is “readable” by the cell, then it can drive aberrant activation of one or both genes.⁷ Gene fusions often involve kinase enzymes that are essential players in cell signaling pathways regulating hallmark cancer processes, such as unchecked cell proliferation. The fusion drives the constitutive activation of the kinase and, thus, these downstream signaling pathways.

One of the first chromosomal rearrangements linked to cancer, BCR-ABL1 – more commonly known as the Philadelphia chromosome – results in aberrant activation of the ABL1 kinase. It is present in nearly all cases of chronic myeloid leukemia (CML) and 3% to 5% of patients with ALL, and thus became the central focus of targeted drug development. Imatinib was initially approved by the US Food and Drug Administration (FDA) in 2001 for the treatment of adult patients with CML and had such a significant impact on the treatment landscape that it made the cover of Time magazine as a “magic bullet” in the war on cancer.⁸

Approval was expanded into pediatric patients in 2006 and for pediatric patients with ALL in 2013. However, as with the use of most kinase inhibitors, tumors can evolve under the selective pressure of treatment, developing additional molecular abnormalities that drive resistance.⁹

Next-generation multikinase inhibitors that more potently inhibit the BCR-ABL1 fusion protein have been developed to provide additional treatment options for patients who become resistant to imatinib. Dasatinib and nilotinib are among several drugs that have recently been approved for pediatric cancer therapy (Table 1). Both therapies were approved to treat children with Philadelphia chromosome-positive CML in the chronic phase in either the front- or second-line setting after failure of imatinib.

Other prominent gene fusions

Gene fusions involving the anaplastic lymphoma kinase (ALK) occur in patients with non–small-cell lung cancer and ALK inhibitors have provided an effective new treatment option for patients whose tumors display this abnormality.

ALK fusions are also a prominent feature of several kinds of pediatric cancers and ALK inhibitors offer promise in this setting.^7,12 An NPM-ALK fusion is found in 90% of pediatric anaplastic large cell lymphoma (ALCL) cases,¹³ whereas a variety of ALK fusions are found in up to half of patients with inflammatory myofibroblastic tumor (IMT), a rare form of soft tissue sarcoma.¹⁴ ALK inhibitors are being tested in a variety of clinical trials in pediatric patients (Table 2).

CAR T cells transformative in ALL

A variety of different types of immunotherapy have been tested in patients with pediatric cancers. In general, immunotherapy has proved less effective than in adult cancers, possibly because of the lower tumor mutation burden in pediatric cancers, which means there are likely fewer cancer antigens to provoke an anti-tumor immune response.

There are notable exceptions among the disappointments, however, and most exciting is the development of chimeric antigen receptor (CAR) T cells. CAR T cells fall into a category of immunotherapy known as adoptive cell therapy (ACT), in which immune cells are harvested from a patient and grown outside the body to increase their numbers before being reinfused into the patient.

In the case of CAR T-cell therapy, the cells are genetically engineered to express a CAR that endows them with tumor-targeting capabilities. To date, the development of CAR T cells has focused on the use of the CD19 antigen as a target, which is highly expressed on a variety of B-cell malignancies, including several of the most common forms of pediatric cancer. ASCO shined the spotlight on CAR T-cell therapy this year, naming it the Advance of the Year for 2018, saying that the treatment is “poised to transform childhood ALL.”¹⁹

Two CD19-targeted CAR T-cell therapies – tisagenlecleucel and axicabtagene ciloleucel – were brought to market in 2017. Only tisagenlecleucel is approved in the pediatric ALL population, however, having been awarded approval for the treatment of patients aged up to 25 years whose disease is refractory to or relapsed after receiving at least 2 prior therapies. In the pivotal trial, complete responses were observed in more than 60% of patients.²⁰ Clinical trials of both CAR T-cell therapies in pediatric ALL and non-Hodgkin lymphoma are ongoing (Table 3).

More immunotherapy approvals

The immune checkpoint inhibitors, which work by blocking inhibitory receptors on the surface of T cells, have also had recent approvals in pediatric patient populations. Pembrolizumab and nivolumab, inhibitors of the programmed cell death receptor 1 (PD-1) protein, have both been approved for use in adult and pediatric patients (older than 12 years) with relapsed/refractory metastatic colorectal cancer (and other solid tumors in the case of pembrolizumab) that display defects in the mismatch repair pathway that fixes damaged DNA or in patients that have high levels of microsatellite instability. Both deficient mismatch repair and microsatellite instability–high can indicate a high mutation burden in a tumor, which may predict increased sensitivity to immunotherapy.²⁹

The approval in pediatric patients in both of those instances, however, was not based on data in pediatric patient populations but extrapolated from adult patients. Pembrolizumab is also approved for the treatment of adults and pediatric patients with classical Hodgkin lymphoma (cHL) after 3 or more previous treatments, but once again efficacy in the pediatric population was inferred from clinical trials performed in adults. Most recently, pembrolizumab was approved for the treatment of adult and pediatric patients with relapsed or refractory primary mediastinal large B-cell lymphoma.³⁰Ipilimumab, which targets a different T cell receptor – cytotoxic T lymphocyte antigen-4 (CTLA-4) – has been approved for the treatment of pediatric patients aged 12 years and older with metastatic melanoma. This expanded indication, following on from its approval in adult patients in 2011, was based on data from 2 trials in which objective responses were observed in 2 out of 17 patients, including 1 partial response that lasted 16 months.³¹Finally, antibody-drug conjugates (ADC), in which tumor antigen-targeting monoclonal antibodies are conjugated to cytotoxic payloads to combine the specificity of an antibody with the cell-killing potency of chemotherapy, have also generated some recent successes in pediatric cancers.

Gemtuzumab ozogamicin is an ADC that targets the CD33 protein, which is highly expressed on 85%-90% of cases of acute myeloid leukemia (AML). In 2000, it was the first ADC to be brought to market in the United States, but it was subsequently voluntarily withdrawn by the manufacturer in 2010 after confirmatory trials failed to show a survival benefit.

Recently, a meta-analysis of gemtuzumab ozogamicin trials suggested that the drug likely does improve long-term overall survival (OS) and reduce the risk of relapse and researchers developed an intermittent dosing schedule to help mitigate toxicity.³² This new dosing regimen received FDA approval in 2017 for the treatment of pediatric patients aged 2 years and older on the basis of 2 clinical trials.

In the MyloFrance-1 trial, 57 patients were administered 3 mg/m² gemtuzumab ozogamicin on days 1, 4, and 7 followed by cytarabine consolidation therapy and demonstrated a 26% CR rate and median recurrence-free survival of 11.6 months. In the phase 3 AML-19 trial, 237 patients received gemtuzumab ozogamicin at a dose of 6 mg/m² on day 1 and 3 mg/m² on day 8 or best supportive care. Gemtuzumab ozogamicin improved OS from 3.6 to 4.9 months.^33,34

Inotuzumab ozogamicin is a CD22-targeting ADC that has been FDA approved for the treatment of adult patients with relapsed/refractory B-cell precursor ALL since last year. The therapy has been available to pediatric patients through a compassionate access program, but it has not been extensively evaluated in this population. The results of a retrospective analysis of pediatric patients who received at least 1 dose of inotuzumab ozogamicin were presented at ASCO in 2017. Among 29 patients with heavily pretreated disease the CR rate was 62%, 72% of whom achieved MRD negativity.³⁵

Although there have been significant improvements in patient outcomes for some forms of pediatric cancer, progress has been painfully slow for others. An increasing understanding of pediatric cancers is highlighting the unique molecular drivers and challenging the assumption that drugs developed in adults can be applied to children and young adults. Here, we discuss game-changing therapeutic advances and a shifting view of childhood cancers.

Unique genomic background

Although pediatric cancers are rare, representing just 1% of all new cancers diagnosed annually in the United States, they are the second leading cause of death in children aged 1 to 14 years. There are many different histological tumor types under the umbrella of childhood cancers, of which the most common are leukemias, central nervous system tumors, and lymphomas (Figure 1).^1,2

A ‘magic bullet’?

Chromosomal rearrangements are common in pediatric cancers. This type of molecular abnormality can result in a fusion of 2 different genes when the chromosome breaks apart and the pieces join back together in a muddled order. If the genetic code fuses in a manner that is “readable” by the cell, then it can drive aberrant activation of one or both genes.⁷ Gene fusions often involve kinase enzymes that are essential players in cell signaling pathways regulating hallmark cancer processes, such as unchecked cell proliferation. The fusion drives the constitutive activation of the kinase and, thus, these downstream signaling pathways.

One of the first chromosomal rearrangements linked to cancer, BCR-ABL1 – more commonly known as the Philadelphia chromosome – results in aberrant activation of the ABL1 kinase. It is present in nearly all cases of chronic myeloid leukemia (CML) and 3% to 5% of patients with ALL, and thus became the central focus of targeted drug development. Imatinib was initially approved by the US Food and Drug Administration (FDA) in 2001 for the treatment of adult patients with CML and had such a significant impact on the treatment landscape that it made the cover of Time magazine as a “magic bullet” in the war on cancer.⁸

Approval was expanded into pediatric patients in 2006 and for pediatric patients with ALL in 2013. However, as with the use of most kinase inhibitors, tumors can evolve under the selective pressure of treatment, developing additional molecular abnormalities that drive resistance.⁹

Next-generation multikinase inhibitors that more potently inhibit the BCR-ABL1 fusion protein have been developed to provide additional treatment options for patients who become resistant to imatinib. Dasatinib and nilotinib are among several drugs that have recently been approved for pediatric cancer therapy (Table 1). Both therapies were approved to treat children with Philadelphia chromosome-positive CML in the chronic phase in either the front- or second-line setting after failure of imatinib.

Other prominent gene fusions

Gene fusions involving the anaplastic lymphoma kinase (ALK) occur in patients with non–small-cell lung cancer and ALK inhibitors have provided an effective new treatment option for patients whose tumors display this abnormality.

ALK fusions are also a prominent feature of several kinds of pediatric cancers and ALK inhibitors offer promise in this setting.^7,12 An NPM-ALK fusion is found in 90% of pediatric anaplastic large cell lymphoma (ALCL) cases,¹³ whereas a variety of ALK fusions are found in up to half of patients with inflammatory myofibroblastic tumor (IMT), a rare form of soft tissue sarcoma.¹⁴ ALK inhibitors are being tested in a variety of clinical trials in pediatric patients (Table 2).

CAR T cells transformative in ALL

A variety of different types of immunotherapy have been tested in patients with pediatric cancers. In general, immunotherapy has proved less effective than in adult cancers, possibly because of the lower tumor mutation burden in pediatric cancers, which means there are likely fewer cancer antigens to provoke an anti-tumor immune response.

There are notable exceptions among the disappointments, however, and most exciting is the development of chimeric antigen receptor (CAR) T cells. CAR T cells fall into a category of immunotherapy known as adoptive cell therapy (ACT), in which immune cells are harvested from a patient and grown outside the body to increase their numbers before being reinfused into the patient.

In the case of CAR T-cell therapy, the cells are genetically engineered to express a CAR that endows them with tumor-targeting capabilities. To date, the development of CAR T cells has focused on the use of the CD19 antigen as a target, which is highly expressed on a variety of B-cell malignancies, including several of the most common forms of pediatric cancer. ASCO shined the spotlight on CAR T-cell therapy this year, naming it the Advance of the Year for 2018, saying that the treatment is “poised to transform childhood ALL.”¹⁹

Two CD19-targeted CAR T-cell therapies – tisagenlecleucel and axicabtagene ciloleucel – were brought to market in 2017. Only tisagenlecleucel is approved in the pediatric ALL population, however, having been awarded approval for the treatment of patients aged up to 25 years whose disease is refractory to or relapsed after receiving at least 2 prior therapies. In the pivotal trial, complete responses were observed in more than 60% of patients.²⁰ Clinical trials of both CAR T-cell therapies in pediatric ALL and non-Hodgkin lymphoma are ongoing (Table 3).

More immunotherapy approvals

The immune checkpoint inhibitors, which work by blocking inhibitory receptors on the surface of T cells, have also had recent approvals in pediatric patient populations. Pembrolizumab and nivolumab, inhibitors of the programmed cell death receptor 1 (PD-1) protein, have both been approved for use in adult and pediatric patients (older than 12 years) with relapsed/refractory metastatic colorectal cancer (and other solid tumors in the case of pembrolizumab) that display defects in the mismatch repair pathway that fixes damaged DNA or in patients that have high levels of microsatellite instability. Both deficient mismatch repair and microsatellite instability–high can indicate a high mutation burden in a tumor, which may predict increased sensitivity to immunotherapy.²⁹

The approval in pediatric patients in both of those instances, however, was not based on data in pediatric patient populations but extrapolated from adult patients. Pembrolizumab is also approved for the treatment of adults and pediatric patients with classical Hodgkin lymphoma (cHL) after 3 or more previous treatments, but once again efficacy in the pediatric population was inferred from clinical trials performed in adults. Most recently, pembrolizumab was approved for the treatment of adult and pediatric patients with relapsed or refractory primary mediastinal large B-cell lymphoma.³⁰Ipilimumab, which targets a different T cell receptor – cytotoxic T lymphocyte antigen-4 (CTLA-4) – has been approved for the treatment of pediatric patients aged 12 years and older with metastatic melanoma. This expanded indication, following on from its approval in adult patients in 2011, was based on data from 2 trials in which objective responses were observed in 2 out of 17 patients, including 1 partial response that lasted 16 months.³¹Finally, antibody-drug conjugates (ADC), in which tumor antigen-targeting monoclonal antibodies are conjugated to cytotoxic payloads to combine the specificity of an antibody with the cell-killing potency of chemotherapy, have also generated some recent successes in pediatric cancers.

Gemtuzumab ozogamicin is an ADC that targets the CD33 protein, which is highly expressed on 85%-90% of cases of acute myeloid leukemia (AML). In 2000, it was the first ADC to be brought to market in the United States, but it was subsequently voluntarily withdrawn by the manufacturer in 2010 after confirmatory trials failed to show a survival benefit.

Recently, a meta-analysis of gemtuzumab ozogamicin trials suggested that the drug likely does improve long-term overall survival (OS) and reduce the risk of relapse and researchers developed an intermittent dosing schedule to help mitigate toxicity.³² This new dosing regimen received FDA approval in 2017 for the treatment of pediatric patients aged 2 years and older on the basis of 2 clinical trials.

In the MyloFrance-1 trial, 57 patients were administered 3 mg/m² gemtuzumab ozogamicin on days 1, 4, and 7 followed by cytarabine consolidation therapy and demonstrated a 26% CR rate and median recurrence-free survival of 11.6 months. In the phase 3 AML-19 trial, 237 patients received gemtuzumab ozogamicin at a dose of 6 mg/m² on day 1 and 3 mg/m² on day 8 or best supportive care. Gemtuzumab ozogamicin improved OS from 3.6 to 4.9 months.^33,34

Inotuzumab ozogamicin is a CD22-targeting ADC that has been FDA approved for the treatment of adult patients with relapsed/refractory B-cell precursor ALL since last year. The therapy has been available to pediatric patients through a compassionate access program, but it has not been extensively evaluated in this population. The results of a retrospective analysis of pediatric patients who received at least 1 dose of inotuzumab ozogamicin were presented at ASCO in 2017. Among 29 patients with heavily pretreated disease the CR rate was 62%, 72% of whom achieved MRD negativity.³⁵

Although there have been significant improvements in patient outcomes for some forms of pediatric cancer, progress has been painfully slow for others. An increasing understanding of pediatric cancers is highlighting the unique molecular drivers and challenging the assumption that drugs developed in adults can be applied to children and young adults. Here, we discuss game-changing therapeutic advances and a shifting view of childhood cancers.

Unique genomic background

Although pediatric cancers are rare, representing just 1% of all new cancers diagnosed annually in the United States, they are the second leading cause of death in children aged 1 to 14 years. There are many different histological tumor types under the umbrella of childhood cancers, of which the most common are leukemias, central nervous system tumors, and lymphomas (Figure 1).^1,2

A ‘magic bullet’?

Chromosomal rearrangements are common in pediatric cancers. This type of molecular abnormality can result in a fusion of 2 different genes when the chromosome breaks apart and the pieces join back together in a muddled order. If the genetic code fuses in a manner that is “readable” by the cell, then it can drive aberrant activation of one or both genes.⁷ Gene fusions often involve kinase enzymes that are essential players in cell signaling pathways regulating hallmark cancer processes, such as unchecked cell proliferation. The fusion drives the constitutive activation of the kinase and, thus, these downstream signaling pathways.

One of the first chromosomal rearrangements linked to cancer, BCR-ABL1 – more commonly known as the Philadelphia chromosome – results in aberrant activation of the ABL1 kinase. It is present in nearly all cases of chronic myeloid leukemia (CML) and 3% to 5% of patients with ALL, and thus became the central focus of targeted drug development. Imatinib was initially approved by the US Food and Drug Administration (FDA) in 2001 for the treatment of adult patients with CML and had such a significant impact on the treatment landscape that it made the cover of Time magazine as a “magic bullet” in the war on cancer.⁸

Approval was expanded into pediatric patients in 2006 and for pediatric patients with ALL in 2013. However, as with the use of most kinase inhibitors, tumors can evolve under the selective pressure of treatment, developing additional molecular abnormalities that drive resistance.⁹

Next-generation multikinase inhibitors that more potently inhibit the BCR-ABL1 fusion protein have been developed to provide additional treatment options for patients who become resistant to imatinib. Dasatinib and nilotinib are among several drugs that have recently been approved for pediatric cancer therapy (Table 1). Both therapies were approved to treat children with Philadelphia chromosome-positive CML in the chronic phase in either the front- or second-line setting after failure of imatinib.

Other prominent gene fusions

Gene fusions involving the anaplastic lymphoma kinase (ALK) occur in patients with non–small-cell lung cancer and ALK inhibitors have provided an effective new treatment option for patients whose tumors display this abnormality.

ALK fusions are also a prominent feature of several kinds of pediatric cancers and ALK inhibitors offer promise in this setting.^7,12 An NPM-ALK fusion is found in 90% of pediatric anaplastic large cell lymphoma (ALCL) cases,¹³ whereas a variety of ALK fusions are found in up to half of patients with inflammatory myofibroblastic tumor (IMT), a rare form of soft tissue sarcoma.¹⁴ ALK inhibitors are being tested in a variety of clinical trials in pediatric patients (Table 2).

CAR T cells transformative in ALL

A variety of different types of immunotherapy have been tested in patients with pediatric cancers. In general, immunotherapy has proved less effective than in adult cancers, possibly because of the lower tumor mutation burden in pediatric cancers, which means there are likely fewer cancer antigens to provoke an anti-tumor immune response.

There are notable exceptions among the disappointments, however, and most exciting is the development of chimeric antigen receptor (CAR) T cells. CAR T cells fall into a category of immunotherapy known as adoptive cell therapy (ACT), in which immune cells are harvested from a patient and grown outside the body to increase their numbers before being reinfused into the patient.

In the case of CAR T-cell therapy, the cells are genetically engineered to express a CAR that endows them with tumor-targeting capabilities. To date, the development of CAR T cells has focused on the use of the CD19 antigen as a target, which is highly expressed on a variety of B-cell malignancies, including several of the most common forms of pediatric cancer. ASCO shined the spotlight on CAR T-cell therapy this year, naming it the Advance of the Year for 2018, saying that the treatment is “poised to transform childhood ALL.”¹⁹

Two CD19-targeted CAR T-cell therapies – tisagenlecleucel and axicabtagene ciloleucel – were brought to market in 2017. Only tisagenlecleucel is approved in the pediatric ALL population, however, having been awarded approval for the treatment of patients aged up to 25 years whose disease is refractory to or relapsed after receiving at least 2 prior therapies. In the pivotal trial, complete responses were observed in more than 60% of patients.²⁰ Clinical trials of both CAR T-cell therapies in pediatric ALL and non-Hodgkin lymphoma are ongoing (Table 3).

More immunotherapy approvals

The immune checkpoint inhibitors, which work by blocking inhibitory receptors on the surface of T cells, have also had recent approvals in pediatric patient populations. Pembrolizumab and nivolumab, inhibitors of the programmed cell death receptor 1 (PD-1) protein, have both been approved for use in adult and pediatric patients (older than 12 years) with relapsed/refractory metastatic colorectal cancer (and other solid tumors in the case of pembrolizumab) that display defects in the mismatch repair pathway that fixes damaged DNA or in patients that have high levels of microsatellite instability. Both deficient mismatch repair and microsatellite instability–high can indicate a high mutation burden in a tumor, which may predict increased sensitivity to immunotherapy.²⁹

The approval in pediatric patients in both of those instances, however, was not based on data in pediatric patient populations but extrapolated from adult patients. Pembrolizumab is also approved for the treatment of adults and pediatric patients with classical Hodgkin lymphoma (cHL) after 3 or more previous treatments, but once again efficacy in the pediatric population was inferred from clinical trials performed in adults. Most recently, pembrolizumab was approved for the treatment of adult and pediatric patients with relapsed or refractory primary mediastinal large B-cell lymphoma.³⁰Ipilimumab, which targets a different T cell receptor – cytotoxic T lymphocyte antigen-4 (CTLA-4) – has been approved for the treatment of pediatric patients aged 12 years and older with metastatic melanoma. This expanded indication, following on from its approval in adult patients in 2011, was based on data from 2 trials in which objective responses were observed in 2 out of 17 patients, including 1 partial response that lasted 16 months.³¹Finally, antibody-drug conjugates (ADC), in which tumor antigen-targeting monoclonal antibodies are conjugated to cytotoxic payloads to combine the specificity of an antibody with the cell-killing potency of chemotherapy, have also generated some recent successes in pediatric cancers.

Gemtuzumab ozogamicin is an ADC that targets the CD33 protein, which is highly expressed on 85%-90% of cases of acute myeloid leukemia (AML). In 2000, it was the first ADC to be brought to market in the United States, but it was subsequently voluntarily withdrawn by the manufacturer in 2010 after confirmatory trials failed to show a survival benefit.

Recently, a meta-analysis of gemtuzumab ozogamicin trials suggested that the drug likely does improve long-term overall survival (OS) and reduce the risk of relapse and researchers developed an intermittent dosing schedule to help mitigate toxicity.³² This new dosing regimen received FDA approval in 2017 for the treatment of pediatric patients aged 2 years and older on the basis of 2 clinical trials.

In the MyloFrance-1 trial, 57 patients were administered 3 mg/m² gemtuzumab ozogamicin on days 1, 4, and 7 followed by cytarabine consolidation therapy and demonstrated a 26% CR rate and median recurrence-free survival of 11.6 months. In the phase 3 AML-19 trial, 237 patients received gemtuzumab ozogamicin at a dose of 6 mg/m² on day 1 and 3 mg/m² on day 8 or best supportive care. Gemtuzumab ozogamicin improved OS from 3.6 to 4.9 months.^33,34

Inotuzumab ozogamicin is a CD22-targeting ADC that has been FDA approved for the treatment of adult patients with relapsed/refractory B-cell precursor ALL since last year. The therapy has been available to pediatric patients through a compassionate access program, but it has not been extensively evaluated in this population. The results of a retrospective analysis of pediatric patients who received at least 1 dose of inotuzumab ozogamicin were presented at ASCO in 2017. Among 29 patients with heavily pretreated disease the CR rate was 62%, 72% of whom achieved MRD negativity.³⁵

Photo from Flickr

BOSTON—Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, according to investigators.

In a single-center study, rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 and cut the rate of platelet wastage from expiration by more than half.

Adam L. Booth, MD, of the University of Texas in Galveston, and his colleagues described this study in a poster presentation at AABB 2018 (abstract INV4).

Platelets typically have a shelf life of 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted.

In March 2016, the U.S. Food and Drug Administration (FDA) published a draft guidance proposing a change in regulations to allow for an extended shelf life if platelets are collected in an FDA-approved, 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

Dr. Booth and his colleagues wanted to see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets.

The investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

The team looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and they excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, the annual wastage rate was 24%, or 332 of 1,371 platelet units purchased. Using a mean per-unit cost of $516.96, the annual cost was more than $171,000.

After the start of testing, the annualized rate of wastage dropped to 10%, or 117 of 1,168 platelet units. So the annualized cost was more than $60,000.

The difference in cost—minus the cost of rapid bacterial testing (roughly $22,500)—resulted in an annual savings for the institution of nearly $89,000.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

This study was internally funded. The authors reported having no conflicts of interest.

Photo from Flickr

BOSTON—Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, according to investigators.

In a single-center study, rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 and cut the rate of platelet wastage from expiration by more than half.

Adam L. Booth, MD, of the University of Texas in Galveston, and his colleagues described this study in a poster presentation at AABB 2018 (abstract INV4).

Platelets typically have a shelf life of 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted.

In March 2016, the U.S. Food and Drug Administration (FDA) published a draft guidance proposing a change in regulations to allow for an extended shelf life if platelets are collected in an FDA-approved, 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

Dr. Booth and his colleagues wanted to see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets.

The investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

The team looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and they excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, the annual wastage rate was 24%, or 332 of 1,371 platelet units purchased. Using a mean per-unit cost of $516.96, the annual cost was more than $171,000.

After the start of testing, the annualized rate of wastage dropped to 10%, or 117 of 1,168 platelet units. So the annualized cost was more than $60,000.

The difference in cost—minus the cost of rapid bacterial testing (roughly $22,500)—resulted in an annual savings for the institution of nearly $89,000.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

This study was internally funded. The authors reported having no conflicts of interest.

Photo from Flickr

BOSTON—Rapid bacterial testing of platelets in a hospital blood bank can result in both significant cost savings and reduced wastage of blood products, according to investigators.

In a single-center study, rapid bacterial testing of 6- or 7-day-old apheresis platelets resulted in projected annual cost savings of nearly $89,000 and cut the rate of platelet wastage from expiration by more than half.

Adam L. Booth, MD, of the University of Texas in Galveston, and his colleagues described this study in a poster presentation at AABB 2018 (abstract INV4).

Platelets typically have a shelf life of 5 days because longer storage increases the risk for bacterial growth and the potential for transfusion-transmitted infections, Dr. Booth and his colleagues noted.

In March 2016, the U.S. Food and Drug Administration (FDA) published a draft guidance proposing a change in regulations to allow for an extended shelf life if platelets are collected in an FDA-approved, 7-day storage container with labeling that requires testing every product with a bacterial detection device, or if the platelets are individually tested for bacterial detection using an approved device.

Dr. Booth and his colleagues wanted to see what effect the regulations, if implemented as expected, might have on acquisition costs and wastage of apheresis platelets.

The investigators reviewed their center’s platelet acquisition costs and wastage from expiration 12 months before and 6 months after implementation of a rapid bacterial testing protocol, with 6-month results projected out to 1 year for comparison purposes.

The team looked at data on bacterial testing of 6-day and 7-day-old apheresis platelets, and they excluded data on platelet units that were due to expire on day 5 because they were not stored in FDA-approved containers.

Prior to testing, the annual wastage rate was 24%, or 332 of 1,371 platelet units purchased. Using a mean per-unit cost of $516.96, the annual cost was more than $171,000.

After the start of testing, the annualized rate of wastage dropped to 10%, or 117 of 1,168 platelet units. So the annualized cost was more than $60,000.

The difference in cost—minus the cost of rapid bacterial testing (roughly $22,500)—resulted in an annual savings for the institution of nearly $89,000.

The number of units transfused and the associated costs of transfusions were similar between the time periods studied.

This study was internally funded. The authors reported having no conflicts of interest.

Image courtesy of P. Eyers

Researchers have found the cancer-associated pseudokinase Tribbles 2 (TRIB2) to be a potential therapeutic target in solid tumors and blood cancers, including acute myeloid leukemia (AML).

Previous research had described TRIB2 as a target of small-molecule protein kinase inhibitors originally designed to interfere with kinase domains of the epidermal growth factor receptor (EGFR) tyrosine kinase family.

Using a thermal shift assay, the team discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS). They then employed a biochemical drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro.

The researchers found that afatinib, which is already approved by the U.S. Food and Drug Administration to treat non-small cell lung cancer, led to rapid TRIB2 degradation in human AML cells.

Patrick A. Eyers, PhD, of the University of Liverpool in the U.K., and his colleagues published their findings in Science Signaling.

The team found afatinib to be relatively specific for EGFR and human epidermal growth factor receptor 2 (HER2) at nanomolar concentrations in cells.

The researchers confirmed that at least two TRIB2 Cys residues interact with afatinib in vitro.

The team also discovered TRIB2 could be destabilized by neratinib and osimertinib in vitro.

“Our data prove that the cellular mechanism by which TRIB2 stability is regulated by compounds is proteasome-based,” the researchers wrote, “and we speculate that an afatinib-induced conformational change might induce TRIB2 ubiquitination.”

The researchers plan to study further TRIB2 small-molecule interactions with dynamic changes in ubiquitination status.

Furthermore, they report their work demonstrates that covalent inhibitors such as afatinib have TRIB2-degrading activity in human cells at micromolar concentrations.

The researchers determined that afatinib has similar efficacy to the TRIB2-destabilizing quinazoline neratinib at similar ranges.

The team believes their data “raise the intriguing possibility that clinical inhibitors might be used as TRIB2-degrading agents in research, and possibly clinical, contexts.”

“A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins,” Dr. Eyers commented. “Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer.”

The TRIB proteins play many diverse roles in cell signaling, development, and cancer. According to a paper in Developmental Dynamics, they were named after the small, round, fictional organisms from the original Star Trek television series. Their major role was to eat and reproduce.

This work was funded by two U.K. Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentships, a Tools and Resources Development Fund award, Royal Society Research Grants, North West Cancer Research grants, and funding from the National Institutes of Health.

The authors disclosed no perceived conflicts of interest, although several authors are affiliated with the Structural Genomics Consortium at the University of North Carolina at Chapel Hill, which receives direct funds from various pharmaceutical companies but remains entirely independent. 

Image courtesy of P. Eyers

Researchers have found the cancer-associated pseudokinase Tribbles 2 (TRIB2) to be a potential therapeutic target in solid tumors and blood cancers, including acute myeloid leukemia (AML).

Previous research had described TRIB2 as a target of small-molecule protein kinase inhibitors originally designed to interfere with kinase domains of the epidermal growth factor receptor (EGFR) tyrosine kinase family.

Using a thermal shift assay, the team discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS). They then employed a biochemical drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro.

The researchers found that afatinib, which is already approved by the U.S. Food and Drug Administration to treat non-small cell lung cancer, led to rapid TRIB2 degradation in human AML cells.

Patrick A. Eyers, PhD, of the University of Liverpool in the U.K., and his colleagues published their findings in Science Signaling.

The team found afatinib to be relatively specific for EGFR and human epidermal growth factor receptor 2 (HER2) at nanomolar concentrations in cells.

The researchers confirmed that at least two TRIB2 Cys residues interact with afatinib in vitro.

The team also discovered TRIB2 could be destabilized by neratinib and osimertinib in vitro.

“Our data prove that the cellular mechanism by which TRIB2 stability is regulated by compounds is proteasome-based,” the researchers wrote, “and we speculate that an afatinib-induced conformational change might induce TRIB2 ubiquitination.”

The researchers plan to study further TRIB2 small-molecule interactions with dynamic changes in ubiquitination status.

Furthermore, they report their work demonstrates that covalent inhibitors such as afatinib have TRIB2-degrading activity in human cells at micromolar concentrations.

The researchers determined that afatinib has similar efficacy to the TRIB2-destabilizing quinazoline neratinib at similar ranges.

The team believes their data “raise the intriguing possibility that clinical inhibitors might be used as TRIB2-degrading agents in research, and possibly clinical, contexts.”

“A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins,” Dr. Eyers commented. “Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer.”

The TRIB proteins play many diverse roles in cell signaling, development, and cancer. According to a paper in Developmental Dynamics, they were named after the small, round, fictional organisms from the original Star Trek television series. Their major role was to eat and reproduce.

This work was funded by two U.K. Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentships, a Tools and Resources Development Fund award, Royal Society Research Grants, North West Cancer Research grants, and funding from the National Institutes of Health.

The authors disclosed no perceived conflicts of interest, although several authors are affiliated with the Structural Genomics Consortium at the University of North Carolina at Chapel Hill, which receives direct funds from various pharmaceutical companies but remains entirely independent. 

Image courtesy of P. Eyers

Researchers have found the cancer-associated pseudokinase Tribbles 2 (TRIB2) to be a potential therapeutic target in solid tumors and blood cancers, including acute myeloid leukemia (AML).

Previous research had described TRIB2 as a target of small-molecule protein kinase inhibitors originally designed to interfere with kinase domains of the epidermal growth factor receptor (EGFR) tyrosine kinase family.

Using a thermal shift assay, the team discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS). They then employed a biochemical drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro.

The researchers found that afatinib, which is already approved by the U.S. Food and Drug Administration to treat non-small cell lung cancer, led to rapid TRIB2 degradation in human AML cells.

Patrick A. Eyers, PhD, of the University of Liverpool in the U.K., and his colleagues published their findings in Science Signaling.

The team found afatinib to be relatively specific for EGFR and human epidermal growth factor receptor 2 (HER2) at nanomolar concentrations in cells.

The researchers confirmed that at least two TRIB2 Cys residues interact with afatinib in vitro.

The team also discovered TRIB2 could be destabilized by neratinib and osimertinib in vitro.

“Our data prove that the cellular mechanism by which TRIB2 stability is regulated by compounds is proteasome-based,” the researchers wrote, “and we speculate that an afatinib-induced conformational change might induce TRIB2 ubiquitination.”

The researchers plan to study further TRIB2 small-molecule interactions with dynamic changes in ubiquitination status.

Furthermore, they report their work demonstrates that covalent inhibitors such as afatinib have TRIB2-degrading activity in human cells at micromolar concentrations.

The researchers determined that afatinib has similar efficacy to the TRIB2-destabilizing quinazoline neratinib at similar ranges.

The team believes their data “raise the intriguing possibility that clinical inhibitors might be used as TRIB2-degrading agents in research, and possibly clinical, contexts.”

“A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins,” Dr. Eyers commented. “Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer.”

The TRIB proteins play many diverse roles in cell signaling, development, and cancer. According to a paper in Developmental Dynamics, they were named after the small, round, fictional organisms from the original Star Trek television series. Their major role was to eat and reproduce.

This work was funded by two U.K. Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentships, a Tools and Resources Development Fund award, Royal Society Research Grants, North West Cancer Research grants, and funding from the National Institutes of Health.

The authors disclosed no perceived conflicts of interest, although several authors are affiliated with the Structural Genomics Consortium at the University of North Carolina at Chapel Hill, which receives direct funds from various pharmaceutical companies but remains entirely independent. 

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Cancer of unknown primary (CUP) represents 3% to 5% of all cancer malignancies in the world.¹ Since 2003, CUP has been divided into 2 subsets – favorable (20% of the cases) and unfavorable (80% of the cases) – based on histopathologic and clinical manifestations.² The impact of locoregional therapies, such as surgery and radiation, in addition to systemic chemotherapy in adenocarcinomas of unknown primary is not well described in the literature. We report here the case of a patient with adenocarcinoma of unknown primary with lymph-node–only metastases who has remained free of tumor progression for 2 years since completion of systemic multiagent chemotherapy followed by consolidation chemoradiotherapy (CRT).

Case presentation and summary

A 37-year-old Bengali woman born and raised in Bangladesh, with a history of gallstones diagnosed in 2010, presented to the emergency department at an outside community hospital in New York in the fall of 2014 with right upper-quadrant pain that was more severe after meals during the previous 3 to 6 months. Her past medical history was significant for hypertension, gastroesophageal reflux disease, and kidney stones. She had no past surgical procedures. On family history, both her parents were deceased, and her mother had been diagnosed with hypertension. Her 4 siblings and 2 daughters had no known medical conditions. She did not smoke or drink alcohol and lived with her husband in Queens, New York. On physical exam, her abdomen was soft, nontender, and with normal bowel sounds. An ultrasound on November 10, 2014, showed a shadowing stone measuring 1.5 x 0.9 cm in the gallbladder fundus. She therefore underwent a cholecystectomy at an outside community hospital in December 2014 and was found to have gallstones and a metastatic adenocarcinoma of a pericholecystic lymph node. No mass was found in the gallbladder. A positron-emission and computed-tomographic (PET-CT) scan in January 2015 showed hypermetabolic activity in the porta hepatis. She was scheduled for an upper endoscopy that was cancelled because the results of her beta human chorionic gonadotropin (hCG) test were elevated.

The patient was frustrated by the lack of diagnosis and extensive work-up and decided to travel to Bangladesh for several months. Upon her return in May 2015, the patient underwent dilation and curettage at an outside tertiary care center because of her persistently elevated beta-hCG levels (>500 mIU/mL; reference range for nonpregnant woman, <5 mIU/mL) that found no products of conception and excluded a malignant process. Endoscopy and colonoscopy at that time failed to reveal a primary tumor.

She was then referred to our institution. Her level of beta-hCG remained elevated, and another transvaginal ultrasound was performed but failed to reveal any masses or evidence of pregnancy. Mammogram and a breast ultrasound showed left breast lesions. Biopsy of the breast lesions was performed, and the pathology demonstrated fibrocystic changes.

Because the lymph node was located near the liver, we also measured the patient’s alpha fetoprotein (AFP), which is a marker for hepatocellular carcinoma. It was found to be elevated at 1,800.7 ng/mL (reference range, 0.0-9.0 ng/mL). Elevated serum AFP occurs in pregnancy, nonseminatous germ cell tumors, hepatocellular carcinoma, and other gastrointestinal tumors. The test for AFP has a low sensitivity, so an elevated AFP is not clinically useful in helping identify the origin of the primary tumor. The patient’s level of lactate dehydrogenase (LDH), a tumor marker for germ cell tumors, was also elevated at 296 U/L (reference range, 100-220 U/L). CA 19-9, CA 125, and carcinoembryonic antigen, tumor markers of gastrointestinal carcinomas, did not demonstrate elevated levels at 19.8 U/mL (reference range, 0.0-35.0 U/mL), 16 U/mL (reference range, 0-35 U/mL), and 0.7 ng/mL (reference range, 0.0-3.0 ng/mL), respectively. No hepatitis serologies were measured at the time of diagnosis.

The results of a PET-CT scan in August 2015 showed a lobulated abdominal mass of 5.7 x 3.7 cm, consisting of multiple periportal necrotic lymph nodes with a standardized uptake value (SUV) of 14 (Figure 1A) and a 2.0-cm hypermetabolic retroperitoneal lymph node at the aortic bifurcation level with an SUV of 8.6. The SUV is a ratio of activity per unit volume of a region of interest to the activity per unit whole body volume. An SUV of 2.5 or higher is generally considered to be indicative of malignant tissue. We conducted a detailed review of the lymph node pathologic specimen. Immunohistochemical (IHC) studies were positive for CK7, CDX2, and EMA; focally positive for PR and mammaglobin; and negative for CK20, ER, TTF-1, and WT-1. Nonspecific staining was seen with BRST2, and there was no staining with GATA3. IHC stain for HER2-NEU was equivocal. Molecular analysis did not detect BRAF, KRAS, NRAS, and PIK3CA mutations, but did find a CTNNB1 mutation. The IHC pattern suggested pancreatobiliary origin of the tumor.³

Discussion

CUP is divided into favorable and unfavorable subsets.¹ The favorable subset includes women with adenocarcinoma involving axillary lymph nodes, women with papillary adenocarcinoma of peritoneal cavity, and adenocarcinoma with a colon profile. The unfavorable subset includes moderate to poorly differentiated adenocarcinomas (64%) and undifferentiated tumors (36%). It involves the liver in 40% to 50% of the cases, followed by lymph nodes (35%), lungs (31%), bones (28%), and the brain (15%).^1,2,6 Although data suggest that CUP with lymph-node–only metastases generally fall into an unfavorable prognosis group, our patient’s survival and progression-free survival have been especially prolonged. Remarkably, our patient is still alive 44 months after the diagnosis.

The combined platinum–paclitaxel-based regimens are the treatment of choice in this unfavorable subset of CUP,^7,8 with patients showing 16% to 38% response rates and median overall survival times of 6.5 to 13 months.⁷ Platinum–gemcitabine combinations can also be used as an alternative first-line regimen, with an overall response rate of 55% and a median survival of 8 months.⁹ The addition of the targeted agents bevacizumab and erlotinib to the carboplatin–paclitaxel combination, followed by bevacizumab and erlotinib maintenance, has been shown to yield a median survival of 12.6 months but was not meaningfully superior to historical studies with chemotherapy alone.¹⁰

We chose the FOLFIRINOX regimen for our patient. Conroy and colleagues reported a notably improved survival of 11.1 months with that combination chemotherapy in patients with metastatic pancreatic cancer compared with 6.8 months with gemcitabine alone.⁵ Given the possible pancreatobiliary site of tumor origin on IHC, the lymph node pattern of spread, and the patient’s young age and robust performance status, we felt that this multiagent systemic therapy would offer the best chance of prolonged survival. FOLFIRINOX includes a platinum agent, oxaliplatin, and platinum agents are recommended to be included in chemotherapy combinations for CUP.^9,10 Although there is no data to suggest the superiority of a triplet regimen over a doublet regimen in a CUP, a triplet chemotherapy regimen may be considered in select cases.

There have been only a few reports showing the effectiveness of radiotherapy in the treatment of adenocarcinomas of unknown primary outside of the head and neck. Kubisch and colleagues have reported a case of a woman with hepatic adenocarcinoma of unknown primary that was treated with chemotherapy and surgery. Upon recurrence, the patient was then treated with selective internal radiation therapy (SIRT). She was still alive 3 years after diagnosis, and there had been no tumor relapse 21 months after SIRT.¹¹ Shiota and colleagues have reported a case of a mediastinal lymph node CUP that was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.¹² The patient remained free of symptoms without regrowth of the primary site 22 months after disease onset, and exploration of the body with enhanced and PET-CT scan showed no further abnormalities.

Other reports suggest that locoregional therapy such as surgery and radiation may be of benefit to select patients with CUP. A retrospective study by Löffler and colleagues reported that patients with a limited local involvement who received radical surgery had a median overall survival of 52.7 months compared with those who received radiation (median overall survival, 19.4 months) and those who received chemotherapy alone (median overall survival, 16 months).¹³ A case of a metastatic undifferentiated CUP also reported a long-term (>5 years), disease-free survivor after pancreaticoduodenectomy and systemic adjuvant chemotherapy.¹⁴

Our case further demonstrates that a multidisciplinary approach to CUP may lead to excellent clinical outcomes. Chemotherapy followed by chemoradiation in our patient increased local tumor control and survival. Our patient’s 44-month survival was superior to the historic 6.5- to 13-month median survival in CUP patients treated with chemotherapy alone. Consolidation chemoradiation treatment may therefore be a viable and more effective therapy in the treatment of adenocarcinoma of unknown primary, in which anatomical disease concentration is amenable to radiotherapy following control with systemic chemotherapy. Nevertheless, it is difficult to draw conclusions from select cases. Another case of mediastinal adenocarcinoma, favoring a colorectal primary but with no evidence of a primary lesion on endoscopy, had a poorer outcome than did our patient, with the cancer recurring 6 months after completion of chemotherapy, surgical excision, and adjuvant radiotherapy.¹⁵

Adenocarcinomas of unknown primary cases should involve management by a multidisciplinary team. Clinical trials incorporating locoregional therapies for CUP in addition to systemic therapy are warranted.

Cancer of unknown primary (CUP) represents 3% to 5% of all cancer malignancies in the world.¹ Since 2003, CUP has been divided into 2 subsets – favorable (20% of the cases) and unfavorable (80% of the cases) – based on histopathologic and clinical manifestations.² The impact of locoregional therapies, such as surgery and radiation, in addition to systemic chemotherapy in adenocarcinomas of unknown primary is not well described in the literature. We report here the case of a patient with adenocarcinoma of unknown primary with lymph-node–only metastases who has remained free of tumor progression for 2 years since completion of systemic multiagent chemotherapy followed by consolidation chemoradiotherapy (CRT).

Case presentation and summary

A 37-year-old Bengali woman born and raised in Bangladesh, with a history of gallstones diagnosed in 2010, presented to the emergency department at an outside community hospital in New York in the fall of 2014 with right upper-quadrant pain that was more severe after meals during the previous 3 to 6 months. Her past medical history was significant for hypertension, gastroesophageal reflux disease, and kidney stones. She had no past surgical procedures. On family history, both her parents were deceased, and her mother had been diagnosed with hypertension. Her 4 siblings and 2 daughters had no known medical conditions. She did not smoke or drink alcohol and lived with her husband in Queens, New York. On physical exam, her abdomen was soft, nontender, and with normal bowel sounds. An ultrasound on November 10, 2014, showed a shadowing stone measuring 1.5 x 0.9 cm in the gallbladder fundus. She therefore underwent a cholecystectomy at an outside community hospital in December 2014 and was found to have gallstones and a metastatic adenocarcinoma of a pericholecystic lymph node. No mass was found in the gallbladder. A positron-emission and computed-tomographic (PET-CT) scan in January 2015 showed hypermetabolic activity in the porta hepatis. She was scheduled for an upper endoscopy that was cancelled because the results of her beta human chorionic gonadotropin (hCG) test were elevated.

The patient was frustrated by the lack of diagnosis and extensive work-up and decided to travel to Bangladesh for several months. Upon her return in May 2015, the patient underwent dilation and curettage at an outside tertiary care center because of her persistently elevated beta-hCG levels (>500 mIU/mL; reference range for nonpregnant woman, <5 mIU/mL) that found no products of conception and excluded a malignant process. Endoscopy and colonoscopy at that time failed to reveal a primary tumor.

She was then referred to our institution. Her level of beta-hCG remained elevated, and another transvaginal ultrasound was performed but failed to reveal any masses or evidence of pregnancy. Mammogram and a breast ultrasound showed left breast lesions. Biopsy of the breast lesions was performed, and the pathology demonstrated fibrocystic changes.

Because the lymph node was located near the liver, we also measured the patient’s alpha fetoprotein (AFP), which is a marker for hepatocellular carcinoma. It was found to be elevated at 1,800.7 ng/mL (reference range, 0.0-9.0 ng/mL). Elevated serum AFP occurs in pregnancy, nonseminatous germ cell tumors, hepatocellular carcinoma, and other gastrointestinal tumors. The test for AFP has a low sensitivity, so an elevated AFP is not clinically useful in helping identify the origin of the primary tumor. The patient’s level of lactate dehydrogenase (LDH), a tumor marker for germ cell tumors, was also elevated at 296 U/L (reference range, 100-220 U/L). CA 19-9, CA 125, and carcinoembryonic antigen, tumor markers of gastrointestinal carcinomas, did not demonstrate elevated levels at 19.8 U/mL (reference range, 0.0-35.0 U/mL), 16 U/mL (reference range, 0-35 U/mL), and 0.7 ng/mL (reference range, 0.0-3.0 ng/mL), respectively. No hepatitis serologies were measured at the time of diagnosis.

The results of a PET-CT scan in August 2015 showed a lobulated abdominal mass of 5.7 x 3.7 cm, consisting of multiple periportal necrotic lymph nodes with a standardized uptake value (SUV) of 14 (Figure 1A) and a 2.0-cm hypermetabolic retroperitoneal lymph node at the aortic bifurcation level with an SUV of 8.6. The SUV is a ratio of activity per unit volume of a region of interest to the activity per unit whole body volume. An SUV of 2.5 or higher is generally considered to be indicative of malignant tissue. We conducted a detailed review of the lymph node pathologic specimen. Immunohistochemical (IHC) studies were positive for CK7, CDX2, and EMA; focally positive for PR and mammaglobin; and negative for CK20, ER, TTF-1, and WT-1. Nonspecific staining was seen with BRST2, and there was no staining with GATA3. IHC stain for HER2-NEU was equivocal. Molecular analysis did not detect BRAF, KRAS, NRAS, and PIK3CA mutations, but did find a CTNNB1 mutation. The IHC pattern suggested pancreatobiliary origin of the tumor.³

Discussion

CUP is divided into favorable and unfavorable subsets.¹ The favorable subset includes women with adenocarcinoma involving axillary lymph nodes, women with papillary adenocarcinoma of peritoneal cavity, and adenocarcinoma with a colon profile. The unfavorable subset includes moderate to poorly differentiated adenocarcinomas (64%) and undifferentiated tumors (36%). It involves the liver in 40% to 50% of the cases, followed by lymph nodes (35%), lungs (31%), bones (28%), and the brain (15%).^1,2,6 Although data suggest that CUP with lymph-node–only metastases generally fall into an unfavorable prognosis group, our patient’s survival and progression-free survival have been especially prolonged. Remarkably, our patient is still alive 44 months after the diagnosis.

The combined platinum–paclitaxel-based regimens are the treatment of choice in this unfavorable subset of CUP,^7,8 with patients showing 16% to 38% response rates and median overall survival times of 6.5 to 13 months.⁷ Platinum–gemcitabine combinations can also be used as an alternative first-line regimen, with an overall response rate of 55% and a median survival of 8 months.⁹ The addition of the targeted agents bevacizumab and erlotinib to the carboplatin–paclitaxel combination, followed by bevacizumab and erlotinib maintenance, has been shown to yield a median survival of 12.6 months but was not meaningfully superior to historical studies with chemotherapy alone.¹⁰

We chose the FOLFIRINOX regimen for our patient. Conroy and colleagues reported a notably improved survival of 11.1 months with that combination chemotherapy in patients with metastatic pancreatic cancer compared with 6.8 months with gemcitabine alone.⁵ Given the possible pancreatobiliary site of tumor origin on IHC, the lymph node pattern of spread, and the patient’s young age and robust performance status, we felt that this multiagent systemic therapy would offer the best chance of prolonged survival. FOLFIRINOX includes a platinum agent, oxaliplatin, and platinum agents are recommended to be included in chemotherapy combinations for CUP.^9,10 Although there is no data to suggest the superiority of a triplet regimen over a doublet regimen in a CUP, a triplet chemotherapy regimen may be considered in select cases.

There have been only a few reports showing the effectiveness of radiotherapy in the treatment of adenocarcinomas of unknown primary outside of the head and neck. Kubisch and colleagues have reported a case of a woman with hepatic adenocarcinoma of unknown primary that was treated with chemotherapy and surgery. Upon recurrence, the patient was then treated with selective internal radiation therapy (SIRT). She was still alive 3 years after diagnosis, and there had been no tumor relapse 21 months after SIRT.¹¹ Shiota and colleagues have reported a case of a mediastinal lymph node CUP that was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.¹² The patient remained free of symptoms without regrowth of the primary site 22 months after disease onset, and exploration of the body with enhanced and PET-CT scan showed no further abnormalities.

Other reports suggest that locoregional therapy such as surgery and radiation may be of benefit to select patients with CUP. A retrospective study by Löffler and colleagues reported that patients with a limited local involvement who received radical surgery had a median overall survival of 52.7 months compared with those who received radiation (median overall survival, 19.4 months) and those who received chemotherapy alone (median overall survival, 16 months).¹³ A case of a metastatic undifferentiated CUP also reported a long-term (>5 years), disease-free survivor after pancreaticoduodenectomy and systemic adjuvant chemotherapy.¹⁴

Our case further demonstrates that a multidisciplinary approach to CUP may lead to excellent clinical outcomes. Chemotherapy followed by chemoradiation in our patient increased local tumor control and survival. Our patient’s 44-month survival was superior to the historic 6.5- to 13-month median survival in CUP patients treated with chemotherapy alone. Consolidation chemoradiation treatment may therefore be a viable and more effective therapy in the treatment of adenocarcinoma of unknown primary, in which anatomical disease concentration is amenable to radiotherapy following control with systemic chemotherapy. Nevertheless, it is difficult to draw conclusions from select cases. Another case of mediastinal adenocarcinoma, favoring a colorectal primary but with no evidence of a primary lesion on endoscopy, had a poorer outcome than did our patient, with the cancer recurring 6 months after completion of chemotherapy, surgical excision, and adjuvant radiotherapy.¹⁵

Adenocarcinomas of unknown primary cases should involve management by a multidisciplinary team. Clinical trials incorporating locoregional therapies for CUP in addition to systemic therapy are warranted.

Cancer of unknown primary (CUP) represents 3% to 5% of all cancer malignancies in the world.¹ Since 2003, CUP has been divided into 2 subsets – favorable (20% of the cases) and unfavorable (80% of the cases) – based on histopathologic and clinical manifestations.² The impact of locoregional therapies, such as surgery and radiation, in addition to systemic chemotherapy in adenocarcinomas of unknown primary is not well described in the literature. We report here the case of a patient with adenocarcinoma of unknown primary with lymph-node–only metastases who has remained free of tumor progression for 2 years since completion of systemic multiagent chemotherapy followed by consolidation chemoradiotherapy (CRT).

Case presentation and summary

A 37-year-old Bengali woman born and raised in Bangladesh, with a history of gallstones diagnosed in 2010, presented to the emergency department at an outside community hospital in New York in the fall of 2014 with right upper-quadrant pain that was more severe after meals during the previous 3 to 6 months. Her past medical history was significant for hypertension, gastroesophageal reflux disease, and kidney stones. She had no past surgical procedures. On family history, both her parents were deceased, and her mother had been diagnosed with hypertension. Her 4 siblings and 2 daughters had no known medical conditions. She did not smoke or drink alcohol and lived with her husband in Queens, New York. On physical exam, her abdomen was soft, nontender, and with normal bowel sounds. An ultrasound on November 10, 2014, showed a shadowing stone measuring 1.5 x 0.9 cm in the gallbladder fundus. She therefore underwent a cholecystectomy at an outside community hospital in December 2014 and was found to have gallstones and a metastatic adenocarcinoma of a pericholecystic lymph node. No mass was found in the gallbladder. A positron-emission and computed-tomographic (PET-CT) scan in January 2015 showed hypermetabolic activity in the porta hepatis. She was scheduled for an upper endoscopy that was cancelled because the results of her beta human chorionic gonadotropin (hCG) test were elevated.

The patient was frustrated by the lack of diagnosis and extensive work-up and decided to travel to Bangladesh for several months. Upon her return in May 2015, the patient underwent dilation and curettage at an outside tertiary care center because of her persistently elevated beta-hCG levels (>500 mIU/mL; reference range for nonpregnant woman, <5 mIU/mL) that found no products of conception and excluded a malignant process. Endoscopy and colonoscopy at that time failed to reveal a primary tumor.

She was then referred to our institution. Her level of beta-hCG remained elevated, and another transvaginal ultrasound was performed but failed to reveal any masses or evidence of pregnancy. Mammogram and a breast ultrasound showed left breast lesions. Biopsy of the breast lesions was performed, and the pathology demonstrated fibrocystic changes.

Because the lymph node was located near the liver, we also measured the patient’s alpha fetoprotein (AFP), which is a marker for hepatocellular carcinoma. It was found to be elevated at 1,800.7 ng/mL (reference range, 0.0-9.0 ng/mL). Elevated serum AFP occurs in pregnancy, nonseminatous germ cell tumors, hepatocellular carcinoma, and other gastrointestinal tumors. The test for AFP has a low sensitivity, so an elevated AFP is not clinically useful in helping identify the origin of the primary tumor. The patient’s level of lactate dehydrogenase (LDH), a tumor marker for germ cell tumors, was also elevated at 296 U/L (reference range, 100-220 U/L). CA 19-9, CA 125, and carcinoembryonic antigen, tumor markers of gastrointestinal carcinomas, did not demonstrate elevated levels at 19.8 U/mL (reference range, 0.0-35.0 U/mL), 16 U/mL (reference range, 0-35 U/mL), and 0.7 ng/mL (reference range, 0.0-3.0 ng/mL), respectively. No hepatitis serologies were measured at the time of diagnosis.

The results of a PET-CT scan in August 2015 showed a lobulated abdominal mass of 5.7 x 3.7 cm, consisting of multiple periportal necrotic lymph nodes with a standardized uptake value (SUV) of 14 (Figure 1A) and a 2.0-cm hypermetabolic retroperitoneal lymph node at the aortic bifurcation level with an SUV of 8.6. The SUV is a ratio of activity per unit volume of a region of interest to the activity per unit whole body volume. An SUV of 2.5 or higher is generally considered to be indicative of malignant tissue. We conducted a detailed review of the lymph node pathologic specimen. Immunohistochemical (IHC) studies were positive for CK7, CDX2, and EMA; focally positive for PR and mammaglobin; and negative for CK20, ER, TTF-1, and WT-1. Nonspecific staining was seen with BRST2, and there was no staining with GATA3. IHC stain for HER2-NEU was equivocal. Molecular analysis did not detect BRAF, KRAS, NRAS, and PIK3CA mutations, but did find a CTNNB1 mutation. The IHC pattern suggested pancreatobiliary origin of the tumor.³

Discussion

CUP is divided into favorable and unfavorable subsets.¹ The favorable subset includes women with adenocarcinoma involving axillary lymph nodes, women with papillary adenocarcinoma of peritoneal cavity, and adenocarcinoma with a colon profile. The unfavorable subset includes moderate to poorly differentiated adenocarcinomas (64%) and undifferentiated tumors (36%). It involves the liver in 40% to 50% of the cases, followed by lymph nodes (35%), lungs (31%), bones (28%), and the brain (15%).^1,2,6 Although data suggest that CUP with lymph-node–only metastases generally fall into an unfavorable prognosis group, our patient’s survival and progression-free survival have been especially prolonged. Remarkably, our patient is still alive 44 months after the diagnosis.

The combined platinum–paclitaxel-based regimens are the treatment of choice in this unfavorable subset of CUP,^7,8 with patients showing 16% to 38% response rates and median overall survival times of 6.5 to 13 months.⁷ Platinum–gemcitabine combinations can also be used as an alternative first-line regimen, with an overall response rate of 55% and a median survival of 8 months.⁹ The addition of the targeted agents bevacizumab and erlotinib to the carboplatin–paclitaxel combination, followed by bevacizumab and erlotinib maintenance, has been shown to yield a median survival of 12.6 months but was not meaningfully superior to historical studies with chemotherapy alone.¹⁰

We chose the FOLFIRINOX regimen for our patient. Conroy and colleagues reported a notably improved survival of 11.1 months with that combination chemotherapy in patients with metastatic pancreatic cancer compared with 6.8 months with gemcitabine alone.⁵ Given the possible pancreatobiliary site of tumor origin on IHC, the lymph node pattern of spread, and the patient’s young age and robust performance status, we felt that this multiagent systemic therapy would offer the best chance of prolonged survival. FOLFIRINOX includes a platinum agent, oxaliplatin, and platinum agents are recommended to be included in chemotherapy combinations for CUP.^9,10 Although there is no data to suggest the superiority of a triplet regimen over a doublet regimen in a CUP, a triplet chemotherapy regimen may be considered in select cases.

There have been only a few reports showing the effectiveness of radiotherapy in the treatment of adenocarcinomas of unknown primary outside of the head and neck. Kubisch and colleagues have reported a case of a woman with hepatic adenocarcinoma of unknown primary that was treated with chemotherapy and surgery. Upon recurrence, the patient was then treated with selective internal radiation therapy (SIRT). She was still alive 3 years after diagnosis, and there had been no tumor relapse 21 months after SIRT.¹¹ Shiota and colleagues have reported a case of a mediastinal lymph node CUP that was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.¹² The patient remained free of symptoms without regrowth of the primary site 22 months after disease onset, and exploration of the body with enhanced and PET-CT scan showed no further abnormalities.

Other reports suggest that locoregional therapy such as surgery and radiation may be of benefit to select patients with CUP. A retrospective study by Löffler and colleagues reported that patients with a limited local involvement who received radical surgery had a median overall survival of 52.7 months compared with those who received radiation (median overall survival, 19.4 months) and those who received chemotherapy alone (median overall survival, 16 months).¹³ A case of a metastatic undifferentiated CUP also reported a long-term (>5 years), disease-free survivor after pancreaticoduodenectomy and systemic adjuvant chemotherapy.¹⁴

Our case further demonstrates that a multidisciplinary approach to CUP may lead to excellent clinical outcomes. Chemotherapy followed by chemoradiation in our patient increased local tumor control and survival. Our patient’s 44-month survival was superior to the historic 6.5- to 13-month median survival in CUP patients treated with chemotherapy alone. Consolidation chemoradiation treatment may therefore be a viable and more effective therapy in the treatment of adenocarcinoma of unknown primary, in which anatomical disease concentration is amenable to radiotherapy following control with systemic chemotherapy. Nevertheless, it is difficult to draw conclusions from select cases. Another case of mediastinal adenocarcinoma, favoring a colorectal primary but with no evidence of a primary lesion on endoscopy, had a poorer outcome than did our patient, with the cancer recurring 6 months after completion of chemotherapy, surgical excision, and adjuvant radiotherapy.¹⁵

Adenocarcinomas of unknown primary cases should involve management by a multidisciplinary team. Clinical trials incorporating locoregional therapies for CUP in addition to systemic therapy are warranted.

BARCELONA – Prenatal exposure to selective serotonin reuptake inhibitors late in pregnancy was associated with a significantly increased risk of anxious and/or depressed behaviors at 5 years of age in the prospective Norwegian Mother and Child Cohort Study.

Bruce Jancin/MDedge News

Other than that specific red flag, however, the outcomes of in utero exposure to maternal SSRIs were reassuringly benign. Prenatal exposure during early- or mid-pregnancy was not associated with increased risk of anxious/depressed behaviors, compared with nonexposure; that adverse effect was restricted to exposure at week 29 of pregnancy or later. Nor did in utero exposure to maternal SSRIs during any time in pregnancy pose an increased risk for pediatric externalizing, emotional, or social problems in this observational study of 8,359 Norwegian mother-child dyads, Josefina Castro-Fornieles, MD, PhD, observed at the annual congress of the European College of Neuropsychopharmacology.

The huge Norwegian study was among what she considers the four most important studies in child/adolescent psychiatry published through the first three quarters of 2018. The others she highlighted were a large longitudinal observational study that demonstrated that persistent maternal postnatal depression was strongly associated with a variety of pediatric behavioral disturbances documented during assessments at ages 3.5, 16, and 18 years; a Philadelphia study showing that multiple traumatic stressful events or any assaultive trauma experienced by children or adolescents were independently associated with significant psychopathology and neurocognitive deficits; and a Dutch brain MRI study that pinpointed a reduction in gray matter volume in the anterior cingulate cortex as a potential key mediator of the neurobiologic aftereffects of childhood sexual abuse.

She selected those studies because they shared a common theme, one that constituted her key take-home message: “When recording antecedents during a clinical assessment, both with adults and children, it is clear that we have to ask in a more detailed way – using validated scales and interviews if possible – about the mother’s prenatal problems, including psychopharmacological treatment. That is something we often don’t do in a sufficiently detailed way in our clinical practice. And it’s also important to ask about life events; abuse during childhood and adolescence can be really important. We can modulate our treatment depending upon whether there is an influence of any of these aspects,” said Dr. Castro-Fornieles, director of the Clinical Institute of Neuroscience at the Hospital Clinic of Barcelona and a recent past-president of the Spanish Society for Child and Adolescent Psychiatry.

The following are her Top 4 studies:

The Norwegian Mother and Child Cohort Study

The increased risk of anxious and/or depressed behaviors in children exposed to selective serotonin reuptake inhibitors (SSRIs) late in pregnancy did not emerge until the year-5 assessment; it wasn’t evident at the 1.5- or 3-year evaluations.

The investigators emphasized a key lesson from their study: The importance of following children with late-pregnancy exposure to maternal SSRI therapy for development of symptoms of anxiety and/or depression (J Am Acad Child Adolesc Psychiatry. 2018 Mar;57[3]:200-8). Dr. Castro-Fornieles strongly endorsed that recommendation. However, she noted what she considers an important limitation to the study: even though the University of Oslo investigators adjusted for numerous potential confounders in their risk models – including maternal body mass index, parity, education, smoking, substance use, breastfeeding, folic acid use, and other medications used during pregnancy – it’s not possible in a study such as this to control for genetic and environmental risk factors, which she suspects also were at work.

The Avon Longitudinal Study of Parents and Children in the United Kingdom

Maternal postnatal depression is common, affecting roughly 10% of mothers. But it is not invariably associated with adverse mental health outcomes in their children. This study of nearly 10,000 mothers and their children sought to identify which children were at most risk. Using the Edinburgh Postnatal Depression Scale, the international team of investigators categorized maternal postnatal depression as moderate, marked, or severe. The affective disorder was deemed persistent if scores on the Edinburgh scale were elevated at both 2 and 8 months after delivery.

Postnatal depression, whether persistent or not, was associated with roughly a 2- to 2.4-fold increase for child behavioral disturbances when assessed at age 3.5 years using the Rutter Total Problems Scale. But postnatal depression that was persistent was the real difference maker: It carried a much higher risk of adverse behavioral outcomes and cognitive deficits than did the nonpersistent version. Indeed, persistent severe postnatal depression was associated a 4.8-fold increased risk of behavioral problems at age 3.5 years, a 2.65-fold greater risk of markedly lower grades in mathematics at age 16 years, and a 7.4-fold increased prevalence of depression at 18 years of age. The investigators advised screening mothers during the first postpartum year in order to identify those with persistent postpartum depression (JAMA Psychiatry. 2018 Mar 1;75[3]:247-53).

Dr. Castro-Fornieles said an important shortcoming of the Avon study was that it did not record paternal data.

“The study didn’t consider depression or other functional measures in the father, his commitment to childrearing, and whether the family was together or divorced. I feel this is an important limitation in many studies. For me, it’s really important to consider what’s happening with the fathers,” she said.

Traumatic stress load, psychopathology, and cognition

An eye-opening report from the Philadelphia Neurodevelopmental Cohort documented a surprisingly high level of lifetime exposure to traumatic events among 9,498 youth aged 8-21 years, and the stepwise manner by which a greater traumatic stress load was associated with increasing severity of psychopathology and cognitive deficits. Notably, the study participants were recruited from general pediatric clinics in the Children’s Hospital of Philadelphia health care network; they were not patients seeking psychiatric help. And yet, extensive structured psychiatric evaluation showed that 23% of them had a history of one traumatic stressful event, 12% had two, and 1% had three or more.

In analyses adjusted for lifetime history of depression or PTSD, a higher traumatic event load was associated with increased risk of externalizing behaviors, mood/anxiety disorders, psychosis spectrum, and fear. Moreover, a high trauma stress load was associated with a 5.3-fold increased risk of suicidal thoughts and a 3.2-fold increased likelihood of cannabis use, compared with youth who had never been exposed to a traumatic event. Increased stress load also was associated with worse cognitive performance on tests of executive functioning, social cognition, and complex reasoning.

A history of assaultive trauma – being badly beaten, threatened with a weapon, or sexually abused – was associated with more severe psychopathology than in subjects with a history of nonassaultive traumatic events (Psychol Med. 2018 Apr 15:1-10).

Session moderator Carmen Moreno, MD, a child and adolescent psychiatrist at Gregorio Marañón University Hospital in Madrid, commented, “It was striking to me that the prevalence of childhood traumatic events was so high in a pediatric community sample. Is the measure the investigators chose the right measure?”

Dr. Castro-Fornieles replied that it was a very sensitive measure, in that an event many would consider part of normal life – for example, seeing a relative’s body on display in a funeral home – was scored as a traumatic exposure.

“Only one exposure is not that important,” she said. “The impact increases as you increase the number of traumatic events. And also the assaultive ones.”

Sexual abuse leaves a fingerprint

Investigators at Leiden (the Netherlands) University performed neuroimaging that looked at numerous brain regions of interest in 21 adolescents with childhood sexual abuse–related PTSD and 25 matched healthy controls. The standout finding was that the dorsal gray matter volume of the anterior cingulate cortex was significantly smaller in the teens with PTSD and a history of childhood sexual abuse (Eur Neuropsychopharmacol. 2017 Nov;27[11]:1163-71).

The investigators wanted a pure sample of patients with PTSD after childhood sexual abuse, so they excluded individuals who had experienced childhood sexual abuse and had a diagnosis of attention-deficit/hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder, conduct disorder, pervasive developmental disorder, bipolar disorder, or a psychotic disorder. That is both a strength and a limitation of the study, in Dr. Castro-Fornieles’ view.

“To me, that excludes too many of the children we see in our clinical settings. This work needs to be corroborated in a bigger sample, including patients with other diagnoses,” she said.

She reported having no financial conflicts regarding her presentation.
 

[email protected]

BARCELONA – Prenatal exposure to selective serotonin reuptake inhibitors late in pregnancy was associated with a significantly increased risk of anxious and/or depressed behaviors at 5 years of age in the prospective Norwegian Mother and Child Cohort Study.

Bruce Jancin/MDedge News

Other than that specific red flag, however, the outcomes of in utero exposure to maternal SSRIs were reassuringly benign. Prenatal exposure during early- or mid-pregnancy was not associated with increased risk of anxious/depressed behaviors, compared with nonexposure; that adverse effect was restricted to exposure at week 29 of pregnancy or later. Nor did in utero exposure to maternal SSRIs during any time in pregnancy pose an increased risk for pediatric externalizing, emotional, or social problems in this observational study of 8,359 Norwegian mother-child dyads, Josefina Castro-Fornieles, MD, PhD, observed at the annual congress of the European College of Neuropsychopharmacology.

The huge Norwegian study was among what she considers the four most important studies in child/adolescent psychiatry published through the first three quarters of 2018. The others she highlighted were a large longitudinal observational study that demonstrated that persistent maternal postnatal depression was strongly associated with a variety of pediatric behavioral disturbances documented during assessments at ages 3.5, 16, and 18 years; a Philadelphia study showing that multiple traumatic stressful events or any assaultive trauma experienced by children or adolescents were independently associated with significant psychopathology and neurocognitive deficits; and a Dutch brain MRI study that pinpointed a reduction in gray matter volume in the anterior cingulate cortex as a potential key mediator of the neurobiologic aftereffects of childhood sexual abuse.

She selected those studies because they shared a common theme, one that constituted her key take-home message: “When recording antecedents during a clinical assessment, both with adults and children, it is clear that we have to ask in a more detailed way – using validated scales and interviews if possible – about the mother’s prenatal problems, including psychopharmacological treatment. That is something we often don’t do in a sufficiently detailed way in our clinical practice. And it’s also important to ask about life events; abuse during childhood and adolescence can be really important. We can modulate our treatment depending upon whether there is an influence of any of these aspects,” said Dr. Castro-Fornieles, director of the Clinical Institute of Neuroscience at the Hospital Clinic of Barcelona and a recent past-president of the Spanish Society for Child and Adolescent Psychiatry.

The following are her Top 4 studies:

The Norwegian Mother and Child Cohort Study

The increased risk of anxious and/or depressed behaviors in children exposed to selective serotonin reuptake inhibitors (SSRIs) late in pregnancy did not emerge until the year-5 assessment; it wasn’t evident at the 1.5- or 3-year evaluations.

The investigators emphasized a key lesson from their study: The importance of following children with late-pregnancy exposure to maternal SSRI therapy for development of symptoms of anxiety and/or depression (J Am Acad Child Adolesc Psychiatry. 2018 Mar;57[3]:200-8). Dr. Castro-Fornieles strongly endorsed that recommendation. However, she noted what she considers an important limitation to the study: even though the University of Oslo investigators adjusted for numerous potential confounders in their risk models – including maternal body mass index, parity, education, smoking, substance use, breastfeeding, folic acid use, and other medications used during pregnancy – it’s not possible in a study such as this to control for genetic and environmental risk factors, which she suspects also were at work.

The Avon Longitudinal Study of Parents and Children in the United Kingdom

Maternal postnatal depression is common, affecting roughly 10% of mothers. But it is not invariably associated with adverse mental health outcomes in their children. This study of nearly 10,000 mothers and their children sought to identify which children were at most risk. Using the Edinburgh Postnatal Depression Scale, the international team of investigators categorized maternal postnatal depression as moderate, marked, or severe. The affective disorder was deemed persistent if scores on the Edinburgh scale were elevated at both 2 and 8 months after delivery.

Postnatal depression, whether persistent or not, was associated with roughly a 2- to 2.4-fold increase for child behavioral disturbances when assessed at age 3.5 years using the Rutter Total Problems Scale. But postnatal depression that was persistent was the real difference maker: It carried a much higher risk of adverse behavioral outcomes and cognitive deficits than did the nonpersistent version. Indeed, persistent severe postnatal depression was associated a 4.8-fold increased risk of behavioral problems at age 3.5 years, a 2.65-fold greater risk of markedly lower grades in mathematics at age 16 years, and a 7.4-fold increased prevalence of depression at 18 years of age. The investigators advised screening mothers during the first postpartum year in order to identify those with persistent postpartum depression (JAMA Psychiatry. 2018 Mar 1;75[3]:247-53).

Dr. Castro-Fornieles said an important shortcoming of the Avon study was that it did not record paternal data.

“The study didn’t consider depression or other functional measures in the father, his commitment to childrearing, and whether the family was together or divorced. I feel this is an important limitation in many studies. For me, it’s really important to consider what’s happening with the fathers,” she said.

Traumatic stress load, psychopathology, and cognition

An eye-opening report from the Philadelphia Neurodevelopmental Cohort documented a surprisingly high level of lifetime exposure to traumatic events among 9,498 youth aged 8-21 years, and the stepwise manner by which a greater traumatic stress load was associated with increasing severity of psychopathology and cognitive deficits. Notably, the study participants were recruited from general pediatric clinics in the Children’s Hospital of Philadelphia health care network; they were not patients seeking psychiatric help. And yet, extensive structured psychiatric evaluation showed that 23% of them had a history of one traumatic stressful event, 12% had two, and 1% had three or more.

In analyses adjusted for lifetime history of depression or PTSD, a higher traumatic event load was associated with increased risk of externalizing behaviors, mood/anxiety disorders, psychosis spectrum, and fear. Moreover, a high trauma stress load was associated with a 5.3-fold increased risk of suicidal thoughts and a 3.2-fold increased likelihood of cannabis use, compared with youth who had never been exposed to a traumatic event. Increased stress load also was associated with worse cognitive performance on tests of executive functioning, social cognition, and complex reasoning.

A history of assaultive trauma – being badly beaten, threatened with a weapon, or sexually abused – was associated with more severe psychopathology than in subjects with a history of nonassaultive traumatic events (Psychol Med. 2018 Apr 15:1-10).

Session moderator Carmen Moreno, MD, a child and adolescent psychiatrist at Gregorio Marañón University Hospital in Madrid, commented, “It was striking to me that the prevalence of childhood traumatic events was so high in a pediatric community sample. Is the measure the investigators chose the right measure?”

Dr. Castro-Fornieles replied that it was a very sensitive measure, in that an event many would consider part of normal life – for example, seeing a relative’s body on display in a funeral home – was scored as a traumatic exposure.

“Only one exposure is not that important,” she said. “The impact increases as you increase the number of traumatic events. And also the assaultive ones.”

Sexual abuse leaves a fingerprint

Investigators at Leiden (the Netherlands) University performed neuroimaging that looked at numerous brain regions of interest in 21 adolescents with childhood sexual abuse–related PTSD and 25 matched healthy controls. The standout finding was that the dorsal gray matter volume of the anterior cingulate cortex was significantly smaller in the teens with PTSD and a history of childhood sexual abuse (Eur Neuropsychopharmacol. 2017 Nov;27[11]:1163-71).

The investigators wanted a pure sample of patients with PTSD after childhood sexual abuse, so they excluded individuals who had experienced childhood sexual abuse and had a diagnosis of attention-deficit/hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder, conduct disorder, pervasive developmental disorder, bipolar disorder, or a psychotic disorder. That is both a strength and a limitation of the study, in Dr. Castro-Fornieles’ view.

“To me, that excludes too many of the children we see in our clinical settings. This work needs to be corroborated in a bigger sample, including patients with other diagnoses,” she said.

She reported having no financial conflicts regarding her presentation.
 

[email protected]

BARCELONA – Prenatal exposure to selective serotonin reuptake inhibitors late in pregnancy was associated with a significantly increased risk of anxious and/or depressed behaviors at 5 years of age in the prospective Norwegian Mother and Child Cohort Study.

Bruce Jancin/MDedge News

Other than that specific red flag, however, the outcomes of in utero exposure to maternal SSRIs were reassuringly benign. Prenatal exposure during early- or mid-pregnancy was not associated with increased risk of anxious/depressed behaviors, compared with nonexposure; that adverse effect was restricted to exposure at week 29 of pregnancy or later. Nor did in utero exposure to maternal SSRIs during any time in pregnancy pose an increased risk for pediatric externalizing, emotional, or social problems in this observational study of 8,359 Norwegian mother-child dyads, Josefina Castro-Fornieles, MD, PhD, observed at the annual congress of the European College of Neuropsychopharmacology.

The huge Norwegian study was among what she considers the four most important studies in child/adolescent psychiatry published through the first three quarters of 2018. The others she highlighted were a large longitudinal observational study that demonstrated that persistent maternal postnatal depression was strongly associated with a variety of pediatric behavioral disturbances documented during assessments at ages 3.5, 16, and 18 years; a Philadelphia study showing that multiple traumatic stressful events or any assaultive trauma experienced by children or adolescents were independently associated with significant psychopathology and neurocognitive deficits; and a Dutch brain MRI study that pinpointed a reduction in gray matter volume in the anterior cingulate cortex as a potential key mediator of the neurobiologic aftereffects of childhood sexual abuse.

She selected those studies because they shared a common theme, one that constituted her key take-home message: “When recording antecedents during a clinical assessment, both with adults and children, it is clear that we have to ask in a more detailed way – using validated scales and interviews if possible – about the mother’s prenatal problems, including psychopharmacological treatment. That is something we often don’t do in a sufficiently detailed way in our clinical practice. And it’s also important to ask about life events; abuse during childhood and adolescence can be really important. We can modulate our treatment depending upon whether there is an influence of any of these aspects,” said Dr. Castro-Fornieles, director of the Clinical Institute of Neuroscience at the Hospital Clinic of Barcelona and a recent past-president of the Spanish Society for Child and Adolescent Psychiatry.

The following are her Top 4 studies:

The Norwegian Mother and Child Cohort Study

The increased risk of anxious and/or depressed behaviors in children exposed to selective serotonin reuptake inhibitors (SSRIs) late in pregnancy did not emerge until the year-5 assessment; it wasn’t evident at the 1.5- or 3-year evaluations.

The investigators emphasized a key lesson from their study: The importance of following children with late-pregnancy exposure to maternal SSRI therapy for development of symptoms of anxiety and/or depression (J Am Acad Child Adolesc Psychiatry. 2018 Mar;57[3]:200-8). Dr. Castro-Fornieles strongly endorsed that recommendation. However, she noted what she considers an important limitation to the study: even though the University of Oslo investigators adjusted for numerous potential confounders in their risk models – including maternal body mass index, parity, education, smoking, substance use, breastfeeding, folic acid use, and other medications used during pregnancy – it’s not possible in a study such as this to control for genetic and environmental risk factors, which she suspects also were at work.

The Avon Longitudinal Study of Parents and Children in the United Kingdom

Maternal postnatal depression is common, affecting roughly 10% of mothers. But it is not invariably associated with adverse mental health outcomes in their children. This study of nearly 10,000 mothers and their children sought to identify which children were at most risk. Using the Edinburgh Postnatal Depression Scale, the international team of investigators categorized maternal postnatal depression as moderate, marked, or severe. The affective disorder was deemed persistent if scores on the Edinburgh scale were elevated at both 2 and 8 months after delivery.

Postnatal depression, whether persistent or not, was associated with roughly a 2- to 2.4-fold increase for child behavioral disturbances when assessed at age 3.5 years using the Rutter Total Problems Scale. But postnatal depression that was persistent was the real difference maker: It carried a much higher risk of adverse behavioral outcomes and cognitive deficits than did the nonpersistent version. Indeed, persistent severe postnatal depression was associated a 4.8-fold increased risk of behavioral problems at age 3.5 years, a 2.65-fold greater risk of markedly lower grades in mathematics at age 16 years, and a 7.4-fold increased prevalence of depression at 18 years of age. The investigators advised screening mothers during the first postpartum year in order to identify those with persistent postpartum depression (JAMA Psychiatry. 2018 Mar 1;75[3]:247-53).

Dr. Castro-Fornieles said an important shortcoming of the Avon study was that it did not record paternal data.

“The study didn’t consider depression or other functional measures in the father, his commitment to childrearing, and whether the family was together or divorced. I feel this is an important limitation in many studies. For me, it’s really important to consider what’s happening with the fathers,” she said.

Traumatic stress load, psychopathology, and cognition

An eye-opening report from the Philadelphia Neurodevelopmental Cohort documented a surprisingly high level of lifetime exposure to traumatic events among 9,498 youth aged 8-21 years, and the stepwise manner by which a greater traumatic stress load was associated with increasing severity of psychopathology and cognitive deficits. Notably, the study participants were recruited from general pediatric clinics in the Children’s Hospital of Philadelphia health care network; they were not patients seeking psychiatric help. And yet, extensive structured psychiatric evaluation showed that 23% of them had a history of one traumatic stressful event, 12% had two, and 1% had three or more.

In analyses adjusted for lifetime history of depression or PTSD, a higher traumatic event load was associated with increased risk of externalizing behaviors, mood/anxiety disorders, psychosis spectrum, and fear. Moreover, a high trauma stress load was associated with a 5.3-fold increased risk of suicidal thoughts and a 3.2-fold increased likelihood of cannabis use, compared with youth who had never been exposed to a traumatic event. Increased stress load also was associated with worse cognitive performance on tests of executive functioning, social cognition, and complex reasoning.

A history of assaultive trauma – being badly beaten, threatened with a weapon, or sexually abused – was associated with more severe psychopathology than in subjects with a history of nonassaultive traumatic events (Psychol Med. 2018 Apr 15:1-10).

Session moderator Carmen Moreno, MD, a child and adolescent psychiatrist at Gregorio Marañón University Hospital in Madrid, commented, “It was striking to me that the prevalence of childhood traumatic events was so high in a pediatric community sample. Is the measure the investigators chose the right measure?”

Dr. Castro-Fornieles replied that it was a very sensitive measure, in that an event many would consider part of normal life – for example, seeing a relative’s body on display in a funeral home – was scored as a traumatic exposure.

“Only one exposure is not that important,” she said. “The impact increases as you increase the number of traumatic events. And also the assaultive ones.”

Sexual abuse leaves a fingerprint

Investigators at Leiden (the Netherlands) University performed neuroimaging that looked at numerous brain regions of interest in 21 adolescents with childhood sexual abuse–related PTSD and 25 matched healthy controls. The standout finding was that the dorsal gray matter volume of the anterior cingulate cortex was significantly smaller in the teens with PTSD and a history of childhood sexual abuse (Eur Neuropsychopharmacol. 2017 Nov;27[11]:1163-71).

The investigators wanted a pure sample of patients with PTSD after childhood sexual abuse, so they excluded individuals who had experienced childhood sexual abuse and had a diagnosis of attention-deficit/hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder, conduct disorder, pervasive developmental disorder, bipolar disorder, or a psychotic disorder. That is both a strength and a limitation of the study, in Dr. Castro-Fornieles’ view.

“To me, that excludes too many of the children we see in our clinical settings. This work needs to be corroborated in a bigger sample, including patients with other diagnoses,” she said.

She reported having no financial conflicts regarding her presentation.
 

[email protected]

MONTEREY, CALIF. – “Consort dermatitis” – when a patient is allergic to his or her partner. “Lime dermatitis” – when gin and tonics are the culprit. And “sample dermatitis” – when an unprescribed drug sample turns out to be the cause of a mysterious reaction.

Pcholik/getty images

Dermatologist Vincent DeLeo, MD, of the University of Southern California, Los Angeles, has seen them all. He provided insight about how to diagnose these unusual conditions at the Coastal Dermatology Symposium.

The following are a few unusual causes of dermatitis that he discussed:

• Romantic partners. A patient’s partner can be the cause of a reaction, as in the case of a 25-year-old woman who turned out to be allergic to her boyfriend’s cologne. In another case, a 50-year-old man had a 3-year history of recurrent dermatitis on his left arm and the left side of his chest. The cause was a mystery until it became clear that it was caused by exposure to hair dye, but not his. “He didn’t color his hair, but his wife did, and she always slept on that side of him,” Dr. DeLeo recalled. “When she stopped coloring her hair, his disease cleared.”
• Black henna. The dye known as “black henna,” or just “henna,” can cause reactions in adults (who use it as a hair dye or to decorate the skin) and children (who can be exposed to it with temporary tattoos). “Because henna typically produces a brown, orange-brown, or reddish-brown tint, other ingredients must be added to produce other colors, such as those marketed as ‘black henna’ and ‘blue henna,’ ” according to a Food and Drug Administration statement. “Even brown shades of products marketed as henna may contain other ingredients intended to make them darker or make the stain last longer on the skin. The problem? “The extra ingredient used to blacken henna is often a coal-tar hair dye containing p-Phenylenediamine, an ingredient that can cause dangerous skin reactions in some people,” the statement says. Dr. DeLeo said that one good rule of thumb is to consider a reaction to black henna if a patient acknowledges using a henna dye and their hair is any color but red. That’s a sign, he said, that they’re actually using black henna.
• Makeup applicators. Dr. DeLeo has seen two cases of patients with facial dermatitis who turned out to be allergic to thiuram, a component of rubber. Their skin was reacting to the rubber in some sponges used to apply makeup.
• Lime and sun exposure. Patients are impressed when Dr. DeLeo correctly guesses what they were drinking the previous weekend, because of their telltale blisters indicating a lime allergy. Noninflammatory blisters on the fingers or hyperpigmentation can be caused by touching the skin of a lime and then having subsequent exposure to ultraviolet light. It may take days for the blisters to appear, he noted. A weekend after mixing gin and tonics with lime, for example, a patient “may show up on Tuesday of the following week. The patient doesn’t always think of what they did over the weekend.”
• Liquid detergents. As a general rule, laundry detergents do not cause dermatitis, Dr. DeLeo said. “By the time that clothing is rinsed in your washer, there’s not enough left of anything on the clothing to cause a problem.” But there’s an exception: When people hand wash clothing with liquid detergents, such as Woolite. “It’s not the fragrance,” he said. “It’s the preservative in the detergent.”
• Unexpected nickel. Skin allergy to nickel is common, and the metal can lurk in unexpected places, as he discovered when he treated a Columbia University student who was “allergic to his tuba.” The tuba was made of brass, not nickel. But “the little things connecting the tubes to each other are alloy metals,” he said, including nickel.
• Drug samples. Dr. DeLeo recalled the case of a dermatology office administrator with a recurrent neck rash. Dermatologist after dermatologist failed to find the cause. Patch and photopatch testing turned up nothing. Then Dr. DeLeo asked her to bring in every skin product she was using. She returned with a large bag full of dermatologic samples, including Drithocreme (anthralin), which can be an irritant. None of the drugs were prescribed. “This is case of sample dermatitis,” which may occur among employees and family members of dermatologists, he said. “Always think of having patients bring in what they’re using,” he added, “because you can be surprised.”

The Coastal Dermatology Symposium is jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

Dr. DeLeo disclosed consulting work for Estée Lauder.

MONTEREY, CALIF. – “Consort dermatitis” – when a patient is allergic to his or her partner. “Lime dermatitis” – when gin and tonics are the culprit. And “sample dermatitis” – when an unprescribed drug sample turns out to be the cause of a mysterious reaction.

Pcholik/getty images

Dermatologist Vincent DeLeo, MD, of the University of Southern California, Los Angeles, has seen them all. He provided insight about how to diagnose these unusual conditions at the Coastal Dermatology Symposium.

The following are a few unusual causes of dermatitis that he discussed:

• Romantic partners. A patient’s partner can be the cause of a reaction, as in the case of a 25-year-old woman who turned out to be allergic to her boyfriend’s cologne. In another case, a 50-year-old man had a 3-year history of recurrent dermatitis on his left arm and the left side of his chest. The cause was a mystery until it became clear that it was caused by exposure to hair dye, but not his. “He didn’t color his hair, but his wife did, and she always slept on that side of him,” Dr. DeLeo recalled. “When she stopped coloring her hair, his disease cleared.”
• Black henna. The dye known as “black henna,” or just “henna,” can cause reactions in adults (who use it as a hair dye or to decorate the skin) and children (who can be exposed to it with temporary tattoos). “Because henna typically produces a brown, orange-brown, or reddish-brown tint, other ingredients must be added to produce other colors, such as those marketed as ‘black henna’ and ‘blue henna,’ ” according to a Food and Drug Administration statement. “Even brown shades of products marketed as henna may contain other ingredients intended to make them darker or make the stain last longer on the skin. The problem? “The extra ingredient used to blacken henna is often a coal-tar hair dye containing p-Phenylenediamine, an ingredient that can cause dangerous skin reactions in some people,” the statement says. Dr. DeLeo said that one good rule of thumb is to consider a reaction to black henna if a patient acknowledges using a henna dye and their hair is any color but red. That’s a sign, he said, that they’re actually using black henna.
• Makeup applicators. Dr. DeLeo has seen two cases of patients with facial dermatitis who turned out to be allergic to thiuram, a component of rubber. Their skin was reacting to the rubber in some sponges used to apply makeup.
• Lime and sun exposure. Patients are impressed when Dr. DeLeo correctly guesses what they were drinking the previous weekend, because of their telltale blisters indicating a lime allergy. Noninflammatory blisters on the fingers or hyperpigmentation can be caused by touching the skin of a lime and then having subsequent exposure to ultraviolet light. It may take days for the blisters to appear, he noted. A weekend after mixing gin and tonics with lime, for example, a patient “may show up on Tuesday of the following week. The patient doesn’t always think of what they did over the weekend.”
• Liquid detergents. As a general rule, laundry detergents do not cause dermatitis, Dr. DeLeo said. “By the time that clothing is rinsed in your washer, there’s not enough left of anything on the clothing to cause a problem.” But there’s an exception: When people hand wash clothing with liquid detergents, such as Woolite. “It’s not the fragrance,” he said. “It’s the preservative in the detergent.”
• Unexpected nickel. Skin allergy to nickel is common, and the metal can lurk in unexpected places, as he discovered when he treated a Columbia University student who was “allergic to his tuba.” The tuba was made of brass, not nickel. But “the little things connecting the tubes to each other are alloy metals,” he said, including nickel.
• Drug samples. Dr. DeLeo recalled the case of a dermatology office administrator with a recurrent neck rash. Dermatologist after dermatologist failed to find the cause. Patch and photopatch testing turned up nothing. Then Dr. DeLeo asked her to bring in every skin product she was using. She returned with a large bag full of dermatologic samples, including Drithocreme (anthralin), which can be an irritant. None of the drugs were prescribed. “This is case of sample dermatitis,” which may occur among employees and family members of dermatologists, he said. “Always think of having patients bring in what they’re using,” he added, “because you can be surprised.”

The Coastal Dermatology Symposium is jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

Dr. DeLeo disclosed consulting work for Estée Lauder.

MONTEREY, CALIF. – “Consort dermatitis” – when a patient is allergic to his or her partner. “Lime dermatitis” – when gin and tonics are the culprit. And “sample dermatitis” – when an unprescribed drug sample turns out to be the cause of a mysterious reaction.

Pcholik/getty images

Dermatologist Vincent DeLeo, MD, of the University of Southern California, Los Angeles, has seen them all. He provided insight about how to diagnose these unusual conditions at the Coastal Dermatology Symposium.

The following are a few unusual causes of dermatitis that he discussed:

• Romantic partners. A patient’s partner can be the cause of a reaction, as in the case of a 25-year-old woman who turned out to be allergic to her boyfriend’s cologne. In another case, a 50-year-old man had a 3-year history of recurrent dermatitis on his left arm and the left side of his chest. The cause was a mystery until it became clear that it was caused by exposure to hair dye, but not his. “He didn’t color his hair, but his wife did, and she always slept on that side of him,” Dr. DeLeo recalled. “When she stopped coloring her hair, his disease cleared.”
• Black henna. The dye known as “black henna,” or just “henna,” can cause reactions in adults (who use it as a hair dye or to decorate the skin) and children (who can be exposed to it with temporary tattoos). “Because henna typically produces a brown, orange-brown, or reddish-brown tint, other ingredients must be added to produce other colors, such as those marketed as ‘black henna’ and ‘blue henna,’ ” according to a Food and Drug Administration statement. “Even brown shades of products marketed as henna may contain other ingredients intended to make them darker or make the stain last longer on the skin. The problem? “The extra ingredient used to blacken henna is often a coal-tar hair dye containing p-Phenylenediamine, an ingredient that can cause dangerous skin reactions in some people,” the statement says. Dr. DeLeo said that one good rule of thumb is to consider a reaction to black henna if a patient acknowledges using a henna dye and their hair is any color but red. That’s a sign, he said, that they’re actually using black henna.
• Makeup applicators. Dr. DeLeo has seen two cases of patients with facial dermatitis who turned out to be allergic to thiuram, a component of rubber. Their skin was reacting to the rubber in some sponges used to apply makeup.
• Lime and sun exposure. Patients are impressed when Dr. DeLeo correctly guesses what they were drinking the previous weekend, because of their telltale blisters indicating a lime allergy. Noninflammatory blisters on the fingers or hyperpigmentation can be caused by touching the skin of a lime and then having subsequent exposure to ultraviolet light. It may take days for the blisters to appear, he noted. A weekend after mixing gin and tonics with lime, for example, a patient “may show up on Tuesday of the following week. The patient doesn’t always think of what they did over the weekend.”
• Liquid detergents. As a general rule, laundry detergents do not cause dermatitis, Dr. DeLeo said. “By the time that clothing is rinsed in your washer, there’s not enough left of anything on the clothing to cause a problem.” But there’s an exception: When people hand wash clothing with liquid detergents, such as Woolite. “It’s not the fragrance,” he said. “It’s the preservative in the detergent.”
• Unexpected nickel. Skin allergy to nickel is common, and the metal can lurk in unexpected places, as he discovered when he treated a Columbia University student who was “allergic to his tuba.” The tuba was made of brass, not nickel. But “the little things connecting the tubes to each other are alloy metals,” he said, including nickel.
• Drug samples. Dr. DeLeo recalled the case of a dermatology office administrator with a recurrent neck rash. Dermatologist after dermatologist failed to find the cause. Patch and photopatch testing turned up nothing. Then Dr. DeLeo asked her to bring in every skin product she was using. She returned with a large bag full of dermatologic samples, including Drithocreme (anthralin), which can be an irritant. None of the drugs were prescribed. “This is case of sample dermatitis,” which may occur among employees and family members of dermatologists, he said. “Always think of having patients bring in what they’re using,” he added, “because you can be surprised.”

The Coastal Dermatology Symposium is jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are both owned by Frontline Medical Communications.

Dr. DeLeo disclosed consulting work for Estée Lauder.

Editors’ Note: Herbert D. Kleber, MD, a pioneer in the field of addiction medicine, died Oct. 5, at the age of 84. At the time of his death, Dr. Kleber was professor of psychiatry and emeritus director of the division on substance use disorders at Columbia University in New York.

I met Herb Kleber in the fall of 1967, when my center at National Institute of Mental Health funded six new programs to treat opiate addiction in selected cities across the United States. Fifty-one years later, only one still survives – in New Haven, Conn.

Herb began his work at Yale University in an academic/psychoanalytic environment that, with few exceptions, had too little respect for, or understanding of, his work; with a state mental health administration that placed addiction treatment at the very bottom of its priorities; and, in a racially polarized community reeling from a murder and a highly politicized jury trial.

It was Herb’s creative genius that led to the formation and maintenance of the APT Foundation with a laserlike focus on successive waves of heroin, crack cocaine, and other drug epidemics. The board structure, the clientele, and the challenges of building and maintaining a program that supported cutting-edge treatment, education, and research could have made him feel like the principal character in a book by Mario Puzo. But Herb generated loyalty in those who worked for and with him not by fear, but by his generosity of spirit, his crediting the work of others, his supporting the advancement of junior colleagues, and by his deep respect and appreciation for everyone on the team. When I last checked, Roz (his dedicated administrator) was still on the job – and the program was still being led by people whom he trained.

Most importantly, in spite of his very busy work schedule, his top priority was his family.

In 1977, I became chairman of the department of psychiatry at the University of Connecticut. In 1978, my group received a 4-year center grant from the National Institute on Alcohol Abuse and Alcoholism. By 1982, we had recruited three full professors and a talented assistant professor to our affiliated Veterans Affairs hospital. But in 1985, unfavorable changes at the Newington VA hospital led to the departure of those key faculty. Herb generously agreed to my request that we try to build collaborative bridges between our center and his programs in New Haven. This made it possible for Hank Kranzler at UConn and Stephanie O’Malley at Yale to launch their careers in clinical trials research. The collaboration that Herb generously provided likely saved our alcohol center. On a personal level, Herb and I began to have lunches halfway between New Haven and Farmington. We looked for ways to strengthen each other’s programs – but in 1989, Herb accepted an offer from President George H.W. Bush to join with William Bennett to launch a new White House Office of National Drug Control Policy.

On a trip to Washington, I visited Herb in his White House office. I watched as he mentored young staff about the intricacies of federal drug policy, and he proudly showed off the first draft of the national action plan. When Bill Bennett decided to move on, Herb and his wife, Marian Fischman, got an offer from Herb Pardes (then chair of psychiatry and dean of the College of Medicine at Columbia) to create a dedicated addiction research center at that institution. Their success at Columbia was unprecedented in an environment that had no previous commitment to addiction treatment and research. The result has been a research program that spans neuroscience, clinical trials, and clinical quality improvement. Herb enabled the research careers of a whole new generation of leaders. Combining his years at Yale and Columbia, there has been no one in this field, or (I believe) in the rest of psychiatry, who comes close to being his equal in terms of the consequences of his mentorship: in the numbers, diversity, and success of his mentees.

In 1993, my wife and I moved to Washington. Despite the distance between New York and Washington, Herb and I remained good friends. Herb and Marian attended our daughter’s wedding. When Marian became ill, we feared the worst. After she died, we felt the depth of Herb’s loss. When, several years later, we met Annie Burlock Lawver, we felt profound joy. We were honored to be present at their wedding – and we truly enjoyed traveling together with them in Colombia, Spain, and Iceland.

Herb and Annie were on vacation in Greece with his son and daughter-in-law when he died suddenly of a heart attack while on the island of Santorini. When Annie called from Athens to tell us of Herb’s death, I felt a powerful unease – a sense that the world suddenly seemed more vulnerable. Especially in the age of Trump, Herb’s honesty, integrity, humility, and effectiveness served as an essential counterweight to frustration and despair.

To those who knew his love (like Annie, his children, grandchildren, and great granddaughter, and his dog Sparky), it was total and unconditional. He brought this boundless caring to mentorship and to friendship. His humor could light up a room. His generosity of spirit is matched by too few leaders in academia. It was my privilege to be counted among his friends. He was one of a kind, and I will miss him.
 

Dr. Meyer is former chair of psychiatry at the University of Connecticut, New Haven. He also served as principal investigator of the Alcohol Research Center and executive dean at UConn. In addition, Dr. Meyer is former vice president of health affairs at George Washington University in Washington, former CEO of Best Practice Project Management (a consulting company), and former professor of psychiatry at Pennsylvania State University, Hershey.

Editors’ Note: Herbert D. Kleber, MD, a pioneer in the field of addiction medicine, died Oct. 5, at the age of 84. At the time of his death, Dr. Kleber was professor of psychiatry and emeritus director of the division on substance use disorders at Columbia University in New York.

I met Herb Kleber in the fall of 1967, when my center at National Institute of Mental Health funded six new programs to treat opiate addiction in selected cities across the United States. Fifty-one years later, only one still survives – in New Haven, Conn.

Herb began his work at Yale University in an academic/psychoanalytic environment that, with few exceptions, had too little respect for, or understanding of, his work; with a state mental health administration that placed addiction treatment at the very bottom of its priorities; and, in a racially polarized community reeling from a murder and a highly politicized jury trial.

It was Herb’s creative genius that led to the formation and maintenance of the APT Foundation with a laserlike focus on successive waves of heroin, crack cocaine, and other drug epidemics. The board structure, the clientele, and the challenges of building and maintaining a program that supported cutting-edge treatment, education, and research could have made him feel like the principal character in a book by Mario Puzo. But Herb generated loyalty in those who worked for and with him not by fear, but by his generosity of spirit, his crediting the work of others, his supporting the advancement of junior colleagues, and by his deep respect and appreciation for everyone on the team. When I last checked, Roz (his dedicated administrator) was still on the job – and the program was still being led by people whom he trained.

Most importantly, in spite of his very busy work schedule, his top priority was his family.

In 1977, I became chairman of the department of psychiatry at the University of Connecticut. In 1978, my group received a 4-year center grant from the National Institute on Alcohol Abuse and Alcoholism. By 1982, we had recruited three full professors and a talented assistant professor to our affiliated Veterans Affairs hospital. But in 1985, unfavorable changes at the Newington VA hospital led to the departure of those key faculty. Herb generously agreed to my request that we try to build collaborative bridges between our center and his programs in New Haven. This made it possible for Hank Kranzler at UConn and Stephanie O’Malley at Yale to launch their careers in clinical trials research. The collaboration that Herb generously provided likely saved our alcohol center. On a personal level, Herb and I began to have lunches halfway between New Haven and Farmington. We looked for ways to strengthen each other’s programs – but in 1989, Herb accepted an offer from President George H.W. Bush to join with William Bennett to launch a new White House Office of National Drug Control Policy.

On a trip to Washington, I visited Herb in his White House office. I watched as he mentored young staff about the intricacies of federal drug policy, and he proudly showed off the first draft of the national action plan. When Bill Bennett decided to move on, Herb and his wife, Marian Fischman, got an offer from Herb Pardes (then chair of psychiatry and dean of the College of Medicine at Columbia) to create a dedicated addiction research center at that institution. Their success at Columbia was unprecedented in an environment that had no previous commitment to addiction treatment and research. The result has been a research program that spans neuroscience, clinical trials, and clinical quality improvement. Herb enabled the research careers of a whole new generation of leaders. Combining his years at Yale and Columbia, there has been no one in this field, or (I believe) in the rest of psychiatry, who comes close to being his equal in terms of the consequences of his mentorship: in the numbers, diversity, and success of his mentees.

In 1993, my wife and I moved to Washington. Despite the distance between New York and Washington, Herb and I remained good friends. Herb and Marian attended our daughter’s wedding. When Marian became ill, we feared the worst. After she died, we felt the depth of Herb’s loss. When, several years later, we met Annie Burlock Lawver, we felt profound joy. We were honored to be present at their wedding – and we truly enjoyed traveling together with them in Colombia, Spain, and Iceland.

Herb and Annie were on vacation in Greece with his son and daughter-in-law when he died suddenly of a heart attack while on the island of Santorini. When Annie called from Athens to tell us of Herb’s death, I felt a powerful unease – a sense that the world suddenly seemed more vulnerable. Especially in the age of Trump, Herb’s honesty, integrity, humility, and effectiveness served as an essential counterweight to frustration and despair.

To those who knew his love (like Annie, his children, grandchildren, and great granddaughter, and his dog Sparky), it was total and unconditional. He brought this boundless caring to mentorship and to friendship. His humor could light up a room. His generosity of spirit is matched by too few leaders in academia. It was my privilege to be counted among his friends. He was one of a kind, and I will miss him.
 

Dr. Meyer is former chair of psychiatry at the University of Connecticut, New Haven. He also served as principal investigator of the Alcohol Research Center and executive dean at UConn. In addition, Dr. Meyer is former vice president of health affairs at George Washington University in Washington, former CEO of Best Practice Project Management (a consulting company), and former professor of psychiatry at Pennsylvania State University, Hershey.

Editors’ Note: Herbert D. Kleber, MD, a pioneer in the field of addiction medicine, died Oct. 5, at the age of 84. At the time of his death, Dr. Kleber was professor of psychiatry and emeritus director of the division on substance use disorders at Columbia University in New York.

I met Herb Kleber in the fall of 1967, when my center at National Institute of Mental Health funded six new programs to treat opiate addiction in selected cities across the United States. Fifty-one years later, only one still survives – in New Haven, Conn.

Herb began his work at Yale University in an academic/psychoanalytic environment that, with few exceptions, had too little respect for, or understanding of, his work; with a state mental health administration that placed addiction treatment at the very bottom of its priorities; and, in a racially polarized community reeling from a murder and a highly politicized jury trial.

It was Herb’s creative genius that led to the formation and maintenance of the APT Foundation with a laserlike focus on successive waves of heroin, crack cocaine, and other drug epidemics. The board structure, the clientele, and the challenges of building and maintaining a program that supported cutting-edge treatment, education, and research could have made him feel like the principal character in a book by Mario Puzo. But Herb generated loyalty in those who worked for and with him not by fear, but by his generosity of spirit, his crediting the work of others, his supporting the advancement of junior colleagues, and by his deep respect and appreciation for everyone on the team. When I last checked, Roz (his dedicated administrator) was still on the job – and the program was still being led by people whom he trained.

Most importantly, in spite of his very busy work schedule, his top priority was his family.

In 1977, I became chairman of the department of psychiatry at the University of Connecticut. In 1978, my group received a 4-year center grant from the National Institute on Alcohol Abuse and Alcoholism. By 1982, we had recruited three full professors and a talented assistant professor to our affiliated Veterans Affairs hospital. But in 1985, unfavorable changes at the Newington VA hospital led to the departure of those key faculty. Herb generously agreed to my request that we try to build collaborative bridges between our center and his programs in New Haven. This made it possible for Hank Kranzler at UConn and Stephanie O’Malley at Yale to launch their careers in clinical trials research. The collaboration that Herb generously provided likely saved our alcohol center. On a personal level, Herb and I began to have lunches halfway between New Haven and Farmington. We looked for ways to strengthen each other’s programs – but in 1989, Herb accepted an offer from President George H.W. Bush to join with William Bennett to launch a new White House Office of National Drug Control Policy.

On a trip to Washington, I visited Herb in his White House office. I watched as he mentored young staff about the intricacies of federal drug policy, and he proudly showed off the first draft of the national action plan. When Bill Bennett decided to move on, Herb and his wife, Marian Fischman, got an offer from Herb Pardes (then chair of psychiatry and dean of the College of Medicine at Columbia) to create a dedicated addiction research center at that institution. Their success at Columbia was unprecedented in an environment that had no previous commitment to addiction treatment and research. The result has been a research program that spans neuroscience, clinical trials, and clinical quality improvement. Herb enabled the research careers of a whole new generation of leaders. Combining his years at Yale and Columbia, there has been no one in this field, or (I believe) in the rest of psychiatry, who comes close to being his equal in terms of the consequences of his mentorship: in the numbers, diversity, and success of his mentees.

In 1993, my wife and I moved to Washington. Despite the distance between New York and Washington, Herb and I remained good friends. Herb and Marian attended our daughter’s wedding. When Marian became ill, we feared the worst. After she died, we felt the depth of Herb’s loss. When, several years later, we met Annie Burlock Lawver, we felt profound joy. We were honored to be present at their wedding – and we truly enjoyed traveling together with them in Colombia, Spain, and Iceland.

Herb and Annie were on vacation in Greece with his son and daughter-in-law when he died suddenly of a heart attack while on the island of Santorini. When Annie called from Athens to tell us of Herb’s death, I felt a powerful unease – a sense that the world suddenly seemed more vulnerable. Especially in the age of Trump, Herb’s honesty, integrity, humility, and effectiveness served as an essential counterweight to frustration and despair.

To those who knew his love (like Annie, his children, grandchildren, and great granddaughter, and his dog Sparky), it was total and unconditional. He brought this boundless caring to mentorship and to friendship. His humor could light up a room. His generosity of spirit is matched by too few leaders in academia. It was my privilege to be counted among his friends. He was one of a kind, and I will miss him.
 

Dr. Meyer is former chair of psychiatry at the University of Connecticut, New Haven. He also served as principal investigator of the Alcohol Research Center and executive dean at UConn. In addition, Dr. Meyer is former vice president of health affairs at George Washington University in Washington, former CEO of Best Practice Project Management (a consulting company), and former professor of psychiatry at Pennsylvania State University, Hershey.

AUSTIN, TEX. – The question of where and how to house transgender inmates is a challenging one that involves a range of factors and considerations, according to Ariana Nesbit, MD, a psychiatrist at San Diego Central Jail in California.

RapidEye/iStock/Getty Images Plus

The transgender community makes up about 0.1%-0.5% of the U.S. population, but 19%-65% of transgender individuals have been* incarcerated, compared with just 3% of the cisgender U.S. population, she said at the annual meeting of the American Academy of Psychiatry and the Law. (“Cisgender” refers to individuals whose gender identity matches the sex assigned to them at birth.)

The high incarceration rate likely results from the difficult lives these individuals have led: “Pervasive stigma begins early in life,” Dr. Nesbit said.

More than a third (36%) of transgender individuals report having to leave school because of harassment related to their gender identity, and more 90% report experiencing discrimination at work. About one in seven transgender people are unemployed, and 19-30% have histories of homelessness.*

Their social marginalization leads many to seek illegal means of securing income and housing: Prostitution is one of the two most common offenses that land transgender people in prison. The other is substance use.

“There is a high comorbidity of mental illness and substance use in this population, which confounds the issue because these are also risk factors for incarceration,” Dr. Nesbit explained, though noting that being transgender itself is not a mental illness.

Once incarcerated, transgender people are at much higher risk for victimization because of the hierarchical, hypermasculine culture of the correctional environment, Dr. Nesbit said.

“Inmates rank-order one another based on how masculine they seem, and hypermasculinity is associated with sexual or physical aggression or bias toward women, and transgender people in these facilities are often classified as ‘queens,’ ” Dr. Nesbit said. They experience verbal harassment, beatings, and rape, and they might seek protection from other inmates to survive, she said.

“On the one hand, this may decrease their overall risk of violence,” Dr. Nesbit said. “On the other hand, to maintain this partnership, the transgender inmate is usually forced into subservience to this other partner and that often includes things such as performing sexual favors.”

Correctional staff also can contribute to victimization, by doing mandatory strip searches that humiliate them or placing them in administrative segregation, or ad seg, for protection, which then worsens their mental health, Dr. Nesbit said. Ad seg, also known as “the hole,” is solitary confinement in a tiny cell with little furniture and no windows.

Research also has shown far greater victimization among transgender inmates than the cisgender incarcerated population. A 2007 study involving one-on-one interviews with 322 cisgender and 39 transgender inmates showed that 59% of the transgender inmates had experienced sexual abuse, compared with 4.4% of the cisgender ones.

• The person’s name, because it might pose to safety and security of facility.
• Charges against the inmate.
• The inmate’s personal characteristics.
• Risk to the inmate or other inmates at the facility.
• Hormone status.
• Recommendations by the inmate’s medical doctor.
• The inmate’s preference.
• Any concerns about staff threats to the inmate’s safety.

But it’s unlikely that the United States will see similar policies become widespread under the current administration: The Trump administration made changes in 2018 that mandate officials to “use biological sex as the initial determination” for housing placement decisions and allow consideration of gender identity only in “rare cases,” Dr. Nesbit said.

Despite protests from the National Center for Transgender Equality, which said the change directly defies PREA requirements, Bureau of Prisons spokesperson Nancy Ayers reportedly said that “the manual now addresses and articulates the balance of safety needs of transgender inmates as well as other inmates, including those with histories of trauma, privacy concerns, etc., on a case-by-case basis.” That leaves where to house transgender inmates as an open questions still. No data exist regarding the safest arrangements, and housing based only on genitalia is problematic, Dr. Nesbit said. Placement based on gender identity only is problematic also, since it’s not always the inmate’s preference and violence concerns remain, both for transgender males in male facilities and for transgender females in female facilities.

Though some advocate for placement in separate facilities entirely, which San Francisco does, this is a resource-intensive solution that “may limit access to educational, medical, rehabilitative, and vocational services,” Dr. Nesbit said.

“One-size-fit-all policies that rigidly assign housing do not work,” Dr. Nesbit said, yet no empirical studies exist on individualized approaches. Meanwhile, the best recommendations are to train correctional staff to improve their knowledge about transgender inmates, implement correctional intervention programs that address hypermasculinity, and recognize that transgender incarceration rates and inmate victimization are part of a larger problem of social marginalization, she said.

*Correction, 11/1/2018: An earlier version of this story misstated the timing of transgender individuals' incarceration and homelessness.

AUSTIN, TEX. – The question of where and how to house transgender inmates is a challenging one that involves a range of factors and considerations, according to Ariana Nesbit, MD, a psychiatrist at San Diego Central Jail in California.

RapidEye/iStock/Getty Images Plus

The transgender community makes up about 0.1%-0.5% of the U.S. population, but 19%-65% of transgender individuals have been* incarcerated, compared with just 3% of the cisgender U.S. population, she said at the annual meeting of the American Academy of Psychiatry and the Law. (“Cisgender” refers to individuals whose gender identity matches the sex assigned to them at birth.)

The high incarceration rate likely results from the difficult lives these individuals have led: “Pervasive stigma begins early in life,” Dr. Nesbit said.

More than a third (36%) of transgender individuals report having to leave school because of harassment related to their gender identity, and more 90% report experiencing discrimination at work. About one in seven transgender people are unemployed, and 19-30% have histories of homelessness.*

Their social marginalization leads many to seek illegal means of securing income and housing: Prostitution is one of the two most common offenses that land transgender people in prison. The other is substance use.

“There is a high comorbidity of mental illness and substance use in this population, which confounds the issue because these are also risk factors for incarceration,” Dr. Nesbit explained, though noting that being transgender itself is not a mental illness.

Once incarcerated, transgender people are at much higher risk for victimization because of the hierarchical, hypermasculine culture of the correctional environment, Dr. Nesbit said.

“Inmates rank-order one another based on how masculine they seem, and hypermasculinity is associated with sexual or physical aggression or bias toward women, and transgender people in these facilities are often classified as ‘queens,’ ” Dr. Nesbit said. They experience verbal harassment, beatings, and rape, and they might seek protection from other inmates to survive, she said.

“On the one hand, this may decrease their overall risk of violence,” Dr. Nesbit said. “On the other hand, to maintain this partnership, the transgender inmate is usually forced into subservience to this other partner and that often includes things such as performing sexual favors.”

Correctional staff also can contribute to victimization, by doing mandatory strip searches that humiliate them or placing them in administrative segregation, or ad seg, for protection, which then worsens their mental health, Dr. Nesbit said. Ad seg, also known as “the hole,” is solitary confinement in a tiny cell with little furniture and no windows.

Research also has shown far greater victimization among transgender inmates than the cisgender incarcerated population. A 2007 study involving one-on-one interviews with 322 cisgender and 39 transgender inmates showed that 59% of the transgender inmates had experienced sexual abuse, compared with 4.4% of the cisgender ones.

• The person’s name, because it might pose to safety and security of facility.
• Charges against the inmate.
• The inmate’s personal characteristics.
• Risk to the inmate or other inmates at the facility.
• Hormone status.
• Recommendations by the inmate’s medical doctor.
• The inmate’s preference.
• Any concerns about staff threats to the inmate’s safety.

But it’s unlikely that the United States will see similar policies become widespread under the current administration: The Trump administration made changes in 2018 that mandate officials to “use biological sex as the initial determination” for housing placement decisions and allow consideration of gender identity only in “rare cases,” Dr. Nesbit said.

Despite protests from the National Center for Transgender Equality, which said the change directly defies PREA requirements, Bureau of Prisons spokesperson Nancy Ayers reportedly said that “the manual now addresses and articulates the balance of safety needs of transgender inmates as well as other inmates, including those with histories of trauma, privacy concerns, etc., on a case-by-case basis.” That leaves where to house transgender inmates as an open questions still. No data exist regarding the safest arrangements, and housing based only on genitalia is problematic, Dr. Nesbit said. Placement based on gender identity only is problematic also, since it’s not always the inmate’s preference and violence concerns remain, both for transgender males in male facilities and for transgender females in female facilities.

Though some advocate for placement in separate facilities entirely, which San Francisco does, this is a resource-intensive solution that “may limit access to educational, medical, rehabilitative, and vocational services,” Dr. Nesbit said.

“One-size-fit-all policies that rigidly assign housing do not work,” Dr. Nesbit said, yet no empirical studies exist on individualized approaches. Meanwhile, the best recommendations are to train correctional staff to improve their knowledge about transgender inmates, implement correctional intervention programs that address hypermasculinity, and recognize that transgender incarceration rates and inmate victimization are part of a larger problem of social marginalization, she said.

*Correction, 11/1/2018: An earlier version of this story misstated the timing of transgender individuals' incarceration and homelessness.

AUSTIN, TEX. – The question of where and how to house transgender inmates is a challenging one that involves a range of factors and considerations, according to Ariana Nesbit, MD, a psychiatrist at San Diego Central Jail in California.

RapidEye/iStock/Getty Images Plus

The transgender community makes up about 0.1%-0.5% of the U.S. population, but 19%-65% of transgender individuals have been* incarcerated, compared with just 3% of the cisgender U.S. population, she said at the annual meeting of the American Academy of Psychiatry and the Law. (“Cisgender” refers to individuals whose gender identity matches the sex assigned to them at birth.)

The high incarceration rate likely results from the difficult lives these individuals have led: “Pervasive stigma begins early in life,” Dr. Nesbit said.

More than a third (36%) of transgender individuals report having to leave school because of harassment related to their gender identity, and more 90% report experiencing discrimination at work. About one in seven transgender people are unemployed, and 19-30% have histories of homelessness.*

Their social marginalization leads many to seek illegal means of securing income and housing: Prostitution is one of the two most common offenses that land transgender people in prison. The other is substance use.

“There is a high comorbidity of mental illness and substance use in this population, which confounds the issue because these are also risk factors for incarceration,” Dr. Nesbit explained, though noting that being transgender itself is not a mental illness.

Once incarcerated, transgender people are at much higher risk for victimization because of the hierarchical, hypermasculine culture of the correctional environment, Dr. Nesbit said.

“Inmates rank-order one another based on how masculine they seem, and hypermasculinity is associated with sexual or physical aggression or bias toward women, and transgender people in these facilities are often classified as ‘queens,’ ” Dr. Nesbit said. They experience verbal harassment, beatings, and rape, and they might seek protection from other inmates to survive, she said.

“On the one hand, this may decrease their overall risk of violence,” Dr. Nesbit said. “On the other hand, to maintain this partnership, the transgender inmate is usually forced into subservience to this other partner and that often includes things such as performing sexual favors.”

Correctional staff also can contribute to victimization, by doing mandatory strip searches that humiliate them or placing them in administrative segregation, or ad seg, for protection, which then worsens their mental health, Dr. Nesbit said. Ad seg, also known as “the hole,” is solitary confinement in a tiny cell with little furniture and no windows.

Research also has shown far greater victimization among transgender inmates than the cisgender incarcerated population. A 2007 study involving one-on-one interviews with 322 cisgender and 39 transgender inmates showed that 59% of the transgender inmates had experienced sexual abuse, compared with 4.4% of the cisgender ones.

• The person’s name, because it might pose to safety and security of facility.
• Charges against the inmate.
• The inmate’s personal characteristics.
• Risk to the inmate or other inmates at the facility.
• Hormone status.
• Recommendations by the inmate’s medical doctor.
• The inmate’s preference.
• Any concerns about staff threats to the inmate’s safety.

But it’s unlikely that the United States will see similar policies become widespread under the current administration: The Trump administration made changes in 2018 that mandate officials to “use biological sex as the initial determination” for housing placement decisions and allow consideration of gender identity only in “rare cases,” Dr. Nesbit said.

Despite protests from the National Center for Transgender Equality, which said the change directly defies PREA requirements, Bureau of Prisons spokesperson Nancy Ayers reportedly said that “the manual now addresses and articulates the balance of safety needs of transgender inmates as well as other inmates, including those with histories of trauma, privacy concerns, etc., on a case-by-case basis.” That leaves where to house transgender inmates as an open questions still. No data exist regarding the safest arrangements, and housing based only on genitalia is problematic, Dr. Nesbit said. Placement based on gender identity only is problematic also, since it’s not always the inmate’s preference and violence concerns remain, both for transgender males in male facilities and for transgender females in female facilities.

Though some advocate for placement in separate facilities entirely, which San Francisco does, this is a resource-intensive solution that “may limit access to educational, medical, rehabilitative, and vocational services,” Dr. Nesbit said.

“One-size-fit-all policies that rigidly assign housing do not work,” Dr. Nesbit said, yet no empirical studies exist on individualized approaches. Meanwhile, the best recommendations are to train correctional staff to improve their knowledge about transgender inmates, implement correctional intervention programs that address hypermasculinity, and recognize that transgender incarceration rates and inmate victimization are part of a larger problem of social marginalization, she said.

*Correction, 11/1/2018: An earlier version of this story misstated the timing of transgender individuals' incarceration and homelessness.