MAUI, HAWAII – The herpes zoster vaccine is particularly important in patients with rheumatic diseases because their risks of shingles and postherpetic neuralgia are substantially higher than in the general population, Dr. John J. Cush observed at the 2016 Rheumatology Winter Clinical Symposium.

This is a live attenuated virus vaccine, and the rules regarding its use in patients with rheumatic diseases are fairly complicated. Here’s what physicians need to know: the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices say the shingles vaccine can safely be given to patients on prednisone at less than 20 mg/day, azathioprine at up to 3 mg/kg/day, or methotrexate at up to 0.4 mg/kg/week, which works out to about 25 mg/week in anyone weighing more than 136 pounds.

jancin

However, the shingles vaccine is contraindicated in patients on recombinant biologic agents, including tumor necrosis factor (TNF) inhibitors, abatacept (Orencia), rituximab (Rituxan), or Janus kinase inhibitors, explained Dr. Cush, professor of medicine and rheumatology at Baylor University, Dallas, and director of clinical rheumatology at the Baylor Research Institute.

The lifetime risk of shingles in the general population is roughly one in three. The risk in patients with rheumatoid arthritis is roughly twice that of the age-matched general population, and the risks are substantially greater than that in individuals with other rheumatic diseases, including lupus and granulomatosis with polyangiitis.

Payers cover the vaccine in patients age 60 or older. The vaccine is approved for and has been shown to be effective in 50- to 59-year-olds as well, but that typically entails an out-of-pocket expense of around $200.

Given that close to 60% of all rheumatoid arthritis patients will eventually be placed on biologic therapy, Dr. Cush believes in seizing any opportunity to give the shingles vaccine in age-appropriate patients beforehand. However, he advises against temporarily stopping a biologic for the express purpose of administering the live virus vaccine.

“Find the opportunity: between changes in medication, after they have surgery, during a lapse in therapy,” he suggested.

It’s recommended that Zostavax be deferred until after a patient has been off biologic therapy or high-dose steroids for at least 4 weeks, and that a biologic agent shouldn’t be started for 2-4 weeks after vaccination.

The shingles vaccine can safely be given with multiple inactivated virus vaccines such as an influenza vaccine or pneumococcal vaccine on a single day.

Controversy surrounds the issue of whether TNF inhibitors increase the risk of shingles. Several retrospective studies have reported they do. But the largest retrospective study, involving more than 33,000 new users of anti-TNF agents, found that patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases who initiated anti-TNF therapy weren’t at any higher risk of herpes zoster than those who started on methotrexate or other nonbiologic disease-modifying antirheumatic drugs (JAMA. 2013 Mar 6;309[9]:887-95). The lead investigator in this study, Dr. Kevin L. Winthrop of Oregon Health and Science University, Portland, is currently conducting a prospective study in an effort to confirm these findings.

The recommendation against giving the zoster vaccine to patients while on biologics is based upon the theoretical risk that exposure to the live attenuated virus will trigger an acute shingles attack. However, when Dr. Cush conducted a survey of his fellow rheumatologists, they reported that among more than a collective 200 patients inadvertently given the vaccine while on biologic therapy, not one case of shingles subsequently occurred over the short term.

More persuasively, Dr. Jeffrey R. Curtis of the University of Alabama at Birmingham and coinvestigators conducted a formal retrospective study of close to a half-million Medicare patients and found there were no cases of herpes zoster or varicella within 42 days following inadvertent vaccination of 633 patients while on biologics. During a median 2-year follow-up of Medicare patients with rheumatoid arthritis and other immune-mediated diseases, herpes zoster vaccination was associated with a 39% reduction in the risk of shingles (JAMA. 2012 Jul 4;308[1]:43-9).

“You shouldn’t be vaccinating for herpes zoster while patients are on a biologic, but you know what? If it happens, don’t wig out. Move on and try to avoid it,” Dr. Cush advised.

In any event, this is an issue that is eventually likely to go away. An inactivated virus vaccine for the prevention of shingles is now in clinical trials. It appears to be more effective than the current vaccine, according to the rheumatologist.

He reported having no financial interests relevant to his presentation.

bjancin@frontlinemedcom.com

MAUI, HAWAII – The herpes zoster vaccine is particularly important in patients with rheumatic diseases because their risks of shingles and postherpetic neuralgia are substantially higher than in the general population, Dr. John J. Cush observed at the 2016 Rheumatology Winter Clinical Symposium.

This is a live attenuated virus vaccine, and the rules regarding its use in patients with rheumatic diseases are fairly complicated. Here’s what physicians need to know: the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices say the shingles vaccine can safely be given to patients on prednisone at less than 20 mg/day, azathioprine at up to 3 mg/kg/day, or methotrexate at up to 0.4 mg/kg/week, which works out to about 25 mg/week in anyone weighing more than 136 pounds.

jancin

However, the shingles vaccine is contraindicated in patients on recombinant biologic agents, including tumor necrosis factor (TNF) inhibitors, abatacept (Orencia), rituximab (Rituxan), or Janus kinase inhibitors, explained Dr. Cush, professor of medicine and rheumatology at Baylor University, Dallas, and director of clinical rheumatology at the Baylor Research Institute.

The lifetime risk of shingles in the general population is roughly one in three. The risk in patients with rheumatoid arthritis is roughly twice that of the age-matched general population, and the risks are substantially greater than that in individuals with other rheumatic diseases, including lupus and granulomatosis with polyangiitis.

Payers cover the vaccine in patients age 60 or older. The vaccine is approved for and has been shown to be effective in 50- to 59-year-olds as well, but that typically entails an out-of-pocket expense of around $200.

Given that close to 60% of all rheumatoid arthritis patients will eventually be placed on biologic therapy, Dr. Cush believes in seizing any opportunity to give the shingles vaccine in age-appropriate patients beforehand. However, he advises against temporarily stopping a biologic for the express purpose of administering the live virus vaccine.

“Find the opportunity: between changes in medication, after they have surgery, during a lapse in therapy,” he suggested.

It’s recommended that Zostavax be deferred until after a patient has been off biologic therapy or high-dose steroids for at least 4 weeks, and that a biologic agent shouldn’t be started for 2-4 weeks after vaccination.

The shingles vaccine can safely be given with multiple inactivated virus vaccines such as an influenza vaccine or pneumococcal vaccine on a single day.

Controversy surrounds the issue of whether TNF inhibitors increase the risk of shingles. Several retrospective studies have reported they do. But the largest retrospective study, involving more than 33,000 new users of anti-TNF agents, found that patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases who initiated anti-TNF therapy weren’t at any higher risk of herpes zoster than those who started on methotrexate or other nonbiologic disease-modifying antirheumatic drugs (JAMA. 2013 Mar 6;309[9]:887-95). The lead investigator in this study, Dr. Kevin L. Winthrop of Oregon Health and Science University, Portland, is currently conducting a prospective study in an effort to confirm these findings.

The recommendation against giving the zoster vaccine to patients while on biologics is based upon the theoretical risk that exposure to the live attenuated virus will trigger an acute shingles attack. However, when Dr. Cush conducted a survey of his fellow rheumatologists, they reported that among more than a collective 200 patients inadvertently given the vaccine while on biologic therapy, not one case of shingles subsequently occurred over the short term.

More persuasively, Dr. Jeffrey R. Curtis of the University of Alabama at Birmingham and coinvestigators conducted a formal retrospective study of close to a half-million Medicare patients and found there were no cases of herpes zoster or varicella within 42 days following inadvertent vaccination of 633 patients while on biologics. During a median 2-year follow-up of Medicare patients with rheumatoid arthritis and other immune-mediated diseases, herpes zoster vaccination was associated with a 39% reduction in the risk of shingles (JAMA. 2012 Jul 4;308[1]:43-9).

“You shouldn’t be vaccinating for herpes zoster while patients are on a biologic, but you know what? If it happens, don’t wig out. Move on and try to avoid it,” Dr. Cush advised.

In any event, this is an issue that is eventually likely to go away. An inactivated virus vaccine for the prevention of shingles is now in clinical trials. It appears to be more effective than the current vaccine, according to the rheumatologist.

He reported having no financial interests relevant to his presentation.

bjancin@frontlinemedcom.com

MAUI, HAWAII – The herpes zoster vaccine is particularly important in patients with rheumatic diseases because their risks of shingles and postherpetic neuralgia are substantially higher than in the general population, Dr. John J. Cush observed at the 2016 Rheumatology Winter Clinical Symposium.

This is a live attenuated virus vaccine, and the rules regarding its use in patients with rheumatic diseases are fairly complicated. Here’s what physicians need to know: the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices say the shingles vaccine can safely be given to patients on prednisone at less than 20 mg/day, azathioprine at up to 3 mg/kg/day, or methotrexate at up to 0.4 mg/kg/week, which works out to about 25 mg/week in anyone weighing more than 136 pounds.

jancin

However, the shingles vaccine is contraindicated in patients on recombinant biologic agents, including tumor necrosis factor (TNF) inhibitors, abatacept (Orencia), rituximab (Rituxan), or Janus kinase inhibitors, explained Dr. Cush, professor of medicine and rheumatology at Baylor University, Dallas, and director of clinical rheumatology at the Baylor Research Institute.

The lifetime risk of shingles in the general population is roughly one in three. The risk in patients with rheumatoid arthritis is roughly twice that of the age-matched general population, and the risks are substantially greater than that in individuals with other rheumatic diseases, including lupus and granulomatosis with polyangiitis.

Payers cover the vaccine in patients age 60 or older. The vaccine is approved for and has been shown to be effective in 50- to 59-year-olds as well, but that typically entails an out-of-pocket expense of around $200.

Given that close to 60% of all rheumatoid arthritis patients will eventually be placed on biologic therapy, Dr. Cush believes in seizing any opportunity to give the shingles vaccine in age-appropriate patients beforehand. However, he advises against temporarily stopping a biologic for the express purpose of administering the live virus vaccine.

“Find the opportunity: between changes in medication, after they have surgery, during a lapse in therapy,” he suggested.

It’s recommended that Zostavax be deferred until after a patient has been off biologic therapy or high-dose steroids for at least 4 weeks, and that a biologic agent shouldn’t be started for 2-4 weeks after vaccination.

The shingles vaccine can safely be given with multiple inactivated virus vaccines such as an influenza vaccine or pneumococcal vaccine on a single day.

Controversy surrounds the issue of whether TNF inhibitors increase the risk of shingles. Several retrospective studies have reported they do. But the largest retrospective study, involving more than 33,000 new users of anti-TNF agents, found that patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases who initiated anti-TNF therapy weren’t at any higher risk of herpes zoster than those who started on methotrexate or other nonbiologic disease-modifying antirheumatic drugs (JAMA. 2013 Mar 6;309[9]:887-95). The lead investigator in this study, Dr. Kevin L. Winthrop of Oregon Health and Science University, Portland, is currently conducting a prospective study in an effort to confirm these findings.

The recommendation against giving the zoster vaccine to patients while on biologics is based upon the theoretical risk that exposure to the live attenuated virus will trigger an acute shingles attack. However, when Dr. Cush conducted a survey of his fellow rheumatologists, they reported that among more than a collective 200 patients inadvertently given the vaccine while on biologic therapy, not one case of shingles subsequently occurred over the short term.

More persuasively, Dr. Jeffrey R. Curtis of the University of Alabama at Birmingham and coinvestigators conducted a formal retrospective study of close to a half-million Medicare patients and found there were no cases of herpes zoster or varicella within 42 days following inadvertent vaccination of 633 patients while on biologics. During a median 2-year follow-up of Medicare patients with rheumatoid arthritis and other immune-mediated diseases, herpes zoster vaccination was associated with a 39% reduction in the risk of shingles (JAMA. 2012 Jul 4;308[1]:43-9).

“You shouldn’t be vaccinating for herpes zoster while patients are on a biologic, but you know what? If it happens, don’t wig out. Move on and try to avoid it,” Dr. Cush advised.

In any event, this is an issue that is eventually likely to go away. An inactivated virus vaccine for the prevention of shingles is now in clinical trials. It appears to be more effective than the current vaccine, according to the rheumatologist.

He reported having no financial interests relevant to his presentation.

bjancin@frontlinemedcom.com

Tranexamic acid

Photo courtesy of NIH

ORLANDO, FL—Results of a large, retrospective study suggest tranexamic acid (TXA) can reduce the need for transfusion in patients undergoing hip and knee replacement surgery without increasing the overall risk of venous thromboembolism (VTE).

However, patients treated with TXA were significantly more likely to develop deep vein thrombosis (DVT) than patients who did not receive the drug.

There was no significant difference between the treatment groups with regard to pulmonary embolism (PE).

These results were presented at the American Academy of Orthopaedic Surgeons (AAOS) 2016 Annual Meeting (abstract P101).

“[C]onflicting results have been published regarding the use of TXA in patients undergoing hip and knee replacement,” said study investigator Geoffrey Westrich, MD, of the Hospital for Special Surgery in New York, New York.

To assess the safety and efficacy of TXA in this patient population, Dr Westrich and his colleagues retrospectively reviewed the records of 4449 patients who had hip or knee replacement over a 6-month period.

There were 720 patients who received TXA topically, 636 who received TXA intravenously, and 3093 patients who did not receive the drug.

The investigators found that 9.7% of patients treated with either type of TXA received a blood transfusion, as did 22.1% of patients who were not treated with TXA.

TXA-treated patients received an average of 0.13 units of blood, compared to 0.37 units for patients in the non-TXA group.

The investigators said there was no significant difference in efficacy between topical and intravenous TXA.

“At our institution, TXA in either intravenous or topical form was effective in decreasing the amount of blood transfusions, as well as the number of units of blood transfused in primary and revision hip and knee replacement,” Dr Westrich said.

“Furthermore, when safety was evaluated, there was no statistically significant difference in blood clots in patients who received IV or topical TXA, reconfirming its safety.”

The odds of developing a hospital-acquired VTE was 1.63 among patients treated with TXA, which was not significantly higher than the odds for patients who did not receive the drug (P=0.24).

When the investigators evaluated DVT and PE separately, they found the TXA group had a significant increase in DVT (P=0.03) but not PE (P=0.94).

Tranexamic acid

Photo courtesy of NIH

ORLANDO, FL—Results of a large, retrospective study suggest tranexamic acid (TXA) can reduce the need for transfusion in patients undergoing hip and knee replacement surgery without increasing the overall risk of venous thromboembolism (VTE).

However, patients treated with TXA were significantly more likely to develop deep vein thrombosis (DVT) than patients who did not receive the drug.

There was no significant difference between the treatment groups with regard to pulmonary embolism (PE).

These results were presented at the American Academy of Orthopaedic Surgeons (AAOS) 2016 Annual Meeting (abstract P101).

“[C]onflicting results have been published regarding the use of TXA in patients undergoing hip and knee replacement,” said study investigator Geoffrey Westrich, MD, of the Hospital for Special Surgery in New York, New York.

To assess the safety and efficacy of TXA in this patient population, Dr Westrich and his colleagues retrospectively reviewed the records of 4449 patients who had hip or knee replacement over a 6-month period.

There were 720 patients who received TXA topically, 636 who received TXA intravenously, and 3093 patients who did not receive the drug.

The investigators found that 9.7% of patients treated with either type of TXA received a blood transfusion, as did 22.1% of patients who were not treated with TXA.

TXA-treated patients received an average of 0.13 units of blood, compared to 0.37 units for patients in the non-TXA group.

The investigators said there was no significant difference in efficacy between topical and intravenous TXA.

“At our institution, TXA in either intravenous or topical form was effective in decreasing the amount of blood transfusions, as well as the number of units of blood transfused in primary and revision hip and knee replacement,” Dr Westrich said.

“Furthermore, when safety was evaluated, there was no statistically significant difference in blood clots in patients who received IV or topical TXA, reconfirming its safety.”

The odds of developing a hospital-acquired VTE was 1.63 among patients treated with TXA, which was not significantly higher than the odds for patients who did not receive the drug (P=0.24).

When the investigators evaluated DVT and PE separately, they found the TXA group had a significant increase in DVT (P=0.03) but not PE (P=0.94).

Tranexamic acid

Photo courtesy of NIH

ORLANDO, FL—Results of a large, retrospective study suggest tranexamic acid (TXA) can reduce the need for transfusion in patients undergoing hip and knee replacement surgery without increasing the overall risk of venous thromboembolism (VTE).

However, patients treated with TXA were significantly more likely to develop deep vein thrombosis (DVT) than patients who did not receive the drug.

There was no significant difference between the treatment groups with regard to pulmonary embolism (PE).

These results were presented at the American Academy of Orthopaedic Surgeons (AAOS) 2016 Annual Meeting (abstract P101).

“[C]onflicting results have been published regarding the use of TXA in patients undergoing hip and knee replacement,” said study investigator Geoffrey Westrich, MD, of the Hospital for Special Surgery in New York, New York.

To assess the safety and efficacy of TXA in this patient population, Dr Westrich and his colleagues retrospectively reviewed the records of 4449 patients who had hip or knee replacement over a 6-month period.

There were 720 patients who received TXA topically, 636 who received TXA intravenously, and 3093 patients who did not receive the drug.

The investigators found that 9.7% of patients treated with either type of TXA received a blood transfusion, as did 22.1% of patients who were not treated with TXA.

TXA-treated patients received an average of 0.13 units of blood, compared to 0.37 units for patients in the non-TXA group.

The investigators said there was no significant difference in efficacy between topical and intravenous TXA.

“At our institution, TXA in either intravenous or topical form was effective in decreasing the amount of blood transfusions, as well as the number of units of blood transfused in primary and revision hip and knee replacement,” Dr Westrich said.

“Furthermore, when safety was evaluated, there was no statistically significant difference in blood clots in patients who received IV or topical TXA, reconfirming its safety.”

The odds of developing a hospital-acquired VTE was 1.63 among patients treated with TXA, which was not significantly higher than the odds for patients who did not receive the drug (P=0.24).

When the investigators evaluated DVT and PE separately, they found the TXA group had a significant increase in DVT (P=0.03) but not PE (P=0.94).

Micrograph showing T-cell

acute lymphoblastic leukemia

Image by Hind Medyouf

Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.

These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.

In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.

“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.

By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.

All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.

The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.

Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.

By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.

The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.

“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”

The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.

“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.

“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”

In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.

The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.

“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.

Micrograph showing T-cell

acute lymphoblastic leukemia

Image by Hind Medyouf

Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.

These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.

In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.

“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.

By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.

All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.

The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.

Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.

By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.

The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.

“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”

The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.

“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.

“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”

In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.

The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.

“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.

Micrograph showing T-cell

acute lymphoblastic leukemia

Image by Hind Medyouf

Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.

These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.

In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.

“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.

By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.

All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.

The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.

Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.

By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.

The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.

“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”

The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.

“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.

“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”

In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.

The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.

“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.

Sound clinical reasoning is the foundation of patient safety, yet discussions of a physician’s raw thinking ability have become a “third rail” in hospitals, according to “Incorporating Metacognition into Morbidity and Mortality Rounds: The Next Frontier in Quality Improvement,” published in the Journal of Hospital Medicine. Authors David Katz, MD, MSc, and Allan S. Detsky, MD, PhD, suggest introducing concepts from cognitive psychology could help address this issue.

The underlying problem is that the search for causes of medical error focuses on systems-based issues—medication administration and dosing, communication, physician handover, etc. There’s a reluctance to talk about human decision making. In fact, in the authors’ own hospitals, improving diagnostic accuracy is almost never discussed; they suspect the same is true at other institutions.

But cognitive errors occur predictably and often, especially at times of high cognitive load (i.e., when many complex decisions are being made in a short period of time), according to research from cognitive psychology. The authors therefore suggest that introducing metacognition (or “thinking about thinking”) discussions during morbidity and mortality rounds (MMRs) might help expand the discussions so that human error can be recognized and addressed.

They suggest that cognitive heuristics be introduced to MMRs by experienced and respected clinicians who can tell stories of their own errors and the shortcuts in thinking that may have caused them.

“Thereafter, the traditional MMR format can be used: presenting a case, describing how an experienced clinician might manage the case, and then asking the audience members for comment,” they write. “Incorporating discussions of cognitive missteps, in medical and nonmedical contexts, would help normalize the understanding that even the most experienced and smartest people fall prey to them. The tone must be positive.”

Reference

1. Katz D, Detsky AS. Incorporating metacognition into morbidity and mortality rounds: the next frontier in quality improvement. J Hosp Med. 2016;11(2):120-122. doi:10.1002/jhm.2505.

Sound clinical reasoning is the foundation of patient safety, yet discussions of a physician’s raw thinking ability have become a “third rail” in hospitals, according to “Incorporating Metacognition into Morbidity and Mortality Rounds: The Next Frontier in Quality Improvement,” published in the Journal of Hospital Medicine. Authors David Katz, MD, MSc, and Allan S. Detsky, MD, PhD, suggest introducing concepts from cognitive psychology could help address this issue.

The underlying problem is that the search for causes of medical error focuses on systems-based issues—medication administration and dosing, communication, physician handover, etc. There’s a reluctance to talk about human decision making. In fact, in the authors’ own hospitals, improving diagnostic accuracy is almost never discussed; they suspect the same is true at other institutions.

But cognitive errors occur predictably and often, especially at times of high cognitive load (i.e., when many complex decisions are being made in a short period of time), according to research from cognitive psychology. The authors therefore suggest that introducing metacognition (or “thinking about thinking”) discussions during morbidity and mortality rounds (MMRs) might help expand the discussions so that human error can be recognized and addressed.

They suggest that cognitive heuristics be introduced to MMRs by experienced and respected clinicians who can tell stories of their own errors and the shortcuts in thinking that may have caused them.

“Thereafter, the traditional MMR format can be used: presenting a case, describing how an experienced clinician might manage the case, and then asking the audience members for comment,” they write. “Incorporating discussions of cognitive missteps, in medical and nonmedical contexts, would help normalize the understanding that even the most experienced and smartest people fall prey to them. The tone must be positive.”

Reference

1. Katz D, Detsky AS. Incorporating metacognition into morbidity and mortality rounds: the next frontier in quality improvement. J Hosp Med. 2016;11(2):120-122. doi:10.1002/jhm.2505.

Sound clinical reasoning is the foundation of patient safety, yet discussions of a physician’s raw thinking ability have become a “third rail” in hospitals, according to “Incorporating Metacognition into Morbidity and Mortality Rounds: The Next Frontier in Quality Improvement,” published in the Journal of Hospital Medicine. Authors David Katz, MD, MSc, and Allan S. Detsky, MD, PhD, suggest introducing concepts from cognitive psychology could help address this issue.

The underlying problem is that the search for causes of medical error focuses on systems-based issues—medication administration and dosing, communication, physician handover, etc. There’s a reluctance to talk about human decision making. In fact, in the authors’ own hospitals, improving diagnostic accuracy is almost never discussed; they suspect the same is true at other institutions.

But cognitive errors occur predictably and often, especially at times of high cognitive load (i.e., when many complex decisions are being made in a short period of time), according to research from cognitive psychology. The authors therefore suggest that introducing metacognition (or “thinking about thinking”) discussions during morbidity and mortality rounds (MMRs) might help expand the discussions so that human error can be recognized and addressed.

They suggest that cognitive heuristics be introduced to MMRs by experienced and respected clinicians who can tell stories of their own errors and the shortcuts in thinking that may have caused them.

“Thereafter, the traditional MMR format can be used: presenting a case, describing how an experienced clinician might manage the case, and then asking the audience members for comment,” they write. “Incorporating discussions of cognitive missteps, in medical and nonmedical contexts, would help normalize the understanding that even the most experienced and smartest people fall prey to them. The tone must be positive.”

Reference

1. Katz D, Detsky AS. Incorporating metacognition into morbidity and mortality rounds: the next frontier in quality improvement. J Hosp Med. 2016;11(2):120-122. doi:10.1002/jhm.2505.

NEW YORK (Reuters Health) - Cardiac resynchronization therapy (CRT) in patients with heart failure (HF) without left bundle branch block (LBBB) may not help and might even harm, according to an international group of investigators.

As Dr. Yitschak Biton told Reuters Health by email, "Our findings suggest that patients without LBBB electrocardiogram (ECG) morphology are not likely to benefit from CRT implantation and a subgroup of patients with short QRS duration might even be at higher risk for mortality."

In a January 28 online paper in Circulation: Heart Failure, Dr. Biton, of the University of Rochester Medical Center, New York, and colleagues note that the efficacy of CRT is well established in patients with both mild and moderate to severe HF symptoms. However, data on non-LBBB patients "are more limited and conflicting."

To investigate, the team examined data on 537 such patients with mild HF taking part in a larger study. At seven years, the cumulative probability of HF hospitalization or death was 45% in those randomized to an implantable cardioverter-defibrillator (ICD) and 56% in those given CRT with a defibrillator (CRT-D).

Multivariable-adjusted subgroup analysis by QRS duration showed that patients from the lower quartile (134 ms or less) had a 2.4-fold greater risk of HF hospitalization or death with CRT-D versus those with ICD-only therapy.

However, the effect of CRT-D in patients from the upper quartiles group (QRS greater than 134 ms) was neutral (hazard ratio 0.97).

In a further analysis based on PR interval, patients with prolonged QRS (more than 134 ms) and prolonged PR (at least 230 ms) were protected with CRT-D (HR 0.31). The association was neutral with prolonged QRS and shorter PR.

"Overall," the researchers conclude, "patients with mild HF but without left bundle branch block morphology did not derive clinical benefit with CRT-D during long-term follow-up. Relatively shorter QRS was associated with a significantly increased risk with CRT-D relative to implantable cardioverter-defibrillator only."

"This information should be taken into account when CRT therapy is considered in this subgroup of patients," Dr. Biton told Reuters Health.

Boston Scientific Corporation funded the clinical trial this research is based on. Five coauthors reported disclosures.

NEW YORK (Reuters Health) - Cardiac resynchronization therapy (CRT) in patients with heart failure (HF) without left bundle branch block (LBBB) may not help and might even harm, according to an international group of investigators.

As Dr. Yitschak Biton told Reuters Health by email, "Our findings suggest that patients without LBBB electrocardiogram (ECG) morphology are not likely to benefit from CRT implantation and a subgroup of patients with short QRS duration might even be at higher risk for mortality."

In a January 28 online paper in Circulation: Heart Failure, Dr. Biton, of the University of Rochester Medical Center, New York, and colleagues note that the efficacy of CRT is well established in patients with both mild and moderate to severe HF symptoms. However, data on non-LBBB patients "are more limited and conflicting."

To investigate, the team examined data on 537 such patients with mild HF taking part in a larger study. At seven years, the cumulative probability of HF hospitalization or death was 45% in those randomized to an implantable cardioverter-defibrillator (ICD) and 56% in those given CRT with a defibrillator (CRT-D).

Multivariable-adjusted subgroup analysis by QRS duration showed that patients from the lower quartile (134 ms or less) had a 2.4-fold greater risk of HF hospitalization or death with CRT-D versus those with ICD-only therapy.

However, the effect of CRT-D in patients from the upper quartiles group (QRS greater than 134 ms) was neutral (hazard ratio 0.97).

In a further analysis based on PR interval, patients with prolonged QRS (more than 134 ms) and prolonged PR (at least 230 ms) were protected with CRT-D (HR 0.31). The association was neutral with prolonged QRS and shorter PR.

"Overall," the researchers conclude, "patients with mild HF but without left bundle branch block morphology did not derive clinical benefit with CRT-D during long-term follow-up. Relatively shorter QRS was associated with a significantly increased risk with CRT-D relative to implantable cardioverter-defibrillator only."

"This information should be taken into account when CRT therapy is considered in this subgroup of patients," Dr. Biton told Reuters Health.

Boston Scientific Corporation funded the clinical trial this research is based on. Five coauthors reported disclosures.

NEW YORK (Reuters Health) - Cardiac resynchronization therapy (CRT) in patients with heart failure (HF) without left bundle branch block (LBBB) may not help and might even harm, according to an international group of investigators.

As Dr. Yitschak Biton told Reuters Health by email, "Our findings suggest that patients without LBBB electrocardiogram (ECG) morphology are not likely to benefit from CRT implantation and a subgroup of patients with short QRS duration might even be at higher risk for mortality."

In a January 28 online paper in Circulation: Heart Failure, Dr. Biton, of the University of Rochester Medical Center, New York, and colleagues note that the efficacy of CRT is well established in patients with both mild and moderate to severe HF symptoms. However, data on non-LBBB patients "are more limited and conflicting."

To investigate, the team examined data on 537 such patients with mild HF taking part in a larger study. At seven years, the cumulative probability of HF hospitalization or death was 45% in those randomized to an implantable cardioverter-defibrillator (ICD) and 56% in those given CRT with a defibrillator (CRT-D).

Multivariable-adjusted subgroup analysis by QRS duration showed that patients from the lower quartile (134 ms or less) had a 2.4-fold greater risk of HF hospitalization or death with CRT-D versus those with ICD-only therapy.

However, the effect of CRT-D in patients from the upper quartiles group (QRS greater than 134 ms) was neutral (hazard ratio 0.97).

In a further analysis based on PR interval, patients with prolonged QRS (more than 134 ms) and prolonged PR (at least 230 ms) were protected with CRT-D (HR 0.31). The association was neutral with prolonged QRS and shorter PR.

"Overall," the researchers conclude, "patients with mild HF but without left bundle branch block morphology did not derive clinical benefit with CRT-D during long-term follow-up. Relatively shorter QRS was associated with a significantly increased risk with CRT-D relative to implantable cardioverter-defibrillator only."

"This information should be taken into account when CRT therapy is considered in this subgroup of patients," Dr. Biton told Reuters Health.

Boston Scientific Corporation funded the clinical trial this research is based on. Five coauthors reported disclosures.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.

BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

BMN 270 is under development by BioMarin Pharmaceutical Inc.

BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.

Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.

The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.

Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.

BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

BMN 270 is under development by BioMarin Pharmaceutical Inc.

BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.

Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.

The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.

Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.

BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

BMN 270 is under development by BioMarin Pharmaceutical Inc.

BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.

Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.

The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.

Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

A central catheter maintenance bundle can decrease the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in the American Journal of Critical Care.

A team from the healthcare company Select Medical developed and implemented the bundle at 30 long-term acute care hospitals.

The team used infection prevention guidelines from the Centers for Disease Control and Prevention as the core of the bundle, with mandatory use of alcohol-based central catheter caps and chlorhexidine gluconate dressings.

Ongoing education of clinical staff about the protocol and a checklist to track compliance were also key elements of the initiative.

At each hospital, staff nurses who demonstrated competency in the care of central catheters monitored implementation of the bundle for the initial 6 months of the study.

Researchers reviewed the medical records of 6660 patients discharged during the 14 months prior to the study and 6559 patients discharged after implementation of the bundle. Patient days and central catheter days before and after the bundle was implemented were comparable.

Six months after the bundle was implemented, the CLABSI standardized infection rate had dropped 29%. The rate was 1.28 in the 6 months before the bundle was implemented and 0.96 six months after implementation.

There was a mean reduction of 4.5 CLABSIs per hospital for 14 months after the bundle was implemented.

“Our results encourage the development and implementation of similar bundles as effective infection reduction strategies in [long-term acute care hospitals],” said study author Antony Grigonis, PhD, vice-president of quality and healthcare analytics at Select Medical.

“Preventing these infections can help reduce complications and the length of stay for other patients. This infection reduction could also translate to a savings of approximately $3.7 million annually for the 30 long-term acute care hospitals studied.”

Select Medical, which is based in Mechanicsburg, Pennsylvania, owns long-term acute care and inpatient rehabilitation hospitals, as well as occupational health and physical therapy clinics.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

A central catheter maintenance bundle can decrease the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in the American Journal of Critical Care.

A team from the healthcare company Select Medical developed and implemented the bundle at 30 long-term acute care hospitals.

The team used infection prevention guidelines from the Centers for Disease Control and Prevention as the core of the bundle, with mandatory use of alcohol-based central catheter caps and chlorhexidine gluconate dressings.

Ongoing education of clinical staff about the protocol and a checklist to track compliance were also key elements of the initiative.

At each hospital, staff nurses who demonstrated competency in the care of central catheters monitored implementation of the bundle for the initial 6 months of the study.

Researchers reviewed the medical records of 6660 patients discharged during the 14 months prior to the study and 6559 patients discharged after implementation of the bundle. Patient days and central catheter days before and after the bundle was implemented were comparable.

Six months after the bundle was implemented, the CLABSI standardized infection rate had dropped 29%. The rate was 1.28 in the 6 months before the bundle was implemented and 0.96 six months after implementation.

There was a mean reduction of 4.5 CLABSIs per hospital for 14 months after the bundle was implemented.

“Our results encourage the development and implementation of similar bundles as effective infection reduction strategies in [long-term acute care hospitals],” said study author Antony Grigonis, PhD, vice-president of quality and healthcare analytics at Select Medical.

“Preventing these infections can help reduce complications and the length of stay for other patients. This infection reduction could also translate to a savings of approximately $3.7 million annually for the 30 long-term acute care hospitals studied.”

Select Medical, which is based in Mechanicsburg, Pennsylvania, owns long-term acute care and inpatient rehabilitation hospitals, as well as occupational health and physical therapy clinics.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

A central catheter maintenance bundle can decrease the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in the American Journal of Critical Care.

A team from the healthcare company Select Medical developed and implemented the bundle at 30 long-term acute care hospitals.

The team used infection prevention guidelines from the Centers for Disease Control and Prevention as the core of the bundle, with mandatory use of alcohol-based central catheter caps and chlorhexidine gluconate dressings.

Ongoing education of clinical staff about the protocol and a checklist to track compliance were also key elements of the initiative.

At each hospital, staff nurses who demonstrated competency in the care of central catheters monitored implementation of the bundle for the initial 6 months of the study.

Researchers reviewed the medical records of 6660 patients discharged during the 14 months prior to the study and 6559 patients discharged after implementation of the bundle. Patient days and central catheter days before and after the bundle was implemented were comparable.

Six months after the bundle was implemented, the CLABSI standardized infection rate had dropped 29%. The rate was 1.28 in the 6 months before the bundle was implemented and 0.96 six months after implementation.

There was a mean reduction of 4.5 CLABSIs per hospital for 14 months after the bundle was implemented.

“Our results encourage the development and implementation of similar bundles as effective infection reduction strategies in [long-term acute care hospitals],” said study author Antony Grigonis, PhD, vice-president of quality and healthcare analytics at Select Medical.

“Preventing these infections can help reduce complications and the length of stay for other patients. This infection reduction could also translate to a savings of approximately $3.7 million annually for the 30 long-term acute care hospitals studied.”

Select Medical, which is based in Mechanicsburg, Pennsylvania, owns long-term acute care and inpatient rehabilitation hospitals, as well as occupational health and physical therapy clinics.

Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.

Mammography

Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.² found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.³ According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.⁴

Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.⁵

The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.

Highlighting the importance of location in breast cancer care, Gehlert et al.⁶ asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.

With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).⁷

Delays in treatment

A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.⁸ investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.⁹ also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.¹⁰ demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.

Misuse of treatment

Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.¹¹ found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.

Underuse of treatment

In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.

The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.¹²

Silber et al.⁸ also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.

Bickell et al.¹³ explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.

Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.¹⁴ The study by Bickell et al.¹³ documented underuse of this treatment in African American patients. Partridge et al.¹⁵ conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.¹⁶ analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.¹⁷ More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.

The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.^18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,²⁰ but that assumption becomes more nuanced when the clinical trial experience is reviewed.

Clinical trial experience

Dignam²⁰ examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.

In contrast to Dignam’s findings²⁰, Hershman et al.²¹ assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs²² speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).

In their survival analysis, Hershman et al.²¹ controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”²¹ The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,²² and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.

In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.

Other installments of this column can be found in the Related Content box.

1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.

2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.

3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.

4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.

5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.

6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.

7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.

8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.

9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.

10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.

11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.

12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.

13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62.
14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.

15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.

16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.

17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.

18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.

19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.

20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.

21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.

22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.

Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.

Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.

Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.

Published in conjunction with Susan G. Komen®.

Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.

Mammography

Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.² found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.³ According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.⁴

Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.⁵

The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.

Highlighting the importance of location in breast cancer care, Gehlert et al.⁶ asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.

With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).⁷

Delays in treatment

A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.⁸ investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.⁹ also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.¹⁰ demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.

Misuse of treatment

Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.¹¹ found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.

Underuse of treatment

In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.

The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.¹²

Silber et al.⁸ also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.

Bickell et al.¹³ explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.

Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.¹⁴ The study by Bickell et al.¹³ documented underuse of this treatment in African American patients. Partridge et al.¹⁵ conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.¹⁶ analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.¹⁷ More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.

The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.^18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,²⁰ but that assumption becomes more nuanced when the clinical trial experience is reviewed.

Clinical trial experience

Dignam²⁰ examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.

In contrast to Dignam’s findings²⁰, Hershman et al.²¹ assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs²² speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).

In their survival analysis, Hershman et al.²¹ controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”²¹ The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,²² and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.

In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.

Other installments of this column can be found in the Related Content box.

1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.

2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.

3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.

4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.

5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.

6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.

7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.

8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.

9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.

10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.

11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.

12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.

13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62.
14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.

15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.

16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.

17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.

18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.

19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.

20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.

21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.

22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.

Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.

Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.

Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.

Published in conjunction with Susan G. Komen®.

Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.

Mammography

Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.² found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.³ According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.⁴

Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.⁵

The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.

Highlighting the importance of location in breast cancer care, Gehlert et al.⁶ asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.

With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).⁷

Delays in treatment

A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.⁸ investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.⁹ also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.¹⁰ demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.

Misuse of treatment

Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.¹¹ found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.

Underuse of treatment

In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.

The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.¹²

Silber et al.⁸ also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.

Bickell et al.¹³ explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.

Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.¹⁴ The study by Bickell et al.¹³ documented underuse of this treatment in African American patients. Partridge et al.¹⁵ conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.¹⁶ analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.¹⁷ More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.

The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.^18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,²⁰ but that assumption becomes more nuanced when the clinical trial experience is reviewed.

Clinical trial experience

Dignam²⁰ examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.

In contrast to Dignam’s findings²⁰, Hershman et al.²¹ assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs²² speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).

In their survival analysis, Hershman et al.²¹ controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”²¹ The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,²² and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.

In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.

Other installments of this column can be found in the Related Content box.

1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.

2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.

3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.

4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.

5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.

6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.

7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.

8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.

9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.

10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.

11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.

12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.

13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62.
14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.

15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.

16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.

17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.

18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.

19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.

20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.

21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.

22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.

Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.

Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.

Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.

Published in conjunction with Susan G. Komen®.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.

The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

s-photo/iStockphoto.com

In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.

In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).

The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.

No evidence was found for associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).

llaubach@frontlinemedcom.com

High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.

The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

s-photo/iStockphoto.com

In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.

In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).

The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.

No evidence was found for associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).

llaubach@frontlinemedcom.com

High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.

The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

s-photo/iStockphoto.com

In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.

In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).

The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.

No evidence was found for associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).

llaubach@frontlinemedcom.com