Lenalidomide led to independence from red blood cell transfusions for 27% of patients with lower-risk non-del(5q) myelodysplastic syndromes who were refractory to or ineligible for erythropoiesis-stimulating agents, based on the results of a phase III placebo-controlled study.

Patients were most likely to reach this primary endpoint if their baseline erythropoietin (EPO) level was less than 100 mU/mL, Dr. Valeria Santini of the University of Florence (Italy) and her associates wrote online June 27 in the Journal of Clinical Oncology.

ksena32/ThinkStock

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemia in lower-risk myelodysplastic syndrome (MDS) patients without a deletion 5q, but most patients stop responding over time. “Although azacitidine and decitabine are approved in the United States and other countries in this setting, no approved treatments exist in the European Union and other countries for ESA-refractory patients who are dependent on red blood cell transfusions,” the researchers wrote.

Their international double-blind study enrolled 239 adults with International Prognostic Scoring System lower- or intermediate-risk MDS who lacked the del(5q) mutation and needed at least 2 U of packed red blood cells every 28 days. Patients were randomly assigned 2:1 to lenalidomide (160 patients) or placebo (79 patients), given once daily for 28-day cycles. Patients whose creatinine clearance was 40-60 mL/min received 5 mg lenalidomide, while the rest received 10 mg. Randomization was stratified based on MDS treatment history, baseline transfusion requirements, and time from MDS diagnosis (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2015.66.0118). A total of 43 lenalidomide patients (27%) and 2 placebo patients (2.5%; P less than .001) did not require packed red blood cell transfusions for at least 8 weeks. Transfusion independence persisted through 24 weeks for 17% of lenalidomide patients and no placebo patients. Of 39 patients given 5-mg lenalidomide, 18% reached the primary endpoint (P = .006, compared with placebo). The median duration of response was nearly 31 weeks (95% confidence interval, 21-59 weeks). Prior use of ESAs was the only significant predictor of response in the multivariate analysis (odds ratio, 4.6; 95% confidence interval, 1.3-16.1; P = .01), although low baseline transfusion burden reached significance in the univariate model and borderline significance in the multivariate model (OR, 2.7; 95% CI, 0.96-7.6; P = .06).

The highest response rate (43%) occurred among the 40 patients who had previously received ESAs and had a baseline erythropoietin level under 100 mU/mL. The response rates for other patients previously treated with ESAs fell as baseline EPO level increased, and the response rate was only 9% among patients whose relatively high endogenous EPO level had made them ineligible for ESA treatment. “Patients with higher endogenous EPO levels may be less responsive due to marked intrinsic defects in erythroid signaling pathways, including signal transducer and activator of transcription extracellular regulated kinase 1/2, and lipid raft assembly, which are restored or stimulated by lenalidomide exposure,” the researchers wrote.

As in previous studies, grade 3-4 adverse events with lenalidomide usually were due to myelosuppression. Grade 3-4 neutropenia affected 99 lenalidomide patients (62%) and 10 placebo patients (13%). Grade 3-4 thrombocytopenia affected 57 lenalidomide patients (36%) and 3 placebo patients (4%). Lenalidomide was associated with a 3% rate of venous thrombosis but did not cause detectable pulmonary embolism. Lenalidomide was stopped in 32% of patients because of thrombocytopenia, neutropenia, or other adverse events, compared with 11% of placebo patients. In all, 2.5% of patients in each group died while on treatment.

Celgene makes lenalidomide and funded the study. Dr. Santini disclosed consulting or advisory roles and honoraria from Celgene, Janssen Pharmaceuticals, and Novartis. Seventeen coinvestigators also disclosed ties to Celgene.

Lenalidomide led to independence from red blood cell transfusions for 27% of patients with lower-risk non-del(5q) myelodysplastic syndromes who were refractory to or ineligible for erythropoiesis-stimulating agents, based on the results of a phase III placebo-controlled study.

Patients were most likely to reach this primary endpoint if their baseline erythropoietin (EPO) level was less than 100 mU/mL, Dr. Valeria Santini of the University of Florence (Italy) and her associates wrote online June 27 in the Journal of Clinical Oncology.

ksena32/ThinkStock

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemia in lower-risk myelodysplastic syndrome (MDS) patients without a deletion 5q, but most patients stop responding over time. “Although azacitidine and decitabine are approved in the United States and other countries in this setting, no approved treatments exist in the European Union and other countries for ESA-refractory patients who are dependent on red blood cell transfusions,” the researchers wrote.

Their international double-blind study enrolled 239 adults with International Prognostic Scoring System lower- or intermediate-risk MDS who lacked the del(5q) mutation and needed at least 2 U of packed red blood cells every 28 days. Patients were randomly assigned 2:1 to lenalidomide (160 patients) or placebo (79 patients), given once daily for 28-day cycles. Patients whose creatinine clearance was 40-60 mL/min received 5 mg lenalidomide, while the rest received 10 mg. Randomization was stratified based on MDS treatment history, baseline transfusion requirements, and time from MDS diagnosis (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2015.66.0118). A total of 43 lenalidomide patients (27%) and 2 placebo patients (2.5%; P less than .001) did not require packed red blood cell transfusions for at least 8 weeks. Transfusion independence persisted through 24 weeks for 17% of lenalidomide patients and no placebo patients. Of 39 patients given 5-mg lenalidomide, 18% reached the primary endpoint (P = .006, compared with placebo). The median duration of response was nearly 31 weeks (95% confidence interval, 21-59 weeks). Prior use of ESAs was the only significant predictor of response in the multivariate analysis (odds ratio, 4.6; 95% confidence interval, 1.3-16.1; P = .01), although low baseline transfusion burden reached significance in the univariate model and borderline significance in the multivariate model (OR, 2.7; 95% CI, 0.96-7.6; P = .06).

The highest response rate (43%) occurred among the 40 patients who had previously received ESAs and had a baseline erythropoietin level under 100 mU/mL. The response rates for other patients previously treated with ESAs fell as baseline EPO level increased, and the response rate was only 9% among patients whose relatively high endogenous EPO level had made them ineligible for ESA treatment. “Patients with higher endogenous EPO levels may be less responsive due to marked intrinsic defects in erythroid signaling pathways, including signal transducer and activator of transcription extracellular regulated kinase 1/2, and lipid raft assembly, which are restored or stimulated by lenalidomide exposure,” the researchers wrote.

As in previous studies, grade 3-4 adverse events with lenalidomide usually were due to myelosuppression. Grade 3-4 neutropenia affected 99 lenalidomide patients (62%) and 10 placebo patients (13%). Grade 3-4 thrombocytopenia affected 57 lenalidomide patients (36%) and 3 placebo patients (4%). Lenalidomide was associated with a 3% rate of venous thrombosis but did not cause detectable pulmonary embolism. Lenalidomide was stopped in 32% of patients because of thrombocytopenia, neutropenia, or other adverse events, compared with 11% of placebo patients. In all, 2.5% of patients in each group died while on treatment.

Celgene makes lenalidomide and funded the study. Dr. Santini disclosed consulting or advisory roles and honoraria from Celgene, Janssen Pharmaceuticals, and Novartis. Seventeen coinvestigators also disclosed ties to Celgene.

Lenalidomide led to independence from red blood cell transfusions for 27% of patients with lower-risk non-del(5q) myelodysplastic syndromes who were refractory to or ineligible for erythropoiesis-stimulating agents, based on the results of a phase III placebo-controlled study.

Patients were most likely to reach this primary endpoint if their baseline erythropoietin (EPO) level was less than 100 mU/mL, Dr. Valeria Santini of the University of Florence (Italy) and her associates wrote online June 27 in the Journal of Clinical Oncology.

ksena32/ThinkStock

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemia in lower-risk myelodysplastic syndrome (MDS) patients without a deletion 5q, but most patients stop responding over time. “Although azacitidine and decitabine are approved in the United States and other countries in this setting, no approved treatments exist in the European Union and other countries for ESA-refractory patients who are dependent on red blood cell transfusions,” the researchers wrote.

Their international double-blind study enrolled 239 adults with International Prognostic Scoring System lower- or intermediate-risk MDS who lacked the del(5q) mutation and needed at least 2 U of packed red blood cells every 28 days. Patients were randomly assigned 2:1 to lenalidomide (160 patients) or placebo (79 patients), given once daily for 28-day cycles. Patients whose creatinine clearance was 40-60 mL/min received 5 mg lenalidomide, while the rest received 10 mg. Randomization was stratified based on MDS treatment history, baseline transfusion requirements, and time from MDS diagnosis (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2015.66.0118). A total of 43 lenalidomide patients (27%) and 2 placebo patients (2.5%; P less than .001) did not require packed red blood cell transfusions for at least 8 weeks. Transfusion independence persisted through 24 weeks for 17% of lenalidomide patients and no placebo patients. Of 39 patients given 5-mg lenalidomide, 18% reached the primary endpoint (P = .006, compared with placebo). The median duration of response was nearly 31 weeks (95% confidence interval, 21-59 weeks). Prior use of ESAs was the only significant predictor of response in the multivariate analysis (odds ratio, 4.6; 95% confidence interval, 1.3-16.1; P = .01), although low baseline transfusion burden reached significance in the univariate model and borderline significance in the multivariate model (OR, 2.7; 95% CI, 0.96-7.6; P = .06).

The highest response rate (43%) occurred among the 40 patients who had previously received ESAs and had a baseline erythropoietin level under 100 mU/mL. The response rates for other patients previously treated with ESAs fell as baseline EPO level increased, and the response rate was only 9% among patients whose relatively high endogenous EPO level had made them ineligible for ESA treatment. “Patients with higher endogenous EPO levels may be less responsive due to marked intrinsic defects in erythroid signaling pathways, including signal transducer and activator of transcription extracellular regulated kinase 1/2, and lipid raft assembly, which are restored or stimulated by lenalidomide exposure,” the researchers wrote.

As in previous studies, grade 3-4 adverse events with lenalidomide usually were due to myelosuppression. Grade 3-4 neutropenia affected 99 lenalidomide patients (62%) and 10 placebo patients (13%). Grade 3-4 thrombocytopenia affected 57 lenalidomide patients (36%) and 3 placebo patients (4%). Lenalidomide was associated with a 3% rate of venous thrombosis but did not cause detectable pulmonary embolism. Lenalidomide was stopped in 32% of patients because of thrombocytopenia, neutropenia, or other adverse events, compared with 11% of placebo patients. In all, 2.5% of patients in each group died while on treatment.

Celgene makes lenalidomide and funded the study. Dr. Santini disclosed consulting or advisory roles and honoraria from Celgene, Janssen Pharmaceuticals, and Novartis. Seventeen coinvestigators also disclosed ties to Celgene.

Although acute otitis media (AOM) has decreased in number, and especially the more severe difficult to treat versions, I was reminded that this still is a problem for young children based on personal experience with grandchildren. What can be baffling to some families is the fact that some strains of the same organism species cause AOM and some simply colonize the nasopharynx (NP) of children without causing any disease at all. These organisms include Streptococcus pneumoniae (SPN) and nontypeable Haemophilus influenzae (ntHi).

Recent studies have uncovered several molecular reasons for the pathogen vs. colonizer dichotomy:

• Strains within a species can have variants of a gene that make them more disease producing.

• Some usually colonizing strains produce disease after acquiring new genes.

• Some strains have native genes with on-off switches that convert them from a colonizing to disease producing under selected circumstances.

• Molecular targets in the respiratory tract increase, allowing more dense colonization that increases chances of AOM.

Variant gene

J.R. Gilsdorf, MD, and his group at the University of Michigan,¹ Ann Arbor, recently showed that among the various high-molecular-weight molecules (HMW) produced by 170 ntHi from three different geographically diverse countries, one variant in particular (HMW-A) was more likely to be found in strains producing AOM than strains simply colonizing the nasopharynx. The protein product of this gene allows better adherence to respiratory epithelia. So more bacteria sticking in the NP near the eustachian tube opening make development of AOM more likely. Some call this the “more barbarians at the gate” phenomenon.

Gene acquisition

SPN inherently has a somewhat incomplete arginine synthesis pathway. Because arginine is essential for growth of SPN, S. pneumoniae utilizes some host factors to compensate; but this compensation is inefficient. However, SPN strains can acquire new genes – usually from other gram-positive organisms in their environment – by a process called conjugation.

One recently reported acquired gene set is that which completes functionality of SPN’s arginine synthesis pathway.² Investigators showed that SPN that acquire these arginine synthesis genes replicate more readily in bodily fluids, such as serum or cerebrospinal fluid, making these strains more aggressive, more virulent, and more likely to produce disease. More efficient replication makes it very difficult for host immune responses to handle these SPN. This is not limited to AOM alone, but seems important in invasive disease (such as meningitis) from SPN type 7, which had recently become more frequent after introduction of pneumococcal conjugate vaccines.

On-off gene switches

Another group of investigators reported that a thing called “phasevarion,” which is fancy lingo for an on-off switch is at the root of more virulence in ntHi.³ It seems that some strains of ntHi have a version of the ModA2 gene, which is always turned off, while other strains have a gene that is always on. Then, there is a third version in which the gene is usually off, but turns on when in places like the middle ear. The ModA2 gene appears to affect several other downstream protein groups that include HMW-A, antibiotic susceptibility, and biofilm formation. When inoculated into the middle ear in a chinchilla AOM model, the ntHi strains that can turn on their ModA2 gene were much more likely to produce AOM than either version that could not change. Interestingly, the authors postulate that preventing the switch capability could be a novel way to prevent ntHi disease, such as pediatric AOM, acute bacterial sinusitis, or some bronchitis in adults.

Molecular environment becomes more favorable

Another group⁴ reported that adherence receptor for ntHi is intercellular adhesion molecule 1 (ICAM1), a molecule found in modest quantities on respiratory epithelium. You may know it as the attachment molecule for rhinovirus and enteroviruses. What makes this interesting is that adenovirus, respiratory syncytial virus, and exposure to cigarette smoke⁵ markedly increase expression of ICAM1 on respiratory epithelium, predisposing to more ntHi adhering and more likely to produce an inflammatory process, such as AOM. This is another version of the barbarians at the gate phenomenon.

So when families ask why SPN or ntHi sometimes exist quietly (colonize) the nasopharynx and sometimes they cause AOM or acute bacterial sinusitis, you can hopefully use these four examples as partial explanations of why the same bacterial species has strains that can be either colonizers or pathogens.

References

1. Infect Genet Evol. 2014 Dec;28:223-32

2. J Infect Dis. 2014 Jun 1;209:1781-91.

3. J Infect Dis. 2016 Jun 10. pii: jiw243. [Epub ahead of print]

4. Cell Microbiol. 2016 Feb 9. doi: 10.1111/cmi.12575. [Epub ahead of print]

5. Am J Respir Cell Mol Biol. 2003 Oct;29:472-82.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

Although acute otitis media (AOM) has decreased in number, and especially the more severe difficult to treat versions, I was reminded that this still is a problem for young children based on personal experience with grandchildren. What can be baffling to some families is the fact that some strains of the same organism species cause AOM and some simply colonize the nasopharynx (NP) of children without causing any disease at all. These organisms include Streptococcus pneumoniae (SPN) and nontypeable Haemophilus influenzae (ntHi).

Recent studies have uncovered several molecular reasons for the pathogen vs. colonizer dichotomy:

• Strains within a species can have variants of a gene that make them more disease producing.

• Some usually colonizing strains produce disease after acquiring new genes.

• Some strains have native genes with on-off switches that convert them from a colonizing to disease producing under selected circumstances.

• Molecular targets in the respiratory tract increase, allowing more dense colonization that increases chances of AOM.

Variant gene

J.R. Gilsdorf, MD, and his group at the University of Michigan,¹ Ann Arbor, recently showed that among the various high-molecular-weight molecules (HMW) produced by 170 ntHi from three different geographically diverse countries, one variant in particular (HMW-A) was more likely to be found in strains producing AOM than strains simply colonizing the nasopharynx. The protein product of this gene allows better adherence to respiratory epithelia. So more bacteria sticking in the NP near the eustachian tube opening make development of AOM more likely. Some call this the “more barbarians at the gate” phenomenon.

Gene acquisition

SPN inherently has a somewhat incomplete arginine synthesis pathway. Because arginine is essential for growth of SPN, S. pneumoniae utilizes some host factors to compensate; but this compensation is inefficient. However, SPN strains can acquire new genes – usually from other gram-positive organisms in their environment – by a process called conjugation.

One recently reported acquired gene set is that which completes functionality of SPN’s arginine synthesis pathway.² Investigators showed that SPN that acquire these arginine synthesis genes replicate more readily in bodily fluids, such as serum or cerebrospinal fluid, making these strains more aggressive, more virulent, and more likely to produce disease. More efficient replication makes it very difficult for host immune responses to handle these SPN. This is not limited to AOM alone, but seems important in invasive disease (such as meningitis) from SPN type 7, which had recently become more frequent after introduction of pneumococcal conjugate vaccines.

On-off gene switches

Another group of investigators reported that a thing called “phasevarion,” which is fancy lingo for an on-off switch is at the root of more virulence in ntHi.³ It seems that some strains of ntHi have a version of the ModA2 gene, which is always turned off, while other strains have a gene that is always on. Then, there is a third version in which the gene is usually off, but turns on when in places like the middle ear. The ModA2 gene appears to affect several other downstream protein groups that include HMW-A, antibiotic susceptibility, and biofilm formation. When inoculated into the middle ear in a chinchilla AOM model, the ntHi strains that can turn on their ModA2 gene were much more likely to produce AOM than either version that could not change. Interestingly, the authors postulate that preventing the switch capability could be a novel way to prevent ntHi disease, such as pediatric AOM, acute bacterial sinusitis, or some bronchitis in adults.

Molecular environment becomes more favorable

Another group⁴ reported that adherence receptor for ntHi is intercellular adhesion molecule 1 (ICAM1), a molecule found in modest quantities on respiratory epithelium. You may know it as the attachment molecule for rhinovirus and enteroviruses. What makes this interesting is that adenovirus, respiratory syncytial virus, and exposure to cigarette smoke⁵ markedly increase expression of ICAM1 on respiratory epithelium, predisposing to more ntHi adhering and more likely to produce an inflammatory process, such as AOM. This is another version of the barbarians at the gate phenomenon.

So when families ask why SPN or ntHi sometimes exist quietly (colonize) the nasopharynx and sometimes they cause AOM or acute bacterial sinusitis, you can hopefully use these four examples as partial explanations of why the same bacterial species has strains that can be either colonizers or pathogens.

References

1. Infect Genet Evol. 2014 Dec;28:223-32

2. J Infect Dis. 2014 Jun 1;209:1781-91.

3. J Infect Dis. 2016 Jun 10. pii: jiw243. [Epub ahead of print]

4. Cell Microbiol. 2016 Feb 9. doi: 10.1111/cmi.12575. [Epub ahead of print]

5. Am J Respir Cell Mol Biol. 2003 Oct;29:472-82.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

Although acute otitis media (AOM) has decreased in number, and especially the more severe difficult to treat versions, I was reminded that this still is a problem for young children based on personal experience with grandchildren. What can be baffling to some families is the fact that some strains of the same organism species cause AOM and some simply colonize the nasopharynx (NP) of children without causing any disease at all. These organisms include Streptococcus pneumoniae (SPN) and nontypeable Haemophilus influenzae (ntHi).

Recent studies have uncovered several molecular reasons for the pathogen vs. colonizer dichotomy:

• Strains within a species can have variants of a gene that make them more disease producing.

• Some usually colonizing strains produce disease after acquiring new genes.

• Some strains have native genes with on-off switches that convert them from a colonizing to disease producing under selected circumstances.

• Molecular targets in the respiratory tract increase, allowing more dense colonization that increases chances of AOM.

Variant gene

J.R. Gilsdorf, MD, and his group at the University of Michigan,¹ Ann Arbor, recently showed that among the various high-molecular-weight molecules (HMW) produced by 170 ntHi from three different geographically diverse countries, one variant in particular (HMW-A) was more likely to be found in strains producing AOM than strains simply colonizing the nasopharynx. The protein product of this gene allows better adherence to respiratory epithelia. So more bacteria sticking in the NP near the eustachian tube opening make development of AOM more likely. Some call this the “more barbarians at the gate” phenomenon.

Gene acquisition

SPN inherently has a somewhat incomplete arginine synthesis pathway. Because arginine is essential for growth of SPN, S. pneumoniae utilizes some host factors to compensate; but this compensation is inefficient. However, SPN strains can acquire new genes – usually from other gram-positive organisms in their environment – by a process called conjugation.

One recently reported acquired gene set is that which completes functionality of SPN’s arginine synthesis pathway.² Investigators showed that SPN that acquire these arginine synthesis genes replicate more readily in bodily fluids, such as serum or cerebrospinal fluid, making these strains more aggressive, more virulent, and more likely to produce disease. More efficient replication makes it very difficult for host immune responses to handle these SPN. This is not limited to AOM alone, but seems important in invasive disease (such as meningitis) from SPN type 7, which had recently become more frequent after introduction of pneumococcal conjugate vaccines.

On-off gene switches

Another group of investigators reported that a thing called “phasevarion,” which is fancy lingo for an on-off switch is at the root of more virulence in ntHi.³ It seems that some strains of ntHi have a version of the ModA2 gene, which is always turned off, while other strains have a gene that is always on. Then, there is a third version in which the gene is usually off, but turns on when in places like the middle ear. The ModA2 gene appears to affect several other downstream protein groups that include HMW-A, antibiotic susceptibility, and biofilm formation. When inoculated into the middle ear in a chinchilla AOM model, the ntHi strains that can turn on their ModA2 gene were much more likely to produce AOM than either version that could not change. Interestingly, the authors postulate that preventing the switch capability could be a novel way to prevent ntHi disease, such as pediatric AOM, acute bacterial sinusitis, or some bronchitis in adults.

Molecular environment becomes more favorable

Another group⁴ reported that adherence receptor for ntHi is intercellular adhesion molecule 1 (ICAM1), a molecule found in modest quantities on respiratory epithelium. You may know it as the attachment molecule for rhinovirus and enteroviruses. What makes this interesting is that adenovirus, respiratory syncytial virus, and exposure to cigarette smoke⁵ markedly increase expression of ICAM1 on respiratory epithelium, predisposing to more ntHi adhering and more likely to produce an inflammatory process, such as AOM. This is another version of the barbarians at the gate phenomenon.

So when families ask why SPN or ntHi sometimes exist quietly (colonize) the nasopharynx and sometimes they cause AOM or acute bacterial sinusitis, you can hopefully use these four examples as partial explanations of why the same bacterial species has strains that can be either colonizers or pathogens.

References

1. Infect Genet Evol. 2014 Dec;28:223-32

2. J Infect Dis. 2014 Jun 1;209:1781-91.

3. J Infect Dis. 2016 Jun 10. pii: jiw243. [Epub ahead of print]

4. Cell Microbiol. 2016 Feb 9. doi: 10.1111/cmi.12575. [Epub ahead of print]

5. Am J Respir Cell Mol Biol. 2003 Oct;29:472-82.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

The monoclonal antibody ipilimumab was the first treatment in more than 30 years to improve long-term survival in metastatic melanoma patients. Offering expensive ipilimumab treatment presented significant business challenges and potential financial risks for our private oncology practice and for patients because of the high acquisition cost of this agent. There was initial uncertainty about the willingness of insurance companies to reimburse for this new drug based on previous experiences in our practice with other expensive new drugs. Here we describe how our multiphysician practice methodically introduced ipilimumab treatment into the practice.

Click on the PDF icon at the top of this introduction to read the full article.

The monoclonal antibody ipilimumab was the first treatment in more than 30 years to improve long-term survival in metastatic melanoma patients. Offering expensive ipilimumab treatment presented significant business challenges and potential financial risks for our private oncology practice and for patients because of the high acquisition cost of this agent. There was initial uncertainty about the willingness of insurance companies to reimburse for this new drug based on previous experiences in our practice with other expensive new drugs. Here we describe how our multiphysician practice methodically introduced ipilimumab treatment into the practice.

Click on the PDF icon at the top of this introduction to read the full article.

The monoclonal antibody ipilimumab was the first treatment in more than 30 years to improve long-term survival in metastatic melanoma patients. Offering expensive ipilimumab treatment presented significant business challenges and potential financial risks for our private oncology practice and for patients because of the high acquisition cost of this agent. There was initial uncertainty about the willingness of insurance companies to reimburse for this new drug based on previous experiences in our practice with other expensive new drugs. Here we describe how our multiphysician practice methodically introduced ipilimumab treatment into the practice.

Click on the PDF icon at the top of this introduction to read the full article.

In December 2015, alectinib became the third ALK inhibitor approved by the United States Food and Drug Administration for the treatment of non-small-cell lung cancer (NSCLC) that displays rearrangements of the anaplastic lymphoma kinase (ALK) gene. Alectinib is a second-generation small molecule inhibitor of the ALK protein that joins ceritinib in providing a useful treatment option for patients who have progressed on crizotinib, as a result of its ability to target crizotinib-resistant mutant forms of the ALK protein. Alectinib also displays enhanced penetrance of the blood-brain barrier, which improves efficacy against central nervous system (CNS) metastases.

Click on the PDF icon at the top of this introduction to read the full article.

In December 2015, alectinib became the third ALK inhibitor approved by the United States Food and Drug Administration for the treatment of non-small-cell lung cancer (NSCLC) that displays rearrangements of the anaplastic lymphoma kinase (ALK) gene. Alectinib is a second-generation small molecule inhibitor of the ALK protein that joins ceritinib in providing a useful treatment option for patients who have progressed on crizotinib, as a result of its ability to target crizotinib-resistant mutant forms of the ALK protein. Alectinib also displays enhanced penetrance of the blood-brain barrier, which improves efficacy against central nervous system (CNS) metastases.

Click on the PDF icon at the top of this introduction to read the full article.

In December 2015, alectinib became the third ALK inhibitor approved by the United States Food and Drug Administration for the treatment of non-small-cell lung cancer (NSCLC) that displays rearrangements of the anaplastic lymphoma kinase (ALK) gene. Alectinib is a second-generation small molecule inhibitor of the ALK protein that joins ceritinib in providing a useful treatment option for patients who have progressed on crizotinib, as a result of its ability to target crizotinib-resistant mutant forms of the ALK protein. Alectinib also displays enhanced penetrance of the blood-brain barrier, which improves efficacy against central nervous system (CNS) metastases.

Click on the PDF icon at the top of this introduction to read the full article.

ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.

While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.

Mitchel L. Zoler/Frontline Medical News

“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.

What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.

“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.

“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.

That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

Mitchel L. Zoler/Frontline Medical News

The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.

The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.

“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.

An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.

Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.

“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.

But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.

“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.

Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A_1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.

Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.

[email protected]

On Twitter@mitchelzoler

ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.

While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.

Mitchel L. Zoler/Frontline Medical News

“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.

What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.

“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.

“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.

That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

Mitchel L. Zoler/Frontline Medical News

The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.

The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.

“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.

An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.

Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.

“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.

But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.

“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.

Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A_1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.

Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.

[email protected]

On Twitter@mitchelzoler

ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.

While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.

Mitchel L. Zoler/Frontline Medical News

“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.

What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.

“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.

“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.

That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

Mitchel L. Zoler/Frontline Medical News

The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.

The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.

“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.

An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.

Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.

“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.

But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.

“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.

Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A_1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.

Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.

[email protected]

On Twitter@mitchelzoler

Enlarged facial pores are superficial skin structures that are visualized as small openings on the skin corresponding to the openings of the pilosebaceous apparatus. These openings may be impacted with horny follicular plugs consisting of sebaceous debris that appear as open comedones.¹ Skin pores is a lay term that is poorly defined in the medical literature and often is categorized in terms of arbitrary circular diameters determined through cosmetic skin analyzers.² The term refers to pilosebaceous follicular enlargements (with or without open comedonal horny impactions) that can be visualized by the naked eye, most commonly occurring on the face and scalp. These enlarged pores remain a pervasive cosmetic concern that impacts patient quality of life. Enlarged pores are difficult to treat, in part due to lack of knowledge of the pathophysiology; thus, we review the currently proposed causes of enlarged pilosebaceous openings and the treatments in the scope of this pathogenesis with a focus on therapeutic efficacy.

Pathogenesis of Enlarged Facial Pores

It is now thought that seborrhea, loss of skin elasticity and tension, and hair follicle size are most clinically relevant to the pathogenesis of enlarged pores.² Other potential associated and causative factors include genetic predisposition, acne, comedogenic xenobiotics, chronic photodamage, chronic radiodermatitis, and vitamin A deficiency.^1,3

The direct relationship between sebum output and pore size has been well established, particularly in men who generally have higher sebum output levels than women, which likely is testosterone driven.^4,5 However, there are contradictory data on whether sex affects pore size, as females also exhibit contributory hormonal factors. Sebum output and pore size increase substantially during the ovulation phase of the female menstrual cycle, likely secondary to increased progesterone affecting sebaceous gland activity.^2,4 The presence of acne also is associated with enlarged facial pores, though the extent of seborrhea as a confounding factor is unclear. Furthermore, acne severity does not correlate with increased pore size.⁵ However, the processes of acne and facial pores are interlinked, given the frequent occurrence of open comedones within the pores.

Skin elasticity and tensile strength when defined visually and mechanically has shown a negative correlation with facial pore size and density.⁵ It is well known that cutaneous aging and chronic photodamage cause perturbation in the collagen and elastin framework that allows for the skin to maintain its resilient properties.⁶ Aged and photodamaged skin also demonstrates decreased expression of microfibril-associated glycoprotein-1 (MAGP-1), a crucial component in elastic fiber assembly and skin elasticity in the dermis and perifollicular/pore areas.⁷

Pore density and size appears to range diversely across ethnicities, though Chinese women exhibit notably lower pore size and density across all ages as compared to other ethnicities.⁸ Black individuals have aberrant epidermal architecture, defined as the presence of stalagmitelike structures at the dermoepidermal junction, correlating with enlarged pore size compared to other ethnicities.^2,8

Treating Enlarged Facial Pores

Treatments for enlarged facial pores primarily aim to decrease sebum production, rejuvenate skin, remove hair, and/or decrease follicular size. Evidence-based studies are limited, and many currently used therapies have not been studied with enlarged facial pores as a primary investigative outcome. Here, we include studies that report efficacy in decreasing pore size specifically. It is important to note the lack of a uniform and objective modality with which to report skin pore size. Studies use a wide range of techniques including patient self-reporting, physician observation, and software image analyzers.

Topical Therapies

Topical retinoids are vitamin A derivatives, and they are first-line therapies in reversing the aberrant collagen and elastin-associated epidermal and dermal changes that occur with chronological aging and photoaging. Tretinoin, isotretinoin, and tazarotene have shown efficacy in multiple parameters of skin rejuvenation, including facial pores, skin wrinkling, hyperpigmentation, skin laxity, and sebum production.⁹ However, it is important to note that retinoids treat keratinocyte atypia in acne, and efficacy in facial pores is confounded by improvement in follicular keratinization. Because studies have not distinctly uncoupled this association, it is erroneous to conclude that retinoids reduce facial pore size and density irrespective of concomitant acne vulgaris.

Tazarotene has been evaluated for use in reducing facial pore size. In one investigation, 568 patients with moderate wrinkling or hyperpigmentation were randomized to receive tazarotene cream 0.1% or placebo once daily for 24 weeks and were evaluated for enlarged facial pores as a secondary outcome using a double-blinded physician 5-point scale.¹⁰ At week 24, 42% of tazarotene-treated patients achieved improvement of at least 1 point compared to 20% of placebo-treated patients (P<.001). Adverse events were dermatitic, as can be expected of retinoids, leading to a 4% discontinuation rate in the tazarotene group compared to 1% in the placebo group.¹⁰

Tretinoin has long been used off label for antiaging treatments but has only recently shown efficacy for facial pores. In one study, 60 women who had previously sought antiaging procedures were treated with tretinoin cream 0.025% once daily and no other antiaging products or procedures for 90 days.¹¹ Facial pore evaluations were determined by a modified dermatoscope with a polarized analyzer for clinical scoring using a photonumeric scale. Patients improved from a baseline average score of 3.2 in facial pores to a posttreatment average score of 2.0 (P<.05) at day 84. This improvement was sustained from day 28 of treatment and corresponded to patient self-perception. Adverse events included xerosis, desquamation, burning, and erythema, which led to 3 premature discontinuations.¹¹

Various chemical peel formulations are used in skin rejuvenation and have shown application in enlarged facial pores. Chemical peels act at the epidermal or dermal level to induce temporary breakdown and regeneration of healthier cells and improved skin matrix.¹² Twenty-two Japanese women applied glycolic acid (30% solution) every 2 weeks for a total of 5 treatments and exhibited reduced appearance of conspicuous, open, and dark pores, defined by surface area and shading as determined through dermatoscopic and software analysis, with mean improvement rates of 34.6%, 11%, and 34.3%, respectively. More than 70% of participants exhibited improvement in enlarged facial pores.¹³ A study involving a 40% glycolic acid and vitamin C formulation demonstrated significant improvement in facial pores (28.3%; P<.001).¹⁴

The newest topical therapies studied for use in minimizing facial pilosebaceous openings are natural plant-derived copper chlorophyllin complex sodium salt (CHLcu) and tetra-hydro-jasmonic acid (LR2412). Clinical trials of these botanicals are limited with small sample sizes but are included here as novel treatments requiring further investigation.

Chlorophyllin copper complex sodium salt is derived from chlorophyll, a green pigment found in plants, and has been investigated as a topical gel in liposomal dispersions for application in photodamaged and aged skin. Chlorophyllin copper complex sodium salt exerts in vitro hyaluronidase inhibitory activity to maintain hyaluronic acid in the extracellular matrix and counteract the structural breakdown of cutaneous aging.¹⁵ Two small single-center pilot trials enrolled 10 participants each in a 3-week study of CHLcu 0.1% twice daily and an 8-week study of CHLcu 0.066% twice daily.^16,17 After 3 weeks, patients treated with CHLcu 0.1% exhibited a 22.2% improvement in facial pores by clinical assessment grading, though this improvement was not significant on software imaging analysis. Patients improved the most on parameters of facial seborrhea by clinical assessment.¹⁶ After 8 weeks, patients treated with CHLcu 0.066% exhibited 25.3% improvement in facial pores by clinical assessment grading.¹⁷ Treatments were reported to be well tolerated without noted adverse events in both studies.

Tetra-hydro-jasmonic acid is an analogue of jasmonic acid, a plant hormone derived from linoleic acid. Due to its favorable safety profile and bioavailability, penetration into epidermal and dermal layers, and potential effects in rejuvenating desquamation, LR2412 is currently being assessed for treatment of skin wrinkles, texture, and pores.¹⁸ Its effect is thought to relate to stimulation of laminin-5, collagen IV, and fibrillin deposition at the dermoepidermal junction.¹⁹ In an open-label trial of a topical preparation of LR2412, 15 participants were treated twice daily for 6 weeks and assessed through investigator clinical assessment scoring.²⁰ Investigator scoring of pores improved by 25.2% from baseline (P<.05) after 6 weeks of treatment. Improvement in pores was seen as early as days 1 and 3. No serious adverse events were reported, though 2 participants developed acne on follow-up.²⁰

Tetra-hydro-jasmonic acid also is formulated with retinol (retinol 0.2%/LR2412 2.0%) and demonstrated cosmetic efficacy in a noninferiority trial with tretinoin cream 0.025%.¹¹ Sixty patients each were randomized to retinol/LR2412 or tretinoin at bedtime and treated for 90 days. At day 84, participants in the retinol/LR2412 group exhibited an improvement in investigator clinical assessment scoring from a baseline of 3.6 to 2.5 (P<.05). There were no significant differences in investigator-assessed efficacy between the treatment arms. Participants reported similar or better results and fewer side effects with retinol/LR2412 on self-questionnaires. Eight participants treated with retinol/LR2412 and 15 participants treated with tretinoin reported various incidences of skin irritation, burning, and desquamation.¹¹

Oral Therapies

The most commonly used oral therapies for enlarged pores are antiandrogens, such as combined oral contraceptives, spironolactone, and cyproterone acetate, which modulate sebum production due to the presence of androgen receptors within sebaceous glands.²¹ Forty-four white women in an open-label, phase 4 study were treated with combined oral contraceptives containing chlormadinone acetate–ethinyl estradiol for 6 menstrual cycles, with standardized photography taken before and after the treatment period for software analysis. After 6 treatment cycles, 9.1% (4/44) of participants had visibly enlarged pores of the forehead and cheeks compared to 43.2% (19/44) of participants at baseline (P<.0001).²² The effects of other antiandrogens on facial pores have not been studied in this capacity.

Lasers, Radiofrequency, and Ultrasound Devices

The development of various devices that can deliver targeted thermal or ultrasound energy to the skin offers the newest and most robust modality in cosmetic therapy. The mechanism of their efficacy may be due to a combination of induced remodeling of collagen fibers near pilosebaceous openings to increase skin elasticity and decrease sebum production.^2,23

Devices with established antiaging effects have been extensively reviewed and include the gold particle 800-nm diode laser, 1450-nm diode laser, microneedle apparatuses, fractional radiofrequency devices, 2790-nm erbium:YAG laser, nonablative 1410-nm fractionated erbium-doped fiber laser, and nonablative 1440-nm fractional laser.²

Literature on the use of these devices for minimizing facial pore size is limited. One treatment of intense focused ultrasound using a 3-mm transducer successfully improved overall pore appearance in 91% of sites at 6-week follow-up on a clinical grading scale.²⁴ Three sessions of nonablative 1410-nm fractionated erbium-doped fiber laser treatments yielded facial skin pore minimization of greater than 51% in 14 of 15 participants.²⁵

The nonablative 1440-nm diode fractional laser received 510(k) clearance by the US Food and Drug Administration in 2011 for aesthetic use in chronologically aged and photoaged skin. Twenty participants treated for 2 weeks and a total of 6 facial treatments with this laser system showed a 17% average improvement in facial pore score on software analysis (P≤.002). Adverse events were mild and included erythema and xerosis.²⁶

Conclusion

The reliability of available literature on efficacy of various treatments in diminishing facial skin pores has been challenging given that most studies are low in power, lack control groups, use nonuniform methods of reporting outcomes, and do not report complete adverse events. Thus, all results should be interpreted with caution.

Overall, it is clear that the pathogenesis of enlarged facial pores is multifactorial and complex, necessitating a similar approach to therapeutics. Topical treatments offer a range of diverse therapies with proven benefit in facial pore reduction. The advent of lasers and devices offers constantly evolving therapeutic options with diffuse antiaging effects. Despite the numerous topical, oral, and device-oriented options, enlarged facial pores remain a challenging cosmetic concern. More robust efficacy studies on new treatments are necessary.

Enlarged facial pores are superficial skin structures that are visualized as small openings on the skin corresponding to the openings of the pilosebaceous apparatus. These openings may be impacted with horny follicular plugs consisting of sebaceous debris that appear as open comedones.¹ Skin pores is a lay term that is poorly defined in the medical literature and often is categorized in terms of arbitrary circular diameters determined through cosmetic skin analyzers.² The term refers to pilosebaceous follicular enlargements (with or without open comedonal horny impactions) that can be visualized by the naked eye, most commonly occurring on the face and scalp. These enlarged pores remain a pervasive cosmetic concern that impacts patient quality of life. Enlarged pores are difficult to treat, in part due to lack of knowledge of the pathophysiology; thus, we review the currently proposed causes of enlarged pilosebaceous openings and the treatments in the scope of this pathogenesis with a focus on therapeutic efficacy.

Pathogenesis of Enlarged Facial Pores

It is now thought that seborrhea, loss of skin elasticity and tension, and hair follicle size are most clinically relevant to the pathogenesis of enlarged pores.² Other potential associated and causative factors include genetic predisposition, acne, comedogenic xenobiotics, chronic photodamage, chronic radiodermatitis, and vitamin A deficiency.^1,3

The direct relationship between sebum output and pore size has been well established, particularly in men who generally have higher sebum output levels than women, which likely is testosterone driven.^4,5 However, there are contradictory data on whether sex affects pore size, as females also exhibit contributory hormonal factors. Sebum output and pore size increase substantially during the ovulation phase of the female menstrual cycle, likely secondary to increased progesterone affecting sebaceous gland activity.^2,4 The presence of acne also is associated with enlarged facial pores, though the extent of seborrhea as a confounding factor is unclear. Furthermore, acne severity does not correlate with increased pore size.⁵ However, the processes of acne and facial pores are interlinked, given the frequent occurrence of open comedones within the pores.

Skin elasticity and tensile strength when defined visually and mechanically has shown a negative correlation with facial pore size and density.⁵ It is well known that cutaneous aging and chronic photodamage cause perturbation in the collagen and elastin framework that allows for the skin to maintain its resilient properties.⁶ Aged and photodamaged skin also demonstrates decreased expression of microfibril-associated glycoprotein-1 (MAGP-1), a crucial component in elastic fiber assembly and skin elasticity in the dermis and perifollicular/pore areas.⁷

Pore density and size appears to range diversely across ethnicities, though Chinese women exhibit notably lower pore size and density across all ages as compared to other ethnicities.⁸ Black individuals have aberrant epidermal architecture, defined as the presence of stalagmitelike structures at the dermoepidermal junction, correlating with enlarged pore size compared to other ethnicities.^2,8

Treating Enlarged Facial Pores

Treatments for enlarged facial pores primarily aim to decrease sebum production, rejuvenate skin, remove hair, and/or decrease follicular size. Evidence-based studies are limited, and many currently used therapies have not been studied with enlarged facial pores as a primary investigative outcome. Here, we include studies that report efficacy in decreasing pore size specifically. It is important to note the lack of a uniform and objective modality with which to report skin pore size. Studies use a wide range of techniques including patient self-reporting, physician observation, and software image analyzers.

Topical Therapies

Topical retinoids are vitamin A derivatives, and they are first-line therapies in reversing the aberrant collagen and elastin-associated epidermal and dermal changes that occur with chronological aging and photoaging. Tretinoin, isotretinoin, and tazarotene have shown efficacy in multiple parameters of skin rejuvenation, including facial pores, skin wrinkling, hyperpigmentation, skin laxity, and sebum production.⁹ However, it is important to note that retinoids treat keratinocyte atypia in acne, and efficacy in facial pores is confounded by improvement in follicular keratinization. Because studies have not distinctly uncoupled this association, it is erroneous to conclude that retinoids reduce facial pore size and density irrespective of concomitant acne vulgaris.

Tazarotene has been evaluated for use in reducing facial pore size. In one investigation, 568 patients with moderate wrinkling or hyperpigmentation were randomized to receive tazarotene cream 0.1% or placebo once daily for 24 weeks and were evaluated for enlarged facial pores as a secondary outcome using a double-blinded physician 5-point scale.¹⁰ At week 24, 42% of tazarotene-treated patients achieved improvement of at least 1 point compared to 20% of placebo-treated patients (P<.001). Adverse events were dermatitic, as can be expected of retinoids, leading to a 4% discontinuation rate in the tazarotene group compared to 1% in the placebo group.¹⁰

Tretinoin has long been used off label for antiaging treatments but has only recently shown efficacy for facial pores. In one study, 60 women who had previously sought antiaging procedures were treated with tretinoin cream 0.025% once daily and no other antiaging products or procedures for 90 days.¹¹ Facial pore evaluations were determined by a modified dermatoscope with a polarized analyzer for clinical scoring using a photonumeric scale. Patients improved from a baseline average score of 3.2 in facial pores to a posttreatment average score of 2.0 (P<.05) at day 84. This improvement was sustained from day 28 of treatment and corresponded to patient self-perception. Adverse events included xerosis, desquamation, burning, and erythema, which led to 3 premature discontinuations.¹¹

Various chemical peel formulations are used in skin rejuvenation and have shown application in enlarged facial pores. Chemical peels act at the epidermal or dermal level to induce temporary breakdown and regeneration of healthier cells and improved skin matrix.¹² Twenty-two Japanese women applied glycolic acid (30% solution) every 2 weeks for a total of 5 treatments and exhibited reduced appearance of conspicuous, open, and dark pores, defined by surface area and shading as determined through dermatoscopic and software analysis, with mean improvement rates of 34.6%, 11%, and 34.3%, respectively. More than 70% of participants exhibited improvement in enlarged facial pores.¹³ A study involving a 40% glycolic acid and vitamin C formulation demonstrated significant improvement in facial pores (28.3%; P<.001).¹⁴

The newest topical therapies studied for use in minimizing facial pilosebaceous openings are natural plant-derived copper chlorophyllin complex sodium salt (CHLcu) and tetra-hydro-jasmonic acid (LR2412). Clinical trials of these botanicals are limited with small sample sizes but are included here as novel treatments requiring further investigation.

Chlorophyllin copper complex sodium salt is derived from chlorophyll, a green pigment found in plants, and has been investigated as a topical gel in liposomal dispersions for application in photodamaged and aged skin. Chlorophyllin copper complex sodium salt exerts in vitro hyaluronidase inhibitory activity to maintain hyaluronic acid in the extracellular matrix and counteract the structural breakdown of cutaneous aging.¹⁵ Two small single-center pilot trials enrolled 10 participants each in a 3-week study of CHLcu 0.1% twice daily and an 8-week study of CHLcu 0.066% twice daily.^16,17 After 3 weeks, patients treated with CHLcu 0.1% exhibited a 22.2% improvement in facial pores by clinical assessment grading, though this improvement was not significant on software imaging analysis. Patients improved the most on parameters of facial seborrhea by clinical assessment.¹⁶ After 8 weeks, patients treated with CHLcu 0.066% exhibited 25.3% improvement in facial pores by clinical assessment grading.¹⁷ Treatments were reported to be well tolerated without noted adverse events in both studies.

Tetra-hydro-jasmonic acid is an analogue of jasmonic acid, a plant hormone derived from linoleic acid. Due to its favorable safety profile and bioavailability, penetration into epidermal and dermal layers, and potential effects in rejuvenating desquamation, LR2412 is currently being assessed for treatment of skin wrinkles, texture, and pores.¹⁸ Its effect is thought to relate to stimulation of laminin-5, collagen IV, and fibrillin deposition at the dermoepidermal junction.¹⁹ In an open-label trial of a topical preparation of LR2412, 15 participants were treated twice daily for 6 weeks and assessed through investigator clinical assessment scoring.²⁰ Investigator scoring of pores improved by 25.2% from baseline (P<.05) after 6 weeks of treatment. Improvement in pores was seen as early as days 1 and 3. No serious adverse events were reported, though 2 participants developed acne on follow-up.²⁰

Tetra-hydro-jasmonic acid also is formulated with retinol (retinol 0.2%/LR2412 2.0%) and demonstrated cosmetic efficacy in a noninferiority trial with tretinoin cream 0.025%.¹¹ Sixty patients each were randomized to retinol/LR2412 or tretinoin at bedtime and treated for 90 days. At day 84, participants in the retinol/LR2412 group exhibited an improvement in investigator clinical assessment scoring from a baseline of 3.6 to 2.5 (P<.05). There were no significant differences in investigator-assessed efficacy between the treatment arms. Participants reported similar or better results and fewer side effects with retinol/LR2412 on self-questionnaires. Eight participants treated with retinol/LR2412 and 15 participants treated with tretinoin reported various incidences of skin irritation, burning, and desquamation.¹¹

Oral Therapies

The most commonly used oral therapies for enlarged pores are antiandrogens, such as combined oral contraceptives, spironolactone, and cyproterone acetate, which modulate sebum production due to the presence of androgen receptors within sebaceous glands.²¹ Forty-four white women in an open-label, phase 4 study were treated with combined oral contraceptives containing chlormadinone acetate–ethinyl estradiol for 6 menstrual cycles, with standardized photography taken before and after the treatment period for software analysis. After 6 treatment cycles, 9.1% (4/44) of participants had visibly enlarged pores of the forehead and cheeks compared to 43.2% (19/44) of participants at baseline (P<.0001).²² The effects of other antiandrogens on facial pores have not been studied in this capacity.

Lasers, Radiofrequency, and Ultrasound Devices

The development of various devices that can deliver targeted thermal or ultrasound energy to the skin offers the newest and most robust modality in cosmetic therapy. The mechanism of their efficacy may be due to a combination of induced remodeling of collagen fibers near pilosebaceous openings to increase skin elasticity and decrease sebum production.^2,23

Devices with established antiaging effects have been extensively reviewed and include the gold particle 800-nm diode laser, 1450-nm diode laser, microneedle apparatuses, fractional radiofrequency devices, 2790-nm erbium:YAG laser, nonablative 1410-nm fractionated erbium-doped fiber laser, and nonablative 1440-nm fractional laser.²

Literature on the use of these devices for minimizing facial pore size is limited. One treatment of intense focused ultrasound using a 3-mm transducer successfully improved overall pore appearance in 91% of sites at 6-week follow-up on a clinical grading scale.²⁴ Three sessions of nonablative 1410-nm fractionated erbium-doped fiber laser treatments yielded facial skin pore minimization of greater than 51% in 14 of 15 participants.²⁵

The nonablative 1440-nm diode fractional laser received 510(k) clearance by the US Food and Drug Administration in 2011 for aesthetic use in chronologically aged and photoaged skin. Twenty participants treated for 2 weeks and a total of 6 facial treatments with this laser system showed a 17% average improvement in facial pore score on software analysis (P≤.002). Adverse events were mild and included erythema and xerosis.²⁶

Conclusion

The reliability of available literature on efficacy of various treatments in diminishing facial skin pores has been challenging given that most studies are low in power, lack control groups, use nonuniform methods of reporting outcomes, and do not report complete adverse events. Thus, all results should be interpreted with caution.

Overall, it is clear that the pathogenesis of enlarged facial pores is multifactorial and complex, necessitating a similar approach to therapeutics. Topical treatments offer a range of diverse therapies with proven benefit in facial pore reduction. The advent of lasers and devices offers constantly evolving therapeutic options with diffuse antiaging effects. Despite the numerous topical, oral, and device-oriented options, enlarged facial pores remain a challenging cosmetic concern. More robust efficacy studies on new treatments are necessary.

Enlarged facial pores are superficial skin structures that are visualized as small openings on the skin corresponding to the openings of the pilosebaceous apparatus. These openings may be impacted with horny follicular plugs consisting of sebaceous debris that appear as open comedones.¹ Skin pores is a lay term that is poorly defined in the medical literature and often is categorized in terms of arbitrary circular diameters determined through cosmetic skin analyzers.² The term refers to pilosebaceous follicular enlargements (with or without open comedonal horny impactions) that can be visualized by the naked eye, most commonly occurring on the face and scalp. These enlarged pores remain a pervasive cosmetic concern that impacts patient quality of life. Enlarged pores are difficult to treat, in part due to lack of knowledge of the pathophysiology; thus, we review the currently proposed causes of enlarged pilosebaceous openings and the treatments in the scope of this pathogenesis with a focus on therapeutic efficacy.

Pathogenesis of Enlarged Facial Pores

It is now thought that seborrhea, loss of skin elasticity and tension, and hair follicle size are most clinically relevant to the pathogenesis of enlarged pores.² Other potential associated and causative factors include genetic predisposition, acne, comedogenic xenobiotics, chronic photodamage, chronic radiodermatitis, and vitamin A deficiency.^1,3

The direct relationship between sebum output and pore size has been well established, particularly in men who generally have higher sebum output levels than women, which likely is testosterone driven.^4,5 However, there are contradictory data on whether sex affects pore size, as females also exhibit contributory hormonal factors. Sebum output and pore size increase substantially during the ovulation phase of the female menstrual cycle, likely secondary to increased progesterone affecting sebaceous gland activity.^2,4 The presence of acne also is associated with enlarged facial pores, though the extent of seborrhea as a confounding factor is unclear. Furthermore, acne severity does not correlate with increased pore size.⁵ However, the processes of acne and facial pores are interlinked, given the frequent occurrence of open comedones within the pores.

Skin elasticity and tensile strength when defined visually and mechanically has shown a negative correlation with facial pore size and density.⁵ It is well known that cutaneous aging and chronic photodamage cause perturbation in the collagen and elastin framework that allows for the skin to maintain its resilient properties.⁶ Aged and photodamaged skin also demonstrates decreased expression of microfibril-associated glycoprotein-1 (MAGP-1), a crucial component in elastic fiber assembly and skin elasticity in the dermis and perifollicular/pore areas.⁷

Pore density and size appears to range diversely across ethnicities, though Chinese women exhibit notably lower pore size and density across all ages as compared to other ethnicities.⁸ Black individuals have aberrant epidermal architecture, defined as the presence of stalagmitelike structures at the dermoepidermal junction, correlating with enlarged pore size compared to other ethnicities.^2,8

Treating Enlarged Facial Pores

Treatments for enlarged facial pores primarily aim to decrease sebum production, rejuvenate skin, remove hair, and/or decrease follicular size. Evidence-based studies are limited, and many currently used therapies have not been studied with enlarged facial pores as a primary investigative outcome. Here, we include studies that report efficacy in decreasing pore size specifically. It is important to note the lack of a uniform and objective modality with which to report skin pore size. Studies use a wide range of techniques including patient self-reporting, physician observation, and software image analyzers.

Topical Therapies

Topical retinoids are vitamin A derivatives, and they are first-line therapies in reversing the aberrant collagen and elastin-associated epidermal and dermal changes that occur with chronological aging and photoaging. Tretinoin, isotretinoin, and tazarotene have shown efficacy in multiple parameters of skin rejuvenation, including facial pores, skin wrinkling, hyperpigmentation, skin laxity, and sebum production.⁹ However, it is important to note that retinoids treat keratinocyte atypia in acne, and efficacy in facial pores is confounded by improvement in follicular keratinization. Because studies have not distinctly uncoupled this association, it is erroneous to conclude that retinoids reduce facial pore size and density irrespective of concomitant acne vulgaris.

Tazarotene has been evaluated for use in reducing facial pore size. In one investigation, 568 patients with moderate wrinkling or hyperpigmentation were randomized to receive tazarotene cream 0.1% or placebo once daily for 24 weeks and were evaluated for enlarged facial pores as a secondary outcome using a double-blinded physician 5-point scale.¹⁰ At week 24, 42% of tazarotene-treated patients achieved improvement of at least 1 point compared to 20% of placebo-treated patients (P<.001). Adverse events were dermatitic, as can be expected of retinoids, leading to a 4% discontinuation rate in the tazarotene group compared to 1% in the placebo group.¹⁰

Tretinoin has long been used off label for antiaging treatments but has only recently shown efficacy for facial pores. In one study, 60 women who had previously sought antiaging procedures were treated with tretinoin cream 0.025% once daily and no other antiaging products or procedures for 90 days.¹¹ Facial pore evaluations were determined by a modified dermatoscope with a polarized analyzer for clinical scoring using a photonumeric scale. Patients improved from a baseline average score of 3.2 in facial pores to a posttreatment average score of 2.0 (P<.05) at day 84. This improvement was sustained from day 28 of treatment and corresponded to patient self-perception. Adverse events included xerosis, desquamation, burning, and erythema, which led to 3 premature discontinuations.¹¹

Various chemical peel formulations are used in skin rejuvenation and have shown application in enlarged facial pores. Chemical peels act at the epidermal or dermal level to induce temporary breakdown and regeneration of healthier cells and improved skin matrix.¹² Twenty-two Japanese women applied glycolic acid (30% solution) every 2 weeks for a total of 5 treatments and exhibited reduced appearance of conspicuous, open, and dark pores, defined by surface area and shading as determined through dermatoscopic and software analysis, with mean improvement rates of 34.6%, 11%, and 34.3%, respectively. More than 70% of participants exhibited improvement in enlarged facial pores.¹³ A study involving a 40% glycolic acid and vitamin C formulation demonstrated significant improvement in facial pores (28.3%; P<.001).¹⁴

The newest topical therapies studied for use in minimizing facial pilosebaceous openings are natural plant-derived copper chlorophyllin complex sodium salt (CHLcu) and tetra-hydro-jasmonic acid (LR2412). Clinical trials of these botanicals are limited with small sample sizes but are included here as novel treatments requiring further investigation.

Chlorophyllin copper complex sodium salt is derived from chlorophyll, a green pigment found in plants, and has been investigated as a topical gel in liposomal dispersions for application in photodamaged and aged skin. Chlorophyllin copper complex sodium salt exerts in vitro hyaluronidase inhibitory activity to maintain hyaluronic acid in the extracellular matrix and counteract the structural breakdown of cutaneous aging.¹⁵ Two small single-center pilot trials enrolled 10 participants each in a 3-week study of CHLcu 0.1% twice daily and an 8-week study of CHLcu 0.066% twice daily.^16,17 After 3 weeks, patients treated with CHLcu 0.1% exhibited a 22.2% improvement in facial pores by clinical assessment grading, though this improvement was not significant on software imaging analysis. Patients improved the most on parameters of facial seborrhea by clinical assessment.¹⁶ After 8 weeks, patients treated with CHLcu 0.066% exhibited 25.3% improvement in facial pores by clinical assessment grading.¹⁷ Treatments were reported to be well tolerated without noted adverse events in both studies.

Tetra-hydro-jasmonic acid is an analogue of jasmonic acid, a plant hormone derived from linoleic acid. Due to its favorable safety profile and bioavailability, penetration into epidermal and dermal layers, and potential effects in rejuvenating desquamation, LR2412 is currently being assessed for treatment of skin wrinkles, texture, and pores.¹⁸ Its effect is thought to relate to stimulation of laminin-5, collagen IV, and fibrillin deposition at the dermoepidermal junction.¹⁹ In an open-label trial of a topical preparation of LR2412, 15 participants were treated twice daily for 6 weeks and assessed through investigator clinical assessment scoring.²⁰ Investigator scoring of pores improved by 25.2% from baseline (P<.05) after 6 weeks of treatment. Improvement in pores was seen as early as days 1 and 3. No serious adverse events were reported, though 2 participants developed acne on follow-up.²⁰

Tetra-hydro-jasmonic acid also is formulated with retinol (retinol 0.2%/LR2412 2.0%) and demonstrated cosmetic efficacy in a noninferiority trial with tretinoin cream 0.025%.¹¹ Sixty patients each were randomized to retinol/LR2412 or tretinoin at bedtime and treated for 90 days. At day 84, participants in the retinol/LR2412 group exhibited an improvement in investigator clinical assessment scoring from a baseline of 3.6 to 2.5 (P<.05). There were no significant differences in investigator-assessed efficacy between the treatment arms. Participants reported similar or better results and fewer side effects with retinol/LR2412 on self-questionnaires. Eight participants treated with retinol/LR2412 and 15 participants treated with tretinoin reported various incidences of skin irritation, burning, and desquamation.¹¹

Oral Therapies

The most commonly used oral therapies for enlarged pores are antiandrogens, such as combined oral contraceptives, spironolactone, and cyproterone acetate, which modulate sebum production due to the presence of androgen receptors within sebaceous glands.²¹ Forty-four white women in an open-label, phase 4 study were treated with combined oral contraceptives containing chlormadinone acetate–ethinyl estradiol for 6 menstrual cycles, with standardized photography taken before and after the treatment period for software analysis. After 6 treatment cycles, 9.1% (4/44) of participants had visibly enlarged pores of the forehead and cheeks compared to 43.2% (19/44) of participants at baseline (P<.0001).²² The effects of other antiandrogens on facial pores have not been studied in this capacity.

Lasers, Radiofrequency, and Ultrasound Devices

The development of various devices that can deliver targeted thermal or ultrasound energy to the skin offers the newest and most robust modality in cosmetic therapy. The mechanism of their efficacy may be due to a combination of induced remodeling of collagen fibers near pilosebaceous openings to increase skin elasticity and decrease sebum production.^2,23

Devices with established antiaging effects have been extensively reviewed and include the gold particle 800-nm diode laser, 1450-nm diode laser, microneedle apparatuses, fractional radiofrequency devices, 2790-nm erbium:YAG laser, nonablative 1410-nm fractionated erbium-doped fiber laser, and nonablative 1440-nm fractional laser.²

Literature on the use of these devices for minimizing facial pore size is limited. One treatment of intense focused ultrasound using a 3-mm transducer successfully improved overall pore appearance in 91% of sites at 6-week follow-up on a clinical grading scale.²⁴ Three sessions of nonablative 1410-nm fractionated erbium-doped fiber laser treatments yielded facial skin pore minimization of greater than 51% in 14 of 15 participants.²⁵

The nonablative 1440-nm diode fractional laser received 510(k) clearance by the US Food and Drug Administration in 2011 for aesthetic use in chronologically aged and photoaged skin. Twenty participants treated for 2 weeks and a total of 6 facial treatments with this laser system showed a 17% average improvement in facial pore score on software analysis (P≤.002). Adverse events were mild and included erythema and xerosis.²⁶

Conclusion

The reliability of available literature on efficacy of various treatments in diminishing facial skin pores has been challenging given that most studies are low in power, lack control groups, use nonuniform methods of reporting outcomes, and do not report complete adverse events. Thus, all results should be interpreted with caution.

Overall, it is clear that the pathogenesis of enlarged facial pores is multifactorial and complex, necessitating a similar approach to therapeutics. Topical treatments offer a range of diverse therapies with proven benefit in facial pore reduction. The advent of lasers and devices offers constantly evolving therapeutic options with diffuse antiaging effects. Despite the numerous topical, oral, and device-oriented options, enlarged facial pores remain a challenging cosmetic concern. More robust efficacy studies on new treatments are necessary.

New findings published June 29 suggest that women with frequent religious attendance had substantially lower suicide risk, compared with women who did not attend religious services as often.

“Our results do not imply that health care providers should prescribe attendance at religious services,” wrote Tyler J. VanderWeele, PhD, and his associates. “However, for patients who are already religious, service attendance might be encouraged as a form of meaningful social participation.”

The investigators examined 89,708 women from 1996-2010. Out of the 89,708 women studied, 17,028 attended services more than once per week, 36,488 attended once per week, 14,548 attended fewer than once per week, and 21,644 never attended. In the multivariable regression model, women who attended religious services one time per week or more in 1996 had an approximately fivefold lower rate of suicide (adjusted hazard ratio, 0.16).

Dr. VanderWeele and his associates also found that suicide risks differed between Catholic and Protestant participants. The religious attendance HR for women who attended Catholic services one time a week or more, compared with women who attended fewer than one time a week, was 0.05 (95% confidence interval, 0.006-0.48), which was approximately sevenfold smaller than the corresponding HR for Protestants (HR, 0.34; 95% CI, 0.10-1.10; P = .05 for heterogeneity).

Mediation analysis was used to evaluate whether depressive symptoms in 2000, alcohol consumption in 1998, and subsequent social integration score in 2000 played a role in religious service attendance and suicide. With depressive symptoms, alcohol consumption, and social integration score adjusted, the women who attended religious services fewer than once per week, compared with women who did not attend at all, changed from 0.85 to 0.94. However, the HR for women attending religious services more than once per week, compared with the women who did not attend at all, did not change (0.16).

Read the full study in Jama Psychiatry (doi: 10.1001/jamapsychiatry.2016.1243).

[email protected]

New findings published June 29 suggest that women with frequent religious attendance had substantially lower suicide risk, compared with women who did not attend religious services as often.

“Our results do not imply that health care providers should prescribe attendance at religious services,” wrote Tyler J. VanderWeele, PhD, and his associates. “However, for patients who are already religious, service attendance might be encouraged as a form of meaningful social participation.”

The investigators examined 89,708 women from 1996-2010. Out of the 89,708 women studied, 17,028 attended services more than once per week, 36,488 attended once per week, 14,548 attended fewer than once per week, and 21,644 never attended. In the multivariable regression model, women who attended religious services one time per week or more in 1996 had an approximately fivefold lower rate of suicide (adjusted hazard ratio, 0.16).

Dr. VanderWeele and his associates also found that suicide risks differed between Catholic and Protestant participants. The religious attendance HR for women who attended Catholic services one time a week or more, compared with women who attended fewer than one time a week, was 0.05 (95% confidence interval, 0.006-0.48), which was approximately sevenfold smaller than the corresponding HR for Protestants (HR, 0.34; 95% CI, 0.10-1.10; P = .05 for heterogeneity).

Mediation analysis was used to evaluate whether depressive symptoms in 2000, alcohol consumption in 1998, and subsequent social integration score in 2000 played a role in religious service attendance and suicide. With depressive symptoms, alcohol consumption, and social integration score adjusted, the women who attended religious services fewer than once per week, compared with women who did not attend at all, changed from 0.85 to 0.94. However, the HR for women attending religious services more than once per week, compared with the women who did not attend at all, did not change (0.16).

Read the full study in Jama Psychiatry (doi: 10.1001/jamapsychiatry.2016.1243).

[email protected]

New findings published June 29 suggest that women with frequent religious attendance had substantially lower suicide risk, compared with women who did not attend religious services as often.

“Our results do not imply that health care providers should prescribe attendance at religious services,” wrote Tyler J. VanderWeele, PhD, and his associates. “However, for patients who are already religious, service attendance might be encouraged as a form of meaningful social participation.”

The investigators examined 89,708 women from 1996-2010. Out of the 89,708 women studied, 17,028 attended services more than once per week, 36,488 attended once per week, 14,548 attended fewer than once per week, and 21,644 never attended. In the multivariable regression model, women who attended religious services one time per week or more in 1996 had an approximately fivefold lower rate of suicide (adjusted hazard ratio, 0.16).

Dr. VanderWeele and his associates also found that suicide risks differed between Catholic and Protestant participants. The religious attendance HR for women who attended Catholic services one time a week or more, compared with women who attended fewer than one time a week, was 0.05 (95% confidence interval, 0.006-0.48), which was approximately sevenfold smaller than the corresponding HR for Protestants (HR, 0.34; 95% CI, 0.10-1.10; P = .05 for heterogeneity).

Mediation analysis was used to evaluate whether depressive symptoms in 2000, alcohol consumption in 1998, and subsequent social integration score in 2000 played a role in religious service attendance and suicide. With depressive symptoms, alcohol consumption, and social integration score adjusted, the women who attended religious services fewer than once per week, compared with women who did not attend at all, changed from 0.85 to 0.94. However, the HR for women attending religious services more than once per week, compared with the women who did not attend at all, did not change (0.16).

Read the full study in Jama Psychiatry (doi: 10.1001/jamapsychiatry.2016.1243).

[email protected]

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

VANCOUVER—A diagnosis of concussion is based on clinical observation and testing, and it therefore is susceptible to error. Researchers are seeking biomarkers in CSF, in serum, and on imaging that could provide stronger grounds for a diagnosis of concussion, as well as a method of monitoring recovery, according to an overview provided at the 68th Annual Meeting of the American Academy of Neurology.

Concussion often occurs with no macroscopic evidence of injury. Symptoms of concussion can be subjective and nonspecific, and a patient report of symptoms is not sufficient grounds for a diagnosis of concussion. In addition, athletes may not report their symptoms to avoid being sidelined.

“What we need is an objective biomarker,” said David W. Dodick, MD, Professor of Neurology at Mayo Clinic in Phoenix, Arizona. “We need a biomarker for diagnosis, we need one for recovery, and we need one that could potentially prognosticate how these athletes are going to do over time and whether we should return that athlete ever to play.”

CSF Biomarkers

“The optimal biomarker, of course, would be in the CSF because it’s in direct contact with the extracellular matrix and interstitial fluid of the brain, and its composition reflects what’s going on biochemically in that organ,” said Dr. Dodick.

David W. Dodick, MD

In one study, investigators collected CSF from 30 Olympic boxers at one to six days after a bout and after 14 days of rest. The researchers found increased levels of tau, neurofilament light, and glial fibrillary acidic protein (GFAP) in more than 80% of the boxers after their bouts. Neurofilament light and GFAP remained elevated after the rest period and for more than three months after injury. This result “implies that there may be ongoing degeneration well after a bout,” said Dr. Dodick.

CSF biomarkers, however, are not pragmatic for acute concussion evaluation or management on a large scale, he added. “We’re not going to be pulling out a lumbar puncture tray on the sideline, or even in our office, for most individuals.” But studies like this one suggest which biomarkers might be relevant for the diagnosis of concussion.

Serum Biomarkers

Blood biomarkers are more pragmatic than CSF biomarkers for acute postconcussion evaluation, said Dr. Dodick. In 2014, investigators examined blood biomarkers after concussion in 288 professional hockey players. They found a statistically significant increase in total tau after concussion, compared with preseason measurements. In contrast, they found no significant difference in S100 beta or neuron-specific enolase. These biomarkers did increase after a friendly game without concussion, however.

“Total tau at one hour correlates with symptom duration, so the lower the concentration of total tau increase at one hour, the more likely that athlete was to become asymptomatic more quickly,” said Dr. Dodick. Total tau thus may be a biomarker for recovery as well as for brain injury. Total tau elevations at six days predicted the persistence of symptoms and the development of postconcussion syndrome, Dr. Dodick added.

In 2015, researchers examined total tau in military personnel with and without concussion during the previous six months. Compared with controls, personnel who self-reported concussion had a significant increase in total tau. Personnel with a diagnosis of concussion also had a statistically significant increase in total tau, compared with controls and with personnel with self-reported concussion. In addition, tau concentration was associated with postconcussion syndrome at months to years after concussion, independent of posttraumatic stress disorder and depressive symptoms.

A systematic review of research on S100 beta concluded that extracranial injury, physical activity, intoxication with alcohol, and medications affect the level of this biomarker. S100 beta has a short half-life, and a sample must be collected within 30 minutes of injury to be accurate. “All we can say now is that if you have high levels of S100 beta, that’s a cause for concern, and it may correlate with imaging changes,” said Dr. Dodick. “Maybe it could be used in conjunction with some of the other biomarkers like total tau if you can access the blood early enough.”

A 2013 study published in PLoS One included nine patients presenting to an emergency department with mild traumatic brain injury. Their levels of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) were fivefold higher than those of normal controls, and their levels of GFAP were tenfold higher. Elevation in GFAP correlated with hemorrhage on susceptibility-weighted imaging. These biomarkers may identify patients for whom an MRI would be informative, said Dr. Dodick.

More recently, investigators took blood samples from 584 patients with trauma and found that GFAP and UCHL1 were detectable within one hour of injury. GFAP concentration peaked at 20 hours, declined slowly, and remained detectable at seven days. GFAP distinguished patients with traumatic brain injury from injured controls. The biomarker also correlated with CT lesions and the need for neurosurgical intervention. The researchers concluded that UCHL1 could be used as a point-of-care test at the scene of injury and that GFAP was useful in the subacute and in the acute phase of injury.

Blood biomarkers have limitations, however. Although they are highly expressed in CNS, they are detected in low concentrations in serum. In addition, blood biomarkers such as S100 beta have sources outside the brain, thus they are not specific to concussion. Finally, the precision of current immunoassays for these biomarkers needs improvement, said Dr. Dodick.

Imaging Biomarkers

Imaging biomarkers also could support a diagnosis of concussion. In one study, 142 patients with concussion underwent gadolinium-enhanced MRI scans within 48 hours of injury. Meningeal hemorrhage was seen on CT in about 13% of participants, but almost half had focal gadolinium enhancement on MRI. The results indicate a possible breakdown of the blood–brain barrier, said Dr. Dodick.

An investigation published in Annals of Neurology examined 135 patients with concussion and a normal CT of the head. Approximately 30% of participants had abnormal brain MRI scans. Findings included sulcal subarachnoid hemorrhage, hemosiderin deposition, and focal contusions.

In a study published in 2015 in Neurology, researchers found 60 microbleeds in 26 patients with concussion, compared with 15 microbleeds in 12 control subjects. Approximately 90% of the microbleeds in participants with concussion were cortical or subcortical, compared with 20% in controls. Patients with concussion and microbleeds have poor short-term memory and other neuropsychologic deficits on examination. Microbleeds resulting from concussion usually occur at the juncture of gray matter and white matter, said Dr. Dodick.

Lobar cerebral microbleeds appear to be a biomarker of severity and to indicate risk of adverse long-term outcomes. This biomarker can inform decision-making and is ready to be integrated into clinical practice, said Dr. Dodick.

In another study, 45 male and female university-level ice hockey players underwent susceptibility-weighted imaging before and after the playing season, as well as 72 hours, two weeks, and two months after a concussion. The investigators saw a significant increase in cerebral microbleeds in male athletes at two weeks after concussion, and a significant increase in microbleeds in males without concussion, compared with females, at the beginning and end of the season.

—Erik Greb

DENVER – Poor sleep quality and shorter sleep duration in boys at age 11 years is associated with subsequent accelerated use and misuse of alcohol and cannabis during adolescence and emerging adulthood, Thomas B. Mike reported at the annual meeting of the Associated Professional Sleep Societies.

This association has been reported before in cross-sectional studies. But Mr. Mike presented new findings from the longitudinal prospective Pitt Mother and Child Project.

Bruce Jancin/Frontline Medical News

The study comprised 170 boys aged 11 years whose mothers filled out the Child Sleep Questionnaire, modified for pediatric use from the well known Pittsburgh Sleep Quality Index. At that time, the boys also were assessed for internalizing and externalizing behaviors, neighborhood dangerousness, and socioeconomic status – all of which are factors known to influence teen substance use.

When participants reached ages 20 and 22 years, they underwent detailed interviews including assessment via the validated Lifetime Drinking History and Lifetime Drug History questionnaires.

In a multivariate Cox regression analysis controlling for a history of child internalizing and externalizing problem behavior as well as socioeconomic factors, every hour of sleep duration less than 9.5 hours at age 11 years was associated with a 21% acceleration in the time to first use of alcohol and a 22% acceleration in first use of cannabis, reported Mr. Mike, a medical student at the University of Pittsburgh.

Moreover, every 1 point worse score for sleep quality on the Child Sleep Questionnaire, scored from 0 (best) to 21 (worst), was associated with a 9% acceleration in time to alcohol use and an 8% acceleration to cannabis use.

Subjects with poor sleep duration and quality as 11-year-olds by parental report also experienced intoxication at a younger age than did those who had been better sleepers at that age. And they reported more frequent use of alcohol and cannabis during adolescence.

In an interview, Mr. Mike, who is planning a career in pediatrics, said the study findings contain an important message for pediatricians and family physicians when they meet with the parents of young boys entering adolescence.

“Probably the biggest take-home message is, ‘sleep more, sleep better.’ We don’t have a lot of ways to intervene right now for kids who have poor sleep, but we know based on this and other studies that kids who don’t sleep enough are more likely to use drugs and more likely to engage in other risky behaviors. So any way the parents can intervene will help, perhaps by getting them to bed earlier or trying to get them on a more regular schedule. At a social policy level, having school start later would probably be the most effective measure, but that probably won’t happen for a very long time,” he said.

“The vast majority of people who end up addicted to drugs later in life started when they were kids, so any way we can reduce adolescent substance use should have a downstream effect, including a decreased total substance use burden,” Mr. Mike added.

Possible mechanisms for the observed longitudinal association between poor quality and duration of sleep at age 11 years and earlier and heavier use of alcohol and cannabis later in adolescence include attempted self-medication for sleep problems, reward regulation, and alterations in brain chemistry, making the boys more susceptible to using drugs later in life, perhaps because they obtain a bigger high than their peers do. The investigators plan to delve deeper into the role of self-regulation and mental health as possible mechanisms linking childhood sleep and later substance use, he said.

The Pitt Mother and Child Project is supported by the National Institutes of Health. Mr. Mike reported having no financial conflicts.

DENVER – Poor sleep quality and shorter sleep duration in boys at age 11 years is associated with subsequent accelerated use and misuse of alcohol and cannabis during adolescence and emerging adulthood, Thomas B. Mike reported at the annual meeting of the Associated Professional Sleep Societies.

This association has been reported before in cross-sectional studies. But Mr. Mike presented new findings from the longitudinal prospective Pitt Mother and Child Project.

Bruce Jancin/Frontline Medical News

The study comprised 170 boys aged 11 years whose mothers filled out the Child Sleep Questionnaire, modified for pediatric use from the well known Pittsburgh Sleep Quality Index. At that time, the boys also were assessed for internalizing and externalizing behaviors, neighborhood dangerousness, and socioeconomic status – all of which are factors known to influence teen substance use.

When participants reached ages 20 and 22 years, they underwent detailed interviews including assessment via the validated Lifetime Drinking History and Lifetime Drug History questionnaires.

In a multivariate Cox regression analysis controlling for a history of child internalizing and externalizing problem behavior as well as socioeconomic factors, every hour of sleep duration less than 9.5 hours at age 11 years was associated with a 21% acceleration in the time to first use of alcohol and a 22% acceleration in first use of cannabis, reported Mr. Mike, a medical student at the University of Pittsburgh.

Moreover, every 1 point worse score for sleep quality on the Child Sleep Questionnaire, scored from 0 (best) to 21 (worst), was associated with a 9% acceleration in time to alcohol use and an 8% acceleration to cannabis use.

Subjects with poor sleep duration and quality as 11-year-olds by parental report also experienced intoxication at a younger age than did those who had been better sleepers at that age. And they reported more frequent use of alcohol and cannabis during adolescence.

In an interview, Mr. Mike, who is planning a career in pediatrics, said the study findings contain an important message for pediatricians and family physicians when they meet with the parents of young boys entering adolescence.

“Probably the biggest take-home message is, ‘sleep more, sleep better.’ We don’t have a lot of ways to intervene right now for kids who have poor sleep, but we know based on this and other studies that kids who don’t sleep enough are more likely to use drugs and more likely to engage in other risky behaviors. So any way the parents can intervene will help, perhaps by getting them to bed earlier or trying to get them on a more regular schedule. At a social policy level, having school start later would probably be the most effective measure, but that probably won’t happen for a very long time,” he said.

“The vast majority of people who end up addicted to drugs later in life started when they were kids, so any way we can reduce adolescent substance use should have a downstream effect, including a decreased total substance use burden,” Mr. Mike added.

Possible mechanisms for the observed longitudinal association between poor quality and duration of sleep at age 11 years and earlier and heavier use of alcohol and cannabis later in adolescence include attempted self-medication for sleep problems, reward regulation, and alterations in brain chemistry, making the boys more susceptible to using drugs later in life, perhaps because they obtain a bigger high than their peers do. The investigators plan to delve deeper into the role of self-regulation and mental health as possible mechanisms linking childhood sleep and later substance use, he said.

The Pitt Mother and Child Project is supported by the National Institutes of Health. Mr. Mike reported having no financial conflicts.

DENVER – Poor sleep quality and shorter sleep duration in boys at age 11 years is associated with subsequent accelerated use and misuse of alcohol and cannabis during adolescence and emerging adulthood, Thomas B. Mike reported at the annual meeting of the Associated Professional Sleep Societies.

This association has been reported before in cross-sectional studies. But Mr. Mike presented new findings from the longitudinal prospective Pitt Mother and Child Project.

Bruce Jancin/Frontline Medical News

The study comprised 170 boys aged 11 years whose mothers filled out the Child Sleep Questionnaire, modified for pediatric use from the well known Pittsburgh Sleep Quality Index. At that time, the boys also were assessed for internalizing and externalizing behaviors, neighborhood dangerousness, and socioeconomic status – all of which are factors known to influence teen substance use.

When participants reached ages 20 and 22 years, they underwent detailed interviews including assessment via the validated Lifetime Drinking History and Lifetime Drug History questionnaires.

In a multivariate Cox regression analysis controlling for a history of child internalizing and externalizing problem behavior as well as socioeconomic factors, every hour of sleep duration less than 9.5 hours at age 11 years was associated with a 21% acceleration in the time to first use of alcohol and a 22% acceleration in first use of cannabis, reported Mr. Mike, a medical student at the University of Pittsburgh.

Moreover, every 1 point worse score for sleep quality on the Child Sleep Questionnaire, scored from 0 (best) to 21 (worst), was associated with a 9% acceleration in time to alcohol use and an 8% acceleration to cannabis use.

Subjects with poor sleep duration and quality as 11-year-olds by parental report also experienced intoxication at a younger age than did those who had been better sleepers at that age. And they reported more frequent use of alcohol and cannabis during adolescence.

In an interview, Mr. Mike, who is planning a career in pediatrics, said the study findings contain an important message for pediatricians and family physicians when they meet with the parents of young boys entering adolescence.

“Probably the biggest take-home message is, ‘sleep more, sleep better.’ We don’t have a lot of ways to intervene right now for kids who have poor sleep, but we know based on this and other studies that kids who don’t sleep enough are more likely to use drugs and more likely to engage in other risky behaviors. So any way the parents can intervene will help, perhaps by getting them to bed earlier or trying to get them on a more regular schedule. At a social policy level, having school start later would probably be the most effective measure, but that probably won’t happen for a very long time,” he said.

“The vast majority of people who end up addicted to drugs later in life started when they were kids, so any way we can reduce adolescent substance use should have a downstream effect, including a decreased total substance use burden,” Mr. Mike added.

Possible mechanisms for the observed longitudinal association between poor quality and duration of sleep at age 11 years and earlier and heavier use of alcohol and cannabis later in adolescence include attempted self-medication for sleep problems, reward regulation, and alterations in brain chemistry, making the boys more susceptible to using drugs later in life, perhaps because they obtain a bigger high than their peers do. The investigators plan to delve deeper into the role of self-regulation and mental health as possible mechanisms linking childhood sleep and later substance use, he said.

The Pitt Mother and Child Project is supported by the National Institutes of Health. Mr. Mike reported having no financial conflicts.

DENVER – Poor sleep quality and shorter sleep duration in boys at age 11 years is associated with subsequent accelerated use and misuse of alcohol and cannabis during adolescence and emerging adulthood, Thomas B. Mike reported at the annual meeting of the Associated Professional Sleep Societies.

This association has been reported before in cross-sectional studies. But Mr. Mike presented new findings from the longitudinal prospective Pitt Mother and Child Project.

Bruce Jancin/Frontline Medical News

The study comprised 170 boys aged 11 years whose mothers filled out the Child Sleep Questionnaire, modified for pediatric use from the well known Pittsburgh Sleep Quality Index. At that time, the boys also were assessed for internalizing and externalizing behaviors, neighborhood dangerousness, and socioeconomic status – all of which are factors known to influence teen substance use.

When participants reached ages 20 and 22 years, they underwent detailed interviews including assessment via the validated Lifetime Drinking History and Lifetime Drug History questionnaires.

In a multivariate Cox regression analysis controlling for a history of child internalizing and externalizing problem behavior as well as socioeconomic factors, every hour of sleep duration less than 9.5 hours at age 11 years was associated with a 21% acceleration in the time to first use of alcohol and a 22% acceleration in first use of cannabis, reported Mr. Mike, a medical student at the University of Pittsburgh.

Moreover, every 1 point worse score for sleep quality on the Child Sleep Questionnaire, scored from 0 (best) to 21 (worst), was associated with a 9% acceleration in time to alcohol use and an 8% acceleration to cannabis use.

Subjects with poor sleep duration and quality as 11-year-olds by parental report also experienced intoxication at a younger age than did those who had been better sleepers at that age. And they reported more frequent use of alcohol and cannabis during adolescence.

In an interview, Mr. Mike, who is planning a career in pediatrics, said the study findings contain an important message for pediatricians and family physicians when they meet with the parents of young boys entering adolescence.

“Probably the biggest take-home message is, ‘sleep more, sleep better.’ We don’t have a lot of ways to intervene right now for kids who have poor sleep, but we know based on this and other studies that kids who don’t sleep enough are more likely to use drugs and more likely to engage in other risky behaviors. So any way the parents can intervene will help, perhaps by getting them to bed earlier or trying to get them on a more regular schedule. At a social policy level, having school start later would probably be the most effective measure, but that probably won’t happen for a very long time,” he said.

“The vast majority of people who end up addicted to drugs later in life started when they were kids, so any way we can reduce adolescent substance use should have a downstream effect, including a decreased total substance use burden,” Mr. Mike added.

Possible mechanisms for the observed longitudinal association between poor quality and duration of sleep at age 11 years and earlier and heavier use of alcohol and cannabis later in adolescence include attempted self-medication for sleep problems, reward regulation, and alterations in brain chemistry, making the boys more susceptible to using drugs later in life, perhaps because they obtain a bigger high than their peers do. The investigators plan to delve deeper into the role of self-regulation and mental health as possible mechanisms linking childhood sleep and later substance use, he said.

The Pitt Mother and Child Project is supported by the National Institutes of Health. Mr. Mike reported having no financial conflicts.

[email protected]

DENVER – Poor sleep quality and shorter sleep duration in boys at age 11 years is associated with subsequent accelerated use and misuse of alcohol and cannabis during adolescence and emerging adulthood, Thomas B. Mike reported at the annual meeting of the Associated Professional Sleep Societies.

This association has been reported before in cross-sectional studies. But Mr. Mike presented new findings from the longitudinal prospective Pitt Mother and Child Project.

Bruce Jancin/Frontline Medical News

The study comprised 170 boys aged 11 years whose mothers filled out the Child Sleep Questionnaire, modified for pediatric use from the well known Pittsburgh Sleep Quality Index. At that time, the boys also were assessed for internalizing and externalizing behaviors, neighborhood dangerousness, and socioeconomic status – all of which are factors known to influence teen substance use.

When participants reached ages 20 and 22 years, they underwent detailed interviews including assessment via the validated Lifetime Drinking History and Lifetime Drug History questionnaires.

In a multivariate Cox regression analysis controlling for a history of child internalizing and externalizing problem behavior as well as socioeconomic factors, every hour of sleep duration less than 9.5 hours at age 11 years was associated with a 21% acceleration in the time to first use of alcohol and a 22% acceleration in first use of cannabis, reported Mr. Mike, a medical student at the University of Pittsburgh.

Moreover, every 1 point worse score for sleep quality on the Child Sleep Questionnaire, scored from 0 (best) to 21 (worst), was associated with a 9% acceleration in time to alcohol use and an 8% acceleration to cannabis use.

Subjects with poor sleep duration and quality as 11-year-olds by parental report also experienced intoxication at a younger age than did those who had been better sleepers at that age. And they reported more frequent use of alcohol and cannabis during adolescence.

In an interview, Mr. Mike, who is planning a career in pediatrics, said the study findings contain an important message for pediatricians and family physicians when they meet with the parents of young boys entering adolescence.

“Probably the biggest take-home message is, ‘sleep more, sleep better.’ We don’t have a lot of ways to intervene right now for kids who have poor sleep, but we know based on this and other studies that kids who don’t sleep enough are more likely to use drugs and more likely to engage in other risky behaviors. So any way the parents can intervene will help, perhaps by getting them to bed earlier or trying to get them on a more regular schedule. At a social policy level, having school start later would probably be the most effective measure, but that probably won’t happen for a very long time,” he said.

“The vast majority of people who end up addicted to drugs later in life started when they were kids, so any way we can reduce adolescent substance use should have a downstream effect, including a decreased total substance use burden,” Mr. Mike added.

Possible mechanisms for the observed longitudinal association between poor quality and duration of sleep at age 11 years and earlier and heavier use of alcohol and cannabis later in adolescence include attempted self-medication for sleep problems, reward regulation, and alterations in brain chemistry, making the boys more susceptible to using drugs later in life, perhaps because they obtain a bigger high than their peers do. The investigators plan to delve deeper into the role of self-regulation and mental health as possible mechanisms linking childhood sleep and later substance use, he said.

The Pitt Mother and Child Project is supported by the National Institutes of Health. Mr. Mike reported having no financial conflicts.

[email protected]

DENVER – Poor sleep quality and shorter sleep duration in boys at age 11 years is associated with subsequent accelerated use and misuse of alcohol and cannabis during adolescence and emerging adulthood, Thomas B. Mike reported at the annual meeting of the Associated Professional Sleep Societies.

This association has been reported before in cross-sectional studies. But Mr. Mike presented new findings from the longitudinal prospective Pitt Mother and Child Project.

Bruce Jancin/Frontline Medical News

The study comprised 170 boys aged 11 years whose mothers filled out the Child Sleep Questionnaire, modified for pediatric use from the well known Pittsburgh Sleep Quality Index. At that time, the boys also were assessed for internalizing and externalizing behaviors, neighborhood dangerousness, and socioeconomic status – all of which are factors known to influence teen substance use.

When participants reached ages 20 and 22 years, they underwent detailed interviews including assessment via the validated Lifetime Drinking History and Lifetime Drug History questionnaires.

In a multivariate Cox regression analysis controlling for a history of child internalizing and externalizing problem behavior as well as socioeconomic factors, every hour of sleep duration less than 9.5 hours at age 11 years was associated with a 21% acceleration in the time to first use of alcohol and a 22% acceleration in first use of cannabis, reported Mr. Mike, a medical student at the University of Pittsburgh.

Moreover, every 1 point worse score for sleep quality on the Child Sleep Questionnaire, scored from 0 (best) to 21 (worst), was associated with a 9% acceleration in time to alcohol use and an 8% acceleration to cannabis use.

Subjects with poor sleep duration and quality as 11-year-olds by parental report also experienced intoxication at a younger age than did those who had been better sleepers at that age. And they reported more frequent use of alcohol and cannabis during adolescence.

In an interview, Mr. Mike, who is planning a career in pediatrics, said the study findings contain an important message for pediatricians and family physicians when they meet with the parents of young boys entering adolescence.

“Probably the biggest take-home message is, ‘sleep more, sleep better.’ We don’t have a lot of ways to intervene right now for kids who have poor sleep, but we know based on this and other studies that kids who don’t sleep enough are more likely to use drugs and more likely to engage in other risky behaviors. So any way the parents can intervene will help, perhaps by getting them to bed earlier or trying to get them on a more regular schedule. At a social policy level, having school start later would probably be the most effective measure, but that probably won’t happen for a very long time,” he said.

“The vast majority of people who end up addicted to drugs later in life started when they were kids, so any way we can reduce adolescent substance use should have a downstream effect, including a decreased total substance use burden,” Mr. Mike added.

Possible mechanisms for the observed longitudinal association between poor quality and duration of sleep at age 11 years and earlier and heavier use of alcohol and cannabis later in adolescence include attempted self-medication for sleep problems, reward regulation, and alterations in brain chemistry, making the boys more susceptible to using drugs later in life, perhaps because they obtain a bigger high than their peers do. The investigators plan to delve deeper into the role of self-regulation and mental health as possible mechanisms linking childhood sleep and later substance use, he said.

The Pitt Mother and Child Project is supported by the National Institutes of Health. Mr. Mike reported having no financial conflicts.

[email protected]